1 HSC activation is associated with modulation of transcription f

1 HSC activation is associated with modulation of transcription factors such as the peroxisome proliferator-activated receptor (PPAR) class of nuclear receptors.2 PPARs regulate the expression of responsive genes by forming heterodimers

with retinoid X receptors. These SCH 900776 cell line heterodimers bind to DNA on a specific PPAR response element (PPRE), a hexameric direct repeat (called the DR1 element) separated by a single nucleotide (TGACCTnTGACCT).3 However, imperfect PPREs that are not exact matches of this hexameric repeat have also been identified in several genes with variations in the binding site and spacer sequence.4 Three subtypes of PPAR proteins are known, namely PPARα, PPARβ, and PPARγ, and all three are expressed by normal HSCs.5 PPARγ, an essential transcription factor involved in adipocyte differentiation, is highly expressed in quiescent or differentiated HSCs.6 However, its expression and activity decreases dramatically during HSC activation both in in vitro–cultured

HSCs and in in vivo–activated HSCs from livers of rats undergoing bile duct ligation (BDL).2 PPARγ expression can be restored in activated HSCs by treatment with specific ligands such as rosiglitazone (RSG) that are able to revert the activated phenotype to quiescent state with increased retinyl esters, increased expression of CCAAT/enhancer-binding FK506 in vitro proteins (C/EBP), decrease in collagen and α-SMA, and suppressed cell proliferation.6-8 In contrast to PPARγ, the PPARβ protein is strongly induced during HSC activation, and treatment of HSCs with PPARβ agonists induces cellular proliferation.3 Methionine adenosyltransferases (MATs) are critical for cell survival because they are responsible for the conversion of methionine to S-adenosylmethionine (SAM), an essential biological

methyl donor.9 Mammalian cells express two genes, MAT1A and MAT2A, that encode the two MAT catalytic subunits, α1 and α2, respectively. The α1 subunit organizes into dimers (MATIII) or tetramers (MATI).9, 10 The α2 subunit is found in the MATII isoform.11 A third gene, MAT2B, encodes for a β regulatory 4-Aminobutyrate aminotransferase subunit that regulates the activity of MATII by lowering the inhibition constant (Ki) for SAM and the Michaelis constant (Km) for methionine.12 MAT1A is expressed mainly in hepatocytes and maintains the differentiated state of these cells.12 MAT2A and MAT2B are expressed in extrahepatic tissues and are induced in liver during active growth and dedifferentiation.13, 14 In HSCs, SAM is synthesized only by MAT2A, because these cells do not express MAT1A.14 Recently, we demonstrated that both MAT2A and MAT2B genes are up-regulated during HSC activation.15 Interestingly, despite the increase in MAT2A, there was a rapid drop in the activity of the MATII enzyme and intracellular SAM levels during HSC activation.

These assays could then be used as a component of quality assuran

These assays could then be used as a component of quality assurance to predict the clinical efficacy of individual Emu Oil preparations. Moreover, future studies of Emu Oil in the context of IBD could include targeted microencapsulation, or enema delivery methods, in an attempt to increase the bioavailability of active Emu Oil constituents at the specific click here site of inflammation. S.M.A. conducted a thorough review of the literature and prepared the manuscript. C.D.T. and G.S.H. contributed to manuscript preparation and revision. Professor Gordon S. Howarth is supported by the Sally Birch

Cancer Council Australia Research Fellowship. The authors state that there are no conflicts of interest. This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. “
“Hepatitis A vaccination has dramatically reduced the incidence of hepatitis A virus (HAV) infection, but new infections selleck compound continue to occur. To identify human genetic variants conferring a risk for HAV infection among the three major racial/ethnic

