• compounds
• digestive system diseases
• network pharmacology
• targets
• traditional Chinese medicine

• Schistosoma japonicum
• ATF3
• Schistosoma japonicum protein P40
• hepatic stellate cell
• microRNA‐494‐3p

• Animals
• Activating Transcription Factor 3/metabolism
• Activating Transcription Factor 3/genetics
• Hepatic Stellate Cells/metabolism
• Hepatic Stellate Cells/parasitology
• Schistosomiasis japonica/parasitology
• Schistosomiasis japonica/metabolism
• Schistosomiasis japonica/genetics
• Schistosoma japonicum
• Liver Cirrhosis/parasitology
• Liver Cirrhosis/genetics
• Liver Cirrhosis/pathology
• Liver Cirrhosis/metabolism
• Mice
• Humans
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Helminth Proteins/genetics
• Helminth Proteins/metabolism
• Actins/metabolism
• Actins/genetics
• Cell Line
• Gene Expression Regulation
• Liver/metabolism
• Liver/parasitology
• Liver/pathology
• Disease Models, Animal
• Antigens, Helminth

• NAFLD
• NASH
• miRNAs
• therapeutic effects

• DPK-2022-007 National University of Malaysia
• FF-2022-261 Heze Huiren Chinese Medicine Hospital

• lipoplex
• pDNA
• polyplex
• siRNA
• targeting

• Humans
• Tissue Distribution
• Pandemics
• COVID-19
• RNA, Small Interfering/genetics
• RNA, Messenger/metabolism

• Collaborative Research Centre SFB 1032 sub-project B4 Deutsche Forschungsgemeinschaft
• Ludwig-Maximilians-Universität München (1024)

• Inflammation
• Liver fibrosis
• Liver injury
• Longhu Rendan (LHRD)
• Oxidative stress

Tumor necrosis factor-α (TNF-α)-driven inflammatory reaction plays a crucial role in the initiation of liver fibrosis. We herein attempted to design genetically engineered adipose-derived stem cells (ASCs) producing etanercept (a potent TNF-α inhibitor), and to determine the anti-fibrotic potential of the secretome released from the etanercept-synthesizing ASCs (etanercept-secretome). First, we generated the etanercept-synthesizing ASCs by transfecting the ASCs with mini-circle plasmids containing the gene insert encoding for etanercept. We subsequently collected the secretory material released from the etanercept-synthesizing ASCs and determined its anti-fibrotic effects both in vitro (in thioacetamide [TAA]-treated AML12 and LX2 cells) and in vivo (in TAA-treated mice) models of liver fibrosis. We observed that while etanercept-secretome increased the viability of the TAA-treated AML12 hepatocytes (p = 0.021), it significantly decreased the viability of the TAA-treated LX2 HSCs (p = 0.021). In the liver of mice with liver fibrosis, intravenous administration of the etanercept-secretome induced significant reduction in the expression of both fibrosis-related and inflammation-related markers compared to the control group (all Ps < 0.05). The etanercept-secretome group also showed significantly lower serum levels of liver enzymes as well as pro-inflammatory cytokines, such as TNF-α (p = 0.020) and IL-6 (p = 0.021). Histological examination of the liver showed the highest reduction in the degree of fibrosis in the entanercept-secretome group (p = 0.006). Our results suggest that the administration of etanercept-secretome improves liver fibrosis by inhibiting TNF-α-driven inflammation in the mice with liver fibrosis. Thus, blocking TNF-α-driven inflammation at the appropriate stage of liver fibrosis could be an efficient strategy to prevent fibrosis.

• adipose-derived stem cells
• etanercept
• liver fibrosis
• secretome
• tumor necrosis factor-α (TNF-α)

Recently, the exclusive use of mesenchymal stem cell (MSC)-secreted molecules, called secretome, rather than cells, has been evaluated for overcoming the limitations of cell-based therapy, while maintaining its advantages. However, the use of naïve secretome may not fully satisfy the specificity of each disease. Therefore, it appears to be more advantageous to use the functionally reinforced secretome through a series of processes involving physico-chemical adjustments or genetic manipulation rather than to the use naïve secretome.

