• Cytokine signaling
• DUSP21
• Phosphatase
• STAT3

• STAT3 Transcription Factor/metabolism
• STAT3 Transcription Factor/genetics
• Humans
• Leukemia Inhibitory Factor/metabolism
• Leukemia Inhibitory Factor/genetics
• HeLa Cells
• Feedback, Physiological
• Dual-Specificity Phosphatases/metabolism
• Dual-Specificity Phosphatases/genetics
• Phosphorylation
• Signal Transduction
• Animals
• Mice

• Apoptosis
• Cell cycle
• Hepatocytes
• IL-1β
• Leptin

• Aerides odorata
• PCM‐induced hepatotoxicity
• UPLC‐qTOF‐MS
• animal model
• mRNA expression

• Animals
• Chemical and Drug Induced Liver Injury/drug therapy
• Acetaminophen
• Plant Extracts/pharmacology
• Rats
• Chromatography, High Pressure Liquid
• Molecular Docking Simulation
• Male
• Orchidaceae/chemistry
• Disease Models, Animal
• Liver/drug effects
• Rats, Wistar
• Mass Spectrometry
• Network Pharmacology

• Liver Regeneration/physiology
• Humans
• Animals
• Signal Transduction
• Liver/metabolism
• Liver/physiology
• Hepatectomy

• gut microbiology
• hepatectomy
• metabolomics
• proteomics

• Animals
• Dogs
• Gastrointestinal Microbiome/genetics
• Hepatectomy
• Proteomics
• RNA, Ribosomal, 16S/genetics
• Metabolomics/methods

• partial hepatectomy
• wnt signaling
• pathway redundancy
• liver failure
• hepatocyte proliferation

• Mice
• Animals
• Liver Regeneration/physiology
• beta Catenin/metabolism
• Mechanistic Target of Rapamycin Complex 1/metabolism
• Insulin/metabolism
• Hepatocytes/metabolism
• TOR Serine-Threonine Kinases/metabolism
• Wnt Signaling Pathway/physiology
• Mice, Knockout
• Cell Proliferation
• Sirolimus/pharmacology

• R01 DK116993 NIDDK NIH HHS
• R01 CA251155 NCI NIH HHS
• R01 DK062277 NIDDK NIH HHS
• P30 DK120531 NIDDK NIH HHS
• R01 CA204586 NCI NIH HHS
• R01 CA250227 NCI NIH HHS

• cytokine
• exercise
• heat stroke
• kinase
• stress

• Mice
• Animals
• Disease Models, Animal
• Heat Stroke
• Heat Stress Disorders
• Chemokines
• Inflammation

• DOD | United States Army | MEDCOM | U.S. Army Medical Research and Development Command (MRDC)

• P2X7 Receptor
• adaptive immunity
• immunopathological process.
• inflammation
• innate immunity
• signal pathways

• Acampe ochracea
• Antioxidant
• Biochemical
• Hepatoprotective
• Liver and PCM
• UPLC-qTOF-MS

• Acetaminophen
• Animals
• Antioxidants/isolation & purification
• Antioxidants/pharmacokinetics
• Antioxidants/pharmacology
• Aromatase/genetics
• Aromatase/metabolism
• Chemical and Drug Induced Liver Injury/genetics
• Chemical and Drug Induced Liver Injury/metabolism
• Chemical and Drug Induced Liver Injury/pathology
• Chemical and Drug Induced Liver Injury/prevention & control
• Disease Models, Animal
• Estrogen Receptor alpha/genetics
• Estrogen Receptor alpha/metabolism
• Gene Expression Regulation
• Liver/drug effects
• Liver/metabolism
• Liver/pathology
• Male
• Mitogen-Activated Protein Kinase 14/genetics
• Mitogen-Activated Protein Kinase 14/metabolism
• Molecular Docking Simulation
• Network Pharmacology
• Orchidaceae/chemistry
• Oxidative Stress/drug effects
• Oxidative Stress/genetics
• PPAR gamma/genetics
• PPAR gamma/metabolism
• Phytochemicals/isolation & purification
• Phytochemicals/pharmacokinetics
• Phytochemicals/pharmacology
• Plant Extracts/isolation & purification
• Plant Extracts/pharmacokinetics
• Plant Extracts/pharmacology
• Protein Interaction Maps
• Rats, Wistar
• Signal Transduction
• Vascular Endothelial Growth Factor A/genetics
• Vascular Endothelial Growth Factor A/metabolism
• Rats

