Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.6.1.1 (aspartate aminotransferase)
 21,665 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To investigate the effects of the cholinergic anti-inflammatory pathway on hemodynamics, blood biochemistry, the plasma TNF-alpha level, and the nuclear factor-kappaB (NF-kappaB) activation during septic shock, male Sprague-Dawley rats were subjected to cecal ligation and puncture (CLP, a model of polymicrobial sepsis) or sham operation. Forty-eight rats were randomly assigned into six equal groups: sham CLP group; CLP group; VGX group was subjected to bilateral cervical vagotomy after CLP; STM group was subjected to bilateral cervical vagotomy after CLP plus the left vagus nerve trunk electrical stimulation; THA group was administered tetrahydroaminoacridine after CLP and bilateral cervical vagotomy; and alpha-BGT group was administered alpha-bungarotoxin before electrical stimulation of the vagus nerve. The right carotid artery was cannulated to monitor MAP. The plasma TNF-alpha level was measured using enzyme-linked immunosorbent assays. The hepatic NF-kappaB activation was determined by Western blotting. Cecal ligation and puncture produced progressive hypotension. Serum aspartate transaminase and alanine transaminase levels significantly increased after CLP challenge. The plasma TNF-alpha level and the hepatic NF-kappaB activation significantly increased after CLP alone or with bilateral cervical vagotomy compared with sham-operated group. Application of constant voltage pulses to the caudal vagus trunk significantly prevented the development of CLP-induced hypotension, alleviated the hepatic damage, and reduced the plasma TNF-alpha production, but electrical stimulation had no effect on the hepatic NF-kappaB activation. Tetrahydroaminoacridine administration after bilateral cervical vagotomy reversed hypotension and attenuated the plasma TNF-alpha response; in addition, it had no effect on the hepatic NF-kappaB activation. alpha-Bungarotoxin pretreatment significantly reversed the inhibitory effect of vagal electrical stimulation, but it had no effect on the hepatic NF-kappaB activation. Our results showed that the cholinergic anti-inflammatory pathway might produce a potential protective effect on polymicrobial sepsis in rats.
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PMID:The protective effect of the cholinergic anti-inflammatory pathway against septic shock in rats. 1839 58

We recently discovered that vascular responsiveness to adrenomedullin (AM), a vasoactive hormone, decreases after hemorrhage, which is markedly improved by the addition of its binding protein AMBP-1. One obstacle hampering the development of AM/AMBP-1 as resuscitation agents in trauma victims is the potential immunogenicity of rat proteins in humans. Although less potent than rat AM, human AM has been shown to increase organ perfusion in rats. We therefore hypothesized that administration of human AM/AMBP-1 improves organ function and survival after severe blood loss in rats. To test this, male Sprague-Dawley rats were bled to and maintained at an MAP of 40 mmHg for 90 min. They were then resuscitated with an equal volume of shed blood in the form of Ringer's lactate (i.e., low-volume resuscitation) over 60 min. At 15 min after the beginning of resuscitation, human AM/AMBP-1 (12/40 or 48/160 microg/kg BW) were administered intravenously over 45 min. Various pathophysiological parameters were measured 4h after resuscitation. In additional groups of animals, a 12-day survival study was conducted. Our result showed that tissue injury as evidenced by increased levels of transaminases, lactate, and creatinine, was present at 4h after hemorrhage and resuscitation. Moreover, pro-inflammatory cytokines TNF-alpha and IL-6 were also significantly elevated. Administration of AM/AMBP-1 markedly attenuated tissue injury, reduced cytokine levels, and improved the survival rate from 29% (vehicle) to 62% (low-dose) or 70% (high-dose). However, neither human AM alone nor human AMBP-1 alone prevented the significant increase in ALT, AST, lactate and creatinine at 4h after the completion of hemorrhage and resuscitation. Moreover, the half-life of human AM and human AMBP-1 in rats was 35.8 min and 1.68 h, respectively. Thus, administration of human AM/AMBP-1 may be a useful approach for attenuating organ injury, and reducing mortality after hemorrhagic shock.
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PMID:Human vasoactive hormone adrenomedullin and its binding protein rescue experimental animals from shock. 1840 50

