• antioxidants
• hydroxyproline
• liver fibrosis
• white tea

• extracellular matrix
• flavonoids
• hepatic fibrosis
• matrix metalloproteinase
• terpenoids

• Animals
• Liver Cirrhosis/drug therapy
• Extracellular Matrix/metabolism
• Phytochemicals/pharmacology
• Phytochemicals/therapeutic use
• Disease Progression

• PS 155994 Institute of Nutrition, Metabolism and Diabetes

Liver fibrosis and hepatocellular carcinoma (HCC) have been worldwide threats nowadays. Liver fibrosis is reversible in early stages but will develop precancerosis of HCC in cirrhotic stage. In pathological liver, excessive H₂O₂ is generated and accumulated, which impacts the functionality of hepatocytes, Kupffer cells (KCs) and hepatic stellate cells (HSCs), leading to genesis of fibrosis and HCC. H₂O₂ accumulation is associated with overproduction of superoxide anion (O₂^•−) and abolished antioxidant enzyme systems. Plenty of therapeutics focused on H₂O₂ have shown satisfactory effects against liver fibrosis or HCC in different ways. This review summarized the reasons of liver H₂O₂ accumulation, and the role of H₂O₂ in genesis of liver fibrosis and HCC. Additionally, nanotherapeutics targeting H₂O₂ were summarized for further consideration of antifibrotic or antitumor therapy.

•

Liver fibrosis and HCC are closely related because ROS induced liver damage and inflammation, especially over-cumulated H₂O₂.

• combination therapy
• macrophage polarization
• mitochondrial damage
• nuclear export protein
• tumor metastasis

• DNA damage
• DNA repair mechanism
• Immunotherapy
• Inflammation
• Mutation

• Carcinogens/metabolism
• Carcinogens/toxicity
• DNA/metabolism
• DNA Damage
• DNA Repair
• Humans
• Mutagens/metabolism
• Mutagens/toxicity
• Neoplasms/epidemiology

• endocrine system and metabolic diseases
• cell biology

• cell-free therapy
• extracellular vesicles
• hepatic stellate cells
• liver fibrosis
• mesenchymal stem cells

• 20200216 Biomedical Research Institute Grant of Pusan National University Hospital

Dietary fatty acids play a role in the pathogenesis of obesity-associated non-alcoholic fatty liver disease (NAFLD), which is associated with insulin resistance (IR). Fatty acid composition is critical for IR and subsequent NAFLD development. Extra-virgin olive oil (EVOO) is the main source of monounsaturated fatty acids (MUFA) in Mediterranean diets. This study examined whether EVOO-containing high fat diets may prevent diet-induced NAFLD using Ldlr−/−. Leiden mice. In female Ldlr−/−.Leiden mice, the effects of the following high fat diets (HFDs) were examined: a lard-based HFD (HFD-L); an EVOO-based HFD (HFD-EVOO); a phenolic compounds-rich EVOO HFD (HFD-OL). We studied changes in body weight (BW), lipid profile, transaminases, glucose homeostasis, liver pathology and transcriptome. Both EVOO diets reduced body weight (BW) and improved insulin sensitivity. The EVOOs did not improve transaminase values and increased LDL-cholesterol and liver collagen content. EVOOs and HFD-L groups had comparable liver steatosis. The profibrotic effects were substantiated by an up-regulation of gene transcripts related to glutathione metabolism, chemokine signaling and NF-kappa-B activation and down-regulation of genes relevant for fatty acid metabolism. Collectivelly, EVOO intake improved weight gain and insulin sensitivity but not liver inflammation and fibrosis, which was supported by changes in hepatic genes expression.

Hepatic fibrosis has been associated with a series of pathophysiological processes causing excessive accumulation of extracellular matrix proteins. Several cellular processes and molecular mechanisms have been implicated in the diseased liver that augments fibrogenesis, fibrogenic cytokines and associated liver complications. Liver biopsy remains an essential diagnostic tool for histological evaluation of hepatic fibrosis to establish a prognosis. In addition to being invasive, this methodology presents with several limitations including poor cost-effectiveness, prolonged hospitalizations, and risks of peritoneal bleeding, while the clinical use of this method does not reveal underlying pathogenic mechanisms. Several alternate noninvasive diagnostic strategies have been developed, to determine the extent of hepatic fibrosis, including the use of direct and indirect biomarkers. Immediate diagnosis of hepatic fibrosis by noninvasive means would be more palatable than a biopsy and could assist clinicians in taking early interventions timely, avoiding fatal complications, and improving prognosis. Therefore, we sought to review some common biomarkers of liver fibrosis along with some emerging candidates, including the oxidative stress-mediated biomarkers, epigenetic and genetic markers, exosomes, and miRNAs that needs further evaluation and would have better sensitivity and specificity. We also aim to elucidate the potential role of cardiotonic steroids (CTS) and evaluate the pro-inflammatory and profibrotic effects of CTS in exacerbating hepatic fibrosis. By understanding the underlying pathogenic processes, the efficacy of these biomarkers could allow for early diagnosis and treatment of hepatic fibrosis in chronic liver diseases, once validated.

