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Fig. 6. Schematic representation of the possible mechanisms of action of TR for altering ECM turnover. (A) After latent TGF-β being activated, it binds to the TGF-ΒRII and phosphorylates TGF-ΒRI, forming a tetrameric complex. Activation of TGF-ΒRI leads to the downstream signalling of TGF-β involving SMAD proteins called TGF-β-SMAD dependent signalling pathway or also known as canonical signalling pathway. The phosphorylated receptors cause SMAD2 and SMAD3 to phosphorylate and subsequently attach to SMAD4, which amplifies signalling. The heteromeric SMAD complex accumulates in the nucleus and serves as a transcription factor to activate the transcription of fibrotic genes such as collagen, fibronectin, and α-SMA. SMAD7 is a negative regulator of SMAD 2/3 and inhibits fibrosis. (B) PAI-1 is a member of the serine protease inhibitor superfamily that binds to and inhibits the activity of uPA and tPA. tPA and uPA convert plasminogen into plasmin, which then activates the pro or latent MMPs into active form of MMPs that degrade ECM proteins. TR, resveratrol; ECM, extracellular matrix; TGF-β, transforming growth factor β; TGF-ΒRI, trans-membrane receptor type I; TGF-ΒRII, trans-membrane receptor type II; SMAD, suppressor of mothers against decapentaplegic; α-SMA, α-smooth muscle actin; PAI, plasminogen activator inhibitor; tPA, tissue plasminogen activator; uPA, urokinase plasminogen activator; MMP, matrix metalloproteinase.
Korean J Physiol Pharmacol 2024;28:345-359
© Korean J Physiol Pharmacol