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)

The Fas receptor (APO-1/CD95) is expressed on hepatocytes and is thought to be important in triggering apoptosis after ligation by the Fas ligand carried on cytotoxic T cells. Recent evidence has shown that several splice variants of Fas exist, the major one of which (FasTMDel) may produce a soluble protein which can modulate apoptosis by interacting with ligand. There are no data on the expression of splice variants of Fas in liver disease. RNA was extracted from needle biopsies from 13 patients with hepatitis C virus (HCV) infection and six normal liver samples. By reverse transcriptase polymerase chain reaction (RT-PCR) FasTMDel expression was demonstrated at the mRNA level, in both normal and HCV-infected liver. Quantitative PCR demonstrated an increase in Fas transcript relative to FasTMDel in HCV infection. This difference is due to an induction of Fas, with FasTMDel remaining at constant levels in the two groups. If translated into protein, liver cells may express more Fas and thus be susceptible to apoptosis inducible by ligand-bearing cytotoxic T cells. These findings suggest that mechanisms exist to regulate the differential splicing of Fas and FasTMDel dependent on the cell's environment. The degree of alteration in the levels of Fas relative to FasTMDel occurred independently of the ALT levels and histological grading of the HCV-infected cases. However, an association was noted between increasing Fas:FasTMDel ratio and log viral load in the liver, measured by competitive PCR.
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PMID:Alteration in mRNA levels of Fas splice variants in hepatitis C-infected liver. 942 85

We studied whether the infection with a blood-stage murine malaria lethal Plasmodium berghei NK65 induces IL-12 production, and if so, how the IL-12 production is involved in the protection or pathogenesis. The infection of C57BL/6 mice enhanced mRNA expression of IL-12 p40 and also IFN-gamma, IL-4, and IL-10 in both spleen and liver during the early course of the infection. It also enhanced the mRNA expression of TNF-alpha, Fas ligand, and cytokine-inducible nitric oxide synthase. Increased IL-12 p40 production was also observed in the culture supernatant of spleen cells and in sera of infected mice. In addition, the infection caused massive liver injury with elevated serum glutamic-oxaloacetic transaminase and serum glutamic-pyruvic transaminase activities and body weight loss. Treatment of these infected mice with neutralizing mAb against IL-12 prolonged the survival and diminished the liver injury with reduced elevation of serum serum glutamic-oxaloacetic transaminase and serum glutamic-pyruvic transaminase activities and decreased body weight loss. However, the anti-IL-12 treatment did not affect parasitemia, and all these mice eventually died. Similar results were obtained when infected mice were treated with neutralizing mAb against IFN-gamma. Moreover, anti-IL-12 treatment greatly reduced the secretion and mRNA expression of IFN-gamma in both spleen and liver. These results suggest that the lethal P. berghei NK65 infection induces IL-12 production and that the IL-12 is involved in the pathogenesis of liver injury via IFN-gamma production rather than the protection.
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PMID:A pathogenic role of IL-12 in blood-stage murine malaria lethal strain Plasmodium berghei NK65 infection. 960 53

The Fas ligand (FasL), a member of the tumor necrosis factor family, induces apoptosis in Fas-expressing cells. A matrix metalloproteinase-like enzyme cleaves the membrane-bound FasL to produce the soluble FasL (sFasL). Since FasL has been reported to play a pivotal role in the development of hepatitis, we evaluated clinical significance of serum sFasL in acute liver injury including acute self-limited and fulminant hepatitis. Serum sFasL in 19 patients including 12 with acute self-limited hepatitis and 7 with fulminant hepatitis was measured by an enzyme-linked immunosorbent assay (ELISA). The clinical data consisted of 18 indices including age, sex, liver function tests, hepatocyte growth factor (HGF), outcome and sFasL. Serum sFasL in fulminant hepatitis is 0.06+/-0.01 ng/ml, being identical to that in acute self-limited hepatitis, Serum sFasL is positively correlated with AST and ALT (p<0.0001 and p<0.0001). The factors associated with outcome of the patients were HGF, albumin, prothrombin time, platelet count, cholinesterase and leukocyte count in this order. Serum sFasL serves as an indicator of liver injury in acute self-limited and fulminant hepatitis.
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PMID:Clinical significance of serum soluble Fas ligand in patients with acute self-limited and fulminant hepatitis. 975 39