• cardiotonic steroids
• exosomes
• hepatic fibrosis
• miRNA
• oxidative stress

• EGFR
• Liver fibrosis
• NAFLD
• Oxidative stress
• Stellate cell

• Animals
• Cells, Cultured
• Diet, High-Fat
• Disease Models, Animal
• ErbB Receptors/antagonists & inhibitors
• Hepatic Stellate Cells/drug effects
• Hepatic Stellate Cells/pathology
• Hepatic Stellate Cells/physiology
• Liver Cirrhosis/pathology
• Liver Cirrhosis/prevention & control
• Male
• Mice
• Mice, Inbred C57BL
• Non-alcoholic Fatty Liver Disease/etiology
• Non-alcoholic Fatty Liver Disease/pathology
• Quinazolines/pharmacology
• Rats
• Tyrphostins/pharmacology

• clinical outcomes
• enzyme activity
• gastric adenocarcinoma
• matrix metalloproteinases
• polymorphisms

• Antifibrotic food components
• Hepatic stellate cells
• Liver disease
• Liver fibrosis
• NAFLD

Human hepatitis B virus (HBV) infection is an important public health issue in the Asia-Pacific region and is associated with chronic hepatitis, liver fibrosis, cirrhosis and even liver cancer. However, the underlying mechanisms of HBV-associated liver fibrosis remain incompletely understood.

In the present study, proteomic and transcriptomic approaches as well as biological network analyses were performed to investigate the differentially expressed molecular signature and key regulatory networks that were associated with HBV-mediated liver fibrosis. RNA sequencing and 2DE-MALDI-TOF/TOF were performed on liver tissue samples obtained from HBV-infected C57BL/6 mouse generated via AAV8-HBV virus. The results showed that 322 genes and 173 proteins were differentially expressed, and 28 HBV-specific proteins were identified by comprehensive proteomic and transcriptomic analysis. GO analysis indicated that the differentially expressed proteins were predominantly involved in oxidative stress, which plays a key role in HBV-related liver fibrosis. Importantly, CAT, PRDX1, GSTP1, NXN and BLVRB were shown to be associated with oxidative stress among the differentially expressed proteins. The most striking results were validated by Western blot and RT-qPCR. The RIG-I like receptor signaling pathway was found to be the major signal pathway that changed during HBV-related fibrosis.

This study provides novel insights into HBV-associated liver fibrosis and reveals the significant role of oxidative stress in liver fibrosis. Furthermore, CAT, BLVRB, NXN, PRDX1, and IDH1 may be candidates for detection of liver fibrosis or therapeutic targets for the treatment of liver fibrosis.

The online version of this article (doi:10.1186/s12864-017-3984-z) contains supplementary material, which is available to authorized users.

• HBV
• Liver fibrosis
• Proteomics
• Transcriptomics

Gelatinases are members of the matrix metalloproteinase (MMPs) family; they play an important role in the degradation of the extracellular matrix (ECM). This effect is also crucial in the development and progression of chronic kidney disease (CKD). Its expression, as well as its activity regulation are closely related to the cell signaling pathways, hypoxia and cell membrane structural change. Gelatinases also can affect the development and progression of CKD through the various interactions with tumor necrosis factors (TNFs), monocyte chemoattractant proteins (MCPs), growth factors (GFs), oxidative stress (OS), and so on. Currently, their non-proteolytic function is a hot topic of research, which may also be associated with the progression of CKD. Therefore, with the in-depth understanding about the function of gelatinases, we can have a more specific and accurate understanding of their role in the human body.

