Wyss Department of Plastic Surgery, New York University School of Medicine, New York, NY 10016, United States.
Wyss Department of Plastic Surgery, New York University School of Medicine, New York, NY 10016, United States; NYU, Wyss Department of Plastic Surgery, 430 E 29th Street, Suite 640, New York, NY 10016, United States.
Diabetes Res Clin Pract. 2018 May;139:11-23. doi: 10.1016/j.diabres.2018.02.021. Epub 2018 Feb 21.
Though unmitigated oxidative stress in diabetic chronic non-healing wounds poses a major therapeutic challenge, currently, there are no effective pharmacological agents. We targeted the cytoprotective Nrf2/Keap1 pathway, which is dysfunctional in diabetic skin and the regenerative environment in the diabetic wound. We assessed the efficacy of a potent Nrf2-activator, RTA 408, a semi-synthetic oleanane triterpenoid, on accelerating diabetic wound healing.
Using Leprmice, we made 10 mm-diameter excisional humanized wounds in dorsal skin. We administered RTA 408 formulations daily, and used ANOVA for comparison of time to closure, in vivo real-time ROS, histology, molecular changes.
We found that RTA 408, specifically a 0.1% formulation, significantly reduced wound healing time and increased wound closure rate. While either systemic or topical administration of RTA 408 is effective, wound closure time with the latter was far superior. RTA 408-treated diabetic wounds upregulated Nrf2 and downstream antioxidant genes, and exhibited well-vascularized granulation tissue that aided in re-epithelialization. Reintroduction of redox mechanisms via RTA 408-induced Nrf2 resulted in reduction of the oxidative status of wounds, to coordinate successful wound closure.
This preclinical study shows that promoting Nrf2-mediated antioxidant activity in the localized regenerative milieu of a diabetic wound markedly improves the molecular and cellular composition of diabetic wound beds. RTA 408 treats and corrects the irregularity in redox balance mechanisms involving Nrf2, in an avenue not explored previously for treatment of diabetic wounds and tissue regeneration. Our study supports development of RTA 408 as a therapeutic modality for chronic diabetic wounds.
尽管糖尿病慢性难愈性创面未得到缓解的氧化应激对治疗构成了重大挑战，但目前尚无有效的药物治疗方法。我们将目标对准了保护性 Nrf2/Keap1 通路，该通路在糖尿病皮肤和糖尿病创面的再生环境中功能失调。我们评估了一种有效的 Nrf2 激活剂 RTA 408（一种半合成齐墩果烷三萜）在加速糖尿病创面愈合方面的疗效。
我们在 Lepr 小鼠的背部皮肤上制作了 10mm 直径的切除式人源化创面。我们每天给予 RTA 408 制剂，并使用 ANOVA 比较创面闭合时间、体内实时 ROS、组织学和分子变化。
我们发现，RTA 408，特别是 0.1%的制剂，可显著缩短创面愈合时间并提高创面闭合率。虽然全身性或局部给予 RTA 408 均有效，但后者的创面闭合时间要优越得多。RTA 408 处理的糖尿病创面上调了 Nrf2 和下游抗氧化基因，并表现出血管化良好的肉芽组织，有助于上皮再形成。通过 RTA 408 诱导的 Nrf2 重新引入氧化还原机制，可减少创面的氧化状态，从而协调成功的创面闭合。
这项临床前研究表明，在糖尿病创面的局部再生环境中促进 Nrf2 介导的抗氧化活性可显著改善糖尿病创面床的分子和细胞组成。RTA 408 治疗和纠正了涉及 Nrf2 的氧化还原平衡机制的不规则性，这是以前未探索过的治疗糖尿病创面和组织再生的途径。我们的研究支持将 RTA 408 开发为慢性糖尿病创面的治疗方法。
