Dehydroabietic acid reverses TNF-α-induced the activation of FOXO1 and suppression of TGF-β1/Smad signaling in human adult dermal fibroblasts.
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.
['Wang|Xiao-Wei|XW|', 'Yu|Yong|Y|', 'Gu|Lei|L|']
D045784:Abietanes D000328:Adult D017209:Apoptosis D015153:Blotting, Western D049109:Cell Proliferation D002470:Cell Survival D002478:Cells, Cultured D005347:Fibroblasts D000071161:Forkhead Box Protein O1 D051858:Forkhead Transcription Factors D006801:Humans D020133:Reverse Transcriptase Polymerase Chain Reaction D015398:Signal Transduction D012867:Skin D051785:Smad Proteins D053773:Transforming Growth Factor beta1 D014409:Tumor Necrosis Factor-alpha D014945:Wound Healing
Dehydroabietic acid wound healing diabetes tumor necrosis factor-α forkhead box o1 transforming growth factor-β1