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)

Inchinko-to (TJ-135) is a herbal medicine consisting of three kinds of crude drugs, and in Japan it is administered mainly to patients with cholestasis. The present study evaluated the effects of TJ-135 on concanavalin A (con A)-induced hepatitis in mice in vivo and con A-induced cytokine production in vitro. When mice were pretreated with oral TJ-135 for 1 week before intravenous con A injection, the activities of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) were significantly decreased 8 h after con A administration (-82%, -96% and -66% respectively). In histological investigations, sub-massive hepatic necrosis accompanying inflammatory cell infiltration was not observed in mice pretreated with TJ-135. Serum levels of interleukin-12 (IL-12), interferon-gamma (IFN-gamma) and IL-2 were significantly lower in mice pretreated with TJ-135 compared with controls, while IL-10 levels were higher in these mice. Intrasplenic IL-12 levels were significantly lower in mice pretreated with TJ-135, while intrasplenic IL-10 levels were higher in these mice. In vitro, IL-10 production by splenocytes was increased by the addition of TJ-135 to the culture medium, whereas the production of IL-12 and IFN-gamma was inhibited. These results suggest that con A-induced hepatitis was ameliorated by pretreatment with TJ-135. With regard to the mechanism of these effects of TJ-135, we speculate that TJ-135 inhibits the production of inflammatory cytokine and enhances the production of anti-inflammatory cytokines. Therefore administration of TJ-135 may be useful in patients with severe acute hepatitis accompanying cholestasis or in those with autoimmune hepatitis.
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PMID:Effects of the Japanese herbal medicine 'Inchinko-to' (TJ-135) on concanavalin A-induced hepatitis in mice. 1105 23

In order to copy the clinical situation of concordant xenotransplantation, Rhesus Monkey livers were hemoperfused with human blood. Changes of immunological (TNFalpha, IL-1beta, IL-2, IL-2R, IL-6, IFNgamma, TXB2, 6kPGF1alpha, sICAM-1, sELAM-1, sHLA-I-Ag) and pathophysiological (GOT, GPT, LDH, CK) parameters were followed. Our experiment proves that all phenomena start in the first hour of xenogeneic blood circulation. Xenogeneic rejection in our concordant system is surprisingly severe. Preformed natural antibodies only cannot be the reason of such a damage. We think that beside other important immunological mechanisms, humoral mediators play a considerable role at the beginning of a xenogeneic rejection.
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PMID:Xenogeneic ex vivo hemoperfusion of rhesus monkey livers with human blood. 1127 29

Recent studies in vitro and in animals have suggested that ribavirin may potentiate the antihepatitis C virus (HCV) activity of interferon-alpha (IFN-alpha) by up-modulating the production of T cell-derived cytokines, such as interleukin (IL)-2 and IFN-gamma, which play a key role in the cellular immune response against HCV. To study the immune-modulatory mechanisms of ribavirin further, cytokine production by activated T cells and circulating cytokine levels were studied by FACS analysis and ELISA testing in 25 patients with chronic hepatitis C unresponsive to IFN-alpha, before and after treatment with either ribavirin plus IFN-alpha or IFN-alpha alone. After 16 weeks of treatment, both the expression of IFN-gamma by activated T cells and the blood levels of IFN-gamma, were significantly reduced with respect to pretreatment values in patients treated with ribavirin and IFN-alpha but not in those undergoing treatment with IFN-alpha alone. The expression of IFN-gamma was significantly lower in patients that gained normal ALT levels with respect to those that did not. No modification of the expression of IL-2, IL-4 and IL-10 was found before and after treatment in either group of patients. In conclusion, the results of this study do not support up-modulation of IFN-gamma and IL-2 production as the mechanism by which ribavirin potentiates IFN-alpha anti HCV activity. In addition, our findings suggest that ribavirin may exert an anti-inflammatory effect and may help reducing IFN-gamma-driven T cell activation and liver damage.
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PMID:Treatment with ribavirin and interferon-alpha reduces interferon-gamma expression in patients with chronic hepatitis C. 1129 34

We conducted a series of in vivo experiments to clarify the hepatoprotective activity of green tea against lipopolysaccharide (LPS) + D-galactosamine (GalN)-induced liver injury and to elucidate the mechanism by which green tea exerts its effect in 7-wk-old male Wistar rats. Liver injury was assessed by plasma alanine aminotransferase and aspartate aminotransferase activities. Green tea extract significantly suppressed LPS + GalN-induced liver injury when added to the diet (30 or 35 g/kg) and fed to rats for 14 d or when force-fed alone (0.4-1.2 g/kg body) 1.5 h before the injection of drugs. Although all five of the fractions extracted from green tea extract with different organic solvents had significant suppressive effects, the caffeine-containing fraction exhibited the strongest effect, suggesting that the protective effect of green tea against LPS + GalN-induced liver injury is attributable mainly to caffeine. Authentic caffeine also significantly suppressed LPS + GalN-induced liver injury when added to the diet (2 g/kg) and fed to rats for 14 d. Dietary green tea suppressed LPS + GalN-induced apoptosis of liver cells, as assessed by DNA fragmentation. However, dietary green tea did not suppress LPS-induced enhancement of plasma concentration of tumor necrosis factor (TNF)-alpha, the cytokine that is thought to play a pivotal role in the pathogenesis of LPS-induced liver injury, although it significantly suppressed plasma concentrations of interleukin (IL)-1beta, IL-2, IL-4, IL-6, IL-10 and interferon (IFN)-gamma. TNF-alpha + GalN-induced liver injury and apoptosis were also suppressed by dietary green tea. In contrast, dietary caffeine significantly suppressed LPS-induced enhancement not only of plasma IL-1beta, IL-6, IL-10 and IFN-gamma concentrations, but also of TNF-alpha concentration. The results suggest that green tea might suppress LPS + GalN-induced liver injury mainly through the inhibition of TNF-alpha-induced apoptosis of hepatocytes, rather than through the suppression of TNF-alpha production, although the suppressed production of TNF-alpha may be associated with the hepatoprotective effect of caffeine.
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PMID:Green tea suppresses lipopolysaccharide-induced liver injury in d-galactosamine-sensitized rats. 1134 Jan 16