Triggering receptor expressed on myeloid cells-1 (TREM-1) controls the mobilization of inflammatory cells in response to injury and consequently enhances liver damage. LR12 is a TREM-1 inhibitory peptide. However, the role of LR12 in acute liver failure (ALF) has remained elusive. This study was aimed at indicating whether LR12 could promote liver repair in mice with thioacetamide- (TAA-) induced ALF.

BALB/c mice were intraperitoneally injected with TAA, followed by intravenous injection of LR12. Damage and regeneration of the liver were assessed. LO2 cells and macrophages were used to assess the therapeutic effects of LR12.

Mice treated with TAA for 24 h developed ALF, while liver inflammation was alleviated after LR12 treatment. Moreover, LR12 promoted hepatocyte regeneration in mice with TAA-induced ALF. In vitro, the supernatant from TAA+LR12-treated macrophages promoted the proliferation of LO2 cells. Cytokine protein microarray analysis suggested that LR12 promoted the secretion of C-C chemokine ligand 20 (CCL20) from macrophages. Besides, neutralization of CCL20 blocked the effects of LR12, thus inhibited the proliferation of LO2 cells in vitro, aggregated the liver inflammation, and restrained hepatocyte regeneration in ALF mice in vivo. Furthermore, we also found that LR12 activated the p38 mitogen-activated protein kinase (MAPK) pathway in hepatocytes through promoting the secretion of CCL20 from macrophages.

LR12 could improve the resolution of inflammation and liver regeneration in mice with TAA-induced ALF by promoting the secretion of CCL20 from macrophages and activating the p38 MAPK pathway. Therefore, LR12 could be an attractive therapeutic target for the treatment of ALF.

• Hepatic inflammation
• Liver injury
• MAP kinase
• Obesity

Jie-Du-Hua-Yu (JDHY) granules are a traditional Chinese medicine with known therapeutic effects for the treatment of acute liver failure (ALF). This study explored the potential molecular mechanism(s) of JDHY granules in promoting liver regeneration and preventing ALF.

Rat models of ALF were constructed through administration of D-galactosamine (D-GalN) (600 mg/kg) and lipopolysaccharides (LPS) (20 μg/kg). Rats were gavaged with JDHY granules, and serum and liver samples were collected at 12 h post-D-GalN/LPS administration. The degree of liver injury was evaluated through hepatic pathology and alanine/aspartate aminotransferase (ALT/AST) activity. miRNA chips were used to detect the miRNA expression profiles of rat models. Bioinformatics analysis was used to identify the biological processes and cell signaling pathways mediating the therapeutic effects of JDHY. Real-time PCR (RT-PCR) and western blotting were used to validate the data.

JDHY granules could effectively decrease the levels of ALT and AST, relieve D-GalN/LPS-induced liver injury, and improve hepatic function. JDHY granules were found to regulate the expression of 20 miRNAs and 19 mRNAs, which influenced 21 biological processes and 9 signaling pathways. Upon analysis of the therapeutic mechanism(s) governing the effects of JDHY granules on liver regeneration, enhanced DNA replication and an improved cholesterol metabolic ratio were identified. JDHY granules were also found to increase the expression of MCM3, CDK4, and TC, confirming the involvement of these pathways. Moreover, JDHY granules were found to promote hepatocyte mitosis and inhibit the progression of ALF.

JDHY granules protect against D-GalN/LPS-induced ALF in rats by promoting liver regeneration through enhanced DNA replication and an improved cholesterol metabolic ratio.

