Transforming growth factor-β1 (TGF-β1)-induced myofibroblast transdifferentiation from orbital fibroblasts is known to dominate tissue remodeling and fibrosis in Graves’ ophthalmopathy (GO). However, the signaling pathways through which TGF-β1 activates Graves’ orbital fibroblasts remain unclear. This study investigated the role of the mitogen-activated protein kinase (MAPK) pathway in TGF-β1-induced myofibroblast transdifferentiation in human Graves’ orbital fibroblasts. The MAPK pathway was assessed by measuring the phosphorylation of p38, c-Jun N-terminal kinase (JNK), and extracellular-signal-regulated kinase (ERK) by Western blots. The expression of connective tissue growth factor (CTGF), α-smooth muscle actin (α-SMA), and fibronectin representing fibrogenesis was estimated. The activities of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) responsible for extracellular matrix (ECM) metabolism were analyzed. Specific pharmacologic kinase inhibitors were used to confirm the involvement of the MAPK pathway. After treatment with TGF-β1, the phosphorylation levels of p38 and JNK, but not ERK, were increased. CTGF, α-SMA, and fibronectin, as well as TIMP-1 and TIMP-3, were upregulated, whereas the activities of MMP-2/-9 were inhibited. The effects of TGF-β1 on the expression of these factors were eliminated by p38 and JNK inhibitors. The results suggested that TGF-β1 could induce myofibroblast transdifferentiation in human Graves’ orbital fibroblasts through the p38 and JNK pathways.

• Graves’ ophthalmopathy
• Graves’ orbital fibroblasts
• c-Jun N-terminal kinase
• mitogen-activated protein kinase
• p38
• transforming growth factor-β1

• NF-κB
• NLRP3 inflammasome
• NRF2-KEAP1
• ROS
• extracellular matrix
• hepatic stellate cells
• inflammation
• liver damage

• 53358 Consejo Nacional de Ciencia y Tecnología

Fibrosis is a type of chronic organ failure, resulting in the excessive secretion of extracellular matrix (ECM). ECM protects wound tissue from infection and additional injury, and is gradually degraded during wound healing. For some unknown reasons, myofibroblasts (the cells that secrete ECM) do not undergo apoptosis; this is associated with the continuous secretion of ECM and reduced ECM degradation even during de novo tissue formation. Thus, matrix metalloproteinases (MMPs) are considered to be a potential target of fibrosis treatment because they are the main groups of ECM-degrading enzymes. However, MMPs participate not only in ECM degradation but also in the development of various biological processes that show the potential to treat diseases such as stroke, cardiovascular diseases, and arthritis. Therefore, treatment involving the targeting of MMPs might impede typical functions. Here, we evaluated the links between these MMP functions and possible detrimental effects of fibrosis treatment, and also considered possible approaches for further applications.

• extracellular matrix
• fibrosis
• matrix metalloproteinase

• Animals
• Disease Susceptibility
• Enzyme Activation
• Extracellular Matrix/metabolism
• Fibrosis/drug therapy
• Fibrosis/etiology
• Fibrosis/metabolism
• Gene Expression Regulation
• Humans
• Immunomodulation
• Matrix Metalloproteinases/genetics
• Matrix Metalloproteinases/metabolism
• Matrix Metalloproteinases/pharmacology
• Matrix Metalloproteinases/therapeutic use
• Myofibroblasts/metabolism
• Neovascularization, Pathologic
• Organ Specificity/genetics
• Proteolysis
• Wound Healing

• Fibrosis
• Liver
• NAFLD
• NASH
• PNPLA3

• Animals
• Female
• Gene Silencing
• Humans
• Lipase/genetics
• Lipase/metabolism
• Liver Cirrhosis/genetics
• Liver Cirrhosis/metabolism
• Membrane Proteins/genetics
• Membrane Proteins/metabolism
• Mice
• Mice, Inbred C57BL
• Non-alcoholic Fatty Liver Disease/genetics
• Non-alcoholic Fatty Liver Disease/metabolism
• Oligonucleotides, Antisense/genetics
• Oligonucleotides, Antisense/metabolism
• Phospholipases A2, Calcium-Independent/genetics
• Phospholipases A2, Calcium-Independent/metabolism

• anticoagulation
• cirrhosis
• endothelial dysfunction
• hepatitis
• protease-activated receptors
• thrombin
• von Willebrand factor

