title: Dehydroabietic acid reverses TNF-α-induced the activation of FOXO1 and suppression of TGF-β1/Smad signaling in human adult dermal fibroblasts.
abstract: Wound healing impairment is a well-documented phenomenon in clinical and experimental diabetes, and in diabetic wound healing impaired fibroblast has been linked to increased levels of tumor necrosis factor-α (TNF-α). A number of signaling pathways including TNF-α/forkhead box O1 (FOXO1) and transforming growth factor-β1 (TGF-β1)/Smads in fibroblasts appear to play a cardinal role in diabetic wound healing. Dehydroabietic acid (DAA) is obtained from Commiphora oppbalsamum and inhibits the production of TNF-α in macrophages and adipocytes, decreases the level of TNF-α in obese diabetic KK-Ay mice, but its effect on diabetic wound healing is unknown. This study was to investigate the effect of DAA on TNF-α-stimulated human adult dermal fibroblasts. On the one hand, TNF-α significantly decreased the fibroblast proliferation and the expression of PCNA, Ki67 and cyclin D1, increased the fibroblast apoptosis, caspase-8/3 activity, expressions of cleaved caspase-8 and caspase-3, decreased the Bcl-2/Bax ratio and increased activation of the pro-apoptotic transcription factor FOXO1. All the above-mentioned cell responses were remarkably reversed by DAA. On the other hand, TNF-α also inhibited TGF-β1-induced the Smad3 signaling pathway what is closely related to the fibroblast migration and the differentiation of myofibroblasts. However, DAA significantly promoted the migration and increased the expression of α-smooth muscle actin and fibronectin under the stimulus of a combination of TNF-α and TGF-β1. In conclusion, DAA could reverse several cell responses stimulated by TNF-α, including the activation of FOXO1 and the TGF-β1/Smad3 signaling pathway. These results suggested that DAA could be useful in improving the diabetic wound healing.
authors: Department of Endocrinology, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University Shanghai 201707, People's Republic of China.
authors: Xiao-Wei
authors: XW
authors: Wang
authors: Key Laboratory of Viral Heart Disease Ministry of Public Health, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital Fudan University Shanghai 20032, People's Republic of China.
authors: Yong
authors: Y
authors: Yu
authors: Department of Emergency, Shanghai Tongji Hospital Shanghai 200065, People's Republic of China.
authors: Lei
authors: L
authors: Gu
mesh_terms: D045784:Abietanes / Q000494:pharmacology*; D000328:Adult; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D012867:Skin / Q000187:drug effects* / Q000378:metabolism; D051785:Smad Proteins / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects* / Q000502:physiology
chemical_list: D045784:Abietanes; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; C013913:dehydroabietic acid
keywords: Dehydroabietic acid; diabetes; forkhead box o1; transforming growth factor-β1; tumor necrosis factor-α; wound healing