To determine the therapeutic potential of the secretome released from miR-122-transfected adipose-derived stromal cells (ASCs).

We collected secretory materials released from ASCs that had been transfected with antifibrotic miR-122 (MCM) and compared their antifibrotic effects with those of the naïve secretome (CM). MCM and CM were intravenously administered to the mouse model of thioacetamide-induced liver fibrosis, and their therapeutic potentials were compared.

MCM infusion provided higher therapeutic potential in terms of: (A) Reducing collagen content in the liver; (B) Inhibiting proinflammatory cytokines; and (C) Reducing abnormally elevated liver enzymes than the infusion of the naïve secretome. The proteomic analysis of MCM also indicated that the contents of antifibrotic proteins were significantly elevated compared to those in the naïve secretome.

We could, thus, conclude that the secretome released from miR-122-transfected ASCs has higher antifibrotic and anti-inflammatory properties than the naïve secretome. Because miR-122 transfection into ASCs provides a specific way of potentiating the antifibrotic properties of ASC secretome, it could be considered as an enhanced method for reinforcing secretome effectiveness.

• Adipose-derived stem cells
• Liver fibrosis
• MicroRNAs
• miR-122
• Mesenchymal stem cells
• Secretome

• Adipose-Derived Stem Cells
• Liver Fibrosis
• Mesenchymal Stem Cells
• Secretome
• miR-214
• microRNAs

• Actins/metabolism
• Adipose Tissue/cytology
• Animals
• Cell Proliferation/drug effects
• Cells, Cultured
• Culture Media, Conditioned/chemistry
• Culture Media, Conditioned/pharmacology
• Disease Models, Animal
• Humans
• Liver/metabolism
• Liver/pathology
• Liver Cirrhosis/metabolism
• Liver Cirrhosis/pathology
• Male
• Mesenchymal Stem Cells/cytology
• Mesenchymal Stem Cells/metabolism
• Mice
• Mice, Inbred BALB C
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Proliferating Cell Nuclear Antigen/metabolism
• Transfection

• Genistein
• Non-alcoholic fatty liver disease (NAFLD)
• Nonalcoholic steatohepatitis (NASH)
• Review
• Soy

• biomarker
• cirrhosis
• hepatitis B virus
• liver fibrosis
• microRNA

• Chronic hepatitis C
• Focal nodular hyperplasia
• Hepatic cirrhosis
• Hepatocellular carcinoma
• microRNA

Nonalcoholic fatty liver disease (NAFLD) is a major health issue throughout the world. However, no validated treatments for NAFLD are currently available. In‐depth studies have demonstrated the efficacy of (‐)‐epigallocatechin‐3‐gallate (EGCG), a main bioactive chemical extracted from green tea, in treating NAFLD. EGCG exhibits multi‐pronged preventive and therapeutic activities, including promoting lipid and glucose metabolism, anti‐lipid peroxidation and anti‐inflammation activities, anti‐fibrosis, and anti‐NAFLD related tumor, thus contributing to the mitigation of NAFLD occurrence and progression. The objectives of this paper are to review and discuss the currently known targets, signaling pathways and roles of EGCG that interfere with NAFLD pathogenesis, then providing additional experimental evidence and the foundation for the further studies and clinical applications of EGCG in the prevention and treatment of NAFLD.

• (-)-epigallocatechin-3-gallate
• catechins
• fatty liver
• nonalcoholic fatty liver disease(NAFLD)
• nonalcoholic steatohepatitis (NASH)

• AMP-Activated Protein Kinases/metabolism
• Animals
• Antioxidants/pharmacology
• Autophagy/drug effects
• Body Weight/drug effects
• Catechin/analogs & derivatives
• Catechin/pharmacology
• Catechin/therapeutic use
• Humans
• Lipid Metabolism/drug effects
• Non-alcoholic Fatty Liver Disease/drug therapy
• Non-alcoholic Fatty Liver Disease/etiology
• Receptors, LDL/drug effects

• apoptosis
• cellular senescence
• hepatic fibrogenesis
• hepatic stellate cells
• phenotypic reversion

肝星状细胞(hepatic stellate cells, HSCs)活化、细胞外基质大量形成是肝纤维化发生发展的关键环节. 许多研究发现, 抑制HSCs增殖、促进HSCs凋亡可阻断肝纤维化进程; 同时研究发现, 促进活化HSCs衰老也可为肝纤维化的防治提供新的策略. 本文就HSCs衰老与增殖、凋亡的关系以及在肝纤维化中的作用相关研究进展予以综述.

