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

---

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

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

Nuclear factor kappaB (NF-kappaB) has a central role in coordinating the expression of a wide variety of genes that control immune responses and is also recognized as an antiapoptotic transcription factor. Here, we focused on the role of the NF-kappaB signaling pathway in the interaction between inflammatory cells and hepatocytes in liver inflammation. We found that pretreatment of mice with adenoviruses expressing a mutant form of the inhibitor kappaB superrepressor (Ad5IkappaB), a NF-kappaB inhibitor, reduced the migration of inflammatory cells and cytokine and chemokine expression in the liver 12 hours after a single intravenous injection of an anti-CD40 antibody (alphaCD40) compared with mice infected with control adenoviruses (Ad5LacZ). We also confirmed reductions in cytokine production by macrophages, T cells, and natural killer (NK) cells in the liver of Ad5IkappaB-treated mice by FACS analysis. However, alphaCD40 treatment in Ad5IkappaB-infected mice induced elevation of serum alanine aminotransferase at 24 hours, and the liver injury was associated with massive hepatocyte apoptosis. Furthermore, interferon gamma (IFN-gamma) production by NK cells and T cells was increased and stimulated tumor necrosis factor alpha (TNF-alpha) production by macrophages in the Ad5IkappaB-infected liver. Moreover, the liver injury was completely suppressed by the administration of anti-IFN-gamma and anti-TNF-alpha. These results suggest that inhibition of NF-kappaB activity suppressed alphaCD40-induced liver inflammation at an early phase, resulting in a reduction in cytokine and chemokine production, whereas it sensitized hepatocytes to TNF-alpha-induced apoptosis and exacerbated liver injury at the late phase. In conclusion, NF-kappaB exerts pivotal activities at inflammatory sites, and caution should be exercised in NF-kappaB-targeted therapy of liver disease.
...
PMID:Pivotal role of nuclear factor kappaB signaling in anti-CD40-induced liver injury in mice. 1548 31

Fumonisin B1 (FB1) is a toxic and carcinogenic mycotoxin produced by Fusarium verticillioides found on corn worldwide. The biological effects of FB1 are attributed to sphingolipid metabolism disruption as a result of ceramide synthase inhibition. Tumor necrosis factor alpha (TNFalpha) is an important modulator of FB1 hepatotoxicity. Kupffer cells are major source of cytokine production in liver. In the present study we investigated the effects of Kupffer cell depletion by gadolinium on FB1 hepatotoxicity in female BALB/c mice. Mice were given saline or 50 mg/kg of gadolinium chloride once via the tail vein; 16 h later they were treated with subcutaneous injections of vehicle or 2.25 mg/kg/day FB1 in saline for three successive days. Gadolinium significantly attenuated FB1-induced increases in the activities of circulating alanine aminotransferase and aspartate aminotransferase and reduced the FB1-induced hepatocyte apoptosis and free sphinganine accumulation in liver. Both gadolinium and FB1 treatments individually increased the expression of selected cell signal factors; e.g., TNFalpha, TNF receptor 1, TNF-related apoptosis-inducing ligand, lymphotoxin beta, interferon gamma, and transforming growth factor beta1; gadolinium chloride did not alter FB1-induced expression of the above genes. Results indicated that Kupffer cells play a role in FB1 hepatotoxicity. Decreased FB1-induced sphinganine accumulation and increased protective TNFalpha signaling by gadolinium chloride may in part account for its ameliorating effect on FB1 liver damage.
...
PMID:Fumonisin B1 hepatotoxicity in mice is attenuated by depletion of Kupffer cells by gadolinium chloride. 1559 Jan 29

