鸦鸦油乳剂对伊立替康致小鼠迟发性腹泻的治疗作用。

IF 4.7 2区医学 Q1 CHEMISTRY, MEDICINAL

Drug Design, Development and Therapy Pub Date : 2025-06-24 eCollection Date: 2025-01-01 DOI:10.2147/DDDT.S517973

Zixuan Lai, Yong Zhang, Xiaoxia Hu, Li Chen, Weimu Huang, Juan Wang, Baoyi Chen, Mihong Ren, Bowen Yang, Ziren Su, Jiannan Chen, Jianhui Xie, Zhengquan Lai, Youliang Xie

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引用次数: 0

摘要

背景：化疗引起的腹泻（CID），尤其是迟发性腹泻，常常限制临床应用。鸦鸦油乳剂（BJOE）是一种辅助化疗药物，已被证明可以减少伊立替康相关的胃肠道副作用。然而，其潜在的分子机制尚不清楚。cGAS-STING通路由胞质DNA传感器环GMP-AMP合成酶（cGAS）和干扰素基因适配器蛋白刺激因子（STING）组成，在迟发性腹泻中起重要作用。本研究旨在探讨BJOE对伊立替康致迟发性腹泻的治疗潜力及其机制。方法：采用气相色谱-质谱联用技术（GC-MS）对BJOE的成分进行分析。通过宏观观察、组织学、PCR、免疫组化、Western blotting等方法探讨BJOE对伊立替康致小鼠迟发性腹泻模型的作用机制。结果：GC-MS鉴定亚油酸为BJOE的主要成分，含量为20.67%。BJOE有效地减轻了伊立替康引起的小鼠迟发性腹泻，其特点是减轻体重减轻、结肠缩短、便血和组织病理学损伤。显著抑制炎症介质TNF-α、IL-1β、IL-6和iNOS mRNA表达水平，上调屏障基因ZO-1和occludin表达。此外，BJOE显著提高了粘蛋白的产生，增加了PCNA蛋白的表达。同时，BJOE显著下调结肠cGAS、STING、CXCL10、CCL5和IFN-β的mRNA水平。用激动剂DMXAA激活cGAS-STING通路可显著降低BJOE的治疗、抗炎和屏障保护作用。同样地，刺激STING可以显著逆转BJOE对cGAS-STING通路的抑制作用。结论：BJOE通过抑制伊立替康诱导的迟发性腹泻的cGAS-STING通路，至少部分地有效减轻炎症并保护肠道屏障功能。有效成分，长期安全性和药代动力学研究是必要的，以促进翻译应用。

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Therapeutic Effect of Brucea Javanica Oil Emulsion in Mice with Irinotecan-Induced Delayed Diarrhea.

Background: Chemotherapy-induced diarrhea (CID), particularly delayed diarrhea, often limits clinical use. Brucea javanica oil emulsion (BJOE), an adjuvant chemotherapy agent, has been shown to reduce irinotecan-related gastrointestinal side effects. However, its underlying molecular mechanism remains unclear. The cGAS-STING pathway, composed of the cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) and the adaptor protein stimulator of interferon genes (STING), plays an essential role in delayed diarrhea. This work aimed to investigate the therapeutic potential and underlying mechanism of BJOE on irinotecan-induced delayed diarrhea.

Methods: Gas chromatography-mass spectrometry (GC-MS) was employed to explore the components of BJOE. Macro-observation, histology, PCR, immunohistochemistry, and Western blotting were performed to illuminate the potential mechanism of BJOE on irinotecan-induced delayed diarrhea mice model.

Results: GC-MS analysis identified linoleic acid (20.67%) as BJOE's main component. BJOE effectively mitigated irinotecan-induced delayed diarrhea in mice, as characterized by attenuation of weight loss, colon shortening, hematochezia, and histopathologic damage. It significantly inhibited the mRNA expression levels of inflammatory mediators TNF-α, IL-1β, IL-6, and iNOS, and upregulated barrier gene expression (ZO-1 and occludin). Furthermore, BJOE markedly enhanced mucin production, and increased PCNA protein expression. Concurrently, BJOE remarkably down-regulated the colonic mRNA levels of cGAS, STING, CXCL10, CCL5, and IFN-β. Activation of the cGAS-STING pathway with agonist DMXAA significantly reduced BJOE's therapeutic, anti-inflammatory, and barrier-protective effects. Similarly, stimulating STING substantially reversed BJOE's inhibition on cGAS-STING pathway.

Conclusion: BJOE effectively mitigated inflammation and preserved intestinal barrier function, at least partially, via inhibiting cGAS-STING pathway in irinotecan-induced delayed diarrhea. Active components, long-term safety and pharmacokinetics studies were warranted to facilitate translational application.

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来源期刊

Drug Design, Development and Therapy CHEMISTRY, MEDICINAL-PHARMACOLOGY & PHARMACY

CiteScore

9.00

自引率

0.00%

发文量

382

审稿时长

>12 weeks

期刊介绍： Drug Design, Development and Therapy is an international, peer-reviewed, open access journal that spans the spectrum of drug design, discovery and development through to clinical applications. The journal is characterized by the rapid reporting of high-quality original research, reviews, expert opinions, commentary and clinical studies in all therapeutic areas. Specific topics covered by the journal include: Drug target identification and validation Phenotypic screening and target deconvolution Biochemical analyses of drug targets and their pathways New methods or relevant applications in molecular/drug design and computer-aided drug discovery* Design, synthesis, and biological evaluation of novel biologically active compounds (including diagnostics or chemical probes) Structural or molecular biological studies elucidating molecular recognition processes Fragment-based drug discovery Pharmaceutical/red biotechnology Isolation, structural characterization, (bio)synthesis, bioengineering and pharmacological evaluation of natural products** Distribution, pharmacokinetics and metabolic transformations of drugs or biologically active compounds in drug development Drug delivery and formulation (design and characterization of dosage forms, release mechanisms and in vivo testing) Preclinical development studies Translational animal models Mechanisms of action and signalling pathways Toxicology Gene therapy, cell therapy and immunotherapy Personalized medicine and pharmacogenomics Clinical drug evaluation Patient safety and sustained use of medicines.