populations in the United States, we assessed associations between 67 genetic variants (single nucleotide polymorphisms [SNPs]) among 31 candidate genes and serologic evidence of prior HAV infection using a population-based, cross-sectional study of 6,779 participants, including 2,619 non-Hispanic whites, 2,095 non-Hispanic blacks, and 2,065 Mexican Americans enrolled in phase 2 (1991-1994) of the Third National Health and Nutrition Examination Survey. Among the three racial/ethnic groups, the number (weighted frequency) of seropositivity for antibody to HAV was 958 (24.9%), 802 (39.2%), and 1540 (71.5%), respectively. No significant associations with any of the 67 SNPs were observed among non-Hispanic whites or non-Hispanic blacks. In contrast, among Mexican Americans, variants in two genes were found to be associated

with an increased risk of HAV infection: TGFB1 not rs1800469 (adjusted odds ratio [OR], 1.38; 95% confidence interval [CI], 1.14-1.68; P value adjusted for false discovery rate [FDR-P] = 0.017) and XRCC1 rs1799782 (OR, 1.57; 95% CI, 1.27-1.94; FDR-P = 0.0007). A decreased risk was found with ABCB1 rs1045642 (OR, 0.79; 95% CI, 0.71-0.89; FDR-P = 0.0007). Conclusion: Genetic variants in ABCB1, TGFB1, and XRCC1 appear to be associated with susceptibility to HAV infection among Mexican Americans. Replication studies involving larger population samples are warranted. (HEPATOLOGY 2012) Hepatitis A is a highly contagious liver infection caused by the hepatitis A virus (HAV) that is usually spread by fecal-oral contact or by ingestion of contaminated food or water.1 Lifelong immunity is conferred by infection or vaccination.2 Antibody to HAV (anti-HAV) seroprevalence studies have been used to identify susceptible populations and high-prevalence localities.

[32, 33] In this study, basal QOL was estimated by the SF-8, and

[32, 33] In this study, basal QOL was estimated by the SF-8, and was significantly lower on all subscales than Japanese national standard values. However, no difference was observed by the presence or absence of HCC. In contrast, QOL of cirrhotic patients significantly correlated with the grade of

disease severity as defined by the Child–Pugh classification (data not shown). It was thus suggested that the degree of the hepatic functional reserve contributed to a greater extent than the progression of cancer as for QOL of cirrhotic patients. In conclusion, while PEM is still present in liver cirrhosis, a greater proportion shows obesity in Japanese patients at present. Because exacerbated inflammation, fibrosis and carcinogenesis has check details been reported in obese patients with liver cirrhosis, the present findings urge revision of nutritional and, possibly, establishment of exercise guidelines for obese patients with liver

Opaganib concentration cirrhosis, in addition to the current PEM guidelines. THIS WORK WAS supported in part by Grants-in-Aid from the Ministry of Health, Labor, and Welfare of Japan. “
“Mechanisms of brain edema in acute liver failure (ALF) are not completely understood. We recently demonstrated that matrix metalloproteinase 9 (MMP-9) induces significant alterations to occludin in brain endothelial cells in vitro and in brains of mice with experimental ALF (Hepatology 2009;50:1914). In this study we show that MMP-9-induced transactivation of epidermal growth factor receptor (EGFR) and p38 MAPK/NFκB (mitogen-activated protein kinase/nuclear factor-kappa B) signals participate in regulating brain endothelial occludin level. Mouse brain endothelial bEnd3 cells were exposed to MMP-9 or p38 MAPK up-regulation in the presence and absence of EGFR inhibitor, p38 MAPK inhibitor, NFκB inhibitor, and/or appropriate small interfering RNA. Reverse-transcription

polymerase chain reaction (RT-PCR) and western blotting were used for messenger RNA and protein expression analyses. Immunohistochemical staining and (-)-p-Bromotetramisole Oxalate confocal microscopy were used to demonstrate cellular EGFR activation. Intraperitoneal azoxymethane was use to induce ALF in mice. Brains of comatose ALF mice were processed for histological and biochemical analyses. When bEnd3 cells were exposed to MMP-9, EGFR was significantly transactivated, followed by p38 MAPK activation, I-kappa B alpha (IκBα) degradation, NFκB activation, and suppression of occludin synthesis and expression. Similar EGFR activation and p38 MAPK/NFκB activation were found in the brains of ALF mice, and these changes were attenuated with GM6001 treatment. Conclusion: EGFR activation with p38 MAPK/NFκB signaling contributes to the regulation of tight junction integrity in ALF. EGFR activation may thus play an important role in vasogenic brain edema in ALF.

