naphthoquinones and Liver-Cirrhosis

Hepatic fibrosis in injured liver is characterized by the activation of hepatic stellate cells (HSCs) from their quiescent state. Survivin (BIRC5) is one of the key genes that are upregulated during activation of HSCs but their role in HSC activation and fibrosis progression is unknown. Here, we have investigated the role of survivin protein in early fibrogenic activation of HSCs and fibrosis progression in chronic liver injury.. Primary quiescent HSCs were isolated from healthy mice liver through perfusion and cultured for fibrogenic activation. Survivin expression was suppressed by its pharmacological suppressant, YM155. We developed chronic liver injury induced fibrotic mice model through administrating repeated dose of CCl. Survivin expression gradually increased along with the expression of αSMA, collagen I activation maker in HSCs during their activation from quiescent state. Survivin suppression through YM155 downregulated αSMA, collagen I. Pre-treatment of YM155 in mice ceased the early activation of HSCs and onset of fibrosis in injured liver. However, discontinuation of YM155 initiated the activation of HSCs and fibrosis progression that shows survivin expression in HSCs is essential for their early activation and onset of liver fibrosis.. Survivin expression induces with activation of HSCs and drives onset of liver fibrosis in injured liver. Targeting survivin protein in activated HSCs could be a potential anti-fibrotic therapeutic approach in chronic liver injury.

Topics: Animals; Cells, Cultured; Disease Progression; Dose-Response Relationship, Drug; End Stage Liver Disease; Hepatic Stellate Cells; Imidazoles; Liver Cirrhosis; Male; Mice; Mice, Inbred BALB C; Naphthoquinones; Survivin

In this study, we aim to investigate whether shikonin prevents against NAFLD. After feeding high-fat diet (HFD) for 10 weeks, Sprague-Dawley rats were received different doses of shikonin (5mg/kg/day, 10mg/kg/day and 20mg/kg/day) by gavage for the last 12 weeks of a total of 22 weeks of a HFD. Our results showed that total cholesterol (TC), triacylglycerol (TG), low-density lipoprotein cholesterol, aspartate aminotransferase and alanine aminotransferase were significantly increased, while high-density lipoprotein cholesterol was decrease, accompanied by hepatic injury and lipid accumulation in HFD-fed rats. Shikonin treatment attenuated the above biochemical and histopathological changes. Similarly, HFD-induced the increase of hepatic TC and TG levels were also ameliorated by shikonin treatment. Furthermore, shikonin observably mitigated HFD-induced the liver fibrosis and the increase of plasminogen activator inhibitor type 1, connective tissue growth factor, collagen III and IV expression. Additionally, shikonin markedly inhibited HFD-induced the decrease of proliferator-activated receptor γ (PPARγ) and matrix metalloproteinases-9 (MMP-9) expression and the increase of tissue inhibitor of metalloproteinases-1 (TIMP-1) expression in liver tissue. This study demonstrates that shikonin ameliorates hepatic lipid dysregulation and fibrosis through PPARγ and MMP-9/TIMP-1 axis, suggesting that shikonin may be a potential therapeutic agent for the treatment of NAFLD.

Topics: Animals; Body Weight; Boraginaceae; Diet, High-Fat; Gene Expression Regulation; Lipid Metabolism; Liver; Liver Cirrhosis; Male; Matrix Metalloproteinase 9; Naphthoquinones; Non-alcoholic Fatty Liver Disease; Plants, Medicinal; PPAR gamma; Rats, Sprague-Dawley; Tissue Inhibitor of Metalloproteinase-1

Liver fibrosis is a worldwide clinical challenge during the progression of chronic liver disease to liver cirrhosis. Shikonin is extracted from the root of Lithospermum erythrorhizon with antioxidant, anti-inflammatory, anticancer, and wound-healing properties. The study aims to investigate the protective effect of shikonin on liver fibrosis and its underlying mechanism.. Shikonin significantly inhibited activation of hepatic stellate cells and extracellular matrix formation by downregulating the transforming growth factor-β1 expression and maintaining the normal balance between metalloproteinase-2 and tissue inhibitor of metalloproteinase-1. Shikonin also decreased hepatic stellate cell energy production by inhibiting autophagy.. The results confirmed that shikonin attenuated liver fibrosis by downregulating the transforming growth factor-β1/Smads pathway and inhibiting autophagy.

