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 proto-oncogene product bcl-2 is known to inhibit apoptotic cell death, and its dysregulation might play a critical role in the development of autoimmune disease. To elucidate the role of bcl-2 in autoimmune hepatitis (AIH), its expression in peripheral blood mononuclear cells (PBMC) and in liver-infiltrating lymphocytes (LIL) was investigated. Increased bcl-2 expression in PBMC was found in AIH patients compared with that in chronic hepatitis C (CHC) patients and in healthy controls. The level of bcl-2 expression significantly correlated with serum ALT level. Further analysis showed that CD4+ T cells are enriched in bcl-2-expressing PBMC. To characterize the Th1/Th2 profile of bcl-2-expressing CD4+ T cells, intracellular interferon-gamma (IFN-gamma) and IL-4 were analysed. The results revealed that most of the bcl-2-expressing cells were found to be IFN-gamma-secreting Th1 cells. In three patients for whom their clinical courses could be followed, bcl-2 expression was decreased after the initiation of immunosuppressive therapy with corticosteroids. However, the level of IFN-gamma + cells was not altered. Immunohistochemical analysis also showed that large amounts of bcl-2+ cells were observed in periportal area in the liver. In conclusion, bcl-2-expressing cells were shown to be increased in peripheral blood and liver in AIH and the bcl-2 product was expressed mainly in CD4+ Th1-type cells, suggesting that these cells might promote the cellular immune response and contribute to the development of hepatitis and hepatocellular damage in AIH.
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PMID:Increased bcl-2 expression in lymphocytes and its association with hepatocellular damage in patients with autoimmune hepatitis. 1020 18

The effect of dietary administration of cholic acid on tumorigenesis in the liver was investigated in male Fischer-344 rats after carcinogenic initiation by diethylnitrosamine (DEN); progression of liver tumors was examined in the rats fed 0.4% cholic acid-containing diet (CA group) and the rats fed standard diet (C group) at 15, 20 and 25 weeks after administration of DEN. The total bile acids and cholic acid in serum of CA group were 150 nmol/ml and 117 nmol/ml, being 31-fold and 51-fold higher than those in C group (p<0.0001, each). Serum AST and ALT were significantly higher in CA group than in C group at 15 weeks (p<0.01). Serum ALP was significantly higher in CA group than C group at each time point (p<0.01, each). Liver tumors, whose histology was hepatocellular carcinoma, developed at 15 weeks in both CA and C groups. However, tumor volume and tumor weight were significantly increased in CA group, compared to those in C group at each time point (p<0.001, p<0. 001, p<0.01, p<0.001, p<0.01 and p<0.05). The percentage of apoptotic cells in CA group at each time point was significantly lower than C group (p<0.05, p<0.01 and p<0.05). The percentage of bcl-2 positive tumor cells in C group at 20 weeks was 1.88+/-2.59%. However, it dramatically increased to 34.00+/-13.67% in CA group (p<0.0001). It was also higher in CA group than in C group at 15 and 25 weeks (p<0.05 and p<0.01). In addition, the bax-positive cells were higher in CA group than in C group at 20 weeks (p<0.05). These data suggest that oral administration of cholic acid promotes liver tumorigenesis initiated by DEN through reducing apoptosis mediated by overexpression of bcl-2.
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PMID:Oral administration of cholic acid promotes growth of liver tumors initiated by diethylnitrosamine in rats. 1040 35