• choline-deficient diet
• extracellular matrix
• liver fibrosis
• matrix metalloproteinases
• nonalcoholic liver diseases
• steatohepatitis
• thioacetamide
• tissue inhibitors of matrix metalloproteinases

It has been reported that bone marrow-derived mesenchymal stem cells (BMSCs) alleviated liver fibrosis. We investigated whether BMSCs transfected with human matrix metalloproteinase 1 (BMSCs/MMP1) would improve their therapeutic effect in liver fibrosis induced by carbon tetrachloride (CCl₄) in rats. BMSCs were transfected with an adenovirus carrying enhanced green fluorescence protein (GFP) and human MMP1 gene. BMSCs or BMSCs/MMP1 were directly injected into fibrotic rats via the tail vein. GFP-labeled cells appeared in the fibrotic liver after BMSC transplantation. The expression of BMSCs/MMP1 elevated levels of MMP1 in vitro. Although BMSC administration reduced liver fibrosis, transplantation of BMSCs/MMP1 enhanced the reduction of liver fibrosis to a higher level. Treatment with BMSCs/MMP1 not only decreased collagen content but also suppressed activation of hepatic stellate cells (HSCs) in fibrotic liver, which led to subsequent improvement of both liver injury and fibrosis. Treatment with BMSCs/MMP1 resulted in an improved therapeutic effect compared with BMSCs alone, which is probably because of the sustainably expressed MMP1 level in the liver. BMSCs/MMP1 transplantation not only improved biochemical parameters but also attenuated progression of liver fibrosis, suggesting that BMSCs may be a potential cell source in preventing liver fibrosis and MMP1 gene may enhance the anti-fibrotic effect of BMSCs.

• CCl4
• NFκB
• NFκBia
• fibrose
• fibrosis
• renin–angiotensin system
• système rénine–angiotensine

Chondroitin/dermatan sulfate (CS/DS) rich in N-acetylgalactosamine 4,6-bissulfate (GalNAc(4,6SO₄)) residues is present as decorin and/or biglycan in mouse liver, and GalNAc(4,6SO₄) residues disappeared completely in N-acetylgalactosamine 4-sulfate 6-O-sulfotransferase (GalNAc4S-6ST) knockout (KO) mice. The aim of this study was to investigate whether CS/DS rich in GalNAc(4,6SO₄) residues participate in the progression or resolution of liver fibrosis.

Wild type (WT) and GalNAc4S-6ST KO mice were treated with CCl₄ for 5 weeks. After discontinuation of CCl₄ administration, histochemical and biochemical changes and expression of genes related to matrix components were compared between WT and GalNAc4S-6ST KO mice.

On 2 days after cessation of CCl₄ administration, higher fibrosis was observed in KO mice than in WT mice by Sirius Red staining. Serum alanine aminotransferase activity was higher in KO mice than in WT mice. Hydroxyproline contents and Sirius Red staining showed that repair of liver fibrosis in the recovery stages appeared to be delayed in KO mice. Expression of mRNA of matrix metalloproteinase (MMP)-2, MMP-13 and versican peaked at 2 days after cessation of CCl₄ administration and was higher in KO mice than in WT mice. Expression of MMP-9 in the recovery stage was lower in KO mice than in WT mice. Our findings demonstrate that defect in GalNAc4S-6ST, which resulted in disappearance of CS/DS containing GalNAc(4,6SO₄), appear to contribute to progression of liver fibrosis, delayed recovery from fibrosis, and various changes in the expression of proteoglycans and MMPs in carbon tetrachloride–treated mice.

• Biochemistry
• Cell biology

Soluble cluster of differentiation 40 (sCD40) is proteolytically cleaved from membrane-bound CD40 and binds to CD154, thereby inhibiting CD40-CD154-mediated immune responses. The aim of the present study was to clarify the role of sCD40 in chronic hepatitis B (CHB). The sCD40 levels in sera from 132 patients with CHB and 33 healthy individuals were retrospectively measured. sCD40 concentrations in patients with CHB were higher than those in healthy controls, and sCD40 levels correlated positively with serum levels of the liver dysfunction biomarkers alanine transaminase (ALT) and aspartate transaminase (AST). sCD40 concentrations increased with a rise in the severity of liver necroinflammation and fibrosis. Patients with >75% liver tissue staining positive for hepatitis B virus (HBV) antigen expression showed significantly lower sCD40 levels than those who stained negative for the HBV antigen. The area under the receiver operating characteristic curve of sCD40 was greater than that of ALT and AST; thus, sCD40 levels have a high diagnostic accuracy for detecting severe liver inflammation in patients with CHB, and could serve as an immunological marker of hepatic tissue injury.

