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Concept: Cirrhosis

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Immunosuppressive CD11b(+) Gr-1(+) myeloid-derived suppressor cells (MDSCs) accumulate in the livers of tumor-bearing mice. We studied hepatic MDSCs in two murine models of immune mediated hepatitis. Unexpectedly, treatment of tumor bearing mice with Concanavalin A or α-Galactosylceramide resulted in increased ALT and AST serum levels in comparison to tumor free mice. Adoptive transfer of hepatic MDSCs into naïve mice exacerbated Concanavalin A induced liver damage. Hepatic CD11b(+) Gr-1(+) cells revealed a polarized pro-inflammatory gene signature after Concanavalin A treatment. An IFN-γ-dependent up regulation of CD40 on hepatic CD11b(+) Gr-1(+) cells along with an up regulation of CD80, CD86, and CD1d after Concanavalin A treatment was observed. Concanavalin A treatment resulted in a loss of suppressor function by tumor-induced CD11b(+) Gr-1(+) MDSCs as well as enhanced reactive oxygen species-mediated hepatotoxicity. CD40 knockdown in hepatic MDSCs led to increased arginase activity upon Concanavalin A treatment and lower ALT/AST serum levels. Finally, blockade of arginase activity in Cd40(-/-) tumor-induced myeloid cells resulted in exacerbation of hepatitis and increased reactive oxygen species production in vivo. Our findings indicate that in a setting of acute hepatitis, tumor-induced hepatic MDSCs act as pro-inflammatory immune effector cells capable of killing hepatocytes in a CD40-dependent manner. This article is protected by copyright. All rights reserved.

Concepts: Immune system, Mitochondrion, Cirrhosis, Liver, Glycogen, Alanine transaminase, Hepatitis C, Hepatitis A

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Background Liver disease caused by hepatitis C virus (HCV) is the main indication for liver transplantation (LT) among adults in the US. Recurrent HCV impairs patient and graft survival after LT. The high prevalence of HCV along with scarce organs has lead to increased utilization of HCV+ organs. We estimated the impact of HCV+ donors on patient and graft survival. Material and Methods We conducted a cohort study of LT recipients age 18 years or older from February 2002 through December 2012 utilizing UNOS data. We evaluated differences in patient characteristics between HCV+ and HCV- recipients. We also compared patient and graft survival between these groups and among HCV+ recipients who received HCV+ versus HCV- donor organs using the Kaplan-Meier estimator and multivariate stratified Cox regression models. Results We identified 59,899 LT recipients. Among those, 1,695 (2.8%) were HCV+ who received HCV+ grafts. HCV+ recipients of HCV- grafts were more likely to be female, hospitalized, in the ICU, on a ventilator, had higher MELD scores, and higher bilirubin. Patient and graft survival at 1, 5, and 10 years in HCV+ recipients was inferior to HCV- recipients, but HCV+ recipients who received HCV+ versus HCV- grafts were equivalent. Multivariate regression revealed multiple variables associated with worse outcomes. Conclusions The use of HCV+ grafts in HCV+ recipients is not associated with worse outcomes. With the increase in HCV+ patients awaiting an organ, more consideration should be given to HCV+ donors.

Concepts: Patient, Cirrhosis, Liver, Hepatology, Organ transplant, Hepatitis C, Organ donation, Hepatitis C virus

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Genetic mouse studies suggest that the NF-κB pathway regulator NEMO (also known as IKKγ) controls chronic inflammation and carcinogenesis in the liver. However the molecular mechanisms explaining the function of NEMO are not well defined. Here we report that overexpression of the cell cycle regulator p21 is a critical feature of liver inflammation and carcinogenesis caused by the loss of NEMO. NEMO(Δhepa) mice develop chronic hepatitis characterized by increased hepatocyte apoptosis and proliferation that causes the development of fibrosis and hepatocellular carcinoma, similar to the situation in human liver disease. Having identified p21 overexpression in this model, we evaluated its role in disease progression and LPS-mediated liver injury in double mutant NEMO(Δhepa)/p21(-/-) mice. Eight week-old NEMO(Δhepa)/p21(-/-) animals displayed accelerated liver damage that was not associated with alterations in cell cycle progression or the inflammatory response. However, livers from NEMO(Δhepa)/p21(-/-) mice displayed more severe DNA damage that was further characterized by LPS administration correlating with higher lethality of the animals. This phenotype was attenuated by genetic ablation of the TNF receptor TNF-R1 in NEMO(Δhepa)/p21(-/-) mice, demonstrating that DNA damage is induced via TNF. One year old NEMO(Δhepa)/p21(-/-) mice displayed greater numbers of hepatocellular carcinoma and severe cholestasis compared to NEMO(Δhepa) animals. Therefore, p21 overexpression in NEMO(Δhepa) animals protects against DNA damage, acceleration of hepatocarcinogenesis and cholestasis. Taken together, our findings illustrate how loss of NEMO promotes chronic liver inflammation and carcinogenesis, and they identify a novel protective role for p21 against the generation of DNA damage.

