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

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

Complement activation plays an important role in local and remote tissue injury associated with gastrointestinal ischemia-reperfusion (GI/R). The role of the classical and lectin complement pathways in GI/R injury was evaluated using C1q-deficient (C1q KO), MBL-A/C-deficient (MBL-null), complement factor 2- and factor B-deficient (C2/fB KO), and wild-type (WT) mice. Gastrointestinal ischemia (20 min), followed by 3-h reperfusion, induced intestinal and lung injury in C1q KO and WT mice, but not in C2/fB KO mice. Addition of human C2 to C2/fB KO mice significantly restored GI/R injury, demonstrating that GI/R injury is mediated via the lectin and/or classical pathway. Tissue C3 deposition in C1q KO and WT, but not C2/fB KO, mice after GI/R demonstrated that complement was activated in C1q KO mice. GI/R significantly increased serum alanine aminotransferase, gastrointestinal barrier dysfunction, and neutrophil infiltration into the lung and gut in C1q KO and WT, but not C2/fB KO, mice. MBL-null mice displayed little gut injury after GI/R, but lung injury was present. Addition of recombinant human MBL (rhuMBL) to MBL-null mice significantly increased injury compared with MBL-null mice after GI/R and was reversed by anti-MBL mAb treatment. However, MBL-null mice were not protected from secondary lung injury after GI/R. These data demonstrate that C2 and MBL, but not C1q, are necessary for gut injury after GI/R. Lung injury in mice after GI/R is MBL and C1q independent, but C2 dependent, suggesting a potential role for ficolins in this model.
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PMID:Gastrointestinal ischemia-reperfusion injury is lectin complement pathway dependent without involving C1q. 1587 38

Selective inhibitors of cyclooxygenase-2 have less gastroduodenal toxicity than non selective anti-inflammatory drugs. However, there is little information on their effect on the distal gut. A 91 year old woman presented with acute diarrhoea 5 weeks after beginning celecoxib treatment. Laboratory results showed an inflammatory syndrome and increased alanine aminotransferase (ALT) to 13 N. Endoscopic examination of the colon showed diffuse erythematous lesions of the sigmoid and of part of the right colon. No aetiology has been found for colitis or hepatitis. Diarrhea and blood test anomalies disappeared one week after celecoxib was stopped. The role of celecoxib in the etiology of colitis was considered plausible but not for liver damage. This report and a few other cases in the literature suggest that cyclooxygenase-2 selective non-steroidal anti-inflammatory drug inhibitor toxicity should be investigated in case of unexplained acute colitis.
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PMID:[Acute colitis closely following the beginning of celecoxib treatment]. 1651 92

Reduced blood flow to the gut may contribute to weight loss and gastrointestinal symptoms of acute mountain sickness (AMS) at altitude. A study in humans tested the hypothesis that acute hypobaric hypoxia (ALT) would attenuate the normal postprandial hyperemia in the superior mesenteric artery (SM). Blood pressure, cardiac output (CO), and (SM) were measured with previously validated noninvasive Doppler ultrasonic flowmetry in 9 (3 women) healthy young adults (mean age: 23; range: 18-33 yr) residing at 1700 m. Baseline measurements were made after 2 h at ALT in a chamber at 430 mmHg (asymptotically equal to 4800 m = 15,750 ft) after 10-12-h fasting, and the next day the control (CON) measurements were made at 615 mmHg (1850 m). Postprandial measurements were made 45 to 60 min after ingesting a 1000-cal liquid meal under both conditions. At ALT, 5 of the 9 subjects had AMS by the Lake Louise score criteria of headache > or =1 and total score > or =3. ALT significantly reduced fasting, baseline SM relative to CON by 15%, and increased CO by 16%. The postprandial CO increase was not different between ALT and CON, but (SM) increased 115% at CON, but only 75% at ALT, the attenuation being significant (p < 0.006). Neither the diminution of fasting (SM) at ALT nor the attenuation of the postprandial increase in (SM) correlated significantly with AMS symptom scores. These results suggest that baseline and postprandial gut blood flow are altered during acute altitude exposure because of increased intestinal sympathetic tone, inferred from increased local resistance, and may be related to reduced energy intake if sustained during prolonged exposure.
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PMID:Effects of acute hypobaric hypoxia on resting and postprandial superior mesenteric artery blood flow. 1654 66

