• Hepatic fibrosis
• High starch diet
• Micropterus salmoides
• PRM
• Proteomics

• Animals
• Bass
• Diet
• Liver Cirrhosis/chemically induced
• Proteomics
• Starch/metabolism

Background: Silymarin (SIL) has long been utilized to treat a variety of liver illnesses, but due to its poor water solubility and low membrane permeability, it has a low oral bioavailability, limiting its therapeutic potential. Aim: Design and evaluate hepatic-targeted delivery of safe biocompatible formulated SIL-loaded chitosan nanoparticles (SCNPs) to enhance SIL’s anti-fibrotic effectiveness in rats with CCl₄-induced liver fibrosis. Methods: The SCNPs and chitosan nanoparticles (CNPs) were prepared by ionotropic gelation technique and are characterized by physicochemical parameters such as particle size, morphology, zeta potential, and in vitro release studies. The therapeutic efficacy of successfully formulated SCNPs and CNPs were subjected to in vivo evaluation studies. Rats were daily administered SIL, SCNPs, and CNPs orally for 30 days. Results: The in vivo study revealed that the synthesized SCNPs demonstrated a significant antifibrotic therapeutic action against CCl₄-induced hepatic injury in rats when compared to treated groups of SIL and CNPs. SCNP-treated rats had a healthy body weight, with normal values for liver weight and liver index, as well as significant improvements in liver functions, inflammatory indicators, antioxidant pathway activation, and lipid peroxidation reduction. The antifibrotic activities of SCNPs were mediated by suppressing the expression of the main fibrosis mediators TGFβR1, COL3A1, and TGFβR2 by boosting the hepatic expression of protective miRNAs; miR-22, miR-29c, and miR-219a, respectively. The anti-fibrotic effects of SCNPs were supported by histopathology and immunohistochemistry (IHC) study. Conclusions: According to the above results, SCNPs might be the best suitable carrier to target liver cells in the treatment of liver fibrosis.

• chitosan nanoparticles
• epigenetics
• liver fibrosis
• microRNAs
• oxidative stress
• silymarin

Hepatic stellate cells (HSCs) are crucial for liver injury repair and cirrhosis. However, the mechanism of chemotactic recruitment of HSCs into injury loci is still largely unknown. Here, we demonstrate that serum amyloid A1 (SAA1) acts as a chemokine recruiting HSCs toward injury loci signaling via TLR2, a finding proven by gene manipulation studies in cell and mice models. The mechanistic investigations revealed that SAA1/TLR2 axis stimulates the Rac GTPases through PI3K-dependent pathways and induces phosphorylation of MLC (pSer19). Genetic deletion of TLR2 and pharmacological inhibition of PI3K diminished the phosphorylation of MLCpSer19 and migration of HSCs. In brief, SAA1 serves as a hepatic endogenous chemokine for the TLR2 receptor on HSCs, thereby initiating PI3K-dependent signaling and its effector, Rac GTPases, which consequently regulates actin filament remodeling and cell directional migration. Our findings provide novel targets for anti-fibrosis drug development.

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SAA1 serves as a chemokine to guide migration of HSCs toward injury locus

• Biochemistry
• Cell biology
• Cell engineering

• Fraxetin
• Inflammation
• Liver fibrosis
• MAPKs
• NF-κB

• Animals
• Apoptosis/drug effects
• Carbon Tetrachloride/pharmacology
• Coumarins/pharmacology
• Inflammation/drug therapy
• Inflammation/metabolism
• Liver/drug effects
• Liver/metabolism
• Liver Cirrhosis/chemically induced
• Liver Cirrhosis/drug therapy
• Liver Cirrhosis/metabolism
• Male
• Mitogen-Activated Protein Kinase 1/metabolism
• NF-KappaB Inhibitor alpha/metabolism
• NF-kappa B/metabolism
• Oxidative Stress/drug effects
• Rats
• Rats, Sprague-Dawley
• Signal Transduction/drug effects
• bcl-2-Associated X Protein/metabolism

To evaluate the effects of phosphatase and tension homologue deleted on chromosome ten (PTEN) gene on collagen metabolism in hepatic fibrosis and the underlying mechanisms.

