Phellopterin cream exerts an anti-inflammatory effect that facilitates diabetes-associated cutaneous wound healing via SIRT1,Phytomedicine

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Phellopterin cream exerts an anti-inflammatory effect that facilitates diabetes-associated cutaneous wound healing via SIRT1
Phytomedicine ( IF 6.7 ) Pub Date : 2022-09-20 , DOI: 10.1016/j.phymed.2022.154447
Jialing Zou ₁ , Yanjuan Duan ₂ , Yi Wang ₁ , Aijun Liu ₃ , Yuanran Chen ₁ , Dongjie Guo ₁ , Wanjun Guo ₁ , Shuang Li ₄ , Zhou Su ₅ , Yang Wu ₆ , Hanzhi Lu ₁ , Yu Deng ₅ , Jianyong Zhu ₃ , Fulun Li ₁

Affiliation

Background

Diabetic ulcers, which are characterized by chronic nonhealing wounds with a long-lasting inflammatory state, are a typical symptom in individuals with diabetes, and there is still no effective treatment for these lesions. Angelica dahurica plays a critical role in inflammatory diseases. Among numerous monomeric compounds, phellopterin has been shown to have anti-inflammatory properties.

Purpose

To research the bioactive constituents in Angelica dahurica and their mechanism of action in treating diabetic ulcers.

Study design

Chemical research of Angelica dahurica led to the identification of a new coumarin, dahuricoumarin A (1), along with seven known compounds (2 − 8). All compounds were tested for anti-inflammatory activity, and phellopterin, compound (3), significantly decreased the expression of intercellular cell adhesion molecule-1 (ICAM-1), a representative indicator of inflammation. Phellopterin can also increase SIRT1 protein, a key target for inflammation. In our research, we confirmed the anti-inflammatory effects of phellopterin on diabetic ulcers and explored the underlying mechanism of action.

Methods

The expression of IFN-γ, SIRT1, and ICAM-1 in human diabetic ulcer tissues was studied using immunohistochemistry. Streptozotocin was used to induce a diabetic model in C57BL/6J mice, and ulcers were surgically introduced. After phellopterin treatment, the skin lesions of diabetic mice were observed over a period of time. The protein and mRNA expression levels of SIRT1 and ICAM-1 were measured using H&E, qRT–PCR and immunohistochemical staining. A HaCaT cell inflammatory model was induced by IFN-γ. Using a lentiviral packaging technique, MTT assay, and Western blotting, the effect of phellopterin on the proliferation of HaCaT cells and the expression of ICAM-1 was evaluated under normal and SIRT1 knockdown conditions.

Results

High levels of ICAM-1 and IFN-γ were identified, but low levels of SIRT1 were found in human diabetic ulcer tissues, and phellopterin showed therapeutic benefits in the healing process by attenuating chronic inflammation and promoting re-epithelialization, along with SIRT1 upregulation and ICAM-1 downregulation. However, inhibiting SIRT1 reversed its proliferative and anti-inflammatory effects.

Conclusion

In vitro and in vivo, phellopterin exerts anti-inflammatory and proliferative effects that promote diabetic wound healing, and the potential mechanism depends on SIRT1.

中文翻译：

黄蝶呤乳膏发挥抗炎作用，通过 SIRT1 促进糖尿病相关皮肤伤口愈合

背景

糖尿病性溃疡是糖尿病患者的典型症状，其特点是慢性不愈合伤口和长期炎症状态，目前尚无有效的治疗方法。白芷在炎症性疾病中起关键作用。在众多的单体化合物中，已显示黄蝶呤具有抗炎特性。

目的

研究白芷中的生物活性成分及其治疗糖尿病溃疡的作用机制。

学习规划

白芷的化学研究导致鉴定出一种新的香豆素，白芍素 A ( 1 )，以及七种已知化合物( 2-8 )。所有化合物都进行了抗炎活性测试，化合物 ( 3 ) 黄蝶呤显着降低了炎症的代表性指标细胞间细胞粘附分子-1 (ICAM-1) 的表达。黄蝶呤还可以增加 SIRT1 蛋白，这是炎症的关键目标。在我们的研究中，我们证实了黄蝶呤对糖尿病溃疡的抗炎作用，并探索了潜在的作用机制。

方法

使用免疫组织化学研究了人类糖尿病溃疡组织中 IFN-γ、SIRT1 和 ICAM-1 的表达。链脲佐菌素用于在 C57BL/6J 小鼠中诱导糖尿病模型，并通过手术引入溃疡。黄蝶呤治疗后，观察一段时间内糖尿病小鼠的皮损情况。使用 H&E、qRT-PCR 和免疫组织化学染色测量 SIRT1 和 ICAM-1 的蛋白质和 mRNA 表达水平。HaCaT细胞炎症模型由IFN-γ诱导。使用慢病毒包装技术、MTT 法和蛋白质印迹法，在正常和 SIRT1 敲低条件下评估黄蝶呤对 HaCaT 细胞增殖和 ICAM-1 表达的影响。