The crude extract of Achillea millefolium (Am.Cr) was studied for its possible hepatoprotective effect against d-galactosamine (d-GalN) and lipopolysaccharide (LPS) induced hepatitis in mice and antispasmodic effect in isolated gut preparations to rationalize some of the folklore uses. Co-administration of d-GalN (700 mg/kg) and LPS (25 microg/kg) produced 100% mortality in mice. Pre-treatment of animals with Am.Cr (300 mg/kg) reduced the mortality to 40%. Co-administration of d-GalN (700 mg/kg) and LPS (1 microg/kg) significantly raised the plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels compared with values in the control group (p < 0.05). Pre-treatment of mice with Am.Cr (150-600 mg/kg) significantly prevented the toxins induced rise in plasma ALT and AST (p < 0.05). The hepatoprotective effect of Am.Cr was further verified by histopathology of the liver, which showed improved architecture, absence of parenchymal congestion, decreased cellular swelling and apoptotic cells, compared with the toxin group of animals. In isolated rabbit jejunum preparations, Am.Cr caused a concentration-dependent (0.3-10 mg/mL) relaxation of both spontaneous and K(+)-induced contractions as well as shifting the Ca(++) concentration-response curves (CRCs) to the right, similar to that caused by verapamil. These results indicate that the crude extract of Achillea millefolium exhibits a hepatoprotective effect, which may be partly attributed to its observed calcium channel blocking activity.
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PMID:Studies on hepatoprotective, antispasmodic and calcium antagonist activities of the aqueous-methanol extract of Achillea millefolium. 1661 41

Surgery in obstructive jaundice is associated with complications related to gut-derived endotoxemia. The organs involved in these complications, including liver, kidneys, and gut, are important in the metabolism of taurine, which is implicated in bile acid conjugation and has antioxidative effects. Taurine organ metabolism and liver oxidative status were studied in bile duct-ligated rats (BDL) after laparotomy. Oral cholestyramine treatment inhibits gut-derived endotoxemia and was used to evaluate the role of endotoxin. In BDL rats, postoperative plasma taurine levels were higher compared with SHAM (p < .0001). Cholestyramine treatment reduced plasma taurine in BDL rats (p < .005), but levels remained higher compared with SHAM groups (p < .0001). In contrast to a liver uptake of taurine in SHAM rats, a release from livers of BDL rats was found (p < .005). Cholestyramine treatment in BDL rats resulted in a liver uptake of taurine (p < .05 vs BDL). A higher uptake of taurine by the kidneys was found in both BDL animals after surgery and SHAM controls (p < .005); however, cholestyramine had no effect. A release of taurine from the gut was found in the SHAM groups, which was reversed in both BDL groups (p < .01). Cholestyramine lowered the elevated levels of hepatic enzymes in BDL rats (ALT and AST: p < .05). Total liver glutathione levels were lower in BDL rats (p < .0001) compared with SHAM groups, and cholestyramine significantly attenuated this decrease (p < .01). Liver malondialdehyde levels were higher in BDL rats compared with SHAM (p < .01), whereas cholestyramine completely prevented this increase in lipid peroxidation (p < .0001). Hypertaurinemia in BDL rats after surgery is most likely explained by reduced bile acid conjugation and hepatocellular leakage. Cholestyramine treatment reduced hepatocellular damage by inhibiting gut-derived endotoxemia, and reversed the release of taurine from the jaundiced liver into an uptake and consequently lowered plasma taurine levels. This uptake may contribute to the improved antioxidant status in cholestyramine-treated BDL rats.
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PMID:Hypertaurinemia in bile duct-ligated rats after surgery: the effect of gut endotoxin restriction on organ fluxes and oxidative status. 1663 64