• IBD
• MAPK
• Natural product
• natural dietary supplement
• therapeutic target
• ulcerative colitis

• Animals
• Humans
• Metabolic Diseases/metabolism
• Obesity/metabolism
• Protein Kinases/metabolism
• Stress, Physiological

• ▪▪▪

Non‐alcoholic fatty liver disease (NAFLD) serves as the most common subtype of liver diseases and cause of liver dysfunction, which is closely related to obesity and insulin resistance. In our study, we sought to investigate effect of transcription factor grainyhead‐like 2 (GRHL2) on NAFLD and the relevant mechanism. NAFLD mouse model was established with a high‐fat feed. Then, serum was extracted from NAFLD patients and mice, followed by ectopic expression and depletion experiments in NAFLD mice and L02 cells. Next, the correlation between GRHL2 and microRNA (miR)‐200 and between miR‐200 and sirtuin‐1 (SIRT1) was evaluated. The observations demonstrated that miR‐200 and GRHL2 were overexpressed in the serum of NAFLD patients and mice, while SIRT1 was poorly expressed. GRHL2 positively regulated miR‐200 by binding to miR‐200 promoter region, which negatively targeted SIRT1. The inhibition of miR‐200 and GRHL2 or SIRT1 overexpression lowered HA and LN in mouse liver tissue, occludin and ZO‐1 in mouse small intestine tissue, TNF‐α and IL‐6 in mouse serum, glucose, total cholesterol (TC), triglyceride (TG), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in mouse serum, and also inhibited liver fibrosis and intestinal mucosal barrier dysfunction. Meanwhile, GRHL2 induced activation of MAPK signalling pathway in NAFLD mice. Collectively, GRHL2 played a contributory role in NAFLD by exacerbating liver fibrosis and intestinal mucosal barrier dysfunction with the involvement of miR‐200‐dependent SIRT1 and the MAPK signalling pathway.

• Grainyhead-like 2
• MAPK signalling pathway
• intestinal mucosal barrier dysfunction
• liver fibrosis
• microRNA-200
• non-alcoholic fatty liver disease
• sirtuin-1
• transcription factor

Radiation-induced liver damage (RILD) has become a limitation in radiotherapy for hepatocellular carcinoma. We established a rabbit model of RILD by CyberKnife. Electron microscopy analysis revealed obvious nuclear atrophy and disposition of fat in the nucleus after irradiation. We then utilized a mass spectrometry-based label-free relative quantitative proteomics approach to compare global proteomic changes of rabbit liver in response to radiation. In total, 2365 proteins were identified, including 338 proteins that were significantly dysregulated between irradiated and nonirradiated liver tissues. These differentially expressed proteins included USP47, POLR2A, CSTB, MCFD2, and CSNK2A1. Real-time polymerase chain reaction confirmed that USP47 and CABLES1 transcripts were significantly higher in irradiated liver tissues, whereas MCFD2 and CSNK2A1 expressions were significantly reduced. In Clusters of Orthologous Groups of proteins analysis, differentially expressed proteins were annotated and divided into 24 categories, including posttranslational modification, protein turnover, and chaperones. Kyoto Encyclopedia of Genes and Genomes analysis revealed that the enriched pathways in dysregulated proteins included the vascular endothelial growth factors (VEGF) signaling pathway, the mitogen-activated protein kinase (MAPK) signaling pathway, and the adipocytokine signaling pathway. The identification of proteins and pathways is crucial toward elucidating the radiation response process of the liver, which may facilitate the discovery of novel therapeutic targets.

• animal model
• label-free quantitative proteomics
• radiation
• radiation-induced liver damage

Mammalian p38α MAPK (Mitogen-Activated Protein Kinase) transduces a variety of extracellular signals that regulate cellular processes, such as inflammation, differentiation, proliferation or apoptosis. In the liver, depending of the physiopathological context, p38α acts as a negative regulator of hepatocyte proliferation as well as a promotor of inflammatory processes. However, its function during an acute injury, in adult liver, remains uncharacterized. In this study, using mice that are deficient in p38α specifically in mature hepatocytes, we unexpectedly found that lack of p38α protected against acute injury induced by CCl₄ compound. We demonstrated that the hepatoprotective effect alleviated ROS accumulation and shaped the inflammatory response to promote efficient tissue repair. Mechanistically, we provided strong evidence that Ccl2/Ccl5 chemokines were crucial for a proper hepatoprotective response observed secondary to p38α ablation. Indeed, antibody blockade of Ccl2/Ccl5 was sufficient to abrogate hepatoprotection through a concomitant decrease of both inflammatory cells recruitment and antioxidative response that result ultimately in higher liver damages. Our findings suggest that targeting p38α expression and consequently orientating immune response may represent an attractive approach to favor tissue recovery after acute liver injury.