Concepts: Inflammation, Gene, Cancer, Cirrhosis, Hepatitis, Liver, Cell cycle, Jaundice

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Abstract Context: Nerium indicum Mill. (Apocynaceae) was reported for its efficient in vitro antioxidant and iron-chelating properties. Objective: This study demonstrates the effect of 70% methanol extract of N. indicum leaf (NIME) towards in vitro DNA protection and ameliorating iron-overload-induced liver damage in mice. Materials and methods: Phytochemical and HPLC analyses were carried out to standardize the extract and the effect of Fe(2+)-mediated pUC18 DNA cessation was studied. Thirty-six Swiss Albino mice were divided into six groups of blank, negative control (iron overload only), and iron-overloaded mice receiving 50, 100, and 200 mg/kg b.w. doses of NIME and desirox (20 mg/kg b.w.). The biochemical markers of hepatic damage, various liver and serum parameters, and reductive release of ferritin iron were studied. Results and discussion: The presence of different phytocomponents was revealed from phytochemical and HPLC analyses. A substantial supercoiled DNA protection, with [P]50 of 70.33 ± 0.32 µg, was observed. NIME (200 mg/kg b.w.) significantly normalized the levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and bilirubin by 126.27, 125.25, 188.48, and 45.47%, respectively. NIME (200 mg/kg b.w.) was shown to alleviate the reduced levels of superoxide dismutase, catalase, glutathione-S-transferase, and non-enzymatic-reduced glutathione, by 48.95, 35.9, 35.42, and 13.22%, respectively. NIME also lowered raised levels of lipid peroxidation, protein carbonyl, hydroxyproline, and liver iron by 32.28, 64.58, 136.81, and 83.55%, respectively. Conclusion: These findings suggest that the active substances present in NIME may be capable of lessening iron overload-induced toxicity, and possibly be a useful drug for iron-overloaded diseases.

Concepts: Iron, Antioxidant, Reactive oxygen species, Superoxide dismutase, Cirrhosis, Liver, Liver function tests, Apocynaceae

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Abstract Objective: In order to increase local drug concentration and reduce systemic side effects of liver cancer chemotherapy, it is desirable to develop novel non-invasive technologies for drug targeting, such as ultrasound-targeted microbubble destruction (UTMD). Methods: H22 hepatocellular carcinoma (HCC) xenograft transplantation model was generated in UTMD study. BALB/c mice were randomly divided into six groups: doxorubicin HCl liposomal injection (DOX), DOX + US, UTMD, DOX + UTMD, H22 liver tumor control (CH control) and blank control group. The therapeutic schedule started on day 4 after tumor inoculation. Results: Average survival time of the animal model was approximately 18 d. The UTMD therapy parameters were optimized in the H22 mouse model to be: microbubble (MB) diameter, 2.30 ± 0.25 μm; MB density, 4.0 × 10(9) bubbles/ml; treatment dose, 0.2 ml per 20 g mouse body weight; sonication frequency, 1.3 MHz; and sonication power, 2.06 W/cm(2). Mice treated with DOX + UTMD had the smallest tumor volume and weight (p < 0.001), and the highest tumor inhibition rate (p < 0.01), intratumoral DOX concentration (p < 0.001) and survival rate among all tumor-burden groups (p < 0.001). Cell viability in different treatment groups was also assessed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Conclusion: An improved antitumor effect was observed with the combination therapy of DOX and UTMD, as compared with treatment with DOX, DOX + US or UTMD, which implicates a novel approach for HCC treatment.

Concepts: Cancer, Oncology, Chemotherapy, Animal testing, Cirrhosis, Doxorubicin, Anthracycline, Liposome

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As a central event in liver fibrogenesis, hepatic stellate cell (HSC) transdifferentiation involves loss of regulation by adipogenic transcription factors such as peroxisome proliferator-activated receptor γ; (PPARγ), which is epigenetically silenced during HSC activation. We hypothesized that JMJD1A, an H3K9 demethylase involved in adipogenic metabolism, could regulate PPARγ. In human HSC cell line, rat primary HSCs, and carbontetrachloride-induced mouse liver fibrogenesis model, we down-regulated the expression of JMJD1A using small interfering or short hairpin RNAs, and overexpressed its wild-type and mutant. We analyzed the effects of JMJD1A manipulation on the histone di-methyl-H3K9 (H3k9me2) status of PPARγ gene and the expression of PPARγ and fibrosis markers using chromatin immunoprecipitation, real-time quantitative RT-PCR and Western blot, and also investigated the in vitro and in vivo consequences on liver fibrosis and necrosis by Masson or hematoxylin-eosin staining, respectively. JMJD1A knockdown in HSCs correlated with reinforced H3K9me2 in the PPARγ gene promoter, and its down-regulation in both mRNA and protein led to increased expression of fibrosis markers, which could be consistently rescued by JMJD1A overexpression. Jmjd1a knockdown in situ resulted in significantly increased expression of α-smooth muscle actin (P = 0.005) and Col1a (P = 0.036), strengthened production of collagens (P = 0.028), and remarkably enhanced necrosis (P = 0.007) 4 weeks after treatment. This study suggests JMJD1A as a novel epigenetic regulator that modulates HSC activation and liver fibrosis through targeting PPARγ gene expression.- Jiang, Y., Wang, S., Zhao, Y., Lin, C., Zhong, F., Jin, L., He, F., and Wang, H. Histone H3K9 demethylase JMJD1A modulates hepatic stellate cells activation and liver fibrosis by epigenetically regulating peroxisome proliferator-activated receptor γ.

