Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.6.1.2 (alanine aminotransferase)
 26,722 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously studied the effect of three different treatment regimens with interferon (IFN)-alpha alone or in combination with amantadine or ribavirin on viral kinetics in the first month of therapy. To understand the regulation of cytokine immune response during early inhibition of HCV replication, we analysed the longitudinal profile of proinflammatory markers (soluble TNFRs), of type 1 cytokines [IFN-gamma and interleukin (IL-12)], and of a type 2 cytokine (IL-10). Twenty-two chronic hepatitis C patients received daily therapy for 6 months. Sera were collected at baseline, at 6, 12, 24, 30 and 48 h and at the 3rd, 7th, 15th and 30th days of treatment. All cytokines and receptors were evaluated by enzyme linked immunosorbent assay (ELISA). At baseline, a correlation was found between the two soluble TNFRs (P < 0.0001) and between the soluble TNFRs and ALT levels (P < 0.003), as shown previously. Regardless of the type of treatment, lower levels of soluble TNFR-p75 were present from day 3 in patients who had significant virus decay at day 30 (P < 0.01). Baseline IL-10 levels correlated with TNFR-p75 (P < 0.01) and with treatment response (P < 0.05) and a significant IL-10 reduction from baseline was observed from day 3 among responders, irrespective of the type of treatments (P < 0.05). IL-12 and IFN-gamma levels did not differ according to treatment or outcome. These findings suggest a pivotal role for IL-10 in orchestrating the antiviral immune response. Its early decline can favour the shift from a Th2 to a Th1 immune response, which has been shown to be associated with a long-term virological response to treatment.
 ...
PMID:Kinetics of soluble tumour necrosis factor (TNF)-alpha receptors and cytokines in the early phase of treatment for chronic hepatitis C: comparison between interferon (IFN)-alpha alone, IFN-alpha plus amantadine or plus ribavirin. 1514 53

Ginsan, a polysaccharide isolated from Panax ginseng, has been shown to be a potent immunomodulator, producing a variety of cytokines such as TNF-alpha, IL-1, IL-2, IL-6, IL-12, IFN-gamma and GM-CSF, and stimulating lymphoid cells to proliferate. In the present study, we analyzed some immune functions 1st-5th days after ginsan i.p. injection, including the level of non-protein thiols (NPSH) as antioxidants, heme oxygenase (HO) activity as a marker of oxidative stress, zoxazolamine-induced paralysis time and level of hepatic cytochrome P-450 (CYP450) as indices of drug metabolism system, and activities of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), total bilirubin, and albumin level as indicators of hepatotoxicity. Ginsan in the dose of 100 mg/kg caused marked elevation (1.7 to approximately 2 fold) of HO activity, decrease of total CYP450 level (by 20-34%), and prolongation of zoxazolamine-induced paralysis time (by 65-70%), and showed some differences between male and female mice. Ginsan treatment did not seem to cause hepatic injury, since serum AST, ALT, and ALP activities and levels of total bilirubin and albumin were not changed.
 ...
PMID:Effects of polysaccharide ginsan from Panax ginseng on liver function. 1520 59