Rat primary hepatic stellate cells (HSCs) and human LX-2 cells were transfected with adenovirus containing cDNA constructs encoding wild-type PTEN (Ad-PTEN), PTEN mutant G129E gene (Ad-G129E), and RNA interference constructs targeting the PTEN sequence PTEN short hairpin RNA to up-regulate and down-regulate the expression of PTEN. HSCs were assayed using fluorescent microscopy, real-time polymerase chain reaction, and western blotting. Moreover, a CCl₄-induced rat hepatic fibrosis model was established to investigate the in vivo effects. Hematoxylin and eosin, and Masson’s trichrome were used to assess the histological changes. The expression of collagen I and III was assessed using immunohistochemistry and western blot analysis.

Elevated expression of PTEN gene reduced serum levels of alanine transaminase and aspartate transaminase, decreased collagen deposition in the liver, and reduced hepatocyte necrosis. In contrast, knockdown of PTEN expression had an opposite effect, such as increased collagen deposition in the liver, and was molecularly characterized by the increased expression of matrix metalloproteinase (MMP)-13 (P < 0.01) and MMP-2 (P < 0.01), as well as decreased expression of the tissue inhibitor of metalloproteinase (TIMP)-1 (P < 0.01) and TIMP-2 (P < 0.01).

These data indicated that gene therapy using recombinant adenovirus encoding PTEN might be a novel way of treating hepatic fibrosis.

• Collagen metabolism
• Hepatic stellate cells
• Phosphatase and tension homologue deleted on chromosome ten
• PTEN
• Gene therapy
• Hepatic fibrosis

• Adenoviridae/genetics
• Alanine Transaminase/blood
• Animals
• Aspartate Aminotransferases/blood
• Carbon Tetrachloride/toxicity
• Cell Line
• Collagen Type I/metabolism
• Collagen Type III/metabolism
• Down-Regulation
• Extracellular Matrix/metabolism
• Gene Knockdown Techniques
• Genetic Therapy/methods
• Genetic Vectors/therapeutic use
• Hepatic Stellate Cells
• Humans
• Liver Cirrhosis/blood
• Liver Cirrhosis/chemically induced
• Liver Cirrhosis/pathology
• Liver Cirrhosis/therapy
• Male
• Mutation
• PTEN Phosphohydrolase/genetics
• PTEN Phosphohydrolase/metabolism
• Primary Cell Culture
• RNA, Small Interfering/metabolism
• Rats
• Transfection
• Up-Regulation

To investigate the protective effects of Foeniculum vulgare root bark (FVRB), a traditional Uyghur medicine, against carbon tetrachloride (CCl₄)-induced hepatic fibrosis in mice.

Mice were randomly divided into eight groups (n = 20 each). Except for the normal control group, mice in the rest groups were intraperitoneally injected (i.p.) with 0.1% CCl₄-olive oil mixture at 10 mL/kg twice a week to induce liver fibrosis. After 4 wk, mice were treated concurrently with the 70% ethanol extract of FVRB (88, 176, 352 and 704 mg/kg, respectively) daily by oral gavage for 4 wk to evaluate its protective effects. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), triglyceride (TG), hexadecenoic acid (HA), laminin (LN), glutathione (GSH), superoxide dismutase (SOD), and malondialdehyde (MDA) in liver tissues were measured. Hematoxylin-eosin (H and E) staining and Masson trichrome (MT) staining were performed to assess histopathological changes in the liver. The expression of transforming growth factor β₁ (TGF-β₁), matrix metalloprotein 9 (MMP-9) and metallopeptidase inhibitor 1 (TIMP-1) was detected by immunohistochemical analysis. Additionally, TGF-β₁ and alpha-smooth muscle actin (α-SMA) protein expression was measured by Western blot.