• fibrosis
• hepatocyte
• immune
• necroinflammatory

Hepatocyte growth factor (HGF) gene transfer inhibits liver fibrosis by regulating aberrant cellular functions, while mutant matrix metalloproteinase-9 (mMMP-9) enhances matrix degradation by neutralizing the elevated tissue inhibitor of metalloproteinase-1 (TIMP-1). It was shown that ASH1 and EZH2 methyltransferases are involved in development of liver fibrosis; however, their role in the resolution phase of liver fibrosis has not been investigated. This study evaluated the role of ASH1 and EZH2 in two mechanistically different therapeutic modalities, HGF and mMMP-9 gene transfer in CCl₄ induced rat liver fibrosis. Liver fibrosis was induced in rats with twice a week intraperitoneal injection of CCl₄ for 8 weeks. Adenovirus vectors encoding mMMP-9 or HGF genes were injected through tail vein at weeks six and seven and were sacrificed one week after the second injection. A healthy animal group was likewise injected with saline to serve as a negative control. Rats treated with mMMP-9 showed significantly lower fibrosis score, less Sirius red stained collagen area, reduced hydroxyproline and ALT concentration, decreased transforming growth factor beta 1 (TGF-β1) mRNA and lower labeling indices of α smooth muscle actin (α-SMA) and proliferating cell nuclear antigen (PCNA) stained cells compared with HGF- or saline-treated rats. Furthermore, TIMP-1 protein expression in mMMP-9 group was markedly reduced compared with all fibrotic groups. ASH1 and EZH2 protein expression was significantly elevated in fibrotic liver and significantly decreased in mMMP-9- and HGF-treated compared to saline-treated fibrotic livers with further reduction in the mMMP-9 group. Conclusion: Gene transfer of mMMP-9 and HGF reduced liver fibrosis in rats. ASH1 and EZH2 methyltransferases are significantly reduced in mMMP-9 and HGF treated rats which underlines the central role of these enzymes during fibrogenesis. Future studies should evaluate the role of selective pharmacologic inhibitors of ASH1 and EZH2 in resolution of liver fibrosis.

Nonalcoholic steatohepatitis (NASH) is emerging worldwide because life-styles have changed to include much over-eating and less physical activity. The clinical and pathophysiological features of NASH are very different from those of HBV- and HCV-chronic liver diseases. The prognosis of NASH is worse among those with nonalcoholic fatty liver diseases (NAFLD), and some NASH patients show HCC with or without cirrhosis. In the present review we discuss fibrogenesis and the relationship between fibrosis and HCC occurrence in NASH to clarify the role of MMPs and TIMPs in both mechanisms. Previously we proposed MMP and TIMP expression in the multi-step occurrence of HCC from the literature based on viral-derived HCC. We introduce again these expressions during hepatocarcinogenesis and compare them to those in NASH-derived HCC, although the relationship with hepatic stem/progenitor cells (HPCs) invasion remains unknown. Signal transduction of MMPs and TIMPs is also discussed because it is valuable for the prevention and treatment of NASH and NASH-derived HCC.

• HCC
• MMP-2
• TACE
• TIMP-2

• hepatic stellate cell
• interferon-γ
• macrophage

• Fibrosis
• Hepatic stellate cells
• Procollagen
• Somatostatin
• Somatostatin receptors

• Animals
• Cell Proliferation
• Cells, Cultured
• Collagen/biosynthesis
• Hepatic Stellate Cells/drug effects
• Hepatic Stellate Cells/metabolism
• Liver/pathology
• Liver Cirrhosis/drug therapy
• Male
• Octreotide/pharmacology
• Phosphoproteins/metabolism
• Platelet-Derived Growth Factor/physiology
• Protein Processing, Post-Translational
• Protein Tyrosine Phosphatases/metabolism
• Rats
• Rats, Sprague-Dawley
• Receptors, Somatostatin/metabolism
• Transforming Growth Factor beta/physiology
• Tumor Necrosis Factor-alpha/physiology

Accumulation of extracellular matrix (ECM) and increased matrix metalloproteinase (MMP) activity are hallmarks of liver fibrosis. The aim of the present study was to develop a model of liver fibrosis combining ex vivo tissue culture of livers from CCl₄ treated animals with an ELISA detecting a fragment of type III collagen generated in vitro by MMP-9 (C3M), known to be associated with liver fibrosis and to investigate cAMP modulation of MMP activity and liver tissue turnover in this model.