Interferon is the primary treatment for hepatitis C virus (HCV). However, the long-term success rate is low particularly for African Americans relative to Caucasians and may be due to differential immune abilities. This study compared cytokine production from PHA-stimulated peripheral blood from 25 healthy and 40 HCV-infected African Americans and Caucasians. HCV patients were designated as IFN responders or nonresponders based on outcome after therapy. Ethnicity and genotype were associated with IFN response. IFN responders were 100% Caucasian, whereas nonresponders were 67% Caucasian and 33% African American (P = 0.01). Genotype 1 was present in 100% nonresponders and 50% responders (P < 0.05). Age, sex, liver histology, ALT, and viral titers were equivalent (ns). Cytokine production from healthy individuals showed ethnic variation in cytokine levels. Healthy African Americans produced greater amounts of IL-2 (P = 0.06), TNF-alpha (P = 0.06) and less IL-10 (P = 0.05) than healthy Caucasians. In contrast, IFN-gamma and TGF-beta levels were equivalent. Pretherapy cytokine production among HCV patients showed a similar pattern of ethnic variation. African American nonresponders produced more IL-2 (P = 0.06) and TNF-alpha (P = 0.02) than Caucasian nonresponders. Cytokine levels among Caucasian and African American nonresponders were equivalent (P = ns) to ethnically matched healthy individuals whereas Caucasian responders produced subnormal levels of IL-10 (P < 0.05) and TGF-beta (P < 0.05). Since all African Americans failed IFN therapy, cytokine production could not be compared with therapeutic outcome. However, comparison of cytokine production among Caucasians showed that responders produced less IL-10 (P < 0.001) and more TGF-beta (P = 0.06) than nonresponders and predicted Caucasian nonresponders with 83% sensitivity and 96% specificity. HCV genotype was not relevant to cytokine production (P = ns). Distribution of cytokine genetic polymorphisms (TNF-alpha, TNF-beta, IL-10, TGF-beta) was equivalent in all ethnic groups and did not predict clinical nonresponders. In summary, it appears that ethnicity may contribute to variable immune responses and therapeutic outcome. The cytokine profile among African Americans suggests a more robust immune response, which may complicate therapy with IFN. In contrast, the subnormal cytokine production among Caucasian responders may be more permissive to IFN therapy. Pretherapy cytokine production may allow prediction of drug resistance among Caucasians.
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PMID:Ethnicity and cytokine production gauge response of patients with hepatitis C to interferon-alpha therapy. 1159 86

Interferon regulates the activity of other cytokines. Alterations in non-specific immune response, particularly cytokine level changes result in therapeutic difficulties in patients with chronic hepatitis C. Serum levels of IL-1 beta, IL-2, IL-4, IL-6 and IFN-gamma were measured in patients with chronic hepatitis C before the interferon therapy, in the early phase of the treatment (after the 6th dose of the drug), and in the later stable phase of the treatment (after the 36th dose of the drug). Concentrations of cytokines during the interferon therapy were compared to the changes in alanine aminotransferase activity. The IL-1 beta, IL-2, IL-4 and IL-6 serum concentrations were initially elevated in all patients. The increase in IL-1 beta level after the 6th dose and the decrease after 36th dose of IFN appeared to be an indicator of a good response to treatment. High levels of IL-6 before the IFN therapy followed by a decrease after the 6th dose and high levels of IL-4 followed by a decrease after 36th IFN dose also indicated good response. High levels of IL-2, stable throughout the treatment suggested a poor response. No changes in the IFN-gamma values before or during the treatment were observed.
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PMID:The levels of IL-1 nu beta, IL-2, IL-4, IL-6 and IFN-gamma among patients with chronic hepatitis type C treated with IFN-alpha. 1171 33

T-cell hyporesponsiveness may lead to chronicity of hepatitis C virus (HCV) infection. We evaluated whether interferon (IFN)-gamma injection can bring a Th1-dominant environment to patients with chronic hepatitis C. Seventeen patients with genotype 1b received natural IFN-alpha 5MU daily for the first 2 weeks and three times a week for the next 22 weeks followed by natural IFN-gamma 1 MU daily for 2 weeks. In 4 of 17 patients (23.5%), alanine aminotransferase (ALT) was normalized and 3 of these 4 patients (75.0%) cleared HCV RNA. beta2 microglobulin (BMG), neopterin and soluble (s) Fas increased with IFN-alpha and increased more with IFN-gamma. Serum interleukin (IL)-12, CD4 and CD8 remained unchanged with IFN-alpha but increased after IFN-alpha was replaced by IFN-gamma. IL-10 was not changed either with IFN-alpha or gamma. Productions of IL-2, IFN-gamma and tumor necrosis factor (TNF)-alpha by peripheral blood mononuclear cells did not change by IFN-alpha therapy, however, they were enhanced at the end of IFN-gamma therapy. Productions of IL-2 and 4 were unaffected. These results show that some immune parameters become Th1-dominant by additional IFN-gamma in patients with chronic hepatitis C. Combination of these two IFNs should be explored.
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PMID:Interferon-gamma brings additive anti-viral environment when combined with interferon-alpha in patients with chronic hepatitis C. 1180 30

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.
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PMID:Effects of polysaccharide ginsan from Panax ginseng on liver function. 1520 59

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.
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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

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


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