• chronic kidney disease
• gelatinases
• matrix metalloproteinase
• non-proteolytic function

• Disease Progression
• Extracellular Matrix/metabolism
• Humans
• Intercellular Signaling Peptides and Proteins/metabolism
• Matrix Metalloproteinase 2/metabolism
• Matrix Metalloproteinase 9/metabolism
• Monocyte Chemoattractant Proteins/metabolism
• Protein Binding
• Renal Insufficiency, Chronic/enzymology
• Renal Insufficiency, Chronic/metabolism
• Renal Insufficiency, Chronic/pathology
• Tumor Necrosis Factors/metabolism

• HSC
• Liver fibrosis
• MMP-2
• Nrf2
• Rosmarinic acid

• Animals
• Antioxidants/pharmacology
• Cell Line, Transformed
• Cell Survival/drug effects
• Cell Survival/physiology
• Cinnamates/pharmacology
• Depsides/pharmacology
• Dose-Response Relationship, Drug
• Enzyme Activation/drug effects
• Enzyme Activation/physiology
• Hepatic Stellate Cells/drug effects
• Hepatic Stellate Cells/metabolism
• Matrix Metalloproteinase 2/metabolism
• NF-E2-Related Factor 2/metabolism
• Rats
• Reactive Oxygen Species/antagonists & inhibitors
• Reactive Oxygen Species/metabolism
• Rosmarinic Acid

• Animals
• Humans
• Immunosuppression Therapy
• Inflammation/complications
• Inflammation/pathology
• Liver Diseases/complications
• Liver Diseases/drug therapy
• Liver Diseases/pathology
• Models, Biological
• Oxidative Stress
• Signal Transduction

• liver fibrosis
• obstructive jaundice model
• oxidized low-density lipoprotein
• rosuvastatin

• AFP
• Bcl-2
• Liver fibrosis
• Mesenchymal stem cells
• Rats
• Scaffolds
• TGF-β1
• Ultraweb nanofiber

• ESCC
• Epb41l3
• MMP2
• MMP9
• invasion

• Bile duct ligation
• Gastrodin
• Inflammation
• Liver fibrosis
• Oxidative stress

• Clinical trials
• Heart failure
• Liver
• Shenfu decoction
• Traditional Chinese medicine

• Aconitum/chemistry
• Adjuvants, Pharmaceutic/adverse effects
• Adjuvants, Pharmaceutic/chemistry
• Adjuvants, Pharmaceutic/therapeutic use
• Aged
• Alanine Transaminase/blood
• Blood Pressure/drug effects
• Chronic Disease
• Drugs, Chinese Herbal/adverse effects
• Drugs, Chinese Herbal/chemistry
• Drugs, Chinese Herbal/therapeutic use
• Female
• Ginsenosides/analysis
• Ginsenosides/chemistry
• Heart Failure/blood
• Heart Failure/complications
• Heart Failure/drug therapy
• Heart Rate/drug effects
• Humans
• Liver/drug effects
• Liver/physiopathology
• Liver Diseases/complications
• Liver Diseases/drug therapy
• Liver Diseases/physiopathology
• Male
• Molecular Structure
• Quality of Life
• Tumor Necrosis Factor-alpha/blood
• Ventricular Function, Left/drug effects

Hepatic fibrosis is a common form of wound healing in response to chronic liver injuries and can lead to more serious complications, including mortality. It is well-established that hepatic stellate cells (HSCs) are central mediators of hepatic fibrosis, and matrix metalloproteinase-2 (MMP-2) is important in the formation of liver fibrosis. In addition, HSCs are the primary cells secreting MMP-2 and extracellular matrix, therefore, there has been increasing interest in developing agents with high selectivity towards HSCs. However, no clinical drugs based on MMP-2, directed against HSCs, have been used to prevent fibrosis. Following consideration of the abundant vitamin A (VitA) receptors expressed on the cellular membrane of HSCs, the present study constructed VitA-coupled liposomes (VitA-lips) using dicyclohexylcarbodiimide-1, 3-diaminopentane condensation, rotatory film processing and ultrasonic oscillation. The results revealed that the liposomes exhibited low cytotoxicity and a suitable binding ability to MMP-2 small interference (si)RNA. Furthermore, the liposomes effectively delivered MMP-2 siRNA to the HSC-T6 cells. When HSCs were treated with the liposomes carrying MMP-2 siRNA (VitA-lip-MMP-2 siRNA), the mRNA expression and activity of MMP-2, and the protein expression levels of α-smooth muscle actin and type I collagen were significantly reduced. These results suggested that inhibition of the expression of MMP-2 in HSC-T6 cells may contribute to preventing hepatic fibrosis, and provided experimental support to the development of specific drugs against MMP-2 to prevent fibrogenesis in chronic liver disease.