• 肝星状细胞
• 肝纤维化
• 细胞衰老
• 细胞凋亡

• Aged
• Biomarkers
• Blood Pressure
• Essential Hypertension
• Female
• Humans
• Hypertension/genetics
• Leukocytes, Mononuclear
• Male
• MicroRNAs/genetics
• Middle Aged
• Pulse Wave Analysis/methods
• Vascular Stiffness/genetics

• cell senescence
• hepatic stellate cell
• liver fibrosis
• tumor necrosis factor-like weak inducer of apoptosis

• basal ganglia
• hepatic encephalopathy
• hippocampus
• liver
• stem cells

The aim of the present study was to examine the expression variation of the mouse hepatic fibrosis tissue transforming growth factor (TGF)-βl/Smads signal transduction pathway and its correlation with progression of hepatic fibrosis. The promotion effect of microRNA (miR)-10a on hepatic fibrosis and its possible mechanism was also assessed. Forty healthy female 8-week-old C57BL6/J mice were randomly divided into the control group (intraperitoneal injection of 5 µl/g normal saline, twice per week for 8 weeks) and the hepatic fibrosis group (intraperitoneal injection of 5 µl/g 10% CCI4 olive oil, twice per week for 8 weeks), with 20 mice per group. RT-PCR was used to test miR-10a expression in cells in the control and hepatic fibrosis groups. Cell culture and transfection of miR-10a mimics were conducted in the two groups and a Cell Counting Kit-8 was used to test the expression of TGF-β1 and Smad7 in hepatic fibroblasts. It was found that in comparison with the control group, miR-10a expression was significantly increased in the hepatic fibrosis group compared with the control group (P<0.05). The expression quantity of miR-10a was significantly increased in the transfection group compared with the control group (P<0.05). A high expression of miR-10a significantly improved TGF-β1 expression and reduced Smad7 expression in the hepatic fibrosis group (P<0.05). In conclusion, miR-10a expression was high in mouse hepatic tissues, transfection of miR-10a mimics significantly promoted the cell proliferation of hepatic fibrosis, and miR-10a improved hepatic fibrosis by regulating the TGF-βl/Smads signal transduction pathway.

• Smad protein
• TGF-β1/Smads signal transduction pathway
• hepatic fibrosis
• transforming growth factor βl

AIM: To compare the histological outcome of chronic hepatitis B (CHB) patients treated with entecavir (ETV) or lamivudine (LAM)-based therapy.

METHODS: We conducted a retrospective analysis of data from 42 CHB patients with advanced fibrosis (baseline Ishak score ≥ 2) or cirrhosis who were treated with ETV or LAM-based therapy in Beilun People’s Hospital, Ningbo between January 2005 and May 2012. The patients enrolled were more than 16 years of age and underwent a minimum of 12 mo of antiviral therapy. We collected data on the baseline characteristics of each patient and obtained paired liver biopsies pre- and post-treatment. The Knodell scoring system and Ishak fibrosis scores were used to evaluate each example. An improvement or worsening of necroinflammation was defined as ≥ 2-point change in the Knodell inflammatory score. The progression or regression of fibrosis was defined as ≥ 1-point change in the Ishak fibrosis score. The continuous variables were compared using t-test or Mann-Whitney test, and the binary variables were compared using χ² test or Fisher’s exact test. The results of paired liver biopsies were compared with a Wilcoxon signed rank test.