Fumonisin B1 (FB1) is a mycotoxin produced by Fusarium verticillioides, commonly present in corn and other cereals. Exposure to FB1 causes organ-specific diseases in various species, e.g., equine leukoencephalomalacia and porcine pulmonary edema; in mice the response is hepatotoxicity. We earlier reported that ceramide synthase inhibition by FB1, the initial biochemical effect of this mycotoxin, results in modulation of cytokine network in response to accumulated free sphingoid bases. In the current study we used NZB/NZW-F1 (NZBW) mice that have modified cytokine expression and develop lupus beginning at 5 months of age. The NZBW and C57BL/6J (CBL) mice (appropriate control) were given five daily subcutaneous injections of either saline or 2.25 mg FB1/kg/day and euthanized 24 h after the last treatment. Peripheral leukocyte counts were higher after exposure to FB1 in CBL but not in NZBW. FB1 treatment caused increases of plasma alanine aminotransferase and aspartate aminotransferase activity in CBL mice indicating hepatotoxicity; no elevation of circulating liver enzymes was recorded in NZBW mice. Hepatotoxic responses were confirmed by microscopic evaluation of apoptotic cells. The FB1-induced proliferation of cells observed in CBL strain was abolished in NZBW animals. The sphinganine accumulation in liver after FB1 was equal in both strains of mice. The NZBW strain lacked the FB1-induced increases in the expression of liver tumor necrosis factor alpha, interferon gamma, receptor interacting protein (RIP), and tumor necrosis factor alpha-related apoptosis-inducing ligand (TRAIL), observed in CBL. Results confirmed our hypothesis that initial altered sphingolipid metabolism caused by FB1 leads to perturbation of liver cytokine network and ultimate cellular injury; the mice deficient in cytokine signaling are refractory to FB1 hepatotoxicity.
...
PMID:Lupus-prone NZBWF1/J mice, defective in cytokine signaling, are resistant to fumonisin hepatotoxicity despite accumulation of liver sphinganine. 1615 91

Dietary factors promote obesity and obesity-related disorders, such as fatty liver disease. Natural killer T (NKT) cells are components of the innate immune system that regulate proinflammatory (Th-1) and anti-inflammatory (Th-2) immune responses. Previously, we noted that NKT cells are selectively reduced in the fatty livers of obese, leptin-deficient ob/ob mice and demonstrated that this promotes proinflammatory polarization of hepatic cytokine production, exacerbating lipopolysaccharide (LPS) liver injury in these animals. In the current study, we show that hepatic NKT cells are also depleted by diets that induce obesity and fatty livers in wild-type mice, promoting Th-1 polarization of hepatic cytokine production and sensitization to LPS liver injury despite persistent leptin. Adult male C57BL6 mice fed diets containing high amounts of either fat or sucrose, or combined high-fat, high-sucrose, develop increased hepatic NKT cell apoptosis and reduced liver NKT cells. The hepatic lymphocytes are more Th-1 polarized with increased intracellular interferon gamma and tumor necrosis factor alpha. Mice fed high-fat diets also exhibit more liver injury, reflected by 2-fold greater serum alanine aminotransferase (ALT) than control animals after receiving LPS. In conclusion, when otherwise normal mice are fed with high-fat or sucrose diet, they become obese, develop fatty livers, and acquire hepatic innate immune system abnormalities, including increased NKT cell apoptosis. The latter reduces liver NKT cell populations and promotes excessive hepatic production of Th-1 cytokines that promote hepatic inflammation. These diet-induced alterations in the hepatic innate immune system may contribute to obesity-related liver disease.
...
PMID:Dietary factors alter hepatic innate immune system in mice with nonalcoholic fatty liver disease. 1617 16