A significant reduction in serum levels of AST, ALT, TG, HA and LN was observed in the FVRB-treated groups, suggesting that FVRB displayed hepatoprotective effects. Also, the depletion of GSH, SOD, and MDA accumulation in liver tissues was suppressed by FVRB. The expression of TGF-β₁, MMP-9 and TIMP-1 determined by immunohistochemistry was markedly reduced in a dose-dependent manner by FVRB treatment. Furthermore, protective effects of FVRB against CCl₄-induced liver injury were confirmed by histopathological studies. Protein expression of TGF-β₁ and α-SMA detected by Western blot was decreased by FVRB treatment.

Our results indicate that FVRB may be a promising agent against hepatic fibrosis and its possible mechanisms are inhibiting lipid peroxidation and reducing collagen formation in liver tissue of liver fibrosis mice.

• Hepatic fibrosis
• Foeniculum vulgare root bark
• Histopathology
• Carbon tetrachloride
• TGF-β1

• Animals
• Carbon Tetrachloride/toxicity
• Foeniculum/chemistry
• Humans
• Lipid Peroxidation/drug effects
• Liver/drug effects
• Liver/pathology
• Liver Cirrhosis, Experimental/blood
• Liver Cirrhosis, Experimental/chemically induced
• Liver Cirrhosis, Experimental/drug therapy
• Liver Function Tests
• Male
• Mice
• Plant Extracts/pharmacology
• Plant Extracts/therapeutic use
• Plant Roots/chemistry
• Protective Agents/pharmacology
• Protective Agents/therapeutic use

Chronic liver allograft dysfunction (CLAD) remains the most common cause of patient morbidity and allograft loss in liver transplant patients. However, the pathogenesis of CLAD has not been completely elucidated. By establishing rat CLAD models, in this study, we identified the informative CLAD-associated genes using isobaric tags for relative and absolute quantification (iTRAQ) proteomics analysis and validated these results in recipient rat liver allografts. CXCL4, CXCR3, EGFR, JAK2, STAT3, and Collagen IV were associated with CLAD pathogenesis. We validated that CXCL4 is upstream of these informative genes in the isolated hepatic stellate cells (HSC). Blocking CXCL4 protects against CLAD by reducing liver fibrosis. Therefore, our results indicated that therapeutic approaches that neutralize CXCL4, a newly identified target of fibrosis, may represent a novel strategy for preventing and treating CLAD after liver transplantation.

• Wilson's disease
• hemochromatosis
• laser ablation inductively coupled plasma mass spectrometry
• liver
• metal bioimaging
• metal poisoning
• secondary ion mass spectrometry
• synchrotron X-ray fluorescence

• Humans
• Laser Therapy
• Liver
• Liver Diseases
• Metals
• Spectrometry, Mass, Secondary Ion

• Gene therapy
• Hepatic fibrosis
• Hepatic stellate cell
• PTEN

• Hepatic stellate cells (HSCs)
• liver fibrosis
• macrophages
• myofibroblasts
• retinol

Despite advances in immunosuppressive drugs, long-term success of liver transplantation is still limited by the development of chronic liver allograft dysfunction. Although the exact pathogenesis of chronic liver allograft dysfunction remains to be established, there is strong evidence that chemokines are involved in organ damage induced by inflammatory and immune responses after liver surgery. Chemokines are a group of low-molecular-weight molecules whose function includes angiogenesis, haematopoiesis, mitogenesis, organ fibrogenesis, tumour growth and metastasis, and participating in the development of the immune system and in inflammatory and immune responses. The purpose of this review is to collect all the research that has been done so far concerning chemokines and the pathogenesis of chronic liver allograft dysfunction and helpfully, to pave the way for designing therapeutic strategies and pharmaceutical agents to ameliorate chronic allograft dysfunction after liver transplantation.

