| Liver fibrosis is one of the common liver diseases which has the top incidence rate disease worldwide.Liver fibrosis is not an independent disease in clinically,it is a pathological process that involves the dynamic changes of multiple cytokines and the persistence of injury repair.When the liver is damaged and inflammation,HSCs(hepatic stellate cells,HSCs)are activated through complex signaling pathways,during which the hyperplasia and abnormal deposition of ECM(extracellular matrix,ECM)in liver tissue,leading to the abnormal changes in liver structure and function.This process is characterized by liver fibrosis and cirrhosis.Therefore,liver fibrosis has become a required stage for the development of a variety of chronic liver disease into cirrhosis and hepatocellular carcinoma,which is regarded as a common pathological basis for chronic liver disease.A large number of research confirmed that liver fibrosis is reversible,therefore explore the mechanism of liver fibrosis has important implications for the treatment of liver fibrosis and the prevention of cirrhosis.Epithelial-mesenchymal transition(EMT)is an important mechanism for hepatocytes to obtain high metastatic cell phenotypes.In the process of EMT,liver cells are damaged and cell adhesion capacity is decreased.At the same time,hepatic stellate cells are activated to transform into fibroblasts,promoting ECM deposition and the progression of hepatic fibrosis.Protocatechuic acid is called 3,4-dihydroxybenzoic acid which is a common benzoic acid-type phenolic acid,which is one of the degradation product of anthocyanin in the gut.And it is a polyphenolic substance with anti-oxidation,antibacterial,anti-inflammatory and anti-cancer activities.In this study,we set up the TGF-?1-induced(transforming growth factor-?1,TGF-?1)hepatic parenchymal AML12 model and the TNF-?-induced(tumor necrosis factor-?,TNF-?)HSC-T6(hepatic stellate cells-T6,HSC-T6)model in vitro and the mouse model with TAA(thioacetamide,TAA)in vivo,which were explored PCA for the improvement of liver fibrosis and the potential mechanism.As the results:(1)PCA can improve the viability of AML12 cells by TGF-?1 as well as inhibit metastasis.We found that PCA participated in the regulation of EMT process,upregulating E-cadherin and downregulating the expression of Snail,Vimentin and collagen I to inhibit EMT effectively,it aimed to prevent and treat liver fibrosis.(2)PCA can inhibit the viability of HSC-T6 by TNF-?.Western blot found,decrease expression level of transforming growth factor-?(TGF-?)and transforming growth factor-? receptor I(TR?I).PCA also could down-regulate the expression of p-smad2,transcription factor such as c-fos,c-Jun and smooth muscle actin proteins(?-SMA).Therefore,the results showed that PCA can inhibit the activation of HSC-T6 cells and ECM deposition by inhibiting TGF-?/smad signaling pathway to improve hepatic fibrosis.(3)In vivo,the mice were injected with TAA for ten weeks to establish a model of hepatic fibrosis.At the fourth week,the mice were treated with PCA by gavage at 75 mg/kg and 150 mg/kg for seven weeks in a row.Results show PCA can reduce liver cell damage by TAA and inhibit serum transaminase levels,which also alleviated inflammation and collagen accumulation in the model mouse by TAA.Results suggested that PCA may regulate TGF-?/Smad signaling pathways to improve hepatic fibrosis induced by TAA in mice.In conclusion,PCA can regulate EMT process by TGF-?1,results show it up-regulates the expression of E-cadherin to inhibit AML12 metastasis and protect liver function for metabolism.At the same time PCA can inhibit TNF-?-induced HSC-T6 cell activation by down-regulating the TGF-?/Smad signaling pathway,reducing the metabolic imbalance of collagen and maintaining the ECM homeostasis.The above experimental results suggested protocatechuic acid has the vital significance on preventing and treating liver fibrosis.From a long-term perspective,it will bring new breakthroughs for clinical studies on the prevention and treatment of liver fibrosis. |
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