Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.6.1.2 (alanine aminotransferase)
26,722 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Despite recent advances in the chemotherapy of chronic hepatitis B (CHB), an effective viral suppression after cessation of therapy has not yet been achieved. To investigate whether hepatitis B virus (HBV)-specific T-cell responses are inducible and can contribute to the viral suppression after cessation of the therapy, we conducted a proof-of-concept study with a DNA vaccine comprising of most HBV genes plus genetically engineered interleukin-12 DNA (IL-12N222L) in 12 CHB carriers being treated with lamivudine (LAM). When the ex vivo and/or cultured IFN-gamma enzyme-linked immunospot (ELISPOT) assay was performed, the detectable HBV-specific IFN-gamma secreting T-cell responses were observed at the end of treatment and during a follow-up. These type 1T-cell responses, particularly CD4(+) memory T-cell responses could be maintained for at least 40 weeks after the therapy and correlated with virological responses, but not with alanine aminotransferase elevation. Moreover, DNA vaccination under LAM treatment appeared to be well-tolerated and showed 50% of virological response rate in CHB carriers. Thus, a combination therapy of the DNA vaccine with chemotherapy may be one of new immunotherapeutic methods for the cure of CHB.
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PMID:Correlation of antiviral T-cell responses with suppression of viral rebound in chronic hepatitis B carriers: a proof-of-concept study. 1652 82

CD4+CD25+ T regulatory cells may play a role in the different clinical presentations of chronic hepatitis C virus (HCV) infection by suppressing CD4+ T cell responses. Peripheral CD4+CD25+ T cells from chronic HCV carriers with normal and abnormal alanine aminotransferase (ALT) were analysed for specificity and effect on HCV-specific CD4+ T cell reactivity by flow cytometry for intracellular cytokine production and proliferation assay. HCV-specific CD4+CD25(+high) T cells consistently produced transforming growth factor (TGF)-beta but only limited amounts of interleukin (IL)-10 and no IL-2 and interferon (IFN)-gamma. The HCV-specific TGF-beta response by CD4+CD25(+high) T cells was significantly greater in patients with normal ALT compared to patients with elevated ALT. In addition, a significant inverse correlation was found between the HCV-specific TGF-beta response by CD4+CD25(+high) T cells and liver inflammation. In peripheral blood mononuclear cells (PBMC), both HCV antigen-induced IFN-gamma production and proliferation of CD4+ T cells were greater in patients with elevated ALT compared with patients with normal ALT. Depletion of CD4+CD25+ cells from PBMC resulted in an increase of both IFN-gamma production and proliferation of HCV-specific CD4+ T cells that was significantly greater in patients with normal ALT levels compared with patients with elevated ALT. In addition, CD4+CD25+ T cells from patients with normal ALT levels proved to be significantly more potent to suppress CD4+ T cell reactivity with respect to those from patients with elevated ALT. In conclusion, these data support the hypothesis that CD4+CD25+ cells may play a role in controlling chronic inflammatory response and hepatic damage in chronic HCV carriers.
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PMID:Increased hepatitis C virus (HCV)-specific CD4+CD25+ regulatory T lymphocytes and reduced HCV-specific CD4+ T cell response in HCV-infected patients with normal versus abnormal alanine aminotransferase levels. 1663 90

Fucoidan is a complex of sulfated polysaccharides derived from non-mammalian origin such as marine brown algae and induces cytokine expression. We investigated the effect of fucoidan on concanavalin A (Con A)-induced liver injury in mice. Liver injury was induced by an intravenous injection of Con A (18.5mg/kg). Various doses of fucoidan (1-30mg/kg) were intravenously administered 30min before Con A injection. The plasma alanine aminotransferase (ALT) and several cytokines levels were determined, and hepatic histological changes were also assessed. The effect of fucoidan administration by itself on induction of interleukin (IL)-10 in plasma and liver tissue was investigated. Con A administration induced an elevation of plasma ALT level, and fucoidan administration dose-dependently prevented the Con A-induced elevation of plasma ALT. Con A administration increased plasma TNF-alpha and IFN-gamma levels, and fucoidan pretreatment significantly inhibited these alterations and increased plasma IL-10 level. The inhibitory effect of fucoidan on Con A-induced liver injury and production of proinflammatory cytokines were reversed by anti-mouse IL-10 antibody pretreatment. Fucoidan induced the IL-10 production in plasma and liver tissue. These findings suggest that fucoidan prevents Con A-induced liver injury by mediating the endogenous IL-10 production and the inhibition of proinflammatory cytokine in mice.
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PMID:Fucoidan prevents concanavalin A-induced liver injury through induction of endogenous IL-10 in mice. 1667 79