In vivo: Rats were treated for 8 weeks with CCl₄/Intralipid. Liver slices were cultured for 48 hours. Levels of C3M were determined in the supernatants of slices cultured without treatment, treated with GM6001 (positive control) or treated with IBMX (phosphodiesterase inhibitor). Enzymatic activity of MMP-2 and MMP-9 were studied by gelatin zymography. Ex vivo: The levels of serum C3M increased 77% in the CCl₄-treated rats at week 8 (p < 0.01); Levels of C3M increased significantly by 100% in fibrotic liver slices compared to controls after 48 hrs (p < 0.01). By adding GM6001 or IBMX to the media, C3M was restored to control levels. Gelatin zymography demonstrated CCl₄-treated animals had highly increased MMP-9, but not MMP-2 activity, compared to slices derived from control animals.

We have combined an ex vivo model of liver fibrosis with measurement of a biochemical marker of collagen degradation in the condition medium. This technology may be used to evaluate the molecular process leading to structural fibrotic changes, as collagen species are the predominant structural part of fibrosis. These data suggest that modulation of cAMP may play a role in regulation of collagen degradation associated with liver fibrosis.

• forkhead box a2 gene
• hepatocyte
• mesenchymal stem cell
• stem cell therapy

• Animals
• Bone Marrow Cells/cytology
• Bone Marrow Transplantation
• Cell Differentiation
• Cell Movement
• Chemical and Drug Induced Liver Injury/pathology
• Chemical and Drug Induced Liver Injury/therapy
• Chemokine CXCL12/genetics
• Chemokine CXCL12/metabolism
• Disease Models, Animal
• Hematopoietic Stem Cells/cytology
• Male
• Matrix Metalloproteinase 9/deficiency
• Matrix Metalloproteinase 9/genetics
• Matrix Metalloproteinase 9/metabolism
• Mice
• Mice, Knockout
• Mice, Transgenic
• Receptors, CXCR4/genetics
• Receptors, CXCR4/metabolism
• Transplantation, Homologous

Hepatic fibrosis is characterized by intense tissue remodeling, mainly driven by matrix metalloproteinases. We previously identified CO3-610, a type III collagen neoepitope generated by matrix metalloproteinase (MMP)-9, and tested its performance as a fibrosis marker in rats with bile-duct ligation. In this study, we assessed whether CO3-610 could be used as a surrogate biomarker of liver fibrosis and portal hypertension in carbon tetrachloride-induced experimental fibrosis.

For this study, 68 Wistar rats were used. Serum CO3-610 was measured by ELISA. Liver fibrosis was quantified by Sirius red staining. Serum hyaluronic acid (HA) was measured with a binding-protein assay. Gene expression of collagens I and III, Mmp2 and Mmp9, and tissue inhibitors of matrix metalloproteinase 1 (Timp1) and 2(Timp2) was quantified by PCR. Hemodynamic measurements were taken in a subgroup of animals. A close direct relationship was found between serum CO3-610 and hepatic collagen content (r = 0.78; P < 0.001), superior to that found for serum HA (r = 0.49; P < 0.05). CO3-610 levels in rats with severe fibrosis (43.5 ± 3.3 ng/mL, P < 0.001) and cirrhosis (60.6 ± 4.3 ng/mL, P < 0.001) were significantly higher than those in control animals (26.6 ± 1.3 ng/mL). Importantly, a highly significant relationship was found between serum CO3-610 and portal hypertension (r = 0.84; P < 0.001). Liver Mmp9 expression increased significantly in fibrotic animals but decreased to control levels in cirrhotic ones.

Circulating CO3-610 behaves as a reliable indicator of hepatic remodeling and portal hypertension in experimental fibrosis. This peptide could ultimately be a useful marker for the management of liver disease in patients.

• Animals
• Carbon Tetrachloride Poisoning/metabolism
• Carbon Tetrachloride Poisoning/pathology
• Diet
• Humans
• Lipid Peroxidation
• Liver/metabolism
• Liver/pathology
• Male
• Oxidative Stress
• Rats
• Rats, Wistar
• Zinc/deficiency

• cirrhosis
• fibrogenesis
• type i collagen
• hepatic stellate cell
• matrix metalloproteinase-2

AIM: To investigate the effects of curcumin on the expression of plasminogen activator inhibitor-1 (PAI-1) and urokinase-type plasminogen activator (u-PA) in carbon tetrachloride-induced hepatic fibrosis in rats.