Topics: Alanine Transaminase; Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspartate Aminotransferases; Autophagy; Disease Models, Animal; Down-Regulation; Extracellular Matrix; Hepatic Stellate Cells; Liver Cirrhosis; Male; Matrix Metalloproteinase 2; Mice; Mice, Inbred C57BL; Naphthoquinones; Signal Transduction; Smad Proteins, Receptor-Regulated; Tissue Inhibitor of Metalloproteinase-1; Transforming Growth Factor beta1

To examine the effects of arnebin-1 on nonalcoholic fatty liver disease (NAFLD) induced by a high-fat diet (HFD).. Male Sprague-Dawley rats were fed an HFD for 10 weeks and then treated with arnebin-1 at a dose of 5, 10 or 20 mg/kg/day by gavage for a further 12 weeks of a 22-week HFD. Peripheral blood and liver tissues were collected for biochemical and histopathological examination. The mechanisms of arnebin-1 on liver fibrosis and insulin resistance (IR) were determined by Western blotting and real-time quantitative polymerase chain reaction.. Arnebin-1 treatment attenuated the increase of total cholesterol, triglycerides, low-density lipoprotein cholesterol, aspartate aminotransferase and alanine aminotransferase in serum and lipid accumulation in the livers of HFD-fed rats. Furthermore, arnebin-1 abrogated HFD-induced liver fibrosis and the increase of fibrotic biomarkers. The HFD-induced decrease of hepatic proliferator-activated receptor γ and pro-matrix-metalloproteinase (MMP)-9 levels and the increase of tissue inhibitor of metalloproteinase-1 (TIMP-1) levels were reversed after arnebin-1. Arnebin-1 attenuated IR through activating the insulin receptor substrate-1/Akt/mTOR signalling pathway.. This study demonstrated that arnebin-1 ameliorates NAFLD, in part, by attenuating hepatic fibrosis and IR, suggesting that arnebin-1 may be a therapeutic agent for NAFLD treatment.

Topics: Animals; Diet, High-Fat; Insulin Resistance; Liver Cirrhosis; Male; Naphthoquinones; Non-alcoholic Fatty Liver Disease; Protective Agents; Rats; Rats, Sprague-Dawley

The purpose of this study was to investigate plumbagin (PL) on liver fibrosis in vitro and in vivo and to explore the underlying mechanisms.. Carbon tetrachloride (CCl. The results revealed that PL significantly prevented CCl. The results of our study indicate that PL can mitigate liver fibrosis in vitro and in vivo, which may be related to the ROS-mediated NF-кB signaling pathway.

Topics: Animals; Antioxidants; Cell Nucleus; Collagen Type I; Collagen Type III; Hepatic Stellate Cells; Interleukin-1beta; Liver Cirrhosis; Male; NADPH Oxidase 4; Naphthoquinones; NF-kappa B; NF-KappaB Inhibitor alpha; Oxidative Stress; Phosphorylation; Rats, Sprague-Dawley; Reactive Oxygen Species; RNA, Messenger; Signal Transduction; Transcription Factor RelA

Critical roles for liver sinusoidal endothelial cells (LSECs) in liver fibrosis have been demonstrated, while little is known regarding the underlying molecular mechanisms of drugs delivered to the LSECs. Our previous study revealed that plumbagin plays an antifibrotic role in liver fibrosis. In this study, we investigated whether plumbagin alleviates capillarization of hepatic sinusoids by downregulating endothelin-1 (ET-1), vascular endothelial growth factor (VEGF), laminin (LN), and type IV collagen on leptin-stimulated LSECs. We found that normal LSECs had mostly open fenestrae and no organized basement membrane. Leptin-stimulated LSECs showed the formation of a continuous basement membrane with few open fenestrae, which were the features of capillarization. Expression of ET-1, VEGF, LN, and type IV collagen was enhanced in leptin-stimulated LSECs. Plumbagin was used to treat leptin-stimulated LSECs. The sizes and numbers of open fenestrae were markedly decreased, and no basement membrane production was found after plumbagin administration. Plumbagin decreased the levels of ET-1, VEGF, LN, and type IV collagen in leptin-stimulated LSECs. Plumbagin promoted downregulation of ET-1, VEGF, LN, and type IV collagen mRNA. Altogether, our data reveal that plumbagin reverses capillarization of hepatic sinusoids by downregulation of ET-1, VEGF, LN, and type IV collagen.