T-cell immunoregulatory cytokines influence the persistence of hepatitis C virus (HCV) chronic infection and the extent of liver damage. Th1 cytokines positively correlate with hepatic inflammation in chronic hepatitis B virus (HBV) infection. The pro-inflammatory, cytokines IL-6 and IL-18, are involved in viral clearance and in metabolic and viral hepatic diseases, respectively. The aim of this study was to evaluate the profile of Th1/Th2 cytokines in HCV and HBV hepatitis. HBV-infected patients showed higher plasma IFN-gamma levels than the HCV+ patients or the control group (p <0.0001). Plasma TNF-alpha and IL-2 were higher in HBV+ in comparison to HCV+ patients (p <0.001) or the control group (p <0.005). Plasma IL-6 and IL-18 were higher in both groups of patients compared to the control group (p <0.04). In HCV+ and HBV+ groups, IL-6 was positively correlated with the duration of the illness (p <0.01 and <0.001, respectively) and viral load (p <0.001 and <0.001, respectively), while IL-18 was positively correlated with serum ALT activity (p <0.01 and <0.001, respectively) and serum AST activity (p <0.01 and <0.001, respectively). We found that in HCV+ and HBV+ patients there are higher levels of Th1 cytokines, particularly in the course of chronic hepatitis B, and that IL-18 and IL-6 levels may have important roles as markers of both inflammation and hepatic injury, particularly in the course of hepatitis C.
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PMID:Cytokine patterns correlate with liver damage in patients with chronic hepatitis B and C. 1668 9

Since liver regeneration after partial hepatectomy (PHx) is known to improve by pretreatment with recombinant human G-CSF (rhG-CSF), we investigated the mechanism by evaluating the distribution and activity of sinusoidal NK cells. F344 rats were treated with rhG-CSF (250 microg/kg/day) for 5 days before PHx. Pretreatment with rhG-CSF improved the serum ALT levels and DNA biosynthesis of the remnant liver tissues at 20 h after PHx. Notably, the rhG-CSF pretreatment decreased the number of NK cells in the liver determined by immunohistochemistry using anti-NKR-P1A mAb before and at 20 h after PHx with no significant change in the NK activity per cell base, while also increasing the number of NK cells in the peripheral blood detected by flow cytometry. The rhG-CSF induced a pre-PHx downregulation of the IL-12p70 protein levels, while also promoting the post-PHx reduction of the protein levels of IL-12p70 and IFN-gamma. Conversely, rhG-CSF had no effect on the pre-PHx mRNA levels or the PHx-induced upregulation of mRNA levels of TNF-alpha, IL-1beta, IL-6, TGF-beta, IL-10, HGF, and c-Met determined by real-time RT-PCR. These results strongly suggest that rhG-CSF-induced facilitation of liver regeneration is achieved by immunoregulation through the intrahepatic IL-12 downregulation and evacuation of sinusoidal NK cells.
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PMID:G-CSF-induced evacuation of sinusoidal NK cells and the facilitation of liver regeneration in a partial hepatectomy. 1671

Host immunity plays an important role in viral persistence and progression of liver disease in HCV infected patients. IL-12 induces production of IFN-gamma, a potent antiviral agent. IL-12 comprises two subunits; IL-p35 and IL-12p40, which are encoded by two different genes located on chromosome 3 and 5, respectively. Single nucleotide polymorphism at A1188C in the 3'UTR of IL-12p40 gene is associated with immune mediated diseases. Association of IL-12p40 A1188C polymorphism with the outcome of HCV infection was investigated in this study. Two hundred and fifty three histologically proven chronic hepatitis C patients (43 +/- 13 years, male:female: 185:68) and 380 matched controls were included. Genotyping was performed by RFLP and confirmed by direct sequencing. To assess correlation of immune gene polymorphism with severity of HCV-related liver disease, patients were divided into those with fibrosis score of < or = 2 (mild) or > 2 (severe), and histological activity index (HAI) of = 5 (mild) or > 5 (severe). The distribution of A/A, A/C or C/C alleles in the controls was comparable to the patients. The distribution of C/C allele was significantly more common in patients with mild as compared to severe fibrosis (23.7% vs. 6.25%, P = 0.004). No significant difference was observed for any of the genetic markers with HAI or with normal or raised alanine aminotransferase (ALT). These results show that the C/C allele of IL-12p40 gene could render genetic protection against development of severe liver disease in patients infected with HCV.
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PMID:Studies on TAQ1 polymorphism in the 3'untranslated region of IL-12P40 gene in HCV patients infected predominantly with genotype 3. 1678 8