RESULTS: Nineteen patients were treated with ETV and 23 patients were treated with LAM therapy for a mean duration of 39 and 42 mo, respectively. After long-term antiviral treatment, 94.74% (18/19) of the patients in the ETV arm and 95.65% (22/23) in the LAM arm achieved an HBV DNA level less than 1000 IU/mL. The majority of the patients (94.74% in the ETV arm and 73.91% in the LAM arm) had normalized ALT levels. The median Knodell necroinflammatory score decreased from 11 to 0 in the patients receiving ETV, and the median Knodell score decreased from 9 to 3 in the patients receiving LAM (P = 0.0002 and < 0.0001, respectively). The median Ishak fibrosis score showed a 1-point reduction in ETV-treated patients and a 2-point reduction in LAM-treated patients (P = 0.0019 and 0.0205, respectively). The patients receiving ETV showed a more significant improvement in necroinflammation than the LAM-treated patients (P = 0.0003). However, there was no significant difference in fibrotic improvement between the two arms. Furthermore, two patients in each arm achieved a fibrosis score of 0 post-treatment, which indicates a full reversion of fibrosis after antiviral therapy.

CONCLUSION: CHB patients with advanced fibrosis or cirrhosis benefit from antiviral treatment. ETV is superior to LAM therapy in improving necroinflammatory but not fibrotic outcome.

• Advanced fibrosis
• Chronic hepatitis B
• Cirrhosis
• Entecavir
• Histological outcome
• Lamivudine

• Adult
• Antiviral Agents/therapeutic use
• Biopsy
• Chi-Square Distribution
• China
• DNA, Viral/blood
• Female
• Guanine/analogs & derivatives
• Guanine/therapeutic use
• Hepatitis B virus/drug effects
• Hepatitis B virus/genetics
• Hepatitis B, Chronic/complications
• Hepatitis B, Chronic/drug therapy
• Hepatitis B, Chronic/pathology
• Humans
• Lamivudine/therapeutic use
• Liver/drug effects
• Liver/pathology
• Liver/virology
• Liver Cirrhosis/drug therapy
• Liver Cirrhosis/pathology
• Liver Cirrhosis/virology
• Male
• Middle Aged
• Retrospective Studies
• Time Factors
• Treatment Outcome
• Viral Load

AIM: To explore the effect of the histone deacetylase inhibitor givinostat on proteins related to regulation of hepatic stellate cell proliferation.

METHODS: The cell counting kit-8 assay and flow cytometry were used to observe changes in proliferation, apoptosis, and cell cycle in hepatic stellate cells treated with givinostat. Western blot was used to observe expression changes in p21, p57, CDK4, CDK6, cyclinD1, caspase-3, and caspase-9 in hepatic stellate cells exposed to givinostat. The scratch assay was used to analyze the effect of givinostat on cell migration. Effects of givinostat on the reactive oxygen species profile, mitochondrial membrane potential, and mitochondrial permeability transition pore opening in JS-1 cells were observed by laser confocal microscopy.

RESULTS: Givinostat significantly inhibited JS-1 cell proliferation and promoted cell apoptosis, leading to cell cycle arrest in G0/G1 phases. Treatment with givinostat downregulated protein expression of CDK4, CDK6, and cyclin D1, whereas expression of p21 and p57 was significantly increased. The givinostat-induced apoptosis of hepatic stellate cells was mainly mediated through p38 and extracellular signal-regulated kinase 1/2. Givinostat treatment increased intracellular reactive oxygen species production, decreased mitochondrial membrane potential, and promoted mitochondrial permeability transition pore opening. Acetylation of superoxide dismutase (acetyl K68) and nuclear factor-κB p65 (acetyl K310) was upregulated, while there was no change in protein expression. Moreover, the notable beneficial effect of givinostat on liver fibrosis was also confirmed in the mouse models.

CONCLUSION: Givinostat has antifibrotic activities via regulating the acetylation of nuclear factor-κB and superoxide dismutase 2, thus inhibiting hepatic stellate cell proliferation and inducing apoptosis.