METHODS: One hundred male Sprague-Dawley rats were randomly divided into five groups: normal group, model group, low-, medium- and high-dose curcumin group. Except the normal group, the rats of the other groups were intraperitoneally injected with carbon tetrachloride for 6 wk to induce liver fibrosis. The rats of the low-, medium- and high-dose curcumin groups were administrated different doses of curcumin. On days 4, 7, 21 and 42 after treatment, five rats randomly selected from each group were sacrificed to take liver specimens for pathological examination (HE). The expression of PAI-1 and u-PA in hepatic fibrosis was detected by immunohistochemistry.

RESULTS: The expression levels of PAI-1 and u-PA were much lower in the normal group than in the model group. Compared to the model group, PAI-1 expression was significantly down-regulated (42 d: 5.60 ± 1.673, 3.40 ± 1.673, 2.40 ± 1.140 vs 8.80 ± 2.168, all P < 0.05) and u-PA expression was significantly up-regulated (42 d: 6.00 ± 1.414, 9.20 ± 1.643, 9.80 ± 2.049 vs 4.20 ± 1.095, P < 0.05) in the low-, medium- and high-dose curcumin groups. Curcumin treatment altered the expression of PAI-1 and u-PA in a dose- and time-dependent manner.

CONCLUSION: Curcumin exerts anti-fibrotic effects possibly by decreasing the expression of PAI-1 and increasing the expression of u-PA.

• Curcumin
• Hepatic fibrosis
• Plasminogen activator inhibitor-1
• Urokinase-type plasminogen activator
• Immunohistochemistry

• Animals
• Antioxidants/metabolism
• Antioxidants/pharmacology
• Antioxidants/therapeutic use
• Carbon Tetrachloride
• Carbon Tetrachloride Poisoning/drug therapy
• Carbon Tetrachloride Poisoning/metabolism
• Down-Regulation
• Fraxinus/chemistry
• Gene Expression
• Liver/drug effects
• Liver/metabolism
• Liver/pathology
• Liver Cirrhosis/chemically induced
• Liver Cirrhosis/metabolism
• Liver Cirrhosis/prevention & control
• Male
• Matrix Metalloproteinase 2/genetics
• Matrix Metalloproteinase 2/metabolism
• Matrix Metalloproteinase 9/genetics
• Matrix Metalloproteinase 9/metabolism
• Phytotherapy
• Plant Extracts/chemistry
• Plant Extracts/pharmacology
• Plant Extracts/therapeutic use
• Rats
• Rats, Sprague-Dawley
• Silymarin/therapeutic use
• Tissue Inhibitor of Metalloproteinase-1/genetics
• Tissue Inhibitor of Metalloproteinase-1/metabolism
• Umbelliferones/analysis
• Umbelliferones/pharmacology
• Umbelliferones/therapeutic use
• Urokinase-Type Plasminogen Activator/genetics
• Urokinase-Type Plasminogen Activator/metabolism

Fibrosis can occur in tissues in response to a variety of stimuli. Following tissue injury, cells undergo transformation or activation from a quiescent to an activated state resulting in tissue remodelling. The fibrogenic process creates a tissue environment that allows inflammatory and matrix-producing cells to invade and proliferate. While this process is important for normal wound healing, chronicity can lead to impaired tissue structure and function.

This review examines the major factors involved in transforming or activating tissues towards fibrosis. The role of genetic variation within individuals affected by fibrosis has not been well described and it is in this context that we have examined the mediators of remodelling, including transforming growth factor-beta, T helper 2 cytokines and matrix metalloproteinases.

Finally we examine the role of Toll-like receptors in fibrosis. The inflammatory phenotype that precedes fibrosis has been associated with Toll-like receptor activation. This is particularly important when considering gastrointestinal and hepatic disease, where inappropriate Toll-like receptor signalling, in response to the local microbe-rich environment, is thought to play an important role.