To assess the effect of infliximab, an anti-tumor necrosis factor (TNF)-alpha agent, on the carbon tetrachloride (CCl(4))-induced hepatic fibrosis in rats. Rats were randomized into three groups (n=9). The control group received only intraperitoneal (i.p.) olive oil. Hepatic fibrosis was induced by repeated i.p. injections of 1.5 ml/kg CCl(4) (1:3 mixture with olive oil) for 5 weeks in the remaining two groups which were also injected subcutaneous saline or 2 mg/kg infliximab. Infliximab reduced the levels of aspartate aminotransferase and alanine aminotransferase (p<0.05 for both). The scores of hepatic necrosis, inflammation and fibrosis, and expression of alpha-smooth muscle actin were lower in the infliximab-treated group than the CCI(4)-treated group (p<0.01, p<0.001, p<0.01, p<0.001, respectively). However, there was no significant difference in terms of liver tissue and plasma malondialdehyde, and serum TNF-alpha levels, while infliximab relatively reduced the level of transforming growth factor-beta(1) (373.0+/-153.1 vs. 280.8+/-127.1 pg/ml). Treatment with infliximab attenuated the necro-inflammation and fibrogenesis in the CCI(4)-induced hepatic fibrosis, and thus it might be effective as a therapeutic anti-fibrotic agent.
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PMID:Hepatoprotective effect of infliximab, an anti-TNF-alpha agent, on carbon tetrachloride-induced hepatic fibrosis. 1842 63

To complete a successful liver transplantation (LTx) from non-heart-beating donors (NHBD), it is necessary to both improve the energy status in liver grafts and to reduce the exposure to free radicals. This study investigated the effects of short perfusion with oxygenated buffer on the grafts prior to cold preservation. In addition, the effects of the antioxidant, biliverdin, for reduction of free radicals was investigated. Male Wistar rats were used. Livers were retrieved, preserved in UW solution, and perfused for 60 min with oxygenated Krebs-Henseleit solution. Rats were allocated to six groups as follows (n=5): (i) control group-no warm ischemia (WI) and cold preservation, (ii) HBD group--no WI with cold preservation for 6 h; (iii) NHBD group--with 30 min of WI and cold preservation, (iv) NM group--with WI including nafamostat mesilate infusion before cardiac arrest and cold preservation; (v) PRE group--with WI, 30-min pre-cold preservation perfusion with oxygenated buffer after cardiac arrest, and cold preservation, (vi) BV group-with the same treatment as the PRE group plus the addition of biliverdin to the pre-cold preservation perfusion. The portal flow volume, bile production, AST, and TNF-alpha in perfusate, energy charge (EC), and ATP level in the tissue, and histological findings were investigated. The portal flow volume in the NM, PRE, and BV groups were higher than in the NHBD group. The bile production in the PRE and BV groups were also higher than in the NHBD group. The EC and ATP level of the BV group after reperfusion were higher than those of the NHBD group. Pre-cold preservation perfusion and addition of biliverdin to perfusate improved viability of grafts from NHBD. The results indicate that the preservation of the energy status and microcirculation of the graft is important for successful LTx from NHBD.
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PMID:The significance of preserving the energy status and microcirculation in liver grafts from non-heart-beating donor. 1846 47

Injection of D-galactosamine and lipopolysaccharide (DGaIN/LPS) is useful as an experimental model of acute hepatic damage. Juvenile rats were used for investigation. The hepatoprotective activity of aqueous garlic (Allium sativum) extract (AGE) at a dose of 300 mg/kg body weight for 14 days, intraperitoneal (i.p.) prior to the induction of DGalN/LPS, was investigated against DGalN/LPS-induced hepatitis in rats. DGalN/LPS (300 mg/kg body weight/30 microg/kg body weight, i.p.), induced hepatic damage that was manifested by a significant increase in the activities of marker enzymes [alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), lactate dehydrogenase (LDH) and gamma glutamyl transferase (gamma GT)], bilirubin, lipid peroxides (LPO), tumor necrosis factor (TNF-alpha) and myeloperoxidase (MPO) activity level in serum. Also, the lipid profile in serum and liver homogenate including total cholesterol, triglycerides, free fatty acids and phospholipids were significantly deteriorated. The antioxidant enzyme activities (superoxide dismutase, SOD; reduced glutathione, GSH; catalase, CAT and glutathione peroxidase, GPX) in liver homogenate were significantly decreased in the DGalN/LPS. Pretreatment of rats with AGE reversed these altered parameters near to normal control values. Results of this study revealed that AGE could afford a significant protection in the alleviation of DGalN/LPS-induced hepatic damage.
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PMID:Aqueous garlic extract attenuates hepatitis and oxidative stress induced by galactosamine/lipoploysaccharide in rats. 1857 Feb 25