• Givinostat
• Hepatic stellate cells
• Histone deacetylase inhibitor
• Nuclear factor-κB
• Superoxide dismutase

• Acetylation
• Animals
• Apoptosis/drug effects
• Apoptosis Regulatory Proteins/metabolism
• Carbamates/pharmacology
• Carbon Tetrachloride
• Cell Cycle Checkpoints/drug effects
• Cell Cycle Proteins/metabolism
• Cell Line
• Cell Movement/drug effects
• Cell Proliferation/drug effects
• Chemical and Drug Induced Liver Injury/etiology
• Chemical and Drug Induced Liver Injury/metabolism
• Chemical and Drug Induced Liver Injury/pathology
• Chemical and Drug Induced Liver Injury/prevention & control
• Dose-Response Relationship, Drug
• Hepatic Stellate Cells/drug effects
• Hepatic Stellate Cells/metabolism
• Hepatic Stellate Cells/pathology
• Histone Deacetylase Inhibitors/pharmacology
• Liver Cirrhosis, Experimental/chemically induced
• Liver Cirrhosis, Experimental/metabolism
• Liver Cirrhosis, Experimental/pathology
• Liver Cirrhosis, Experimental/prevention & control
• Male
• Mice, Inbred BALB C
• NF-kappa B/metabolism
• Protein Processing, Post-Translational/drug effects
• Signal Transduction/drug effects
• Superoxide Dismutase/metabolism
• Time Factors

AIM: To investigate whether expression of selected miRNAs obtained from fibrotic liver biopsies correlate with fibrosis stage.

METHODS: Altogether, 52 patients were enrolled in the study representing various etiologic backgrounds of fibrosis: 24 cases with chronic hepatitis infections (types B, C), 19 with autoimmune liver diseases (autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, overlapping syndrome cases), and 9 of mixed etiology (alcoholic and nonalcoholic steatosis, cryptogenic cases). Severity of fibrosis was determined by both histologic staging using the METAVIR scoring system and noninvasive transient elastography. Following RNA isolation, expression levels of miR-21, miR-122, miR-214, miR-221, miR-222, and miR-224 were determined using TaqMan MicroRNA Assays applying miR-140 as the reference. Selection of miRNAs was based on their characteristic up- or downregulation observed in hepatocellular carcinoma. Relative expression of miRNAs was correlated with fibrosis stage and liver stiffness (LS) value measured by transient elastography, as well as with serum alanine aminotransferase (ALT) level.

RESULTS: The expression of individual miRNAs showed deregulated patterns in stages F1-F4 as compared with stage F0, but only the reduced level of miR-122 in stage F4 was statistically significant (P < 0.04). When analyzing miRNA expression in relation to fibrosis, levels of miR-122 and miR-221 showed negative correlations with fibrosis stage, and miR-122 was found to correlate negatively and miR-224 positively with LS values (all P < 0.05). ALT levels displayed a positive correlation with miR-21 (P < 0.04). Negative correlations were observed in the fibrosis samples of mixed etiology between miR-122 and fibrosis stage and LS values (P < 0.05), and in the samples of chronic viral hepatitis, between miR-221 and fibrosis stage (P < 0.01), whereas miR-21 showed positive correlation with ALT values in the samples of autoimmune liver diseases (P < 0.03). The results also revealed a strong correlation between fibrosis stage and LS values (P < 0.01) when etiology of fibrosis was not taken into account.

CONCLUSION: Reduced expression of miR-122 in advanced fibrosis and its correlation with fibrosis stage and LS values seem to be characteristic of hepatic fibrosis of various etiologies.

• Expression
• FibroScan
• Liver fibrosis
• METAVIR
• microRNA
• miR-122

• Alanine Transaminase/blood
• Biomarkers/blood
• Biopsy
• Down-Regulation
• Elasticity Imaging Techniques
• Genetic Markers
• Humans
• Liver/chemistry
• Liver/diagnostic imaging
• Liver/pathology
• Liver Cirrhosis/blood
• Liver Cirrhosis/diagnostic imaging
• Liver Cirrhosis/genetics
• Liver Cirrhosis/pathology
• MicroRNAs/genetics
• Predictive Value of Tests
• Retrospective Studies
• Severity of Illness Index

• DNA methylation
• epigenetics
• hepatic stellate cells
• histone modyfications
• liver fibrosis
• microRNAs

Hepatic fibrosis is characterized by the excessive accumulation of extracellular matrix (ECM), and the activiation of hepatic stellate cells (HSCs) is recognized as the core and initial stage. It is reported that the activiation of HSCs is related to the regulation of a series of cell factors and cell signal pathways. The Wnt signaling pathway plays a key role in the physiology and pathology of the liver, and the abnormal activiation of Wnt results in the activiation of HSCs. Therefore, a further understanding of the role of the Wnt signaling pathway in the pathogeneisis of hepatic fibrosis will be valuable in the development of diagnosic and threputic strategies for this disease.