We investigated the significance of interleukin (IL)-18 levels in the pathophysiology of haemophagocytic lymphohistiocytosis (HLH). IL-18 levels were significantly elevated in all nine patients with active HLH compared with those of healthy controls. Serial determination of IL-18 levels in three cases, showed a gradual decrease compared with those of IL-12, interferon (IFN)-gamma or soluble Fas ligand (sFasL) in the course of clinical improvement, and seemed to be elevated until complete disappearance of disease activity. IL-18 and IFN-gamma (CC 0.711, P = 0.018), and IFN-gamma and sFasL (CC 0.849, P = 0.0049) levels were significantly correlated. On the other hand, correlation between IL-12 and IFN-gamma, IL-18 and sFasL, or IL-18 and IL-12 was not observed. IL-18, IFN-gamma and sFasL levels significantly correlated with disease activity such as fever and alanine transaminase (ALT) levels. IL-18 mRNA expression was enhanced in spleen, but not in peripheral blood mononuclear cells (MNC), bone marrow MNC, liver from patients of active HLH, or the tumour from a patient with lymphoma-associated haemophagocytic syndrome (LAHS). These results suggest that IL-18 may play important roles in the pathogenesis of HLH, particularly through induction of Th1 cells. IL-18 measurement may be useful for the diagnosis and for the detection of smouldering disease activity.
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PMID:Oversecretion of IL-18 in haemophagocytic lymphohistiocytosis: a novel marker of disease activity. 1044 85

Cytotoxic T lymphocytes (CTLs) play an important role in the pathogenesis of viral hepatitis. We studied the expression of mRNAs of perforin and Fas ligand (Fas-L) in biopsy specimens from chronic hepatitis B (CHB) (15 cases) and hepatitis C (CHC) patients (13 cases). Both perforin and Fas-L mRNAs were detected in all cases of both CHB and CHC. No messages were detected in the control livers from two cases of fatty liver, a case of Gilbert's syndrome, and a case of Dubin-Johnson syndrome. Semiquantitative analysis revealed a positive correlation between the intensity of perforin and Fas-L mRNAs in both CHB and CHC. In CHB, the intensity of both perforin and Fas-L mRNAs showed a positive correlation with the histological activity and serum alanine aminotransferase level, while the correlation was not apparent in CHC. These results suggest that both perforin and Fas/Fas-L systems are involved in the pathogenesis of liver cell injury of CHB and CHC.
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PMID:Expression of perforin and Fas ligand mRNA in the liver of viral hepatitis. 1105 Dec 76

Immunity to allogeneic MHC Ags is weak in rodent livers, raising questions as to the mechanisms that might control responses in this organ. Infection with an adenovirus vector reveals that T cell-mediated immunity to nonself-Ags in the liver is self-limiting. Virus-induced liver injury decreases and coincides with disappearance of virus-specific CTL, concomitant to an increase of apoptotic T cells early after infection. But whereas death in CD4 cells is independent of Fas, perforin, and TNF-alpha, that of CD8 cells requires Fas and not perforin or TNF-alpha pathways. Fas ligand is expressed on liver-infiltrating cells, pointing to death by fratricide that causes almost complete disappearance of virus-specific CTL 4 wk after infection. CTL elimination is virus dose dependent, and high doses induced high alanine aminotransferase values, elevated expression of Fas ligand on CD8 cells, and increased CD8 cell migration into the infected liver.
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PMID:Fas-mediated apoptosis causes elimination of virus-specific cytotoxic T cells in the virus-infected liver. 1120 53

The role of mouse liver NK1.1 Ag(+) T (NKT) cells in the antitumor effect of alpha-galactosylceramide (alpha-GalCer) has been unclear. We now show that, whereas alpha-GalCer increased the serum IFN-gamma concentration and alanine aminotransferase activity in NK cell-depleted C57BL/6 (B6) mice and B6-beige/beige mice similarly to its effects in control B6 mice, its enhancement of the antitumor cytotoxicity of liver mononuclear cells (MNCs) was abrogated. Depletion of both NK and NKT cells in B6 mice reduced all these effects of alpha-GALCER: Injection of Abs to IFN-gamma also inhibited the alpha-GalCer-induced increase in antitumor cytotoxicity of MNCS: alpha-GalCer induced the expression of Fas ligand on NKT cells in the liver of B6 mice. Whereas alpha-GalCer did not increase serum alanine aminotransferase activity in B6-lpr/lpr mice and B6-gld/gld mice, it increased the antitumor cytotoxicity of liver MNCS: The alpha-GalCer-induced increase in survival rate apparent in B6 mice injected intrasplenically with B16 tumor cells was abrogated in beige/beige mice, NK cell-depleted B6 mice, and B6 mice treated with Abs to IFN-gamma. Depletion of CD8(+) T cells did not affect the alpha-GalCer-induced antitumor cytotoxicity of liver MNCs but reduced the effect of alpha-GalCer on the survival of B6 mice. Thus, IFN-gamma produced by alpha-GalCer-activated NKT cells increases both the innate antitumor cytotoxicity of NK cells and the adaptive antitumor response of CD8(+) T cells, with consequent inhibition of tumor metastasis to the liver. Moreover, NKT cells mediate alpha-GalCer-induced hepatocyte injury through Fas-Fas ligand signaling.
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PMID:Mechanisms of the antimetastatic effect in the liver and of the hepatocyte injury induced by alpha-galactosylceramide in mice. 1135 10