• DEN
• Fas
• HepG2
• SAC
• p53
• pp38MAPK

• Animals
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Caspases/metabolism
• Cysteine/analogs & derivatives
• Cysteine/pharmacology
• Cysteine/therapeutic use
• Fas Ligand Protein/metabolism
• Hep G2 Cells
• Humans
• Imidazoles/pharmacology
• Liver Neoplasms, Experimental/drug therapy
• Liver Neoplasms, Experimental/enzymology
• Liver Neoplasms, Experimental/metabolism
• Liver Neoplasms, Experimental/pathology
• Male
• Mice
• Phosphorylation/drug effects
• Protein Kinase Inhibitors/pharmacology
• Pyridines/pharmacology
• Tumor Suppressor Protein p53/metabolism
• fas Receptor/metabolism
• p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors
• p38 Mitogen-Activated Protein Kinases/metabolism

• Hepatocytes
• Macrophages
• Pro-inflammatory cytokines
• Steatohepatitis
• p38 MAPK

p38α MAPK negatively regulates the G₁/S and G₂/M cell cycle transitions. However, liver-specific p38α deficiency impairs cytokinesis and reduces hepatocyte proliferation during cirrhosis and aging in mice. In this work, we have studied how p38α down-regulation affects hepatocyte proliferation after partial hepatectomy, focusing on mitotic progression, cytokinesis and oxidative stress. We found that p38α deficiency triggered up-regulation of cyclins A1, B1, B2, and D1 under basal conditions and after hepatectomy. Moreover, p38α-deficient hepatocytes showed enhanced binucleation and increased levels of phospho-histone H3 but impaired phosphorylation of MNK1 after hepatectomy. The recovery of liver mass was transiently delayed in mice with p38α-deficient hepatocytes vs wild type mice. We also found that p38α deficiency caused glutathione oxidation in the liver, increased plasma aminotransferases and lactate dehydrogenase activities, and decreased plasma protein levels after hepatectomy. Interestingly, p38α silencing in isolated hepatocytes markedly decreased phospho-MNK1 levels, and silencing of either p38α or Mnk1 enhanced binucleation of hepatocytes in culture. In conclusion, p38α deficiency impairs mitotic progression in hepatocytes and restrains the recovery of liver mass after partial hepatectomy. Our results also indicate that p38α regulates cytokinesis by activating MNK1 and redox modulation.

Psoralen is a major component of the common traditional Chinese medicine Fructus Psoraleae (FP). In this study, we focused on psoralen to explore FP-induced hepatotoxicity and the underlying mechanisms. The acute oral median lethal dose of psoralen in ICR mice was determined to be 1,673 mg/kg. C57BL/6 mice were administered psoralen intragastrically at doses of 400 mg/kg or 800 mg/kg, and were sacrificed 24 h after treatment. Changes in various hepatotoxicity indicators demonstrated that psoralen can cause mild liver injury in mice. Psoralen inhibited the viability of normal human liver L02 cells in vitro by inducing S-phase arrest. In addition, psoralen in both the mouse livers and L02 cells upregulated cyclin E1 and p27 protein levels. The 2/3 partial hepatectomy mouse model was used to further explore the effects of psoralen on the liver regeneration and hepatocellular cycle arrest in vivo. The results showed that the decrease of liver regenerative and self-healing capabilities induced by hepatocellular cycle arrest may play an important role in the hepatotoxicity of psoralen. The further mechanism researches indicated that psoralen-induced hepatotoxicity was associated with inhibition of mTOR signalling pathway and mitochondrial injury; furthermore, MHY, an mTOR activator, partly alleviated the inhibition of mTOR and S-phase cycle arrest induced by psoralen in L02 cells. In conclusion, in this study we showed for the first time, that psoralen significantly induced liver injury in mice; the decrease of liver regenerative and compensatory capabilities induced by hepatocellular cycle arrest may play an important role in the progression of hepatotoxicity associated with the upregulation of cyclin E1 and p27, as well as the inhibition of mTOR signalling and mitochondrial injury. Our findings may contribute to the reduction of hepatotoxicity risk induced by Fructus Psoraleae.