Idiosyncratic adverse drug reactions (IADRs) represent an important human health problem, yet animal models for preclinical prediction of these reactions are lacking. Recent evidence in animals suggests that some IADRs arise from drug interaction with an inflammatory episode that renders the liver sensitive to injury. Diclofenac (DCLF) is one of those drugs for which the clinical use is limited by idiosyncratic liver injury. We tested the hypothesis that modest inflammation triggered in rats by a small dose of lipopolysaccharide (LPS) renders a nonhepatotoxic dose of DCLF injurious to liver. Cotreatment of rats with nonhepatotoxic doses of LPS and DCLF resulted in elevated serum alanine aminotransferase activity and liver histopathologic changes 6 h after DCLF administration. Neither LPS nor DCLF alone had such an effect. Gene array analysis of livers revealed a unique gene expression pattern in the LPS/DCLF-cotreated group compared with groups given either agent alone. Antiserum-induced neutrophil (PMN) depletion in LPS/DCLF-cotreated rats protected against liver injury, demonstrating a role for PMNs in the pathogenesis of this LPS/DCLF interaction. Gut sterilization of LPS/DCLF-treated rats did not protect against liver injury. In contrast, gut sterilization did attenuate liver injury caused by a large, hepatotoxic dose of DCLF, suggesting that hepatotoxicity induced by large doses of DCLF is caused in part by its ability to increase intestinal permeability to endotoxin or other bacterial products. These results demonstrate that inflammation-DCLF interaction precipitates hepatotoxicity in rats and raise the possibility of creating animal models that predict human IADRs.
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PMID:Modest inflammation enhances diclofenac hepatotoxicity in rats: role of neutrophils and bacterial translocation. 1699 May 11

High-mobility group box 1 (HMGB1) is a 30-kDa DNA-binding protein that displays proinflammatory cytokine-like properties. HMGB1-dependent inflammatory processes have been demonstrated in models of sterile injury, including ischemia-reperfusion injury and hemorrhagic shock. Here, we tested the hypothesis that the systemic inflammatory response and associated remote organ injury that occur after peripheral tissue injury are highly dependent on HMGB1. Toll-like receptor 4 (TLR4) wild-type (WT) mice subjected to bilateral femur fracture after treatment with neutralizing antibodies to HMGB1 had lower serum IL-6 and IL-10 levels compared with mice treated with nonimmune control IgG. Similarly, compared with injured mice treated with control IgG, anti-HMGB1 antibody-treated mice had lower serum alanine aminotransferase levels and decreased hepatic and gut mucosal NF-kappaB DNA binding. TLR4 mutant (C3H/HeJ) mice subjected to bilateral femur fracture had less systemic inflammation and liver injury than WT controls. Residual trauma-induced systemic inflammation and hepatocellular injury were not ameliorated by treatment with a polyclonal anti-HMGB1 antibody, even though HMGB1 levels were transiently elevated just 1 h after injury in both WT and C3H/HeJ mice. Collectively, these data demonstrate a critical role for a TLR4-HMGB1 pathway in the initiation of systemic inflammation and end-organ injury following isolated peripheral tissue injury.
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PMID:Systemic inflammation and remote organ injury following trauma require HMGB1. 1765 66

We tested the hypothesis that laminarin (LAM), a beta (1-3) polysaccharide extracted from brown algae, can modulate the response to a systemic inflammation. Male Wistar rats (n=7 per group) were fed a standard diet (control) or a diet supplemented with LAM for 25 days (5% during 4 days followed by 10% during 21 days). Thereafter, Escherichia coli lipopolysaccharides (LPS; 10 mg/kg i.p.) were injected and the animals were sacrificed 24 h after LPS challenge. The hypothermia, hyperglycemia and hypertriglyceridemia occurring early after LPS administration were less pronounced in LAM-treated rats than in controls. The increase in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) activities - reflecting hepatic alterations - was lessened after LPS injection in LAM-treated rats compared to control rats. LAM treatment decreased serum monocytes number, nitrite (NO2) and tumor necrosis factor-alpha (TNF-alpha). LAM also modulated intra-hepatic immune cells: it lowered the occurrence of peroxidase-positive cells (corresponding to monocytes/neutrophils) and, in contrast, it increased the number of ED2-positive cells, corresponding to resident hepatic macrophages, i.e. Kupffer cells. In conclusion, the hepatoprotective effect of marine beta (1-3) glucan during endotoxic shock may be linked to its immunomodulatory properties. We propose that both lower recruitment of inflammatory cells inside the liver tissue and lower secretion of inflammatory mediators play a role in the tissue protective effect of LAM. These effects could be due to a direct effect of beta-glucan on immune cells, or to an indirect effect through their dietary fibre properties (fermentation in the gut).
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PMID:Dietary supplementation with laminarin, a fermentable marine beta (1-3) glucan, protects against hepatotoxicity induced by LPS in rat by modulating immune response in the hepatic tissue. 1827 7