The intravenous injection of concanavalin A (Con A) activates T cells and induces cytokine dependent liver injury in mice. However, the effect of repeated administrations of Con A has not been fully investigated. Female BALB/c mice were intravenously injected with Con A (20mg/kg) or saline once a week for six times. Mice were rechallenged with Con A 17 days after repeated administrations of Con A. Repeated Con A administrations elicited a sustained inhibition of rechallenged-Con A-induced liver injury. Plasma TNF-alpha and IFN-gamma levels after rechallenge of Con A were decreased compared with that of repeated saline treatments. By contrast, plasma IL-4 and IL-10 levels after rechallenge of Con A were increased. In spleen cells prepared from repeated Con A treated mice, the production of TNF-alpha and IFN-gamma 24h after co-incubation with Con A decreased, and that of IL-4 and IL-10 increased. In naive mice, plasma ALT level after Con A injection was decreased by the transfer of spleen cells prepared from the repeated Con A treated mice. The repeated administrations of Con A elicited Th1 to Th2 cytokine shift and the tolerant state against the Con A-induced liver injury in mice.
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PMID:Repeated administrations of concanavalin A induce Th1 to Th2 cytokine shift and tolerance against liver injury in mice. 1682 Mar 20

Abrogation of Ron receptor tyrosine kinase function results in defects in macrophage activation and dysregulated acute inflammatory responses in vivo. Several naturally occurring constitutively active alternative forms of Ron have been identified, including from primary human tumors and tumor cell lines. One of these alternative forms, short-form (SF) Ron, is generated from an alternative start site in intron 10 of the Ron gene that eliminates most of the extracellular portion of the receptor and is overexpressed in several human cancers. To test the physiological significance of SF-Ron in vivo, mice were generated that solely express the full-length form of Ron (FL-Ron). Our results show that elimination of the capacity to express SF-Ron in vivo leads to augmented production of IFN-gamma from splenocytes following stimulation ex vivo with either concanavalin A or anti-CD3/T cell receptor monoclonal antibody. Moreover, in a concanavalin A-induced murine model of acute liver injury, FL-Ron mice have increased production of serum INF-gamma and serum alanine aminotransferase levels and worsened liver histology and overall survival compared with wild-type control mice. Taken together, these results suggest for the first time that SF-Ron impacts the progression of inflammatory immune responses in vivo and further support a role for the Ron receptor and its various forms in liver pathophysiology.
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PMID:Short-form Ron receptor is required for normal IFN-gamma production in concanavalin A-induced acute liver injury. 1700 58

Nafamostat mesilate (NM) is a synthetic protease inhibitor with various biological effects. To determine its effect on liver injury related to sepsis, we investigated the effects of NM on lipopolysaccharide (LPS)-induced liver injury. Wistar rats were allocated into two groups; the NM group underwent intraperitoneal NM administration 30 min before LPS administration, and the control group underwent PBS administration. Serum AST and ALT levels were significantly decreased in NM-treated rats. Reduced levels of TNF-alpha, IL-1beta, and IFN-gamma were observed after LPS administration in NM-treated rats. No significant differences were observed in IL-6 levels between the NM and the control group. In contrast, HGF levels were significantly increased only in control rats. NM treatment decreased protein and mRNA levels of TLR-4 and CD14. Our data suggest that NM treatment has protective effects against LPS-induced hepatotoxicity through downregulation of TLR4 and CD14 in liver, which decreased TNF-alpha, IL-1beta, and IFN-gammaproduction in liver.
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PMID:Protective effects of nafamostat mesilate on liver injury induced by lipopolysaccharide in rats: possible involvement of CD14 and TLR-4 downregulation on Kupffer cells. 1707 64

Ischemia reperfusion injury results from tissue damage during ischemia and ongoing inflammation and injury during reperfusion. Liver reperfusion injury is reduced by lymphocyte depletion or activation of adenosine A2A receptors (A2ARs) with the selective agonist 4-{3-[6-amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]- prop-2-ynyl}-cyclohexanecarboxylic acid methyl ester (ATL146e). We show that NKT cells are stimulated to produce interferon (IFN)-gamma by 2 h after the initiation of reperfusion, and the use of antibodies to deplete NK1.1-positive cells (NK and NKT) or to block CD1d-mediated glycolipid presentation to NKT cells replicates, but is not additive to, the protection afforded by ATL146e, as assessed by serum alanine aminotransferase elevation, histological necrosis, neutrophil accumulation, and serum IFN-gamma elevation. Reduced reperfusion injury observed in RAG-1 knockout (KO) mice is restored to the wild-type (WT) level by adoptive transfer of NKT cells purified from WT or A2AR KO mice but not IFN-gamma KO mice. Additionally, animals with transferred A2AR-/- NKT cells are not protected from hepatic reperfusion injury by ATL146e. In vitro, ATL146e potently inhibits both anti-CD3 and alpha-galactosylceramide-triggered production of IFN-gamma by NKT cells. These findings suggest that hepatic reperfusion injury is initiated by the CD1d-dependent activation of NKT cells, and the activation of these cells is inhibited by A2AR activation.
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PMID:Adenosine A2A receptor activation reduces hepatic ischemia reperfusion injury by inhibiting CD1d-dependent NKT cell activation. 1708 33


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