Concepts: DNA, Protein, Gene, Gene expression, Cell, Transcription, Cirrhosis, Hepatic stellate cell

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Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver disease, and 10% to 20% of NAFLD patients progress to nonalcoholic steatohepatitis (NASH). The molecular pathways controlling progression to NAFLD/NASH remain poorly understood. We recently identified serine/threonine protein kinase 25 (STK25) as a regulator of whole-body insulin and glucose homeostasis. This study investigates the role of STK25 in liver lipid accumulation and NASH. Stk25 transgenic mice challenged with a high-fat diet displayed a dramatic increase in liver steatosis and hepatic insulin resistance compared to wild-type siblings. Focal fibrosis, hepatocellular damage, and inflammation were readily seen in transgenic but not wild-type livers. Transgenic livers displayed reduced β-oxidation and triacylglycerol secretion, while lipid uptake and synthesis remained unchanged. STK25 was associated with lipid droplets, colocalizing with the main hepatic lipid droplet-coating protein adipose differentiation-related protein, the level of which was increased 3.8 ± 0.7-fold in transgenic livers (P < 0.01), while a key hepatic lipase, adipose triacylglycerol lipase, was translocated from the lipid droplets surface to the cytoplasm, providing the likely mechanism underlying the effect of STK25. In summary, STK25 is a lipid droplet-associated protein that promotes NAFLD through control of lipid release from the droplets for β-oxidation and triacylglycerol secretion. STK25 also drives pathogenesis of NASH.-Amrutkar, M., Cansby, E., Nuñez-Durán, E., Pirazzi, C., Ståhlman, M., Stenfeldt, E., Smith, U., Borén, J., Mahlapuu, M. Protein kinase STK25 regulates hepatic lipid partitioning and progression of liver steatosis and NASH.

Concepts: Insulin, Glucose, Obesity, Cirrhosis, Metabolic syndrome, Non-alcoholic fatty liver disease, Fatty liver, Steatosis

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Hepatocytes express an array of plasma membrane and intracellular ion channels yet their role during the Hepatitis C virus (HCV) lifecycle remains largely undefined. Here, we show that HCV increases intracellular hepatic chloride (Cl(-)) influx that can be inhibited by selective Cl(-) channel blockers. Through pharmacological and siRNA mediated silencing we demonstrate that Cl(-) channel inhibition is detrimental to HCV replication. This represents the first observation of the involvement of Cl(-) channels during the HCV lifecycle.

Concepts: Protein, Cell membrane, Cirrhosis, Liver, Ion channel, Hepatitis C, Hepatitis A, Hepatitis C virus

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Sorafenib is now considered as a standard treatment for advanced hepatocellular carcinoma (HCC). We evaluated the effect of hepatitis B virus (HBV) DNA titers on prognosis in HCC patients treated with sorafenib.

Concepts: Cirrhosis, Hepatitis, Hepatocellular carcinoma, Interferon, Hepatitis C, Hepatitis B, Hepatitis B virus, Hepadnaviridae

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The classical human leukocyte antigen (HLA)-DRB1*03:01 and HLA-DRB1*04:01 alleles are established autoimmune hepatitis (AIH) risk alleles. To study the immune-modifying effect of these alleles, we imputed the genotypes from genome-wide association data in 649 Dutch AIH type-1 patients. We therefore compared the international AIH group (IAIHG) diagnostic scores as well as the underlying clinical characteristics between patients positive and negative for these HLA alleles. Seventy-five percent of the AIH patients were HLA-DRB1*03:01/HLA-DRB1*04:01 positive. HLA-DRB1*03:01/HLA-DRB1*04:01-positive patients had a higher median IAIHG score than HLA-DRB1*03:01/HLA-DRB1*04:01-negative patients (P<0.001). We did not observe associations between HLA alleles and alanine transaminase levels (HLA-DRB1*03:01: P=0.2; HLA-DRB1*04:01; P=0.5); however, HLA-DRB1*03:01 was independently associated with higher immunoglobulin G levels (P=0.04). The HLA-DRB1*04:01 allele was independently associated with presentation at older age (P=0.03) and a female predominance (P=0.04). HLA-DRB1*03:01-positive patients received immunosuppressive medication and liver transplantation. In conclusion, the HLA-DRB1*03:01 and HLA-DRB1*04:01 alleles are both independently associated with the aggregate diagnostic IAIHG score in type-1 AIH patients, but are not essential for AIH development. HLA-DRB1*03:01 is the strongest genetic modifier of disease severity in AIH.Genes and Immunity advance online publication, 22 January 2015; doi:10.1038/gene.2014.82.

Concepts: Immune system, Antibody, Genetics, Genotype, Allele, Immunology, Cirrhosis, Human leukocyte antigen