Topics: Animals; Basement Membrane; Capillaries; Collagen Type IV; Down-Regulation; Endothelial Cells; Endothelin-1; Hepatic Veins; Hepatocytes; Laminin; Liver; Liver Cirrhosis; Male; Naphthoquinones; Rats; Rats, Sprague-Dawley; Vascular Endothelial Growth Factor A

Topics: Animals; beta Catenin; Blotting, Western; Carbon Tetrachloride Poisoning; Cell Differentiation; Dental Pulp; Fluorescent Antibody Technique; Hepatocytes; Humans; Hydroxyproline; In Vitro Techniques; Liver Cirrhosis; Male; Mice; Mice, Nude; Naphthoquinones; NIMA-Interacting Peptidylprolyl Isomerase; Stem Cell Transplantation; Stem Cells; Wnt Signaling Pathway

Plasminogen activator inhibitor-1 (PAI-1) is a key negative regulator of the fibrinolytic system. Elevated levels of PAI-1 are associated with thrombosis and cardiovascular and metabolic diseases. Inhibition of PAI-1 activity represents a new strategy for antithrombotic and antifibrinolysis therapies. In this study, we systematically investigated the inhibitory effect of shikonin on PAI-1 activity. In the chromogenic substrate-based urokinase (uPA)/PAI-1 assay, we found that shikonin inhibited human PAI-1 activity with IC50 values of 30.68±2.32μM. This result was further confirmed by urokinase-type plasminogen activator (uPA)-mediated clot lysis assay. Mechanistic studies indicated that shikonin directly could bind to PAI-1 and prevent the binding of PAI-1 to uPA in a dose-dependent manner. Shikonin also blocked the formation of PAI-1/uPA complex, as shown by SDS/PAGE analysis. In the mouse arterial thrombosis model, intraperitoneal injection of shikonin at 1mgkg(-1) dose significantly prolonged tail bleeding time from 12.956±4.457min to 26.576±2.443min. It also reduced arterial thrombus weight from 0.01±0.001g to 0.006±0.001g (p<0.05). In a liver fibrosis treatment model, when shikonin was continuously injected intraperitoneally at a dose of 1mgkg(-1) over a two-week period, the hydroxyproline content in the mice plasma was significantly reduced and the degree of liver fibrosis was decreased significantly. Thus, shikonin may represent a novel small molecule inhibitor of PAI-1 that could have become a lead drug the treatment of thrombus and fibrosis.

Topics: Animals; Disease Models, Animal; Humans; Liver Cirrhosis; Mice; Naphthoquinones; Plasminogen Activator Inhibitor 1; Thrombosis; Urokinase-Type Plasminogen Activator

Therapeutic management of liver fibrosis remains an unsolved clinical problem. Hepatic accumulation of extracellular matrix, mainly collagen, is mediated by the production of transforming growth factor-β1 (TGF-β1) in stellate cells. Pin1, a peptidyl-prolyl isomerase, plays an important pathophysiological role in several diseases, including neurodegeneration and cancer. Herein, we determined whether Pin1 regulates liver fibrogenesis and examined its mechanism of action by focusing on TGF-β1 signalling and hepatic stellate cell (HSC) activation.. Pin1 expression was assessed by immunohistochemistry, Western blot or real-time-polymerase chain reaction (RT-PCR) analyses of human and mouse fibrotic liver samples. The role of Pin1 during HSC activation was estimated using Pin1-null mouse embryonic fibroblast (MEF) cells and Pin1-overexpressing LX-2 human hepatic stellate cells.. Pin1 expression was elevated in human and mouse fibrotic liver tissues, and Pin1 inhibition improved dimethylnitrosamine (DMN)-induced liver fibrosis in mice. Pin1 inhibition reduced the mRNA or protein expression of TGF-β1 and α-smooth muscle actin (α-SMA) by DMN treatment. Pin1 knockdown suppressed TGFβ1 gene expression in both LX-2 and MEF cells. Pin1-mediated TGFβ1 gene transcription was controlled by extracellular signal-regulated kinase (ERK)- and phosphoinositide 3-kinase/Akt-mediated activator protein-1 (AP-1) activation. Moreover, TGFβ1-stimulated Smad2/3 phosphorylation and plasminogen activator inhibitor-1 expression were inhibited by Pin1 knockdown.. Pin1 induction during liver fibrosis is involved in hepatic stellate cell activation, TGFβ1 expression, and TGFβ1-mediated fibrogenesis signalling.