Hepatic fibrosis is considered a common response to many chronic hepatic injuries. It is a multifunctional process that involves several cell types, cytokines, chemokines and growth factors leading to a disruption of homeostatic mechanisms that maintain the liver ecosystem. In spite of many studies regarding the development of fibrosis, the understanding of the pathogenesis remains obscure. The hepatic tissue remodeling process is highly complex, resulting from the balance between collagen degradation and synthesis. Among the many mediators that take part in this process, the components of the Renin angiotensin system (RAS) have progressively assumed an important role. Angiotensin (Ang) II acts as a profibrotic mediator and Ang-(1-7), the newly recognized RAS component, appears to exert a counter-regulatory role in liver tissue. We briefly review the liver fibrosis process and current aspects of the RAS. This review also aims to discuss some experimental evidence regarding the participation of RAS mediators in the pathogenesis of liver fibrosis, focusing on the putative role of the ACE2-Ang-(1-7)-Mas receptor axis.

• Hepatic fibrosis
• Renin angiotensin system
• Angiotensin II
• Angiotensin-(1-7)
• Receptor Mas
• Angiotensin converting enzyme 2

• hepatic stellate cell
• matrix metalloproteinase
• carbon tetrachloride
• thioacetamide
• bile duct ligation

• Administration, Oral
• Animals
• Apoptosis/drug effects
• Carbon Tetrachloride
• Drugs, Chinese Herbal/pharmacology
• Drugs, Chinese Herbal/therapeutic use
• Hepatic Stellate Cells/drug effects
• Hepatic Stellate Cells/pathology
• Hepatocytes/drug effects
• Hepatocytes/pathology
• Hydroxyproline/metabolism
• Kupffer Cells/drug effects
• Kupffer Cells/pathology
• Liver/drug effects
• Liver/metabolism
• Liver/pathology
• Liver Cirrhosis, Experimental/drug therapy
• Liver Cirrhosis, Experimental/pathology
• Male
• Phytotherapy
• Rats
• Rats, Wistar

• fibrosis
• cirrhosis
• stellate cell
• extracellular matrix
• myofibroblast
• liver biopsy
• complication
• portal hypertension

• Angiotensin II/antagonists & inhibitors
• Chronic Disease
• Colchicine/therapeutic use
• Collagen/antagonists & inhibitors
• Collagen/biosynthesis
• Extracellular Matrix/metabolism
• Hepatic Stellate Cells/metabolism
• Humans
• Interferon-gamma/therapeutic use
• Ligands
• Liver Cirrhosis/drug therapy
• Liver Cirrhosis/pathology
• Liver Cirrhosis/physiopathology
• PPAR gamma/antagonists & inhibitors
• Pyridones/therapeutic use

• R01 DK 50574 NIDDK NIH HHS
• R01 DK063308 NIDDK NIH HHS
• R01 DK063308-06 NIDDK NIH HHS
• R01 DK050574-13 NIDDK NIH HHS
• R01 DK 60338 NIDDK NIH HHS
• R01 DK050574 NIDDK NIH HHS

• Autocrine Communication
• Collagen Type I/genetics
• Collagen Type I/metabolism
• Extracellular Matrix/metabolism
• Gene Expression Regulation
• Hepatic Stellate Cells/metabolism
• Hepatic Stellate Cells/pathology
• Humans
• Liver Cirrhosis/metabolism
• Liver Cirrhosis/pathology
• Liver Cirrhosis, Alcoholic/metabolism
• Metalloproteases/metabolism
• Oxidative Stress
• Paracrine Communication
• Reactive Nitrogen Species/metabolism
• Reactive Oxygen Species/metabolism
• Signal Transduction

• R01 AA017733 NIAAA NIH HHS
• R01 AA017733-01 NIAAA NIH HHS
• R01 DK069286 NIDDK NIH HHS
• R01 DK069286-04 NIDDK NIH HHS

• Angiotensin-Converting Enzyme Inhibitors/therapeutic use
• Animals
• Enalapril/therapeutic use
• Liver/pathology
• Liver Cirrhosis/metabolism
• Liver Cirrhosis/pathology
• Liver Cirrhosis/prevention & control
• Male
• Matrix Metalloproteinase 2/metabolism
• Rats
• Rats, Wistar
• Transforming Growth Factor beta1/metabolism

• Carcinoma, Hepatocellular/metabolism
• Humans
• Liver/metabolism
• Liver Cirrhosis/etiology
• Liver Cirrhosis/metabolism
• Liver Diseases/drug therapy
• Liver Diseases/metabolism
• Liver Neoplasms/metabolism
• Zinc/deficiency
• Zinc/metabolism
• Zinc/therapeutic use