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

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 ??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.

SUBMITTER: Wahedi HM

PROVIDER: S-EPMC7255464 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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

Wahedi Hussain Mustatab HM Chae Jae Khyung JK Subedi Lalita L Kang Min Cheol MC Cho Hyunkyung H Kim Sanghee S Kim Sun Yeou SY

International journal of molecular medicine 20200403 1

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 ac ...[more]

PMID: 32319533

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Project description:Background/Aims: Diabetic non-healing skin ulcers represent a serious challenge in clinical practice, in which the hyperglycemia-induced disturbance of angiogenesis, and endothelial dysfunction play a crucial role. Resveratrol (RES), a silent information regulator 1 (SIRT1) agonist, can improve endothelial function and has strong pro-angiogenic properties, and has thus become a research focus for the treatment of diabetic non-healing skin ulcers; however, the underlying mechanism by which RES regulates these processes remains unclear. Therefore, the present study was intended to determine if RES exerts its observed protective role in diabetic wound healing by alleviating hyperglycemia-induced endothelial dysfunction and the disturbance of angiogenesis. Methods: We investigated the effects of RES on cell migration, cell proliferation, apoptosis, tube formation, and the underlying molecular mechanisms in 33 mM high glucose-stimulated human umbilical vein endothelial cells (HUVECs) by semi-quantitative RT-PCR, western blot analysis, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining, and immunofluorescence in vitro. We further explored the role of RES on endothelial dysfunction and wound healing disturbance in db/db mice by TUNEL staining, immunofluorescence, and photography in vivo. Results: We observed an obvious inhibition of hyperglycemia-triggered endothelial dysfunction and a disturbance of angiogenesis, followed by the promotion of diabetic wound healing via RES, along with restoration of the activity of the hyperglycemia-impaired SIRT1 signaling pathway. Pretreatment with EX-527, a SIRT1 inhibitor, abolished the RES-mediated endothelial protection and pro-angiogenesis action, and then delayed diabetic wound healing. Furthermore, examination of the overexpression of forkhead box O1 (FOXO1), a transcription factor substrate of SIRT1, in HUVECs and db/db mice revealed that RES activated SIRT1 to restore hyperglycemia-triggered endothelial dysfunction and disturbance of angiogenesis, followed by the promotion of diabetic wound healing in a c-Myc-dependent manner. Pretreatment with 10058-F4, a c-Myc inhibitor, repressed RES-mediated endothelial protection, angiogenesis, and diabetic wound healing. Conclusion: Our findings indicate that the positive role of RES in diabetic wound healing via its SIRT1-dependent endothelial protection and pro-angiogenic effects involves the inhibition of FOXO1 and the de-repression of c-Myc expression.

Project description:Skin wound healing is a common challenging clinical issue which requires advanced treatment strategies. The present study investigated the therapeutic effects of exosomes derived from dental pulp stem cells (DPSC‑Exos) on cutaneous wound healing and the underlying mechanisms. The effects of DPSC‑Exos on cutaneous wound healing in mice were examined by measuring wound closure rates, and using histological and immunohistochemical analysis. A series of functional assays were performed to evaluate the effects of DPSC‑Exos on the angiogenic activities of human umbilical vein endothelial cells (HUVECs) in vitro. Tandem mass tag‑based quantitative proteomics analysis of DPSCs and DPSC‑Exos was performed. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were used to evaluate the biological functions and pathways for the differentially expressed proteins in DPSC‑Exos. Western blot analysis was used to assess the protein levels of cell division control protein 42 (Cdc42) and p38 in DPSC‑Exos and in HUVECs subjected to DPSC‑Exos‑induced angiogenesis. SB203580, a p38 mitogen‑activated protein kinase (MAPK) signaling pathway inhibitor, was employed to verify the role of the p38 MAPK pathway in vitro and in vivo. Histological and immunohistochemical staining revealed that the DPSC‑Exos accelerated wound healing by promoting neovascularization. The DPSC‑Exos promoted the migration, proliferation and capillary formation capacity of HUVECs. Proteomics data demonstrated that proteins contained in DPSC‑Exos regulated vasculature development and angiogenesis. Pathway analysis revealed that proteins expressed in DPSC‑Exos were involved in several pathways, including MAPK pathway. Western blot analysis demonstrated that the DPSC‑Exos increased the protein levels of Cdc42 and phosphorylation of p38 in HUVECs. SB203580 suppressed the angiogenesis induced by DPSC‑Exos. On the whole, the present study demonstrates that DPSC‑Exos accelerate cutaneous wound healing by enhancing the angiogenic properties of HUVECs via the Cdc42/p38 MAPK signaling pathway.

Dataset Information

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

Publications

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

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