• cycle arrest
• hepatotoxicity
• liver regeneration
• mTOR
• mitochondrial damage
• psoralen

• CCL2
• HMBOX1
• Hepatocytes
• Inflammation
• Macrophage

• MAPK
• cell signaling
• computational biology
• hepatocyte
• interleukin 1β
• liver
• macrophage
• mathematical modeling
• p38 MAPK
• systems biology

Hepatocyte poliploidization is an age-dependent process, being cytokinesis failure the main mechanism of polyploid hepatocyte formation. Our aim was to study the role of p38α MAPK in the regulation of actin cytoskeleton and cytokinesis in hepatocytes during development and aging.

Wild type and p38α liver-specific knock out mice at different ages (after weaning, adults and old) were used.

We show that p38α MAPK deficiency induces actin disassembly upon aging and also cytokinesis failure leading to enhanced binucleation. Although the steady state levels of cyclin D1 in wild type and p38α knock out old livers remained unaffected, cyclin B1- a marker for G2/M transition- was significantly overexpressed in p38α knock out mice. Our findings suggest that hepatocytes do enter into S phase but they do not complete cell division upon p38α deficiency leading to cytokinesis failure and binucleation. Moreover, old liver-specific p38α MAPK knock out mice exhibited reduced F-actin polymerization and a dramatic loss of actin cytoskeleton. This was associated with abnormal hyperactivation of RhoA and Cdc42 GTPases. Long-term p38α deficiency drives to inactivation of HSP27, which seems to account for the impairment in actin cytoskeleton as Hsp27-silencing decreased the number and length of actin filaments in isolated hepatocytes.

p38α MAPK is essential for actin dynamics with age in hepatocytes.

• Actins/chemistry
• Actins/metabolism
• Animals
• Biomarkers
• Cells, Cultured
• Cellular Senescence
• Cytokinesis/genetics
• Cytoskeleton/metabolism
• Gene Knockout Techniques
• Hepatocytes/physiology
• Immunohistochemistry
• Male
• Mice
• Mice, Knockout
• Mitogen-Activated Protein Kinase 14/genetics
• Mitogen-Activated Protein Kinase 14/metabolism
• Mitosis/genetics
• Protein Binding
• Protein Multimerization
• Protein Serine-Threonine Kinases/metabolism

• Ministerio de Economía y Competitividad
• Consejo Superior de Investigaciones Científicas
• Generalitat Valenciana
• Ministerio de Ciencia e Innovación
• European Commission

• EGF
• HGF p38
• Hepatocytes

• Animals
• Cells, Cultured
• DNA Replication
• Hepatocyte Growth Factor/pharmacology
• Hepatocytes/metabolism
• Imidazoles/pharmacology
• MAP Kinase Signaling System
• Male
• Protein Kinase Inhibitors/pharmacology
• Pyridines/pharmacology
• Rats
• Rats, Wistar
• p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors
• p38 Mitogen-Activated Protein Kinases/metabolism

This study investigated the effects of weaning on the hepatic redox status, apoptosis, function, and the mitogen-activated protein kinase (MAPK) signaling pathways during the first week after weaning in piglets. A total of 12 litters of piglets were weaned at d 21 and divided into the weaning group (WG) and the control group (CG). Six piglets from each group were slaughtered at d 0 (d 20, referred to weaning), d 1, d 4, and d 7 after weaning. Results showed that weaning significantly increased the concentrations of hepatic free radicals H₂O₂ and NO, malondialdehyde (MDA), and 8-hydroxy-2′-deoxyguanosine (8-OHdG), while significantly decreasing the inhibitory hydroxyl ability (IHA) and glutathione peroxidase (GSH-Px), and altered the level of superoxide dismutase (SOD). The apoptosis results showed that weaning increased the concentrations of caspase-3, caspase-8, caspase-9 and the ratio of Bax/Bcl-2. In addition, aspartate aminotransferase transaminase (AST) and alanine aminotransferase (ALT) in liver homogenates increased after weaning. The phosphorylated JNK and ERK1/2 increased, while the activated p38 initially decreased and then increased. Our results suggested that weaning increased the hepatic oxidative stress and aminotransferases and initiated apoptosis, which may be related to the activated MAPK pathways in postweaning piglets.