• hepatocellular carcinoma
• hypoxia
• liver fibrosis
• transarterial chemoembolization

Obstructive sleep apnoea syndrome (OSAS) is a common sleep disorder, affecting over 4% of the general population, and is associated with metabolic syndrome and cardiovascular disease, independent of obesity and traditional risk factors. OSAS has been recently connected to nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disease in the world, which can be found in 30% of the general adult population. Several studies suggest that the chronic intermittent hypoxia (CIH) of OSAS patients may per se trigger liver injury, inflammation, and fibrogenesis, promoting NAFLD development and the progression from steatosis to steatohepatitis, cirrhosis, and hepatocellular carcinoma. In NAFLD patients, liver disease may be caused by hypoxia both indirectly by promoting inflammation and insulin resistance and directly by enhancing proinflammatory cytokine production and metabolic dysregulation in liver cells. In this review, we focus on molecular mechanisms linking OSAS to NAFLD, including hypoxia inducible factor (HIF), nuclear factor kappa B (NF-κB), YKL-40, unfolded protein response, and hypoxic adipose tissue inflammation, which all could provide novel potential therapeutic approaches for the management of NAFLD patients with OSAS.

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.

• hydrogen
• hydrogen water
• hydroxyl radical
• liver cirrhosis
• liver fibrosis
• liver injury

• Antrodia cinnamomea
• Hepatic stellate cells
• Proteomic analysis
• Reversion

• Actins/metabolism
• Animals
• Antrodia/chemistry
• Biomarkers/metabolism
• Cell Survival/drug effects
• Fatty Acids/metabolism
• Functional Food
• Hepatic Stellate Cells/drug effects
• Hepatic Stellate Cells/metabolism
• Male
• Matrix Metalloproteinase 2/metabolism
• Matrix Metalloproteinase Inhibitors/pharmacology
• PPAR gamma/metabolism
• Plant Extracts/pharmacology
• Rats, Sprague-Dawley
• Thioacetamide/toxicity

Peritumoral liver tissue could play a potential role in hepatocellular carcinoma (HCC) progression and patient survival via angiogenesis- and lymphangiogensis-related factors. The prognostic role of these factors in hepatocytes and stromal cells in HCC patients after curative resection remains to be explored.

Tumor tissue and surrounding peritumoral tissue were obtained from 145 resected HCC patients without lymph node metastasis (LNM) and 37 resected HCC patients with LNM. Tissue microarrays were constructed from duplicate cores of tumor tissue and surrounding peritumoral tissue from each resected specimen. Immunohistochemistry and real-time polymerase chain reaction were used to evaluate the expression of vascular endothelial growth factor-A (VEGF-A), VEGF-C, VEGF receptor-1(VEGFR-1), VEGFR-2, and VEGFR-3. Macrophage infiltration was determined by CD68 staining. Correlations between the expression of these factors and overall survival (OS) and time to recurrence (TTR) were studied.

The peritumoral expression of VEGF-A, VEGF-C, VEGFR-1, VEGFR-2, and VEGFR-3 were significantly higher than expression of these factors in tumors. VEGFR-1 was mostly located in peritumoral macrophages, while VEGF-C and VEGFR-3 were mostly located in peritumoral hepatocytes. HCC with high peritumoral co-expression of VEGF-C, VEGFR-1, and VEGFR-3 was associated with higher peritumoral distribution of macrophages (0.87%±0.26% versus 0.45%±0.20%), LNM (32.4% versus 12.0%), shorter TTR (10.2 months versus 34.5 months), and poor prognosis (19.4 months versus 49.3 months).

Expression of VEGF-C, VEGFR-1, and VEGFR-3 in peritumoral liver tissue is associated with a unique type of HCC that has a poorer outcome after hepatectomy.

• Adolescent
• Adult
• Aged
• Carcinoma, Hepatocellular/diagnosis
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/metabolism
• Carcinoma, Hepatocellular/pathology
• Female
• Gene Expression Regulation, Neoplastic
• Hepatocytes/metabolism
• Hepatocytes/pathology
• Humans
• Liver/metabolism
• Liver/pathology
• Liver Neoplasms/diagnosis
• Liver Neoplasms/genetics
• Liver Neoplasms/metabolism
• Liver Neoplasms/pathology
• Male
• Middle Aged
• Prognosis
• Protein Transport
• Recurrence
• Stromal Cells/metabolism
• Stromal Cells/pathology
• Survival Analysis
• Tissue Array Analysis
• Vascular Endothelial Growth Factor C/genetics
• Vascular Endothelial Growth Factor C/metabolism
• Vascular Endothelial Growth Factor Receptor-1/genetics
• Vascular Endothelial Growth Factor Receptor-1/metabolism
• Vascular Endothelial Growth Factor Receptor-3/genetics
• Vascular Endothelial Growth Factor Receptor-3/metabolism
• Young Adult

• fibrotic disease
• fibrosis
• retinoic acid
• extracellular matrix
• signaling pathways

• Animals
• Extracellular Matrix/metabolism
• Fibrosis/metabolism
• Humans
• Organ Specificity
• Signal Transduction
• Tretinoin/metabolism

AIM: To investigate the effects of different types of fluid shear stress on the activation of hepatic stellate cells-T6 (HSC-T6) and expression of α-SMA, collogen-Ⅰ, collogen-Ⅲ, MMP-2, and MMP-9.