Topics: Animals; Cell Communication; Cells, Cultured; Enzyme Inhibitors; Fibroblasts; Gene Expression Regulation, Neoplastic; Hepatic Stellate Cells; Humans; Liver Cirrhosis; Male; Mice, Inbred ICR; Mice, Knockout; Naphthoquinones; NIMA-Interacting Peptidylprolyl Isomerase; Peptidylprolyl Isomerase; Phosphorylation; Signal Transduction; Smad2 Protein; Smad3 Protein; Transforming Growth Factor beta1

To investigate the effect of plumbagin on the expression of TNF-alpha and PDGF-BB in human hepatic stellate cells (HSC-LX2) activated by Leptin.. HSC-LX2 were cultured in vitro and stimulated by Leptin for 24 hours then treated with different concentrations of plumbagin for 24 hours, the expressions of TNF-alpha mRNA and PDGF-BB mRNA were determined by Realtime quantitative PCR, the protein expressions of TNF-alpha and PDGF-BB were determined-by Western blotting.. The expressions of TNF-alpha mRNA and PDGF-BB mRNA of treatment groups were significantly reduced, especially in high dose group (P < 0.01), and Western blotting analyses revealed similar trends in protein expression.. Plumbagin may prevent the formation of hepatic fibrosis and its mechanism may be related to decreasing the level of mRNA of TNF-alpha and PDGF-BB and the protein of PDGF-BB.

Topics: Becaplermin; Cells, Cultured; Gene Expression Regulation; Hepatic Stellate Cells; Humans; Leptin; Liver Cirrhosis; Naphthoquinones; Plumbaginaceae; Polymerase Chain Reaction; Proto-Oncogene Proteins c-sis; RNA, Messenger; Tumor Necrosis Factor-alpha

Topics: Animals; Body Weight; Carcinogens; Carcinoma, Hepatocellular; Chemical and Drug Induced Liver Injury; Chlorine; Diet; Dose-Response Relationship, Drug; Female; Lethal Dose 50; Liver; Liver Cirrhosis; Liver Neoplasms; Lung Neoplasms; Male; Mice; Mice, Inbred Strains; Mycotoxins; Naphthoquinones; Necrosis; Oryza; Penicillium; Peptides, Cyclic; Sex Factors

Topics: Antifibrinolytic Agents; Humans; Hypoprothrombinemias; Liver Cirrhosis; Naphthoquinones; Prothrombin; Vitamin K; Vitamin K 1

Topics: Antifibrinolytic Agents; Heparin Antagonists; Humans; Hypoprothrombinemias; Liver Cirrhosis; Naphthoquinones; Prothrombin; Vitamin K; Vitamin K 1

Topics: Antifibrinolytic Agents; Factor Xa; Humans; Jaundice; Jaundice, Obstructive; Liver Cirrhosis; Naphthoquinones; Vitamin K; Vitamin K 1

Topics: Antifibrinolytic Agents; Humans; Liver Cirrhosis; Naphthoquinones; Retinoids; Vitamin K

Topics: Antifibrinolytic Agents; Humans; Liver Cirrhosis; Naphthoquinones; Retinoids; Vitamin K

Topics: Antifibrinolytic Agents; Humans; Liver Cirrhosis; Naphthoquinones; Retinoids; Vitamin K; Vitamins