• CCL2
• Fibrogenesis
• Foxp3
• GARP
• HCV
• HSC
• Hepatic stellate cells
• Hepatitis C virus
• IL-8
• MMP2
• RT-PCR
• Regulatory T cells
• T effector cells
• TIMP1
• Teffs
• Tregs
• alpha-SMA
• alpha-smooth muscle actin
• chemokine ligand 2
• forkhead box P3
• glycoprotein A repetitions predimonant
• hepatitis C virus
• mRNA
• matrix metalloproteinases 2
• messenger RNA
• primary human hepatic stellate cells
• real-time polymerase chain reaction
• regulatory CD4(+) T cells
• tissue inhibitor of metalloproteinases 1

Hepatic stellate cells (HSCs) play a key role in the development of liver fibrosis caused by schistosomiasis. Chemokines were widely expressed and involved in cellular activation, proliferation and migration in inflammatory and infectious diseases. However, little is known about the expressions of chemokines on HSCs in the schistosoma infection. In addition, the roles of chemokines in pathogenesis of liver fibrosis are not totally clear. In our study, we used microarray to analyze the temporal gene expressions of primary HSCs isolated from mice with both acute and chronic schistosomiasis. Our microarray data showed that most of the chemokines expressed on HSCs were upregulated at 3 weeks post-infection (p.i) when the egg granulomatous response was not obviously evoked in the liver. However, some of them like CXCL9, CXCL10 and CXCL11 were subsequently decreased at 6 weeks p.i when the granulomatous response reached the peak. In the chronic stage, most of the differentially expressed chemokines maintained persistent high-abundances. Furthermore, several chemokines including CCR2, CCR5, CCR7, CXCR3, CXCR4, CCL2, CCL5, CCL21, CXCL9 and CXCL10 were expressed by HCSs and the abundances of them were changed following the praziquantel treatment in the chronic stage, indicating that chemokines were possibly necessary for the persistence of the chronic stage. In vitro experiments, hepatic non-parenchymal cells, primary HSCs and human HSCs line LX-2 were stimulated by chemokines. The results showed that CXCL9 and CXCL10, but not CXCL11 or CXCL4, significantly inhibited the gene expressions of Col1α1, Col3α1 and α-SMA, indicating the potential anti-fibrosis effect of CXCL9 and CXCL10 in schistosomiasis. More interestingly, soluble egg antigen (SEA) of Schistosoma japonicum was able to inhibit transcriptional expressions of some chemokines by LX-2 cells, suggesting that SEA was capable of regulating the expression pattern of chemokine family and modulating the hepatic immune microenvironment in schistosomiasis.

• Animals
• Chemokine CXCL10/metabolism
• Chemokine CXCL11/metabolism
• Chemokine CXCL9/metabolism
• Chemokines/biosynthesis
• Chemokines/metabolism
• Female
• Gene Expression Profiling
• Gene Expression Regulation
• Genome
• Hepatic Stellate Cells/metabolism
• Humans
• Liver/metabolism
• Mice
• Mice, Inbred BALB C
• Platelet Factor 4/metabolism
• Praziquantel/pharmacology
• Schistosoma japonicum/immunology
• Schistosoma japonicum/metabolism
• Schistosomiasis/metabolism

• Adult
• Aged
• Aged, 80 and over
• Alleles
• Biopsy
• Case-Control Studies
• Chemokine CXCL1/genetics
• Chemokine CXCL1/physiology
• Disease Progression
• Female
• Gene Frequency
• Genetic Predisposition to Disease/genetics
• Genotype
• HEK293 Cells
• Hepacivirus/genetics
• Hepatitis C, Chronic/complications
• Humans
• Ligands
• Liver/pathology
• Liver Cirrhosis/ethnology
• Liver Cirrhosis/genetics
• Liver Cirrhosis/virology
• Male
• Middle Aged
• Polymorphism, Single Nucleotide/genetics
• Risk Factors
• Toll-Like Receptor 2/physiology
• White People/ethnology
• White People/genetics