• Wnt signaling pathway
• Liver fibrosis

Liver cirrhosis is the final pathological result of various chronic liver diseases, and fibrosis is the precursor of cirrhosis. Many types of cells, cytokines and miRNAs are involved in the initiation and progression of liver fibrosis and cirrhosis. Activation of hepatic stellate cells (HSCs) is a pivotal event in fibrosis. Defenestration and capillarization of liver sinusoidal endothelial cells are major contributing factors to hepatic dysfunction in liver cirrhosis. Activated Kupffer cells destroy hepatocytes and stimulate the activation of HSCs. Repeated cycles of apoptosis and regeneration of hepatocytes contribute to pathogenesis of cirrhosis. At the molecular level, many cytokines are involved in mediation of signaling pathways that regulate activation of HSCs and fibrogenesis. Recently, miRNAs as a post-transcriptional regulator have been found to play a key role in fibrosis and cirrhosis. Robust animal models of liver fibrosis and cirrhosis, as well as the recently identified critical cellular and molecular factors involved in the development of liver fibrosis and cirrhosis will facilitate the development of more effective therapeutic approaches for these conditions.

• Cirrhosis
• Pathogenesis
• Hepatic stellate cells
• Cytokine
• miRNA
• Animal model
• Therapy

• Animals
• Cytokines/metabolism
• Disease Models, Animal
• Humans
• Inflammation Mediators/metabolism
• Liver/metabolism
• Liver/pathology
• Liver Cirrhosis/diagnosis
• Liver Cirrhosis/etiology
• Liver Cirrhosis/metabolism
• MicroRNAs/metabolism
• Risk Factors
• Signal Transduction

• 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside
• 5-aza-2′-deoxycytidine
• 5-azadC
• AICAR
• APC
• BC
• CK1
• CamKII
• Canonical Wnt signaling pathway
• DKK
• DLK1
• Delta-like 1 homolog
• Dickkopf
• Dvl
• FLS
• Fz
• GFAP
• Gsk3β
• HCV
• HFFs
• HPCs
• HSCs
• Hepatic stellate cell
• KEGG
• LEF
• LOX-1
• Liver fibrosis
• Lrp5/6
• MCP-1
• MMP
• MMPCs
• MeCP2
• Myofibroblastic transdifferentiation
• PCP
• PDGF
• PH
• PITX2c
• PKC
• PPAR response element
• PPRE
• PRA
• RA
• ROK
• SFRP
• T-cell specific transcription factors
• TCF
• TRAIL
• UUO
• Wnt signaling
• a-SMA
• a-smooth muscle actin
• adenomatous polyposis coli
• baicalin
• calmodulin kinase II
• casein kinase 1
• disheveled
• fibroblast-like synoviocytes
• frizzled
• glial fibrillary acidic protein
• glycogen synthase kinase 3β
• hepatic progenitor cells
• hepatic stellate cells
• hepatitis C
• human foreskin fibroblasts
• kyoto encyclopedia of genes and genomes
• lectin-like ox-LDL receptor-1
• lipoprotein receptor-related protein 5/6
• lymphoid enhancer binding factor
• matrix metalloproteinase
• mesoderm-derived multipotent mesenchymal progenitor cells
• methyl-CpG binding protein 2
• monocyte chemotactic protein-1
• ox-LDL
• oxidized low-density lipoprotein
• paired-like homeodomain transcription factor 2c
• partial hepatectomy
• planar cell polarity
• platelet-derived growth factor
• polyphenolic rosmarinic acid
• protein kinase C
• rheumatoid arthritis
• rho kinase
• secreted frizzled-related protein
• tumor necrosis factor-related apoptosis-inducing ligand
• unilateral ureteral obstruction