METHODS: HSC-T6 cells were seeded on slides precoated with rat tail collagen and exposed to different types of fluid shear stress (6, 12, 20 dyn/cm²) for 3 h, and static cells served as controls. The gene expression of α-SMA, collogen-Ⅰ, collogen-Ⅲ, MMP-2 and MMP-9 was assayed by real-time RT-PCR. Intracellular α-SMA protein was analyzed by FACS.

RESULTS: After treatment by fluid shear stress, the expression of α-SMA and collogen-Ⅲ was lower in the low shear stress (6 dyn/cm²) group than that in the control group. However, the expression of α-SMA was higher in the moderate (12 dyn/cm²) and high (20 dyn/cm²) shear stress groups than that in the control group, and the expression of collogen-Ⅲ was higher in the high shear stress group than that in the control group. There was no significant difference in the expression of collogen-Ⅰ among different fluid shear stress groups. The expression of MMP-2 was higher that in three fluid shear stress groups than in the control group.

CONCLUSION: High fluid shear stress can lead to the activation of HSC-T6 cells and promote the mRNA expression of α-SMA, collogen-Ⅲ and MMP-2.

• Hepatic stellate cells
• Fluid shear stress
• Liver fibrosis

AIM: To investigate the potential mechanism of Arg-Gly-Asp (RGD) peptide-labeled liposome loading oxymatrine (OM) therapy in CCl₄-induced hepatic fibrosis in rats.

METHODS: We constructed a rat model of CCl₄-induced hepatic fibrosis and treated the rats with different formulations of OM. To evaluate the antifibrotic effect of OM, we detected levels of alkaline phosphatase, hepatic histopathology (hematoxylin and eosin stain and Masson staining) and fibrosis-related gene expression of matrix metallopeptidase (MMP)-2, tissue inhibitor of metalloproteinase (TIMP)-1 as well as type I procollagen via quantitative real-time polymerase chain reaction. To detect cell viability and apoptosis of hepatic stellate cells (HSCs), we performed 3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-diphenytetrazoliumromide assay and flow cytometry. To reinforce the combination of oxymatrine with HSCs, we constructed fluorescein-isothiocyanate-conjugated Arg-Gly-Asp peptide-labeled liposomes loading OM, and its targeting of HSCs was examined by fluorescent microscopy.

RESULTS: OM attenuated CCl₄-induced hepatic fibrosis, as defined by reducing serum alkaline phosphatase (344.47 ± 27.52 U/L vs 550.69 ± 43.78 U/L, P < 0.05), attenuating liver injury and improving collagen deposits (2.36% ± 0.09% vs 7.70% ± 0.60%, P < 0.05) and downregulating fibrosis-related gene expression, that is, MMP-2, TIMP-1 and type I procollagen (P < 0.05). OM inhibited cell viability and induced apoptosis of HSCs in vitro. RGD promoted OM targeting of HSCs and enhanced the therapeutic effect of OM in terms of serum alkaline phosphatase (272.51 ± 19.55 U/L vs 344.47 ± 27.52 U/L, P < 0.05), liver injury, collagen deposits (0.26% ± 0.09% vs 2.36% ± 0.09%, P < 0.05) and downregulating fibrosis-related gene expression, that is, MMP-2, TIMP-1 and type I procollagen (P < 0.05). Moreover, in vitro assay demonstrated that RGD enhanced the effect of OM on HSC viability and apoptosis.

CONCLUSION: OM attenuated hepatic fibrosis by inhibiting viability and inducing apoptosis of HSCs. The RGD-labeled formulation enhanced the targeting efficiency for HSCs and the therapeutic effect.

• Oxymatrine
• Arg-Gly-Asp peptide
• Hepatic stellate cell
• Hepatic fibrosis
• Target therapy

• cirrhosis
• hepatic fibrosis
• hepatic stellate cell
• non-alcoholic fatty liver disease