• Hepatocyte proliferation
• Immediate early gene response
• In vitro liver culture
• Liver regeneration
• MK2
• TTP

Human adipose-derived stem cells (hADSCs), widely present in the adult human body, are an emerging and attractive tool for the establishment of stem cell-based therapies for the treatment of liver disease. However, the mechanism underlying hADSCs hepatic differentiation remains to be elucidated. Caveolin-1 (Cav-1), a 21–24 kDa membrane structural protein, is important in liver regeneration and development. In the present study, fluorescence immuno-cytochemistry and western blotting were used to analyze the expression levels of Cav-1 and evaluate its effects on the hepatic differentiation of hADSCs. The results revealed that primary hADSCs preserved the ability to proliferate and differentiate into hepatocyte-like cells. As demonstrated by semiquantitative reverse transcription-polymerase chain reaction, hepatocyte-inducing factors significantly increased the expression of Cav-1 in a time-dependent manner, as indicated by increased expression levels of the albumin (ALB) and α-fetoprotein (AFP) markers. In addition the expression levels of ALB and HNF1A significantly decreased following small interfering RNA-mediated knockdown of Cav-1. The mitogen-activated protein kinase (MAPK) signaling pathway was activated during hepatic differentiation and inhibited following Cav-1 knockdown. These results suggested that Cav-1 may regulate the hepatocyte-like differentiation of hADSCs by modulating mitogen-activated protein kinase kinase/MAPK signaling. The results of the present study will provide experimental and theoretical basis for further clinical studies on stem cell transplantation in the treatment of liver disease.

AIM: To investigate a possible association between losartan and sirtuin 1 (SIRT1) in reduced-size orthotopic liver transplantation (ROLT) in rats.

METHODS: Livers of male Sprague-Dawley rats (200-250 g) were preserved in University of Wisconsin preservation solution for 1 h at 4 °C prior to ROLT. In an additional group, an antagonist of angiotensin II type 1 receptor (AT1R), losartan, was orally administered (5 mg/kg) 24 h and 1 h before the surgical procedure to both the donors and the recipients. Transaminase (as an indicator of liver injury), SIRT1 activity, and nicotinamide adenine dinucleotide (NAD⁺, a co-factor necessary for SIRT1 activity) levels were determined by biochemical methods. Protein expression of SIRT1, acetylated FoxO1 (ac-FoxO1), NAMPT (the precursor of NAD+), heat shock proteins (HSP70, HO-1) expression, endoplasmic reticulum stress (GRP78, IRE1α, p-eIF2) and apoptosis (caspase 12 and caspase 3) parameters were determined by Western blot. Possible alterations in protein expression of mitogen activated protein kinases (MAPK), such as p-p38 and p-ERK, were also evaluated. Furthermore, the SIRT3 protein expression and mRNA levels were examined.

RESULTS: The present study demonstrated that losartan administration led to diminished liver injury when compared to ROLT group, as evidenced by the significant decreases in alanine aminotransferase (358.3 ± 133.44 vs 206 ± 33.61, P < 0.05) and aspartate aminotransferase levels (893.57 ± 397.69 vs 500.85 ± 118.07, P < 0.05). The lessened hepatic injury in case of losartan was associated with enhanced SIRT1 protein expression and activity (5.27 ± 0.32 vs 6.08 ± 0.30, P < 0.05). This was concomitant with increased levels of NAD⁺ (0.87 ± 0.22 vs 1.195 ± 0.144, P < 0.05) the co-factor necessary for SIRT1 activity, as well as with decreases in ac-FoxO1 expression. Losartan treatment also provoked significant attenuation of endoplasmic reticulum stress parameters (GRP78, IRE1α, p-eIF2) which was consistent with reduced levels of both caspase 12 and caspase 3. Furthermore, losartan administration stimulated HSP70 protein expression and attenuated HO-1 expression. However, no changes were observed in protein or mRNA expression of SIRT3. Finally, the protein expression pattern of p-ERK and p-p38 were not altered upon losartan administration.