The protein BCL-X(L) and protein product of proto-oncogene bcl-2 act as apoptosis antagonists, and BCL-X(S) serve as a dominant death promoter, including apoptosis following exposure to chemotherapeutic drugs. This investigation examined whether some aspects of the highly integrated process of acetaminophen (AAP)-induced hepatotoxicity involve down-regulation or upregulation of expression of BCL-2, BCL-X(L) and BCL-X(S) in mouse liver in vivo. Male ICR mice (CD-1; 35-45 g) were treated ip with a hepatotoxic dose of AAP (500 mg/kg) and sacrificed 0, 6, and 18 h later. Blood was collected upon sacrifice for determination of serum alanine aminotransferase (ALT) activity and the liver was sectioned for histopathological diagnosis of necrosis/apoptosis. Portions of liver tissues were also used for DNA extraction (for gel electrophoresis) and Western blot analysis. This study demonstrates that administration of a hepatotoxic dose of AAP to ICR mice results in severe liver injury (ALT leakage >200-fold at 6 h and >600-fold at 18 h) leading to massive cell death by apoptosis (diagnosed by nuclear ultrastructure, histopathology, and DNA ladder), in addition to necrosis coupled with spectacular changes in the BCL-X(L) expression (6 and 18 h after AAP administration). Western blot analysis of the liver proteins revealed that mouse liver expresses two proteins, BCL-X(L) and BCL-X(S), and does not express BCL-2. As the toxicity progressed, during 6 and 18 h post-AAP administration, the BCL-X(L) protein band shifted to a slower mobility band which might represent a phosphorylated form of BCL-X(L). Appearance of this higher molecular weight BCL-X(L) protein band correlated with massive apoptotic death of liver cells along with ladder-like DNA fragmentation. In the same time period, death inhibitory gene bcl-2 remained unexpressed, and the level of expression of BCL-X(S) remained unaltered. Whether the consistent level of expression of BCL-X(S) reflected inability of AAP to influence its expression remains unknown. Unaltered expression of BCL-X(S) in the near total absence of BCL-2 expression raises questions regarding the death promoting role of BCL-X(S) in vivo. The precise role of modified form of BCL-X(L) remains elusive. However, this study may have demonstrated for the first time drug-induced changes in the expression of anti-apoptotic gene BCL-X(L), and a positive link between AAP-induced apoptotic death and modification of BCL-X(L) protein in vivo.
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PMID:A hepatotoxic dose of acetaminophen modulates expression of BCL-2, BCL-X(L), and BCL-X(S) during apoptotic and necrotic death of mouse liver cells in vivo. 1066 92

Mitochondria play an important role in the cell death induced by many drugs, including hepatotoxicity from overdose of the popular analgesic, acetaminophen (APAP). To investigate mitochondrial alterations associated with APAP-induced hepatotoxicity, the subcellular distribution of proapoptotic BAX was determined. Based on the antiapoptotic characteristics of BCL-2, we further hypothesized that if a BAX component was evident then BCL-2 overexpression may be hepatoprotective. Mice, either with a human bcl-2 transgene (-/+) or wild-type mice (WT; -/-), were dosed with 500 or 600 mg/kg (i.p.) APAP or a nonhepatotoxic isomer, N-acetyl-m-aminophenol (AMAP). Immunoblot analyses indicated increased mitochondrial BAX-beta content very early after APAP or AMAP treatment. This was paralleled by disappearance of BAX-alpha from the cytosol of APAP treated animals and, to a lesser extent, with AMAP treatment. Early pathological evidence of APAP-induced zone 3 necrosis was seen in bcl-2 (-/+) mice, which progressed to massive panlobular necrosis with hemorrhage by 24 h. In contrast, WT mice dosed with APAP showed a more typical, and less severe, centrilobular necrosis. AMAP-treated bcl-2 (-/+) mice displayed only early microvesicular steatosis without progression to extensive necrosis. Decreased complex III activity, evident as early as 6 h after treatment, correlated well with plasma enzyme activities at 24 h (AST r(2) = 0.89, ALT r(2) = 0.87) thereby confirming a role for mitochondria in APAP-mediated hepatotoxicity. In conclusion, these data suggest for the first time that BAX may be an early determinant of APAP-mediated hepatotoxicity and that BCL-2 overexpression unexpectedly enhances APAP hepatotoxicity.
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PMID:Enhanced acetaminophen hepatotoxicity in transgenic mice overexpressing BCL-2. 1164 18

Apoptosis dysfunction in metastases has been suggested to participate in their poor response to conventional anticancer treatments. To address this question, we have analyzed the sensitivity to cell death induced by non-steroid anti-inflammatory drug, Sulindac, the most common drug used in colon cancer chemotherapy, 5-fluorouracil (5-FU) and the short chain fatty acid, butyrate (Bu) in cell lines derived from a primary colorectal tumor (ALT-I) as well as the liver (ALT-F) and the lymph-node (ALT-G) metastases. We have previously shown both in vitro by analyzing anchorage-independent cell proliferation and in vivo by subcutaneous injection into athymic nude mice that the ALT-F and ALT-G cells were more tumorigenic than the primary ALT-I cells. All these cell lines, derived from an untreated patient, were highly resistant to apoptosis induced by 5-FU and Sulindac but were sensitive to Bu-induced apoptosis. The resistance to apoptosis was, as quantified by the induction of caspase activity and the relative percentage of apoptotic cells, higher in the metastatic cell lines, than in the ALT cell line. When compared to the primary tumor, more anti-apoptotic bcl-2 and less pro-apoptotic bax were expressed in the liver and lymph node metastatic cell lines. Quite remarkably, the expression of bax was up-regulated during Bu-treatment, a feature that could explain its powerful pro-apoptotic activity.
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PMID:Resistance to apoptosis is increased during metastatic dissemination of colon cancer. 1196 82

