GLI family zinc finger protein 2 promotes skin fibroblast proliferation and DNA damage repair by targeting the miR-200/ataxia telangiectasia mutated axis in diabetic wound healing.

The Kaohsiung journal of medical sciences Pub Date : 2024-05-01 Epub Date: 2024-02-22 DOI:10.1002/kjm2.12813
Zun-Hong Liang, Shi-Shuai Lin, Zhi-Yang Qiu, Yun-Chuan Pan, Nan-Fang Pan, Yun Liu
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Abstract

Diabetic foot ulcer (DFU) is a serious complication of diabetic patients which negatively affects their foot health. This study aimed to estimate the role and mechanism of the miR-200 family in DNA damage of diabetic wound healing. Human foreskin fibroblasts (HFF-1 cells) were stimulated with high glucose (HG). Db/db mice were utilized to conduct the DFU in vivo model. Cell viability was evaluated using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assays. Superoxide dismutase activity was determined using detection kits. Reactive oxygen species determination was conducted via dichlorodihydrofluorescein-diacetate assays. Enzyme-linked immunosorbent assay was used to evaluate 8-oxo-7,8-dihydro-2'deoxyguanosine levels. Genes and protein expression were analyzed by quantitative real-time polymerase chain reaction, western blotting, or immunohistochemical analyses. Luciferase reporter gene and RNA immunoprecipitation assays determined the interaction with miR-200a/b/c-3p and GLI family zinc finger protein 2 (GLI2) or ataxia telangiectasia mutated (ATM) kinase. HG repressed cell proliferation and DNA damage repair, promoted miR-200a/b/c-3p expression, and suppressed ATM and GLI2. MiR-200a/b/c-3p inhibition ameliorated HG-induced cell proliferation and DNA damage repair repression. MiR-200a/b/c-3p targeted ATM. Then, the silenced ATM reversed the miR-200a/b/c-3p inhibition-mediated alleviative effects under HG. Next, GLI2 overexpression alleviated the HG-induced cell proliferation and DNA damage repair inhibition via miR-200a/b/c-3p. MiR-200a/b/c-3p inhibition significantly promoted DNA damage repair and wound healing in DFU mice. GLI2 promoted cell proliferation and DNA damage repair by regulating the miR-200/ATM axis to enhance diabetic wound healing in DFU.

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GLI 家族锌指蛋白 2 通过靶向糖尿病伤口愈合中的 miR-200/ataxia telangiectasia mutated 轴促进皮肤成纤维细胞增殖和 DNA 损伤修复。
糖尿病足溃疡(DFU)是糖尿病患者的一种严重并发症,对患者的足部健康造成负面影响。本研究旨在评估 miR-200 家族在糖尿病伤口愈合 DNA 损伤中的作用和机制。研究人员用高糖(HG)刺激人包皮成纤维细胞(HFF-1细胞)。利用 Db/db 小鼠进行 DFU 体内模型试验。使用 3-(4,5-二甲基-2-噻唑基)-2,5-二苯基-2-H-四唑溴化物检测法评估细胞活力。使用检测试剂盒测定超氧化物歧化酶活性。活性氧测定采用二氯二氢荧光素-二乙酸酯测定法。酶联免疫吸附试验用于评估 8-氧代-7,8-二氢-2'脱氧鸟苷水平。基因和蛋白质表达通过定量实时聚合酶链反应、Western 印迹或免疫组织化学分析进行分析。荧光素酶报告基因和 RNA 免疫沉淀测定确定了 miR-200a/b/c-3p 与 GLI 家族锌指蛋白 2(GLI2)或共济失调毛细血管扩张症突变(ATM)激酶的相互作用。HG 抑制了细胞增殖和 DNA 损伤修复,促进了 miR-200a/b/c-3p 的表达,并抑制了 ATM 和 GLI2。抑制 MiR-200a/b/c-3p 可改善 HG 诱导的细胞增殖和 DNA 损伤修复抑制。MiR-200a/b/c-3p靶向ATM。然后,沉默的ATM逆转了miR-200a/b/c-3p抑制介导的对HG的缓解作用。接下来,GLI2 的过表达通过 miR-200a/b/c-3p 缓解了 HG 诱导的细胞增殖和 DNA 损伤修复抑制。抑制MiR-200a/b/c-3p能显著促进DNA损伤修复和DFU小鼠的伤口愈合。GLI2通过调节miR-200/ATM轴促进细胞增殖和DNA损伤修复,从而促进DFU糖尿病伤口愈合。
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