Serum creatinine level (p = 001) was independently


Serum creatinine level (p = 0.01) was independently

related to mortality. Conclusion: TIPS placement effectively controlled ascites and is a reliable option or bridge therapy prior to liver transplantation for the management of refractory ascites in patients with liver cirrhosis. Key Word(s): 1. TIPS; 2. refractory ascites; 3. cirrhosis; Presenting Author: YANGYANG OUYANG Additional Authors: CHENGZHAO LIN, ZHE ZHANG, YIRONG CAO, YUANQIN ZHANG, SHIYAO CHEN, JIYAO WANG, SCOTTL. FRIEDMAN, JINSHENG GUO Corresponding Author: JINSHENG GUO Affiliations: Zhong Shan Hospital, Fu Dan University; Institutes of Biomedical Sciences, Fu Dan University; Mount Sinai Hospital Objective: Toll-like receptor 4 (TLR4) signaling contributes to the activation of hepatic stellate cells (HSC), the major fibrogenic cell type in injured liver, by promoting an inflammatory phenotype, fibrogenesis MEK inhibitor and cell survival. In our previous study immortalized mouse stellate cell lines that were TLR4 wild type (JS1) and TLR4 knockout (-/-) (JS2) were generated (Guo, et al. Hepatology, 2008). The aim of the present study was to investigate the differential gene expression in these cell lines with or without the stimulation by lipopolysacchirde (LPS), the exogenous TLR4 ligand, and high mobility group box 1 (HMGB1), a potential endogenous TLR4 ligand and damage pattern molecule that signals

the presence of necrosis (Zhang, et al, Lif Sci, 2012). Methods: JS1 and JS2 cells that were sub-cultured to 80% Selleck HM781-36B confluence were stimulated with normal saline vehicle (control), or 100 ng/ml LPS, or 100 ng/ml HMGB1 for 24 hours. The cells were collected with Trizol reagent for RNA extraction. The RNA extracts from the control, LPS and HMGB1 groups were hybridized on a 4644 K Agilent whole mouse genome oligo microarray for the gene expression analysis. Functional analysis of the microarray data was performed using KEGG analyses. Gene interaction network and co-expression network were

built on many the base of ontology and pathway analysis to which the differentially expressed genes attributed. Selected genes were validated by real-time polymerase chain reaction (RT-PCR), ELISA and/or Western Blot. Results: The gene expression profiles are different between JS1 and JS2 cells under basal condition and after stimulated with TLR4 ligands. The differentially expressed genes encode extracellular matrix and matrix remodeling proteins, growth factors and receptors, chemokines and receptors, inflammatory and immune related proteins, as well as transcriptional factors and important signaling molecules. In JS1 cells LPS upregulates genes that belong to the signaling pathways of Toll-like receptors, neurotrophic factor, immune, the spliceosome and nucleotide excision repair and downregulates PPAR signaling, with a variety of MHC molecules, MAPKs, Pik3r3, Prkca, Ikbkb as central regulatory factors.

From among them we selected 40 controls who were seropositive for

From among them we selected 40 controls who were seropositive for HBsAb, but had no hepatitis B vaccination history and were healthy, as confirmed

by annual medical examination for the last 5 consecutive years (Supporting Table 2). Written informed consent was obtained from all participants. The project was approved by the Ethics Committee of the University for Human Study and was conducted according to the principles of the 1975 Declaration of Helsinki. Exome sequences were captured by NimbleGen2.1 M array targeting 34 Mb of the human genome, containing 180,000 coding exons and 551 miRNA genes (http://www.nimblegen.com). The enriched library was sequenced on Illumina HighSeq2000. Sequencing reads were aligned to NCBI build 36.3. After removing reads duplicates, the average sequencing depth per sample was 43×. Of the targeted bases 93.54% had coverage of ≥8× SAHA HDAC purchase and genotype quality score ≥30. Single nucleotide variations (SNVs) were identified (“called”) by SOAPsnp (http://soap.genomics.org.cn/index.html)