Penicillin and other antibiotics are routinely incorporated in insect culture media. Although culturing insects in the presence of antibiotics is a decades-old practice, antibiotics can exert deleterious influences on insects. In this article, we test the hypothesis that one of the effects of dietary penicillin is to increase oxidative stress on insects. The effects of penicillin on midgut concentrations of the oxidative stress indicator malondialdehyde (MDA) and on midgut antioxidant enzyme (superoxide dismutase [SOD], catalase [CAT], glutathione S-transferase [GST], and glutathione peroxidase [GPx]) and transaminases (alanine aminotransferase and aspartate aminotransferase) activities in greater wax moth, Galleria mellonella (L.), were investigated. The insects were reared from first instars on artificial diets containing 0.001, 0.01, 0.1, or 1.0 g penicillin per 100 g of diets. MDA content was significantly increased in the midgut tissues of each larval instar reared in the presence of high penicillin concentrations. Activities of antioxidant and transaminase enzymes did not show a consistent pattern with respect to penicillin concentrations in diet or age of larvae. Despite the increased penicillin-induced oxidative stress in gut tissue, antioxidant and transaminase enzymes did not correlate with oxidative stress level or between each other in larvae of other age stages except for the seventh instar. We found a significant negative correlation of MDA content with SOD and GST activities in seventh instars. SOD activity was also negatively correlated with CAT activity in seventh instars. These results suggest that exposure to dietary penicillin resulted in impaired enzymatic antioxidant defense capacity and metabolic functions in wax moth larval midgut tissues and that the resulting oxidative stress impacts midgut digestive physiology.
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PMID:Penicillin-induced oxidative stress: effects on antioxidative response of midgut tissues in instars of Galleria mellonella. 1797 30

Ischemia bowel remains a critical problem resulting in up to 80% mortality. The loss of gut barrier function plays an important role. Our previous studies have shown that administration of adrenomedullin (AM), a novel vasoactive peptide, and its binding protein (AMBP-1), reduces the systemic inflammatory response and organ injury after systemic ischemia induced by hemorrhagic shock. However, it remains unknown whether administration of AM/AMBP-1 preserves gut barrier function after gut ischemia reperfusion (I/R). We therefore hypothesized that AM/AMBP-1 prevents structural and functional damages to the intestinal mucosa after gut I/R. To test this, gut ischemia was induced by placing a microvascular clip across the superior mesenteric artery (SMA) for 90 min in male adult rats. After release of the SMA clamp, AM (12 mug/kg BW) and AMBP-1 (40 mug/kg BW) in combination or vehicle (1-ml normal saline) were administered intravenously over a period of 30 min. The mucosal barrier function in the small intestine was assessed in an isolated everted ileum sac using fluorescein-isothiocyanate dextran (FD4) at 4 h after AM/AMBP-1 treatment. FD4 clearance was used as a measure of gut permeability. In additional groups of animals, blood and small intestine samples were collected at 4 h after the treatment. Morphological changes in the small intestine were assessed by H-E staining. Serum concentrations of alanine aminotransferase, aspartate aminotransferase, total bilirubin, direct bilirubin, lactate and lactate dehydrogenase were also assessed. The gene expression and protein levels of TNF-alpha in the small intestine were determined by RT-PCR and ELISA, respectively. Our results showed that administration of AM/AMBP-1 significantly attenuated the development of intestinal mucosal hyperpermeability during the reperfusion. Treatment with AM/AMBP-1 dramatically improved I/R-induced intestinal mucosal damages, attenuated remote organ injury, and downregulated gene expression and protein levels of TNF-alpha in the small intestine. In conclusion, AM/AMBP-1 attenuates structural and functional damages to the intestinal mucosa, and it appears to be a novel treatment for reperfusion injury after gut ischemia. The beneficial effect of AM/AMBP-1 on gut barrier function after I/R is associated with downregulation of TNF-alpha.
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PMID:Gut hyperpermiability after ischemia and reperfusion: attenuation with adrenomedullin and its binding protein treatment. 1878 25


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