Recurrent hepatitis C virus (HCV) infection after orthotopic liver transplantation (OLT) is nearly universal. Cytokines play an important role in the immune response to viral infection, and cytokine gene polymorphism affects the overall expression and secretion of cytokines. The objective of this study was to define the relationship between cytokine polymorphism and recurrent hepatitis C after OLT. Blood samples were collected from 36 patients at a mean of 44.6+/-30.4 months after OLT for chronic HCV infection. DNA was extracted from peripheral blood mononuclear cells, and polymerase chain reaction-sequence specific primers (PCR-SSP) analysis was performed on promoter sequences of transforming growth factor beta1 (TGF-beta1), interleukin 6 (IL-6) interleukin 10 (IL-10), tumor necrosis factor alpha (TNF-alpha) and interferon gamma (INF-gamma). Liver biopsies performed at diagnosis of recurrent disease were graded with the Knodell score, and hepatic TGF-beta1 expression was determined semiquantitatively by immunohistochemistry. The gene polymorphism of TGF-beta1 was correlated with its expression on hepatocytes and sinusoids. Polymorphism in all studied cytokine genes was correlated with recurrence, and interval to recurrence (>12 or < or =12 months post-OLT), and clinical (ascites, Child-Pugh score and death), biochemical parameters of recurrent HCV (serum alanine aminotransferase (ALT)), INR, albumin, bilirubin), and virological parameters (HCV genotype and load). Biopsies revealed recurrent HCV in 31 patients (86.1%); in 21 (67.7%), the interval to recurrence was 12 months. There was a statistically significant correlation between TGF-beta1 gene polymorphism, i.e., the genetic ability to produce high levels of TGF-beta1, and the intensity of TGF-beta1 staining on hepatocytes (p=0.003) and sinusoids (p=0.003), and the degree of fibrosis (p=0.02). A borderline correlation was found with the presence of ascites (p=0.007), but not with Child-Pugh score, synthetic liver function tests or HCV genotype and load. The genetic ability to produce low levels of IFN-gamma was correlated with recurrent disease (p=0.015). No such correlation was found for TGF-beta1 gene polymorphism. In conclusion, polymorphism in the TGF-beta1 gene correlates with its in situ hepatic expression in patients with recurrent HCV after liver transplantation. INF-gamma, but not TGF-beta1 gene polymorphism, correlates with early recurrent hepatitis C after transplantation. These findings might help to design preemptive prevention therapy in selected patients at risk.
 ...
PMID:Role of cytokine gene polymorphism and hepatic transforming growth factor beta1 expression in recurrent hepatitis C after liver transplantation. 1520 46

IFN-alpha/beta-mediated functions promote production of MIP-1alpha (or CCL3) by mediating the recruitment of MIP-1alpha-producing macrophages to the liver during early infection with murine CMV. These responses are essential for induction of NK cell inflammation and IFN-gamma delivery to support effective control of local infection. Nevertheless, it remains to be established if additional chemokine functions are regulated by IFN-alpha/beta and/or play intermediary roles in supporting macrophage trafficking. The chemokine MCP-1 (or CCL2) plays a distinctive role in the recruitment of macrophages by predominantly stimulating the CCR2 chemokine receptor. Here, we examine the roles of MCP-1 and CCR2 during murine CMV infection in liver. MCP-1 production preceded that of MIP-1alpha during infection and was dependent on IFN-alpha/beta effects for induction. Resident F4/80(+) liver leukocytes were identified as primary IFN-alpha/beta responders and major producers of MCP-1. Moreover, MCP-1 deficiency was associated with a dramatic reduction in the accumulation of macrophages and NK cells, as well as decreased production of MIP-1alpha and IFN-gamma in liver. These responses were also markedly impaired in mice with a targeted disruption of CCR2. Furthermore, MCP-1- and CCR2-deficient mice exhibited increased viral titers and elevated expression of the liver enzyme alanine aminotransferase in serum. These mice also had widespread virus-induced liver pathology and succumbed to infection. Collectively, these results establish MCP-1 and CCR2 interactions as factors promoting early liver inflammatory responses and define a mechanism for innate cytokines in regulation of chemokine functions critical for effective localized antiviral defenses.
 ...
PMID:Monocyte chemoattractant protein-1 and CCR2 interactions are required for IFN-alpha/beta-induced inflammatory responses and antiviral defense in liver. 1566 15

Activation of the A2A adenosine receptor (A(2A)R) during reperfusion of various tissues has been found to markedly reduce ischemia-reperfusion injury. In this study, we used bone marrow transplantation (BMT) to create chimeric mice that either selectively lack or selectively express the A(2A)R on bone marrow-derived cells. Bolus i.p. injection of the selective A2A agonist, 4-[3-[6-amino-9-(5-cyclopropylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl]-piperidine-1-carboxylic acid methyl ester (ATL313; 3 microg/kg), at the time of reperfusion protects wild-type (wt) mice from liver ischemia-reperfusion injury. ATL313 also protects wt/wt (donor/recipient BMT mouse chimera) and wt/knockout chimera but produces modest protection of knockout/wt chimera as assessed by alanine aminotransferase activity, induction of cytokine transcripts (RANTES, IFN-gamma-inducible protein-10, IL-1alpha, IL-1-beta, IL-1Ralpha, IL-18, IL-6, and IFN-gamma), or histological criteria. ATL313, which is highly selective for the A(2A)R, produces more liver protection of chimeric BMT mice than 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, which is rapidly metabolized in mice to produce 4-[3-[6-amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl]-cyclohexanecarboxylic acid, which has similar affinity for the A(2A)R and the proinflammatory A3 adenosine receptor. GFP chimera mice were created to show that vascular endothelial cells in the injured liver do not account for liver protection because they are not derived by transdifferentiation of bone marrow precursors. The data suggest that activation of the A(2A)R on bone marrow-derived cells is primarily responsible for protecting the liver from reperfusion injury.
 ...
PMID:A2A adenosine receptors on bone marrow-derived cells protect liver from ischemia-reperfusion injury. 1581 35