and SAMTools (http://samtools.sourceforge.net). Small insertions and deletions (indels) were called by programs Dindel, Mpileup group, and Mpileup individual (http://www.sanger. ac.uk/resources/software/dindel/). Variants were annotated Selleck H 89 with information from the Consensus Coding Sequences Database at the NCBI. In selecting candidate genetic variants, we modified various existing protocols for Mendelian gene discovery.7 Rare variants were identified by comparing their frequencies in the Chinese Han data in HapMap (August 2010 release) (http://hapmap.ncbi.nlm.nih.gov/)

and our in-house data. Variations novel to HapMap Chinese Han data and our in-house data were treated as rare variants, as the HapMap already included data from 248 Chinese Han subjects and our in-house data from another 100 subjects. We reasoned that the following criteria might provide the most effective approach: (1) generally rare variants that were not shared by sequenced cases and controls and appeared more frequently (i.e., gave higher oxyclozanide “call counts”); (2) those that were predictively deleterious on the genes’ functions (e.g., truncating or missense mutations to highly conserved amino acids and/or were expected to be damaging according to PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) or SIFT (http://sift.jcvi.org/www/SIFT_chr_coords_submit.html)); (3) variants of genes with known antiviral/immune functions. Using these criteria, we performed two rounds of selections. In the first round we focused on rare variants that appeared more frequently and were predictively more deleterious, regardless of their known functions. In the second round we focused on known functions of the genes in combination with call counts. We first selected genes involved in immunity by comparing the genes of the variants with two databases, Gene Ontology (http://wiki.geneontology.org/index.php/Immunologically_Important_Genes) and Ensembl (http://www.

[240] There is uncertainty whether ASC in children and PSC in adu

[240] There is uncertainty whether ASC in children and PSC in adults have similar biological underpinnings or outcomes. In lieu of the phrase “overlap” syndrome, which suggests two separate conditions occurring in the same patient, the International Autoimmune Hepatitis Group posits that patients should be categorized by the predominant condition (e.g., AIH, PSC) and those with “overlapping” features should not be considered to be unique diagnosis.[249] Langerhans cell histiocytosis, primary and secondary immunodeficiencies, and cystic fibrosis have histological findings similar to PSC. LT is the only therapeutic option for endstage liver disease resulting from PSC.[250] Immunoglobulin

G4-associated cholangitis (IAC) is a newly recognized multisystem condition with intra- and extrahepatic selleck products biliary strictures that is often, but not always, associated with autoimmune pancreatitis.[251, 252] Strictures disappear with corticosteroid therapy. Evidence of

IAC in children is currently limited to case reports with a similar clinical and biochemical presentation and response to corticosteroids that is seen in adults.[253] Patients with PSC are at higher risk of developing inflammatory bowel disease (IBD) than the general population, with ulcerative colitis and Crohn’s disease diagnosed Opaganib price before LT in 46% and 3.3% of children, respectively, and IBD diagnosed after LT in another 9.8%.[254] Cholangiocarcinoma in children is rare and not all cases are associated with PSC.[255] Risks associated with cholangiocarcinoma in PSC are not well defined in children,[250] but HCC may be more prevalent among children with Crohn’s disease and PSC.[255] PSC accounts for 3.5% of pediatric patients listed

for LT,[256] and 2.6% pediatric Etomidate transplants.[254] LT is effective therapy for endstage liver disease due from PSC.[257] Patient and graft survival rates are comparable to those of age-matched children who undergo transplantation for other indications.[254] Post-LT complications include intrahepatic biliary strictures, cholangitis, and disease recurrence in the graft.[254] Patients with IBD and PSC have a higher recurrence rate post-LT compared to those with PSC alone. Five-year survival following LT for PSC is >80%.[258, 259] 55. Surveillance for inflammatory bowel disease with a full colonoscopy with biopsy both before and after LT in patients with features of primary sclerosing cholangitis is recommended. (2-B) 56. LT evaluation should be considered for patients with decompensated liver disease, recurrent cholangitis, unmanageable bile duct strictures, and/or concerns for the risk of cholangiocarcinoma. (2-B) Progressive familial intrahepatic cholestasis (PFIC) refers to a group of autosomal recessive cholestatic conditions. The nomenclature for these conditions is evolving as the underlying genetic defects and affected proteins are identified.

