NED416, a novel synthetic Sirt1 activator, promotes cutaneous wound healing via the MAPK/Rho pathway

Wahedi,Hussain Mustatab; Chae,Jae Khyung; Subedi,Lalita; Kang,Min Cheol; Cho,Hyunkyung; Kim,Sanghee; Kim,Sun Yeou

doi:10.3892/ijmm.2020.4564

NED416, a novel synthetic Sirt1 activator, promotes cutaneous wound healing via the MAPK/Rho pathway

Authors:
- Hussain Mustatab Wahedi
- Jae Khyung Chae
- Lalita Subedi
- Min Cheol Kang
- Hyunkyung Cho
- Sanghee Kim
- Sun Yeou Kim
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Affiliations: Department of Biological Sciences, National University of Medical Sciences, C/O Military Hospital, Rawalpindi, Punjab 46000, Pakistan, College of Pharmacy, Gachon University, Incheon 21936, Republic of Korea, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
Published online on: April 3, 2020 https://doi.org/10.3892/ijmm.2020.4564
Pages: 149-158
Copyright: © Wahedi et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Cutaneous wound healing is a highly complex biological process involving major events such as cell migration, angiogenesis, and tissue development. Sirtuin 1 (Sirt1) and its regulators have been suggested to play a role in cell migration and tissue repair. The aim of the present study was to determine the effects of a novel Sirt1 activator, the piper amide derivative (E)‑3‑(2,4‑dichlorophenyl)‑N‑phenylacrylamide, also known as NED416, on cutaneous wound healing. The effects of NED416 on Sirt1 activity, Sirt1 expression, and angiogenesis were measured in skin and endothelial cells (epidermal keratinocytes, dermal fibroblasts and vascular endothelial cells) using a Sirt1 activity assay kit, western blot analysis and tube formation assays, respectively. The effects of NED416 on the rate of wound closure and collagen deposition were measured via H&E staining and Masson's trichrome staining, respectively. Levels of migration‑related [Rac1, cell division cycle 42 (Cdc42) and α‑p21‑activated kinase] and mitogen‑activated protein kinase (MAPK) signaling pathway proteins were measured in hairless mice via western blot analysis. NED416 significantly increased Sirt1 activity in dermal fibroblasts and epidermal keratinocytes to a greater extent than resveratrol, leading to increased cell migration and angiogenesis through Rac1/Cdc42 and ERK/JNK activation. Furthermore, NED416 accelerated wound closure, macrophage infiltration, and epithelium and collagen formation in vivo. The present study demonstrated a role of Sirt1 in cutaneous wound healing, and suggested that NED416 as a Sirt1 activator is more potent than resveratrol in promoting wound healing through Rac1/Cdc42 and MAPK signaling without toxicity, thus serving as a promising candidate for treatment.

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