Concanavalin A (Con A)-induced hepatitis has been investigated as a model of T cell-mediated liver injury, in which IFN-gamma plays an essential role by inducing apoptosis of liver cells. Since a large number of neutrophils infiltrate into the liver in the model, the role of neutrophils was investigated in this study. Con A hardly caused liver injury in neutrophil-depleted mice, as assessed as to the plasma alanine aminotransferase level as well as histochemistry. Neutrophil-depleted mice also failed to produce IFN-gamma. Intracellular IFN-gamma staining revealed that, among liver leukocytes, T and NK cells but not neutrophils are the main producers of IFN-gamma. Nylon wool-purified "T cells", however, failed to produce IFN-gamma in response to Con A in vitro, while the production was restored by the addition of neutrophils. Overall, this study suggests that neutrophils play a novel accessory role in IFN-gamma production in Con A-induced hepatitis.
 ...
PMID:A novel accessory role of neutrophils in concanavalin A-induced hepatitis. 1589 98

Concanavalin A (ConA) induces natural killer T (NKT) cell-mediated liver damage. Glucocerebroside (GC) is a naturally occurring glycolipid. Our aims were to determine the effect of GC in a murine model of ConA-induced hepatitis. Mice in groups A and B were treated with GC 2 h before and 2 h following administration of ConA, respectively; group C mice were treated with ConA; group D mice was treated with GC; group E mice did not receive any treatment. Liver damage was evaluated by serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels and liver histology. The immune effect of GC was determined by fluorescence-activated cell sorter analysis of intrahepatic and intrasplenic NKT lymphocytes, measurement of cytokine levels, and Western blot analysis for STAT 1, 4, 6, and NF-kappaB expression. The effect of GC on NKT cell proliferation was assessed in vitro. Serum AST and ALT levels were markedly reduced in GC-treated group A mice compared with nontreated group C animals, and histological damage was markedly attenuated in group A. The beneficial effect of GC was associated with a 20% decrease of intrahepatic NKT lymphocytes, significant lowering of serum IFN-gamma levels, and decreased STAT1 and STAT6 expression. In vitro administration of GC led to a 42% decrease of NKT cell proliferation in the presence of dendritic cells but not in their absence. Intraperitoneally administered radioactive GC was detected in the liver and bowel. Administration of GC led to amelioration of ConA hepatitis associated with an inhibitory effect on NKT lymphocytes. GC holds promise as a new immune-modulatory agent.
 ...
PMID:Glucocerebroside treatment ameliorates ConA hepatitis by inhibition of NKT lymphocytes. 1597 88

Group A streptococcus (GAS) infection can cause severe invasive diseases, including necrotizing fasciitis and streptococcal toxic shock syndrome. Cordyceps sinensis, a Chinese herbal medicine, is an immunomodulator. In this study the air-pouch bacterial inoculation model was used to investigate the protective efficacy of C. sinensis mycelium extract against GAS infection. Force-feeding mice with C. sinensis mycelium extract for 3 consecutive days before GAS infection increased the survival rate and reduced local skin-tissue injury compared with mice fed PBS. Bacterial numbers in the air pouch exudates from C. sinensis-treated mice were lower than those from PBS-treated mice. Blood and organs in PBS-treated mice showed bacterial dissemination, but those in C. sinensis-treated mice did not. Three days of pretreatment with C. sinensis extract followed by C. sinensis treatment every other day after GAS infection resulted in 100% survival. The post-GAS-infection levels of aspartate aminotransferase, alanine aminotransferase and blood urea nitrogen in the sera of C. sinensis-treated mice were lower than those of PBS-treated mice. Taken together, these results show that C. sinensis mycelium extract protects by decreasing bacterial growth and dissemination, thereby increasing mouse survival rate. IL-12 and IFN-gamma expression and macrophage phagocytic activity also increased after C. sinensis treatment.
 ...
PMID:Cordyceps sinensis mycelium protects mice from group A streptococcal infection. 1601 34