The maximum gene exhibition was shown to be achieved at 48 h after transfection with human bcl-2 (hbcl-2) genes built in an SV40 early promoter-based plasmid vector and HVJ-liposome for cultured rat hepatocytes. The similar procedure of hbcl-2 transfection was therefore conducted for livers in rats via the portal vein, and after 48 h followed by post-ischemic reperfusion (I/R) operation for some hepatic lobes. The I/R-induced hepatic injuries were in situ observed as both cell morphological degeneration and cellular DNA strand cleavages around capillary vessels of the ischemic liver lobes as detected by HE stain and TUNEL assay, and were biochemically observed as release of two hepatic marker enzymes AST and ALT into serum. All the I/R-induced injuries examined were appreciably repressed for rats transfected with hbcl-2; hbcl-2 was expressed in hepatocytes around the capillaries of ischemic regions such as the median lobe and the left lobe, but scarcely around those of non-ischemic regions. Thus cytoprotection against I/R-induced injuries may be attributed to the I/R-promoted expression of transferred hbcl-2 genes. The possibility was examined firstly by methylphenylindole method, which showed that I/R-enhanced lipid peroxidation in the reference vector-transfected livers were markedly repressed in the hbcl-2-transfected livers. Contents of ascorbic acid (Asc) in serum and livers of hbcl-2-transfected rats were enriched, unexpectedly, versus those of non-transfected rats, and were as abundant as 1.90-fold and 1.95- to 2.60-fold versus those in the pre-ischemic state, respectively. After I/R, an immediate decline in serum Asc occurred in hbcl-2-transfectants, and was followed by prompt restoration up to the pre-ischemic Asc levels in contrast to the unaltered lower Asc levels in non-transfectants except a transient delayed increase. Hepatic Asc contents were also diminished appreciably at the initial stage after I/R in the ischemic lobes of hbcl-2-transfectants, which however retained more abundant Asc versus non-transfectants especially at the initial I/R stage when scavenging of the oxidative stress should be most necessary for cytoprotection. The results showed a close correlation between cytoprotection by exogenously transferred hbcl-2 and repressive effects on the lipid peroxidation associated with Asc consumption or redistribution.
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PMID:Cytoprotection by bcl-2 gene transfer against ischemic liver injuries together with repressed lipid peroxidation and increased ascorbic acid in livers and serum. 1544 23

Puerarin is a major isoflavonoid compound isolated from Pueraria lobata, an edible vine used widely for various medicinal purposes. It has been used for centuries in China to counteract alcohol intoxication. However, the effects of puerarin on chemical-induced liver fibrosis have not been reported. In the present study, we investigated the effects of puerarin on liver fibrosis in Wistar rats induced by alcohol plus carbon tetrachloride administration. Liver fibrosis was produced in rats by treatment with a mixture (50% alcohol, 8 g/kg per day; corn oil, 2 g/kg per day; pyrazole, 24 mg/kg per day; ig) once a day and by intraperitoneal injection of 0.25 ml/kg of a 25% solution of carbon tetrachloride in olive oil twice a week for 8 weeks. After 8 weeks, treatment with puerarin (0.4 and 0.8 g/kg ig, daily for 4 weeks) was conducted to examine its therapeutic effects. At the same time, the model group and treatment group continued to receive the chemical mixture, while the control group received saline instead of the chemical mixture. Upon pathological examination, the puerarin-treated rats significantly reversed the symptoms of liver fibrosis and other hepatic lesions. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), as indexes of hepatic cell disruption, were reduced with puerarin treatment, whereas no significant effect was discovered in the levels of alkaline phosphatase (ALP) and gamma-glutamyltransferase (GGT) activities. A significant increase in apoptosis of activated hepatic stellate cell (HSC) was found by flow cytometric analysis of the hepatic tissues. And the expression of bcl-2 mRNA was down-regulated after puerarin administration. Consequently, all these results showed that puerarin could effectively reverse chemical-induced liver fibrosis in experimental rats, via the recovery of hepatic injury as well as the induction of apoptosis in activated HSC.
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PMID:Reversal of chemical-induced liver fibrosis in Wistar rats by puerarin. 1642 32