CONCLUSION: The present study reports that losartan induces SIRT1 expression and activity, and that it reduces hepatic injury in a ROLT model.

• Losartan
• Sirtuin 1
• Endoplasmic reticulum stress
• Liver ischemia reperfusion injury
• Angiotensin II

• Angiotensin II Type 1 Receptor Blockers/pharmacology
• Animals
• Apoptosis/drug effects
• Cytoprotection
• Disease Models, Animal
• Enzyme Activation
• Gene Expression Regulation
• Heat-Shock Proteins/metabolism
• Liver/drug effects
• Liver/enzymology
• Liver/pathology
• Liver/surgery
• Liver Transplantation/adverse effects
• Losartan/pharmacology
• Male
• Mitogen-Activated Protein Kinases/metabolism
• NAD/metabolism
• RNA, Messenger/metabolism
• Rats, Sprague-Dawley
• Reperfusion Injury/enzymology
• Reperfusion Injury/genetics
• Reperfusion Injury/pathology
• Reperfusion Injury/prevention & control
• Signal Transduction/drug effects
• Sirtuin 1/metabolism

Growing recognition of paracrine mechanisms in stem cell plasticity has resulted in considerable interest in stem cell-derived secretome. The aim of this study was to investigate the effects of lipopolysaccharide (LPS) preconditioning on the composition and hepatic regenerative activity of adipose-derived stem cell (ASC) secretome.

Conditioned medium (CM) and LPS-CM were obtained after culturing human ASCs without or with low-dose LPS (0.5 ng/mL) for 24 hours. Untreated and thioacetamide-treated mouse AML12 hepatocytes were incubated for 24 hours with the control medium, LPS (0.5 ng/mL), CM, and LPS-CM and then cell viabilities were compared. CM and LPS-CM were also intravenously administered to partially hepatectomized mice, and their effects on liver regeneration were assessed by using liver weight measurements, immunohistochemistry, and Western blotting.

In the in vitro experiments, LPS preconditioning of ASCs enhanced the mRNA expression levels of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), hepatocyte growth factor, and vascular endothelial growth factor, which evoke inflammatory response or liver regeneration. LPS-CM significantly promoted thioacetamide-damaged AML12 cell viability compared with CM-incubated cells and the control cells (77%, 69%, and 65% P <0.05). In the in vivo experiment, LPS-CM infusion into the partially hepatectomized mice significantly reduced serum IL-6 and TNF-α levels compared with the other groups (P <0.05) on days 1 and 2 after partial hepatectomy. Moreover, LPS-CM infusion enhanced liver regeneration (based on the liver weight changes at day 7 after partial hepatectomy, 3.73% versus 3.22% in the CM group; P <0.05) and significantly reduced the elevated serum levels of aspartate transaminase and alanine transaminase (at day 1, P <0.05).

Our results suggest that LPS preconditioning effectively stimulates ASCs to produce the secretome beneficial to hepatic regeneration. Thus, optimizing ASC secretome profile by LPS preconditioning could be a promising approach to treat liver diseases by using stem cells.

• Administration, Inhalation
• Administration, Oral
• Air
• Animals
• Gene Expression Profiling
• Gene Expression Regulation/drug effects
• Hydrogen/administration & dosage
• Hydrogen/blood
• Hydrogen/pharmacology
• Liver/drug effects
• Liver/metabolism
• Male
• Mice, Inbred BALB C
• Organ Specificity/drug effects
• Rats, Wistar
• Signal Transduction/drug effects
• Signal Transduction/genetics
• Time Factors
• Water/administration & dosage
• Water/pharmacology

