title: Activation of α7nAChR Promotes Diabetic Wound Healing by Suppressing AGE-Induced TNF-α Production.
abstract: Diabetes frequently presents accumulation of advanced glycation end products (AGEs), which might induce excessive TNF-α production from macrophages to cause impaired wound healing. Recent studies have shown that activation of α7 nicotinic acetylcholine receptor (α7nAChR) on macrophages efficiently suppressed TNF-α synthesis. The aim of this study was to investigate the accumulation of AGEs in the wounds and determine whether PNU282987, an α7nAChR agonist, can improve wound repair by inhibiting AGE-mediated TNF-α production in a streptozotocin (STZ)-induced diabetic mouse model. Animals were assigned into four groups: wounded control group, wounded diabetic group, wounded diabetic group treated intraperitoneally with PNU282987, or wounded diabetic group treated intraperitoneally with vehicle. Compared with the non-diabetic control mice, the diabetic mice exhibited delayed wound healing that was characterized by elevated accumulation of AGEs, increased TNF-α level and macrophage infiltration, and decreased fibroblast number and collagen deposition at the late stage of repair. Besides, macrophages of diabetic wounds showed expression of α7nAChR. During late repair, PNU282987 treatment of diabetic mice significantly reduced the level of TNF-α, accelerated wound healing, and elevated fibroblast number and collagen deposition. To investigate the cellular mechanism of these observations, RAW 264.7 cells, a macrophage cell line, were incubated with AGEs in the presence or absence of PNU282987. TNF-α production from AGE-stimulated macrophages was significantly decreased by PNU282987 in a dose-dependent manner. Furthermore, PNU282987 significantly inhibited AGE-induced nuclear factor-κB (NF-κB) activation and receptor for AGE (RAGE) expression. These results strongly suggest that activating α7nAChR can promote diabetic wound healing by suppressing AGE-induced TNF-α production, which may be closely associated with the blockage of NF-κB activation in macrophages.
authors.affiliation: Center of Basic Medical Experiment, School of Basic Medical Science, Wenzhou Medical University, Higher Education District, Wenzhou, Zhejiang Province, 325035, People's Republic of China.
authors.forename: Miao-Wu
authors.initials: MW
authors.lastname: Dong
authors.affiliation: Renji College, Wenzhou Medical University, Higher Education District, Wenzhou, Zhejiang Province, 325035, People's Republic of China.
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.affiliation: Renji College, Wenzhou Medical University, Higher Education District, Wenzhou, Zhejiang Province, 325035, People's Republic of China.
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.affiliation: Renji College, Wenzhou Medical University, Higher Education District, Wenzhou, Zhejiang Province, 325035, People's Republic of China.
authors.forename: Tong-Tong
authors.initials: TT
authors.lastname: Fu
authors.affiliation: Center of Basic Medical Experiment, School of Basic Medical Science, Wenzhou Medical University, Higher Education District, Wenzhou, Zhejiang Province, 325035, People's Republic of China.
authors.forename: Ke-Zhi
authors.initials: KZ
authors.lastname: Lin
authors.affiliation: Department of Forensic Medicine, School of Basic Medical Science, Wenzhou Medical University, Higher Education District, Wenzhou, Zhejiang Province, 325035, People's Republic of China.
authors.forename: Guang-Hua
authors.initials: GH
authors.lastname: Ye
authors.affiliation: Department of Forensic Medicine, School of Basic Medical Science, Wenzhou Medical University, Higher Education District, Wenzhou, Zhejiang Province, 325035, People's Republic of China.
authors.forename: Jun-Ge
authors.initials: JG
authors.lastname: Han
authors.affiliation: Department of Forensic Medicine, School of Basic Medical Science, Wenzhou Medical University, Higher Education District, Wenzhou, Zhejiang Province, 325035, People's Republic of China.
authors.forename: Xiang-Ping
authors.initials: XP
authors.lastname: Feng
authors.affiliation: Department of Forensic Medicine, School of Basic Medical Science, Wenzhou Medical University, Higher Education District, Wenzhou, Zhejiang Province, 325035, People's Republic of China.
authors.forename: Xing-Biao
authors.initials: XB
authors.lastname: Li
authors.affiliation: Department of Forensic Medicine, School of Basic Medical Science, Wenzhou Medical University, Higher Education District, Wenzhou, Zhejiang Province, 325035, People's Republic of China.
authors.forename: Lin-Sheng
authors.initials: LS
authors.lastname: Yu
authors.affiliation: Department of Forensic Medicine, School of Basic Medical Science, Wenzhou Medical University, Higher Education District, Wenzhou, Zhejiang Province, 325035, People's Republic of China. yyfan998@163.com.
authors.forename: Yan-Yan
authors.initials: YY
authors.lastname: Fan
mesh_terms: D000818:Animals; D001549:Benzamides / Q000627:therapeutic use*; D001643:Bridged Bicyclo Compounds / Q000627:therapeutic use*; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000473:pathology*; D004789:Enzyme Activation / Q000187:drug effects; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D000067759:Receptor for Advanced Glycation End Products / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D014945:Wound Healing / Q000187:drug effects* / Q000502:physiology; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000819:agonists / Q000032:analysis / Q000378:metabolism*
chemical_list: C000593873:Ager protein, mouse; D001549:Benzamides; D001643:Bridged Bicyclo Compounds; D017127:Glycation End Products, Advanced; C498513:PNU-282987; D000067759:Receptor for Advanced Glycation End Products; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D064569:alpha7 Nicotinic Acetylcholine Receptor
keywords: AGEs; TNF-α; diabetes; macrophage; wound healing; α7nAChR