Gamma interferon (IFN-gamma) has been shown to inhibit replication of subgenomic and genomic hepatitis C virus (HCV) RNAs in vitro and to noncytolytically suppress hepatitis B virus (HBV) replication in vivo. IFN-gamma is also known for its immunomodulatory effects and as a marker of a successful cellular immune response to HCV. Therapeutic expression of IFN-gamma in the liver may therefore facilitate resolution of chronic hepatitis C, an infection that is rarely resolved spontaneously. To analyze immunomodulatory and antiviral effects of liver-specific IFN-gamma expression in vivo, we intravenously injected two persistently HCV-infected chimpanzees twice with a recombinant, replication-deficient HBV vector and subsequently with a recombinant adenoviral vector. These vectors expressed human IFN-gamma under control of HBV- and liver-specific promoters, respectively. Gene transfer resulted in a transient increase of intrahepatic IFN-gamma mRNA, without increase in serum alanine aminotransferase levels. Ex vivo analysis of peripheral blood lymphocytes demonstrated enhanced CD16 expression on T cells and upregulation of the liver-homing marker CXCR3. Moreover, an increased frequency of HCV-specific T cells was detected ex vivo in the peripheral blood and in vitro in liver biopsy-derived, antigen-nonspecifically expanded T-cell lines. None of these immunologic effects were observed in the third chimpanzee injected with an HBV control vector. Despite these immunologic effects of the experimental vector, however, IFN-gamma gene transfer did not result in a significant and long-lasting decrease of HCV titers. In conclusion, liver-directed IFN-gamma gene delivery resulted in HCV-specific and nonspecific activation of cellular immune responses but did not result in effective control of HCV replication.
 ...
PMID:Liver-directed gamma interferon gene delivery in chronic hepatitis C. 1622 62

P-selectin glycoprotein ligand-1 (PSGL-1) mediates the initial tethering of leukocytes to activated platelets and endothelium. We report molecular cloning and characterization of the rat PSGL-1 gene. A neutralizing Ab was generated, and its binding epitope was mapped to the N-terminal binding region of rat PSGL-1. We examined the effects of early PSGL-1 blockade in rat liver models of cold ischemia, followed by ex vivo reperfusion or transplantation (orthotopic liver transplantation (OLT)) using an anti-PSGL-1 Ab with diminished Fc-mediated effector function. In the ex vivo hepatic cold ischemia and reperfusion model, pretreatment with anti-PSGL-1 Ab improved portal venous flow, increased bile production, and decreased hepatocellular damage. Rat pretreatment with anti-PSGL-1 Ab prevented hepatic insult in a model of cold ischemia, followed by OLT, as assessed by 1) decreased hepatocellular damage (serum glutamic oxaloacetic transaminase/glutamic-pyruvic transaminase levels), and ameliorated histological features of ischemia/reperfusion injury, consistent with extended OLT survival; 2) reduced intrahepatic leukocyte infiltration, as evidenced by decreased expression of P-selectin, ED-1, CD3, and OX-62 cells; 3) inhibited expression of proinflammatory cytokine genes (TNF-alpha, IL-1beta, IL-6, IFN-gamma, and IL-2); and 4) prevented hepatic apoptosis accompanied by up-regulation of antiapoptotic Bcl-2/Bcl-xL protective genes. Thus, targeting PSGL-1 with a blocking Ab that has diminished Fc-mediated effector function is a simple and effective strategy that provides the rationale for novel therapeutic approaches to maximize the organ donor pool through the safer use of liver transplants despite prolonged periods of cold ischemia.
 ...
PMID:Molecular characterization of rat leukocyte P-selectin glycoprotein ligand-1 and effect of its blockade: protection from ischemia-reperfusion injury in liver transplantation. 1636 57


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>