Side effects of interferon-ribavirin combination therapy limit the sustained viral response achievable in hepatitis C virus (HCV) patients. Coupling ribavirin to macromolecular carriers that target the drug to the liver would reduce systemic complications. The aim of this study was to evaluate the efficacy of a hemoglobin-ribavirin conjugate (HRC 203) in murine hepatitis virus strain 3 (MHV-3) induced viral hepatitis. HRC 203 had greater anti-viral activity on both isolated hepatocytes and macrophages, whereas both ribavirin and HRC 203 inhibited production of the pro-inflammatory cytokines interferon gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) by macrophages. In vivo, untreated MHV-3-infected mice all developed clinical and biochemical signs of acute viral hepatitis and died by day 4 post infection. Livers recovered from untreated infected mice showed greater than 90% necrosis. In contrast, survival was enhanced in both ribavirin- and HRC 203-treated mice with a marked reduction in biochemical [ALT(max) 964 +/- 128 IU/L (ribavirin); 848 +/- 212 IU/L (HRC 203)] and histological evidence of hepatic necrosis (<10% in ribavirin/HRC 203 vs. 90% in untreated controls). Clinically, HRC 203-treated mice behaved normally, in contrast to ribavirin-treated mice, which developed lethargy and abnormal fur texture. In conclusion, targeted delivery of ribavirin to the liver alters the course of MHV-3 infection as demonstrated by prolonged survival, improved behavior, and reduced signs of histologically evident disease, as well as inhibition of viral replication and production of inflammatory cytokines in vitro.
...
PMID:Targeted delivery of ribavirin improves outcome of murine viral fulminant hepatitis via enhanced anti-viral activity. 1649 40

We previously reported that liver natural killer (NK) and NKT cells play a critical role in mouse model of acetaminophen (APAP)-induced liver injury by producing interferon gamma (IFN-gamma) and modulating chemokine production and subsequent recruitment of neutrophils into the liver. In this report, we examined the role of neutrophils in the progression of APAP hepatotoxicity. C57BL/6 mice were given an intraperitoneal toxic dose of APAP (500 mg/kg), which caused severe acute liver injury characterized by significant elevation of serum ALT, centrilobular hepatic necrosis, and increased hepatic inflammatory cell accumulation. Flow cytometric analysis of isolated hepatic leukocytes demonstrated that the major fraction of increased hepatic leukocytes at 6 and 24 hours after APAP was neutrophils (Mac-1+ Gr-1+). Depletion of neutrophils by in vivo treatment with anti-Gr-1 antibody (RB6-8C5) significantly protected mice against APAP-induced liver injury, as evidenced by markedly reduced serum ALT levels, centrilobular hepatic necrosis, and improved mouse survival. The protection was associated with decreased FasL-expressing cells, cytotoxicity against hepatocytes, and respiratory burst in hepatic leukocytes. In intracellular adhesion molecule (ICAM)-1-deficient mice, APAP caused markedly reduced liver injury when compared with wild-type mice. The marked protection in ICAM-1-deficient mice was associated with decreased accumulation of neutrophils in the liver. Hepatic GSH depletion and APAP-adducts showed no differences among the antibody-treated, ICAM-1-deficient, and normal mice. In conclusion, accumulated neutrophils in the liver contribute to the progression and severity of APAP-induced liver injury.
...
PMID:Neutrophil depletion protects against murine acetaminophen hepatotoxicity. 1753 19

Steatohepatitis enhances the severity of liver injury caused by acute inflammation. The purpose of this study was to test the hypothesis that fatty liver due to chronic choline-deficient diet exacerbates concanavalin A (ConA)-induced liver hepatitis, which is predominantly facilitated by T cells. Male C57BL/6 mice were fed either control choline-sufficient diet (CSD) or choline-deficient diet (CDD) for 6 weeks before ConA administration. Mice were sacrificed 3, 9, and 24 hours after ConA injection. Liver injury measured by aspartate aminotransferase (AST), alanine aminotransferase (ALT), pathology, and terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) staining was minimal in mice fed either diet before ConA exposure. However, ConA-induced liver injury was significantly greater in CDD-fed mice compared with control-fed mice. Liver cytokines were assessed by quantitative real-time polymerase chain reaction (PCR). The expression of T helper (Th) 1 cytokines tumor necrosis factor alpha (TNF-alpha), interleukin 12 (IL-12), and interferon gamma (IFN-gamma) were dramatically elevated after ConA in CDD-fed mice compared with control-fed mice. CDD also enhanced ConA-induced STAT4 activation, but not STAT6. Notably, regulators of T-cell differentiation were strongly shifted toward a predominant Th1 profile. T-bet, regulator of the Th1 response, was up-regulated in CDD-fed mice, whereas Th2 regulator GATA-3 was significantly suppressed in CDD-fed mice after ConA. Moreover, the expression of suppressor of cytokine signaling (SOCS)-1, SOCS-3, and repressor of GATA-3 (ROG) favored a predominant Th1 cytokine response in CDD-fed mice. In conclusion, these data support the hypothesis that hepatosteatosis caused by CDD is associated with more severe ConA-induced hepatitis due to a predominant shift toward Th1 response.
...
PMID:Favored T helper 1 response in a mouse model of hepatosteatosis is associated with enhanced T cell-mediated hepatitis. 1679 67