Epidemiological studies have established that heavy alcohol consumption in persons with chronic hepatitis C virus (HCV) infection is associated with advanced liver disease, including cirrhosis. The aims of this study were to evaluate the relationship between alcohol consumption and hepatocyte apoptosis in HCV-infected patients and to determine the role of Fas in HCV-mediated apoptosis. Liver tissue from 44 HCV-infected patients with variable alcohol consumption, and 10 normal control subjects who did not consume alcohol was examined for hepatocyte apoptosis, proliferation and Fas expression. Alcohol consumption was assessed using the 'Lifetime Drinking History' alcohol questionnaire. HCV RNA, alanine aminotransferase (ALT) and ferritin were also assessed in addition to demographic data. Hepatocyte apoptosis was significantly greater in HCV-infected patients compared to controls. Expression of Fas (CD95) was found in HCV patients but not in controls. The degree of Fas expression correlated with hepatocyte apoptosis as detected by terminal UTP nick end labelling (TUNEL). Active ethanol consumption led to a significant increase in hepatocyte apoptosis. Fas expression correlated with fibrosis in HCV-infected patients who were not actively drinking ethanol. In summary, HCV leads to increased apoptotic cell death in hepatocytes. Programmed cell death can be further up-regulated by active ethanol consumption. The correlation between Fas expression and TUNEL supports the hypothesis that the Fas-Fas ligand interaction is the major mechanism for HCV-induced hepatocyte apoptosis.
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PMID:Fas-mediated hepatocyte apoptosis is increased by hepatitis C virus infection and alcohol consumption, and may be associated with hepatic fibrosis: mechanisms of liver cell injury in chronic hepatitis C virus infection. 1170 71

M50054, 2,2'-methylenebis (1,3-cyclohexanedione), was identified as a novel inhibitor of apoptosis (programmed cell death) using an in vitro cell death assay system induced in human Fas-expressing WC8 cells by soluble human Fas ligand. Furthermore, M50054 inhibited the apoptotic cell death of U937, a human monocytic leukemic cell line, induced by anticancer agents such as etoposide; it was also confirmed that M50054 inhibited apoptotic features such as DNA fragmentation and phosphatidylserine exposure in these cells. These anti-apoptotic effects were attributable to inhibition of caspase-3 activation. Additionally, M50054 significantly inhibited anti-Fas-antibody-induced elevation of plasma alanine aminotransferase and aspartate aminotransferase. Alopecia (hair loss) symptoms were also significantly improved with topical treatment with M50054. In conclusion, M50054 inhibits apoptosis induced by a variety of stimuli via inhibition of caspase-3 activation, and may thus be effective for hepatitis and chemotherapy-induced alopecia.
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PMID:Inhibitory effect of M50054, a novel inhibitor of apoptosis, on anti-Fas-antibody-induced hepatitis and chemotherapy-induced alopecia. 1175 32

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/Apo2 ligand (Apo2L) has been identified as important in promoting programmed cell death in breast and colon cancer xenografts. More importantly, normal liver tissue appears not to be susceptible to the cytotoxic effects of TRAIL/Apo2L, although activation of the related Fas ligand receptor system is known to promote massive liver apoptosis terminating in fulminant hepatitis. In the present study, we investigated the therapeutic potential of TRAIL/Apo2L gene therapy in hepatocellular carcinoma (HCC) and evaluated its side effects in an immune-competent mouse model. Intratumoral administration of the TRAIL/Apo2L vector by electroporation elevated serum TRAIL/Apo2L through at least day 28 after gene therapy and significantly inhibited the growth not only of the HCC directly administered TRAIL/Apo2L vector, but also of distant subcutaneous HCC. In addition, intratumoral administration of the TRAIL/Apo2L vector inhibited spontaneous lung metastasis. Serum alanine aminotransferase was mildly elevated by TRAIL/Apo2L gene therapy, but without showing such histological signs as TUNEL staining. These results demonstrate that TRAIL/Apo2L gene therapy for HCC by electroporation in vivo is efficient without significant side effects, and is thus promising for use in future clinical trials.
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PMID:Electroporation-mediated tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/Apo2L gene therapy for hepatocellular carcinoma. 1181 83


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