Results: The σmax (MPa) in the crown dentin were: GFD0 = 117; NiC

Results: The σmax (MPa) in the crown dentin were: GFD0 = 117; NiCr0 = 30; Au0 = 64; GFD1 = 113; NiCr1 = 102; Au1 = 84; GFD2 = 102; NiCr2 = 260; Au2 = 266. The σmax (MPa) in the root dentin were: GFD0 = 159; NiCr0 = 151; Au0 = 158; GFD1 = 92; NiCr1 = 60; Au1 = 67; GFD2 = 97; NiCr2 = 87; Au2 = 109. Conclusion: The maximum stress was found for the NiCr dowel, followed by the Au dowel and GFD; teeth without ferrule are more susceptible to the occurrence of fractures in the apical Dasatinib cost root third. “
“Purpose: Successful replacement of posterior teeth using contemporary prosthodontic techniques in esthetically demanding cases relies upon visual replication

of the natural posterior dentition and surrounding gingival architecture. There is currently little in the way of guidance for creating ideal or acceptable gingival relationships for posterior teeth. Materials and Methods: A cross-sectional study was conducted comparing perceptions of four groups of individuals to six digitally manipulated images with various posterior teeth gingival margin position configurations. A total of 120 volunteers aged

12 years to 80 years, comprising 30 patients diagnosed with hypodontia, 30 patients diagnosed with periodontal disease, 30 patients without either condition, and 30 qualified dentists were recruited from the Eastman Dental Institute & Hospital, London. A ranked order of preference for each set was obtained, and this was repeated after a minimum time interval of 10 minutes. Results: Posterior gingival margin configurations from 0 mm to Selleck PLX4032 2 mm (measured at the first premolar) were deemed most esthetic by the majority of the Arachidonate 15-lipoxygenase patient groups; dentists had a strong preference for the 1 mm configuration. Dentists appeared to be more perceptive to the alterations in gingival positions. Conclusions: Posterior gingival margin configurations where the first premolar margins

were 1 mm lower than the canine margins were deemed the most esthetically pleasing; however, it is likely that a range of acceptability of 1 mm deviations from this ideal exists. “
“The use of inserted dental implants is growing every day in order to improve retention and stability of complete removable dental prostheses (RDPs), especially in the mandible. Therefore, the aim of this study was to examine the knowledge and awareness of dental implants among elderly people wearing complete RDPs. This study, based on answers from a questionnaire designed for the purpose of this study, included 301 participants wearing complete RDPs from elderly care homes with average age of 74 years. The awareness of dental implants was statistically significantly (p < 0.05) affected by the participants’ age, residence size, and their level of education. Younger participants ( = 70 years) had heard about dental implants (56.5%; p < 0.

For the treatment study, αVEGFR2 treatment was given 2 weeks afte

For the treatment study, αVEGFR2 treatment was given 2 weeks after starting the MCD diet, when mice already developed steatosis, inflammation, and ballooning. Mice were sacrificed under isoflurane anesthesia (Forene, Hoofddorp, The Netherlands) while blood was obtained from the carotid artery. The liver and spleen were rapidly excised and weighed.