Scutellarin is a natural compound from a Chinese herb. The purpose of this paper was to study the protective effect of scutellarin on concanavalin A (Con A)-induced immunological liver injury and its effect on liver nuclear factor kappaB (NF-kappaB), tumor necrosis factor alpha (TNF-alpha), interferon gamma (IFN-gamma), and inducible nitric oxide synthase (iNOS) expression in mice. Mouse liver injury was produced by injection of Con A 25 mg kg-1 via the tail vein. Scutellarin 50 or 100 mg kg-1 was peritoneally administered to mice 9 or 1 h before injection of Con A. The levels of serum alanine aminotransferase (ALT) and asparatate aminotransferase (AST), NO2-/NO3- and TNF-alpha were determined with biochemical kits, and ELISA using Quantikine Mouse TNF-alpha kit according the manufacturer's instructions. Liver lesions were examined by light microscope. The expression of TNF-alpha, IFN-gamma, iNOS and Fas mRNA in the livers was detected by RT-PCR; and the expression of c-Fos, c-Jun, iNOS and IkappaB proteins was measured by Western Blotting. As a result, pretreatment with scutellarin 100 mg kg-1 significantly decreased the serum ALT, AST, NO2-/NO3- and TNF-alpha levels, and also reduced liver lesions induced by Con A. Scutellarin 100 mg kg-1 down-regulated expression of TNF-alpha and iNOS mRNA, and c-Fos, c-Jun and iNOS protein, while scutellarin enhanced the degradation of IkappaB in the livers of mice injected with Con A. The results suggest that scutellarin has a protective action against Con A-induced liver injury in mice, and its active mechanism may be related to the inhibition of the NF-kappaB-TNF-alpha-iNOS transduction pathway.
...
PMID:The protective action of scutellarin against immunological liver injury induced by concanavalin A and its effect on pro-inflammatory cytokines in mice. 1722 28

This study aims to investigate the potential role of endogenous interleukin (IL)-10 in long-term liver allograft survival induced by delayed immunosuppression (FK506 days 2-7). Liver transplantation was performed by using Dark Agouti and Lewis rats as donors and recipients, respectively. The delayed immunosuppression protocol induced indefinite allograft survival. A transient upregulation of plasma IL-10 levels was detected in the nontreatment and FK506 treatment groups. Macrophages were found to be one of the major sources of IL-10 produced from the liver allografts. Administration of IL-10-neutralizing antibody shortened the long-term isograft survival and FK506-induced indefinite allograft survival, particularly in the FK506 group. Damaged liver graft histology and increase of plasma alanine aminotransferase levels were detected in the groups with IL-10 antibody treatment. In an ex vivo setting, IL-10 recombinant protein augmented the expression of Foxp3, downregulated the expression of IL-2 and interferon gamma, and induced the generation of CD4(+)CD25(+)Foxp3(+) and CD8(+)CD25(+)Foxp3(+) cells, but this effect was blocked by the administration of IL-10 antibody. Finally, administration of IL-10 recombinant protein after the decline of endogenous IL-10 levels improved allograft survival, and a 100% long-term allograft survival was achieved by the combination of IL-10 with low-dose FK506. In conclusion, the delayed immunosuppression could induce long-term liver allograft survival in the presence of endogenous IL-10 produced by the tissue macrophages. Supplementary exogenous IL-10 administration combined with low-dose immunosuppressive drug may be a useful strategy to induce long-term liver allograft survival.
...
PMID:Induction of long-term liver allograft survival by delayed immunosuppression is dependent on interleukin-10. 1739 63


<< Previous 1 2 3 4 5 Next >>

---