Metformin as a Modulator of Autophagy and Hypoxia Responses in the Enhancement of Wound Healing in Diabetic Rats.

IF 4.5 2区 医学 Q2 CELL BIOLOGY Inflammation Pub Date : 2024-08-26 DOI:10.1007/s10753-024-02129-9
Fatma Kubra Tombulturk, Tugba Soydas, Gönül Kanigur-Sultuybek
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Abstract

The molecular mechanisms underlying delayed wound repair in diabetes involve dysregulation of key cellular processes, including autophagy and hypoxia response pathways. Herein, we investigated the role of topical metformin, an established anti-diabetic drug with potential autophagy-inducing properties, in improving wound healing outcomes under hypoxic conditions. Full-thickness skin wounds were created in streptozotocin-induced diabetic rats, and tissue samples were collected at regular intervals for molecular and histological analysis. The expression levels of autophagy markers LC3B and Beclin-1 were evaluated via immunohistochemistry and qRT-PCR, while the amount of AMP-activated protein kinase (AMPK) and hypoxia-inducible factor-1α (HIF-1α) were determined via ELISA. Our results demonstrated that metformin administration resulted in the upregulation of LC3B and Beclin-1 in the wound bed, suggesting induction of autophagy in response to the treatment. Mechanistically, metformin treatment also led to the increased amount of AMPK, a critical regulator of cellular energy homeostasis, and a subsequent reduction in HIF-1α amount under hypoxic conditions. In conclusion, our findings demonstrate that metformin promotes wound healing in diabetes mellitus by enhancing autophagy through AMPK activation and modulating HIF-1α amount in a hypoxic microenvironment. This study offers a new therapeutic approach by shedding light on the potential benefits of metformin as adjunctive therapy in diabetic wound management.

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二甲双胍作为自噬和缺氧反应的调节剂促进糖尿病大鼠的伤口愈合
糖尿病伤口修复延迟的分子机制涉及自噬和缺氧反应途径等关键细胞过程的失调。二甲双胍是一种具有潜在自噬诱导特性的成熟抗糖尿病药物,我们在此研究了它在改善缺氧条件下伤口愈合结果方面的作用。研究人员在链脲佐菌素诱导的糖尿病大鼠身上创建了全厚皮肤伤口,并定期采集组织样本进行分子和组织学分析。自噬标记物 LC3B 和 Beclin-1 的表达水平通过免疫组化和 qRT-PCR 进行了评估,AMPK 和缺氧诱导因子-1α 的含量通过 ELISA 进行了测定。我们的研究结果表明,二甲双胍能导致伤口床中 LC3B 和 Beclin-1 的上调,这表明二甲双胍能诱导自噬。从机理上讲,二甲双胍治疗还导致细胞能量平衡的关键调节因子 AMPK 的数量增加,从而降低了缺氧条件下 HIF-1α 的数量。总之,我们的研究结果表明,二甲双胍在缺氧微环境中通过激活 AMPK 增强自噬并调节 HIF-1α 的含量,从而促进糖尿病患者的伤口愈合。这项研究提供了一种新的治疗方法,揭示了二甲双胍作为糖尿病伤口管理辅助疗法的潜在益处。
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来源期刊
Inflammation
Inflammation 医学-免疫学
CiteScore
9.70
自引率
0.00%
发文量
168
审稿时长
3.0 months
期刊介绍: Inflammation publishes the latest international advances in experimental and clinical research on the physiology, biochemistry, cell biology, and pharmacology of inflammation. Contributions include full-length scientific reports, short definitive articles, and papers from meetings and symposia proceedings. The journal''s coverage includes acute and chronic inflammation; mediators of inflammation; mechanisms of tissue injury and cytotoxicity; pharmacology of inflammation; and clinical studies of inflammation and its modification.
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