肽RL-QN15通过p38丝裂原活化蛋白激酶和smad3/miR-4482-3p/血管内皮生长因子B轴促进糖尿病足溃疡创面愈合

IF 6.3 1区 医学 Q1 DERMATOLOGY Burns & Trauma Pub Date : 2023-11-17 DOI:10.1093/burnst/tkad035
Dandan Sun, Kun Guo, Naixin Liu, Yilin Li, Yuansheng Li, Yan Hu, Shanshan Li, Zhe Fu, Yinglei Wang, Yutong Wu, Yingxuan Zhang, Jiayi Li, Chao Li, Zhuo Wang, Zijian Kang, Jun Sun, Ying Wang, Xinwang Yang
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Methods We investigated the wound-healing efficiency of peptide RL-QN15 under diabetic conditions using in vitro and in vivo experimental models. RNA sequencing, in vitro transfection, quantitative real-time polymerase chain reaction, western blotting, dual luciferase reporter gene detection, in vitro cell scratches, and cell proliferation and migration assays were performed to explore the potential mechanism underlying the promoting effects of RL-QN15 on DFU repair. Results Peptide RL-QN15 enhanced the migration and proliferation of human immortalized keratinocytes (HaCaT cells) in a high-glucose environment and accelerated wound healing in a DFU rat model. Based on results from RNA sequencing, we defined a new microRNA (miR-4482-3p) related to the promotion of wound healing. The bioactivity of miR-4482-3p was verified by inhibiting and overexpressing miR-4482-3p. Inhibition of miR-4482-3p enhanced the migration and proliferation ability of HaCaT cells as well as the expression of vascular endothelial growth factor B (VEGFB). RL-QN15 also promoted the migration and proliferation ability of HaCaT cells, and VEGFB expression was mediated via inhibition of miR-4482-3p expression by the p38 mitogen-activated protein kinase (p38MAPK) and smad3 signaling pathways. Conclusions RL-QN15 is an effective molecule for the treatment of DFUs, with the underlying mechanism related to the inhibition of miR-4482-3p expression via the p38MAPK and smad3 signaling pathways, ultimately promoting re-epithelialization, angiogenesis and wound healing. 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Conclusions RL-QN15 is an effective molecule for the treatment of DFUs, with the underlying mechanism related to the inhibition of miR-4482-3p expression via the p38MAPK and smad3 signaling pathways, ultimately promoting re-epithelialization, angiogenesis and wound healing. 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引用次数: 0

摘要

背景:糖尿病足溃疡(DFUs)的伤口管理是一项复杂而具有挑战性的任务,现有的策略不能满足临床需要。因此,开发新的候选药物和发现新的治疗靶点非常重要。然而,关于多肽作为分子探针解决dfu相关问题的报道仍然很少。本研究利用肽RL-QN15作为外源性分子探针,探讨内源性非编码RNA在DFU创面愈合中的潜在机制。目的是为DFUs的临床管理产生新的见解,并确定潜在的药物靶点。方法采用体外和体内实验模型,研究肽RL-QN15对糖尿病患者创面愈合的影响。通过RNA测序、体外转染、实时定量聚合酶链反应、western blotting、双荧光素酶报告基因检测、体外细胞划痕、细胞增殖和迁移等实验,探讨RL-QN15促进DFU修复的可能机制。结果肽RL-QN15增强了人永生化角质形成细胞(HaCaT细胞)在高糖环境下的迁移和增殖,加速了DFU大鼠模型的伤口愈合。根据RNA测序结果,我们定义了一种新的与促进伤口愈合相关的microRNA (miR-4482-3p)。通过抑制和过表达miR-4482-3p来验证miR-4482-3p的生物活性。抑制miR-4482-3p可增强HaCaT细胞的迁移和增殖能力以及血管内皮生长因子B (VEGFB)的表达。RL-QN15还能促进HaCaT细胞的迁移和增殖能力,通过p38丝裂原活化蛋白激酶(p38MAPK)和smad3信号通路抑制miR-4482-3p表达介导VEGFB的表达。结论RL-QN15是治疗DFUs的有效分子,其机制可能与通过p38MAPK和smad3信号通路抑制miR-4482-3p的表达有关,最终促进再上皮化、血管生成和伤口愈合。本研究为RL-QN15作为分子探针促进DFU创面愈合的临床应用提供了理论依据。
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Peptide RL-QN15 promotes wound healing of diabetic foot ulcers through p38 mitogen-activated protein kinase and smad3/miR-4482-3p/vascular endothelial growth factor B axis
Background Wound management of diabetic foot ulcers (DFUs) is a complex and challenging task, and existing strategies fail to meet clinical needs. Therefore, it is important to develop novel drug candidates and discover new therapeutic targets. However, reports on peptides as molecular probes for resolving issues related to DFUs remain rare. This study utilized peptide RL-QN15 as an exogenous molecular probe to investigate the underlying mechanism of endogenous non-coding RNA in DFU wound healing. The aim was to generate novel insights for the clinical management of DFUs and identify potential drug targets. Methods We investigated the wound-healing efficiency of peptide RL-QN15 under diabetic conditions using in vitro and in vivo experimental models. RNA sequencing, in vitro transfection, quantitative real-time polymerase chain reaction, western blotting, dual luciferase reporter gene detection, in vitro cell scratches, and cell proliferation and migration assays were performed to explore the potential mechanism underlying the promoting effects of RL-QN15 on DFU repair. Results Peptide RL-QN15 enhanced the migration and proliferation of human immortalized keratinocytes (HaCaT cells) in a high-glucose environment and accelerated wound healing in a DFU rat model. Based on results from RNA sequencing, we defined a new microRNA (miR-4482-3p) related to the promotion of wound healing. The bioactivity of miR-4482-3p was verified by inhibiting and overexpressing miR-4482-3p. Inhibition of miR-4482-3p enhanced the migration and proliferation ability of HaCaT cells as well as the expression of vascular endothelial growth factor B (VEGFB). RL-QN15 also promoted the migration and proliferation ability of HaCaT cells, and VEGFB expression was mediated via inhibition of miR-4482-3p expression by the p38 mitogen-activated protein kinase (p38MAPK) and smad3 signaling pathways. Conclusions RL-QN15 is an effective molecule for the treatment of DFUs, with the underlying mechanism related to the inhibition of miR-4482-3p expression via the p38MAPK and smad3 signaling pathways, ultimately promoting re-epithelialization, angiogenesis and wound healing. This study provides a theoretical basis for the clinical application of RL-QN15 as a molecular probe in promoting DFU wound healing.
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来源期刊
Burns & Trauma
Burns & Trauma 医学-皮肤病学
CiteScore
8.40
自引率
9.40%
发文量
186
审稿时长
6 weeks
期刊介绍: The first open access journal in the field of burns and trauma injury in the Asia-Pacific region, Burns & Trauma publishes the latest developments in basic, clinical and translational research in the field. With a special focus on prevention, clinical treatment and basic research, the journal welcomes submissions in various aspects of biomaterials, tissue engineering, stem cells, critical care, immunobiology, skin transplantation, and the prevention and regeneration of burns and trauma injuries. With an expert Editorial Board and a team of dedicated scientific editors, the journal enjoys a large readership and is supported by Southwest Hospital, which covers authors'' article processing charges.
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