Isoliquiritin Ameliorates Ulcerative Colitis in Rats through Caspase 3/HMGB1/TLR4 Dependent Signaling Pathway.

IF 3.8 4区医学 Q2 GENETICS & HEREDITY Current gene therapy Pub Date : 2024-01-01 DOI:10.2174/1566523223666230731115236

Zhiwei Miao, Mingjia Gu, Faisal Raza, Hajra Zafar, Jianyi Huang, Yuhang Yang, Muhammad Sulaiman, Jing Yan, Yi Xu

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Abstract

Background: Isoliquiritin belongs to flavanol glycosides and has a strong antiinflammatory activity. This study sought to investigate the anti-inflammatory effect of isoliquiritin and its underlying mechanism.

Methods: The inflammatory (trinitro-benzene-sulfonic acid-TNBS-induced ulcerative colitis (UC)) model was established to ascertain the effect of isoliquiritin on the caspase-3/HMGB1/TLR4 pathway in rats. We also explored its protective effect on intestinal inflammation and its underlying mechanism using the LPS-induced inflammation model of Caco-2 cells. Besides, Deseq2 was used to analyze UCassociated protein levels.

Results: Isoliquiritin treatment significantly attenuated shortened colon length (induced by TNBS), disease activity index (DAI) score, and body weight loss in rats. A decrease in the levels of inflammatory mediators (IL-1β, I IL-4, L-6, IL-10, PGE2, and TNF-α), coupled with malondialdehyde (MDA) and superoxide dismutase (SOD), was observed in colon tissue and serum of rats after they have received isoliquiritin. Results of techniques (like western blotting, real-time PCR, immunohistochemistry, and immunofluorescence-IF) demonstrated the potential of isoliquiritin to decrease expressions of key genes in the TLR4 downstream pathways, viz., MyD88, IRAK1, TRAF6, NF-κB, p38, and JNK at mRNA and protein levels as well as inhibit HMGB1 expression, which is the upstream ligand of TLR4. Bioinformational analysis showed enteritis to be associated with a high expression of HMGB1, TLR4, and caspase-3.

Conclusion: Isoliquiritin could reduce intestinal inflammation and mucosal damage of TNBS-induced colitis in rats with a certain anti-UC effect. Meanwhile, isoliquiritin treatment also inhibited the expression of HMGB1, TLR4, and MyD88 in LPS-induced Caco-2 cells. These results indicated that isoliquiritin could ameliorate UC through the caspase-3/HMGB1/TLR4-dependent signaling pathway.

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伊索利奎林通过 Caspase 3/HMGB1/TLR4 依赖性信号通路改善大鼠溃疡性结肠炎的病情

背景介绍异水蛭素属于黄烷醇苷类，具有很强的抗炎活性。本研究旨在探讨异桔梗素的抗炎作用及其内在机制：方法：我们建立了炎症（三硝基苯磺酸-TNBS 诱导的溃疡性结肠炎（UC））模型，以确定异桔梗素对大鼠体内 caspase-3/HMGB1/TLR4 通路的影响。我们还利用 LPS 诱导的 Caco-2 细胞炎症模型探讨了其对肠道炎症的保护作用及其内在机制。此外，我们还利用 Deseq2 分析了 UC 相关蛋白水平：结果：异利奎林治疗可明显减轻大鼠结肠长度缩短（TNBS诱导）、疾病活动指数（DAI）评分和体重下降。接受伊索利奎特治疗后，大鼠结肠组织和血清中的炎症介质（IL-1β、I IL-4、L-6、IL-10、PGE2 和 TNF-α）以及丙二醛（MDA）和超氧化物歧化酶（SOD）水平均有所下降。各种技术（如 Western 印迹、实时 PCR、免疫组织化学和免疫荧光-IF）的结果表明，伊立奎灵可能会在 mRNA 和蛋白质水平上降低 TLR4 下游通路中关键基因（即 MyD88、IRAK1、TRAF6、NF-κB、p38 和 JNK）的表达，并抑制 TLR4 的上游配体 HMGB1 的表达。生物信息分析表明，肠炎与 HMGB1、TLR4 和 caspase-3 的高表达有关：结论：异桔梗素能减轻 TNBS 诱导的大鼠结肠炎的肠道炎症和粘膜损伤，具有一定的抗 UC 作用。同时，异桔梗素还能抑制 LPS 诱导的 Caco-2 细胞中 HMGB1、TLR4 和 MyD88 的表达。这些结果表明，异桔梗素可以通过依赖于caspase-3/HMGB1/TLR4的信号通路改善UC。

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来源期刊

Current gene therapy 医学-遗传学

CiteScore

6.70

自引率

2.80%

发文量

期刊介绍： Current Gene Therapy is a bi-monthly peer-reviewed journal aimed at academic and industrial scientists with an interest in major topics concerning basic research and clinical applications of gene and cell therapy of diseases. Cell therapy manuscripts can also include application in diseases when cells have been genetically modified. Current Gene Therapy publishes full-length/mini reviews and original research on the latest developments in gene transfer and gene expression analysis, vector development, cellular genetic engineering, animal models and human clinical applications of gene and cell therapy for the treatment of diseases. Current Gene Therapy publishes reviews and original research containing experimental data on gene and cell therapy. The journal also includes manuscripts on technological advances, ethical and regulatory considerations of gene and cell therapy. Reviews should provide the reader with a comprehensive assessment of any area of experimental biology applied to molecular medicine that is not only of significance within a particular field of gene therapy and cell therapy but also of interest to investigators in other fields. Authors are encouraged to provide their own assessment and vision for future advances. Reviews are also welcome on late breaking discoveries on which substantial literature has not yet been amassed. Such reviews provide a forum for sharply focused topics of recent experimental investigations in gene therapy primarily to make these results accessible to both clinical and basic researchers. Manuscripts containing experimental data should be original data, not previously published.