The recovery of liver mass is mainly mediated by proliferation of hepatocytes after 2/3 partial hepatectomy (PH) in rats. Studying the gene expression profiles of hepatocytes after 2/3 PH will be helpful to investigate the molecular mechanisms of liver regeneration (LR). We report here the first application of weighted gene co-expression network analysis (WGCNA) to analyze the biological implications of gene expression changes associated with LR. WGCNA identifies 12 specific gene modules and some hub genes from hepatocytes genome-scale microarray data in rat LR. The results suggest that upregulated MCM5 may promote hepatocytes proliferation during LR; BCL3 may play an important role by activating or inhibiting NF-kB pathway; MAPK9 may play a permissible role in DNA replication by p38 MAPK inactivation in hepatocytes proliferation stage. Thus, WGCNA can provide novel insight into understanding the molecular mechanisms of LR.

• Animals
• Gene Expression Profiling
• Gene Regulatory Networks
• Hepatectomy
• Hepatocytes/cytology
• Hepatocytes/metabolism
• Liver Regeneration/genetics
• Molecular Sequence Annotation
• Rats
• Rats, Sprague-Dawley
• Signal Transduction/genetics

Intermittent clamping of the portal trial is an effective method to avoid excessive blood loss during hepatic resection, but this procedure may cause ischemic damage to liver. Intermittent selective clamping of the lobes to be resected may represent a good alternative as it exposes the remnant liver only to the reperfusion stress. We compared the effect of intermittent total or selective clamping on hepatocellular injury and liver regeneration. Entire hepatic lobes or only lobes to be resected were subjected twice to 10 min of ischemia followed by 5 min of reperfusion before hepatectomy. We provided evidence that the effect of intermittent clamping can be damaging or beneficial depending to its mode of application. Although transaminase levels were similar in all groups, intermittent total clamping impaired liver regeneration and increased apoptosis. In contrast, intermittent selective clamping improved liver protein secretion and hepatocyte proliferation when compared with standard hepatectomy. This beneficial effect was linked to better adenosine-5′-triphosphate (ATP) recovery, nitric oxide production, antioxidant activities and endoplasmic reticulum adaptation leading to limit mitochondrial damage and apoptosis. Interestingly, transient and early chaperone inductions resulted in a controlled activation of the unfolded protein response concomitantly to endothelial nitric oxide synthase, extracellular signal-regulated kinase-1/2 (ERK1/2) and p38 MAPK activation that favors liver regeneration. Endoplasmic reticulum stress is a central target through which intermittent selective clamping exerts its cytoprotective effect and improves liver regeneration. This procedure could be applied as a powerful protective modality in the field of living donor liver transplantation and liver surgery.

Hepatitis C virus (HCV) is a significant health problem facing the world. This virus infects more than 170 million people worldwide and is considered the major cause of both acute and chronic hepatitis. Persons become infected mainly through parenteral exposure to infected material by blood transfusions or injections with nonsterile needles. Although the sexual behavior is considered as a high risk factor for HCV infection, the transmission of HCV infection through sexual means, is less frequently. Currently, the available treatment for patients with chronic HCV infection is interferon based therapies alone or in combination with ribavirin and protease inhibitors. Although a sustained virological response of patients to the applied therapy, a great portion of patients did not show any response. HCV infection is mostly associated with progressive liver diseases including fibrosis, cirrhosis and hepatocellular carcinoma. Although the focus of many patients and clinicians is sometimes limited to that problem, the natural history of HCV infection (HCV) is also associated with the development of several extrahepatic manifestations including dermatologic, rheumatologic, neurologic, and nephrologic complications, diabetes, arterial hypertension, autoantibodies and cryglobulins. Despite the notion that HCV-mediated extrahepatic manifestations are credible, the mechanism of their modulation is not fully described in detail. Therefore, the understanding of the molecular mechanisms of HCV-induced alteration of intracellular signal transduction pathways, during the course of HCV infection, may offer novel therapeutic targets for HCV-associated both hepatic and extrahepatic manifestations. This review will elaborate the etiopathogenesis of HCV-host interactions and summarize the current knowledge of HCV-associated diseases and their possible therapeutic strategies.

• Hepatitis C virus
• Hepatocellular carcinoma
• Extrahepatic
• Signalling
• Therapy