The left liver lobe was fixed in 4% phosphate buffered formaldehyde (Klinipath, Olen, Belgium). The right liver lobe was collected in RNAlater (Qiagen, Venlo, The Netherlands) and snap-frozen in liquid nitrogen. The left liver lobe was embedded in paraffin, histologically processed, and sections were cut and stained with hematoxylin and eosin staining (H&E) and Sirius Red. All stainings were performed using standard histology protocols and evaluated by an Talazoparib concentration experienced pathologist. Z-IETD-FMK price The degree of steatosis, lobular inflammation, and ballooning were defined as stated previously.19 Degree of steatosis, defined as the percentage of hepatocytes containing fat droplets, was scored using the following scale: 0 (<5%), 1 (5%-33%), 2 (>33%-66%), 3 (>66%). Foci of lobular inflammation were defined as two or more inflammatory foci (averaged from 3-4 200×

fields) and scored as: 0 (no foci), 1 (<2 foci), 2 (2-4 foci), 3 (>4 foci). Ballooning was scored according to number of ballooned hepatocytes: 0 (none), 1 (few), 2 (many). The degree of fibrosis was evaluated separately and scored as: 0 (none), 1 (zone 3 perisinusoidal or portal fibrosis), 2 (zone 3 perisinusoidal and periportal fibrosis without bridging), 3 (bridging fibrosis), 4 (cirrhosis). Primary hepatocytes were prepared by in situ perfusion and collagenase Venetoclax digestion (Liberase Blendzymes, Roche) of livers of adult female C57BL/6 mice as described.20 Cells were plated at a density of 2.5 × 104 cells per well on collagen I-coated 96-well plates (Greiner Bio-One, Frickenhausen, Germany) and cultured in Dulbecco’s modified Eagle’s medium (DMEM)/F12 supplemented with 10% FBS, ITS (insulin

5 μg/mL, transferrin 5 μg/mL, selenium 5 ng/mL) and 1% streptomycin and penicillin in 5% CO2 at 37°C. Two hours after plating, medium was replaced by the same culture medium but without ITS. The cells were used for experiments after an overnight incubation.21 Oleic and palmitic acids stock solutions (100 mM) were prepared in 0.1 M NaOH at 70°C as previously described.20 A 5 mM free fatty acid (FFA) / 5% bovine serum albumin (BSA) working solution was prepared by complexing an appropriate volume of stock solution to 5% BSA (FFA-free low endotoxin; Sigma-Aldrich, Bornem, Belgium) in a 60°C water bath. After filtration and cooling, a mixture of oleic and palmitic acids was prepared at a molar ratio of 2:1. After a 3-hour serum deprivation, hepatocytes were treated 24 hours with 100 μg/mL IgG, 100 μg/mL αVEGFR2, 150 ng/mL VEGF, or 100 μg/mL αVEGFR2 and 150 ng/mL VEGF diluted in DMEM/F12.

2, 0703, V0261], hepatitis C [ICD-9: 07041, 07044, 07051, 07

2, 070.3, V02.61], hepatitis C [ICD-9: 070.41, 070.44, 070.51, 070.54, V02.62], unspecified chronic hepatitis [ICD-9: 070.9, 571.4, 571.8, 571.9], alcoholic liver disease [ICD-9: 571.0, 571.1, 571.2, 571.3], cirrhosis [ICD-9: 571.5, 571.6]) and biliary tract19 (cholangitis [ICD-9: 575.8, 576.1], cholecystitis [ICD-9: 575.0, 575.11, 575.12], cholelithiasis [ICD-9: 574], choledocholithiasis [ICD-9: 574.5], biliary cirrhosis [ICD-9: 571.6]) from inpatient claims (1997-2006) and related

ambulatory care claims of both diabetic and control subjects (1997-2006). We counted the above clinical risk factors occurring in individuals in both groups only when the dates of diagnosis for the selected illnesses (clinical risk factors)

were noted before or the day on which the study subjects’ endpoints or censoring took place. The following criteria were set as censoring dates for the study subjects. First, if a subject died in the hospital Acalabrutinib research buy from causes other than the study endpoints, the date of censoring was the date of death. Second, if a subject did not encounter in-hospital mortality, the date of censoring was either the date of their last withdrawal from NHI or the date of termination of the study (December 31, 2006). We performed two major statistical analyses in this study. First, the age-specific and sex-specific hazard rate was estimated using person-years buy MG-132 as the denominator under the Poisson assumption. Second, to determine the independent effects of diabetes on the risks of malignant neoplasms of the liver and biliary tract, we used