Cytokines have been implicated in the progression of acetaminophen (APAP)-induced acute liver injury. Suppressors of cytokine signaling (SOCS) proteins are negative regulators of cytokine signaling by inhibiting the JAK-STAT pathway, but their role in APAP hepatotoxicity is unknown. In this present study, we attempted to explore the role of SOCS3 in T cells in APAP-induced liver injury. Mice with a cell-specific overexpression of SOCS3 in T cells (SOCS3Tg, in which Tg is transgenic) exhibited exaggerated hepatic injury after APAP challenge, as evidenced by increased serum alanine aminotransferase levels, augmented hepatic necrosis, and decreased survival relative to the wild-type mice. Adaptive transfer of SOCS3Tg-CD4(+) T cells into T and B cell-deficient RAG-2(-/-) mice resulted in an exacerbated liver injury relative to the control. In SOCS3Tg mice, hepatocyte apoptosis was enhanced with decreased expression of antiapoptotic protein bcl-2, whereas hepatocyte proliferation was reduced with altered cell cycle-regulatory proteins. Levels of IFN-gamma and TNF-alpha in the circulation were augmented in SOCS3Tg mice relative to the control. Studies using neutralizing Abs indicated that elevated IFN-gamma and TNF-alpha were responsible for the exacerbated hepatotoxicity in SOCS3Tg mice. Activation of STAT1 that is harmful in liver injury was augmented in SOCS3Tg hepatocytes. Alternatively, hepatoprotective STAT3 activation was decreased in SOCS3Tg hepatocytes, an event that was associated with augmented SOCS3 expression in the hepatocytes. Altogether, these results suggest that forced expression of SOCS3 in T cells is deleterious in APAP hepatotoxicity by increasing STAT1 activation while decreasing STAT3 activation in hepatocytes, possibly through elevated IFN-gamma and TNF-alpha.
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PMID:Overexpression of suppressor of cytokine signaling-3 in T cells exacerbates acetaminophen-induced hepatotoxicity. 1733 76

First-generation adenoviral (Ad) vectors are frequently used vectors for experimental and clinical gene transfer. Earlier it has been shown that parallel overexpression of the cell cycle regulator p21(Waf1/Cip1) (p21) or antiapoptotic bcl-2 from a second vector reduces cytotoxicity and improves transgene expression. Here, we investigate whether the co-expression of p21 and alpha(1)-antitrypsin from a single vector improves vector safety and alpha(1)-antitrypsin expression. Cell lines (A549 and HeLa) and primary cells (small airway epithelial cells and hepatocytes) were infected with adenovirus vectors transducing alpha(1)-antitrypsin with (AdCMV.p21-RSV.hAAT) or without (AdRSV.hAAT) p21. alpha(1)-Antitrypsin expression and cytotoxicity were analyzed using western blot/ELISA and LDH/ALT/AST assays, respectively. Cell cycle profiles were determined by flow cytometry. Co-expression of p21 strongly increased the alpha(1)-antitrypsin expression in all cell types and at all doses tested. No changes in ALT/AST from hepatocytes and only minor increases in the LDH release in A549 and HeLa were observed with either vector. Cell cycle profiles were also not affected adversely. Incorporation of p21 in Ad vectors together with a gene of interest improves the vector performance; such vectors will allow the application of lower doses and thereby reduce immunological side effects.
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PMID:Co-expression of p21(Waf1/Cip1) in adenovirus vectors improves expression of a second transgene. 1922 50

Mitomycin C (MMC) potently suppresses tumour growth. However, its use is limited by its severe toxicity to the kidney and bone marrow. The purpose of this study is to investigate whether the chemoprevention agent curcumin can reduce MMC-associated side-effects and improve MMC efficacy in a breast cancer xenograft model. We first determined the effectiveness of combined MMC and curcumin to inhibit in vitro cell growth and to regress in vivo tumour outgrowth. We then investigated the mechanisms associated with MMC/curcumin-induced cell death by examining the effect of MMC/curcumin treatment on apoptosis, the activation of caspase-3, 8 and 9 and the expression of bcl-2 and bax. We also evaluated the ability of curcumin to alleviate MMC-associated side-effects by comparing the levels of creatinine/blood urea nitrogen (Cr/BUN) and glutamic oxalacetic transaminase/glutamic pyruvic transaminase (GPT/GOT) in serum between animals receiving MMC alone and MMC/curcumin. Curcumin significantly sensitised MCF-7 and MDA-MB-231 cells to MMC-induced cell death and improved MMC's ability to regress MCF-7 xenograft. MMC and curcumin together synergistically enhanced apoptosis in MCF-7 cells and the apoptosis most likely resulted from both the activation of caspases and modulation of bcl-2/bax expression. Most importantly, the inclusion of curcumin in MMC treatment decreased MMC-caused severe side-effects evidenced by significant improvement in the kidney function. Enhancing the tumoricidal effect of MMC, curcumin greatly reduces MMC-associated severe side-effects. Therefore, the combination treatment of MMC and curcumin may be of significant therapeutic benefit in treating breast cancer.
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PMID:Curcumin improves MMC-based chemotherapy by simultaneously sensitising cancer cells to MMC and reducing MMC-associated side-effects. 2161 59


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