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地西他滨通过调节免疫调节细胞和肠道屏障来减轻葡聚糖硫酸钠诱导的溃疡性结肠炎。

Decitabine attenuates dextran sodium sulfate‑induced ulcerative colitis through regulation of immune regulatory cells and intestinal barrier.

机构信息

Department of Surgery, Minhang Hospital, Fudan University, Shanghai 201199, P.R. China.

State Key Laboratory of Bioreactor Engineering and Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, P.R. China.

出版信息

Int J Mol Med. 2020 Aug;46(2):583-594. doi: 10.3892/ijmm.2020.4605. Epub 2020 May 18.

Abstract

To investigate the effect of decitabine on the regulation of intestinal barrier function in mice with inflammatory bowel disease, an experimental model of colitis was established via drinking water with dextran sulfate sodium (DSS). Hematoxylin and eosin staining was used to observe the pathological changes of the colon. Cytokine production was measured by an ELISA assay. Flow cytometry was used to measure the level of regulatory T cells. Immunofluorescence, immunohistochemistry and western blot analyses detected the protein expression and distribution in colon tissue. Following the administration of decitabine, the symptoms of intestinal inflammation in the mice were significantly relieved; the expression of IL‑17 was decreased, and the levels of TGF‑β and IL‑10 were increased. In addition, the induction of forkhead box P3 (Foxp3) in naive T cells increased the proportion of CD4+ Foxp3+ T cells in CD4+ T cells. Furthermore, decitabine increased the levels of zonular occludens‑1 and occludin, and inhibited the phosphorylation of ERK1/2, JNK and p38. In conclusion, the present study suggested that decitabine could alleviate DSS‑induced impaired colon barrier and the weight loss, mucus and bloody stools in mice by releasing the inhibitory factor IL‑10, reducing the pro‑inflammatory factor IL‑17, activating CD4+ Foxp3+ T cells and inhibiting the activation of the MAPK pathway.

摘要

为了研究地西他滨对炎症性肠病小鼠肠道屏障功能调节的影响,通过饮用葡聚糖硫酸钠(DSS)建立了结肠炎实验模型。采用苏木精-伊红(H&E)染色观察结肠的病理变化。通过 ELISA 测定细胞因子的产生。采用流式细胞术测定调节性 T 细胞的水平。免疫荧光、免疫组化和 Western blot 分析检测结肠组织中蛋白质的表达和分布。地西他滨给药后,小鼠的肠道炎症症状明显缓解;IL-17 的表达减少,TGF-β和 IL-10 的水平增加。此外,地西他滨诱导幼稚 T 细胞中叉头框 P3(Foxp3)的表达增加了 CD4+Foxp3+T 细胞在 CD4+T 细胞中的比例。此外,地西他滨增加了紧密连接蛋白-1 和闭合蛋白的水平,并抑制了 ERK1/2、JNK 和 p38 的磷酸化。综上所述,本研究表明,地西他滨通过释放抑制因子 IL-10、减少促炎因子 IL-17、激活 CD4+Foxp3+T 细胞以及抑制 MAPK 通路的激活,可缓解 DSS 诱导的小鼠结肠屏障损伤和体重减轻、黏液和血性粪便。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/be9e/7307821/8201e1df6416/IJMM-46-02-0583-g00.jpg

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