Cox proportional hazard regression models with age, sex, geographic area, urbanization statuses, and related clinical risk factors adjusted simultaneously in the model. We adjusted geographic variables for possible geographic variations in the incidence of hepatocellular carcinoma.28 Furthermore, we explored the relative hazards of malignant neoplasm of the liver and biliary tract in relation to diabetes accompanied by the selected clinical risk factors individually with Cox proportional hazard regression models with age, sex, geographic area, and urbanization statuses adjusted in the model. All statistical analyses were performed with SAS version 9.1 (SAS Institute, Cary, NC). A P value <0.05 was considered Adenosine triphosphate statistically significant. The mean (± standard deviation) age of the diabetic group was 60.09 ± 12.73 years, whereas that of the control subjects was 60.00 ± 12.84 years. The percentages of people aged <45, 45-64, and >64 years were 11.3%, 48.3%, and 40.4% in both the control group and the diabetic population. The ratio of men to women was 51.9:48.1 in both groups. The details of geographic and clinical risk factors distribution are shown in Table 1. The median time of follow-up was similar at 6.9 years for both groups. The overall and age-specific and sex-specific hazard rate of malignant neoplasm of the liver are presented in Table 2.

The liver inflammation

The liver inflammation EGFR inhibitor and injury in 3xTg-iHAP mice were spontaneously resolved through liver regeneration and restitution within 5 days after low-dose Dox challenging. Taken together, we have developed and validated a new murine model of hepatocyte apoptosis-induced sterile liver inflammation and wound healing response. In a pilot study, we further revealed that 3xTg-iHAP mice chronically fed with alcohol-containing Lieber-DeCarli liquid diet developed profound steatohepatitis after treatment with a single low-dose of Dox. This finding suggests that our novel mouse model for sterile liver inflammation

can be combined with other liver disease models for studying the exact role of multi-hits in the pathogenesis of numerous inflammatory liver diseases such as alcoholic hepatitis and nonalcoholic steatohepatitis. Thus, 3xTg-iHAP mice is a novel in vivo research tool and may have a broad range of applications from exploring insights into the pathogenesis of sterile liver inflammation to testing new therapies for various liver diseases and complications (Supported in part by grants from the NIH). The following people have nothing to disclose: Heng-Fu Bu, Fangyi Liu, Xiao Wang, Pauline M. Chou, Catherine Marek, Ke Tian, Peng

Wang, Hua Geng, M. S. Rao, Suhail Akhtar, Monique E. De Paepe, Xiao-Di Tan Background/Aims: Nerve growth factor (NGF) has pro-inflammatory effects in lung and skin inflammatory diseases. During liver regeneration, NGF secreted check details by hepatocytes

induces hepatic stellate cell apoptosis. However, NGF involvement in models of liver damage and inflammation has not yet been assessed. We investigated the possible inflammatory effects of NGF on isolated hepatic stellate cells (HSC), as well as the in vivo effect of silencing NGF on acute liver damage and inflammation. Methods: Primary HSC from rats and mice were isolated and cultured for 7d and 14d to Temsirolimus order obtain activated and fully activated HSC, respectively. HSC were treated with 100ng/ ml NGF and proNGF and inflammatory cytokine expression was assessed by qRT-PCR and ELISA. Acute liver damage was induced by two i.p. injections of CCl4 (1 μl/g body weight) or by bile duct ligation (BDL) and mice received daily treatment with antisense oligodeoxynucleotide to NGF (ODN)(25mg/kg body weight). Results: Both NGF and proNGF induced expression of pro-inflammatory cytokines TNFα and IL-6 in activated and fully activated primary rat and murine HSC. Administration of antisense ODN to NGF in the acute CCl4 and BDL models reduced liver damage, as demonstrated by significantly reduced serum liver enzymes. In addition, antisense ODN to NGF resulted in dramatically reduced (6- fold) hepatic mRNA expression of pro-inflammatory cytokines IL-6, TNFα and MCP1 in the acute CCl4 model.