Emodin, 1,3,8-trihydroxy-6-methyl-anthraquinone, is an anthraquinone derivative from the roots of Rheum officinale Baill that has been used to treat many diseases in digestive system for thousands of years. This study is to disclose the mechanism of Emodin to treat cholestatic hepatitis via anti-inflammatory pathway. Rats were divided into Emodin, ursodeoxycholic acid, Dexamethasone, model and blank control groups with treatment of respective agent after administration of alpha-naphthylisothiocyanate. At 24 h, 48 h and 72 h time points after administration, liver function, pathological changes of hepatic tissue, tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, myeloperoxidase (MPO), malondialdehyde (MDA), superoxide dismutase (SOD), cytokine-induced neutrophil chemoattractant (CINC)-1, macrophage inflammatory protein (MIP)-2, intercellular adhesion molecule (ICAM)-1, nuclear factor (NF)-kappaB and early growth response (Egr)-1, nitric oxide (NO) and inducible nitric oxide synthase (iNOS) were detected. As a result, compared to the controls, Emodin had a notable effect on rat's living condition, pathological manifestation of hepatic tissue, total bilirubin, direct bilirubin, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (P<0.05), but had little effect on alkaline phosphatase (ALP), gamma-glutamyltransferase (GGT) and total bile acid. With Emodin intervention, levels of TNF-alpha, IL-6, MPO, MDA, CINC-1, MIP-2, ICAM-1 and translocation of NF-kappaB were remarkably decreased, and levels of NO and iNOS were markedly increased (P<0.05). Emodin had no effect on Egr-1. In conclusion, Emodin has a protective effect on hepatocytes and a restoring activity on cholestatic hepatitis by anti-inflammation. The effects are mainly due to antagonizing pro-inflammatory cytokines and mediators, inhibiting oxidative damage, improving hepatic microcirculation, reducing impairment signals, and controlling neutrophil infiltration.
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PMID:Exploration of Emodin to treat alpha-naphthylisothiocyanate-induced cholestatic hepatitis via anti-inflammatory pathway. 1859 Jul 20

Tyrphostins, derivatives of benzylidene malononitrile are recognized as tyrosine kinase inhibitors that have been applied in some models of acute inflammatory conditions, like LPS and zymosan-induced shock. In the present study, we have investigated the effects of tyrphostin AG-490, on the development of multiple organ failure induced by i.p. injection of zymosan (1 mg/g body weight) in mice. Organ dysfunction and systemic inflammation was estimated 24 h after zymosan administration. Treatment of mice with AG-490 (dose, 5 mg/kg i.p. simultaneously with zymosan) decreased the number of cells and the level of NO in the peritoneal lavage. The substance attenuated the elevation of creatinine (indicator of renal failure), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin (indicators for liver dysfunction) and prevented the accelerated coagulation time. The injection of zymosan resulted in a substantial increase in the serum level of TNF-alpha and IL-6, which was strongly inhibited by AG-490. Tyrphostin abolished the expression of iNOS and TNF-alphaR in the liver. Moreover, immunohistochemistry of liver showed decreased phosphorylation of Stat1 and Stat3. In conclusion, the administration of tyrphostin AG-490 in zymosan-induced nonseptic shock significantly improved the rate of survival and lead to less exerted signs of multiple organ failure.
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PMID:Tyrphostin AG-490 inhibited the acute phase of zymosan-induced inflammation. 1865 56

The biomedical application of single-walled carbon nanotubes (SWCNTs), such as drug delivery and cancer treatment, requires a clear understanding of their fate and toxicological profile after intravenous administration. In this study, the long-term accumulation and toxicity of intravenously injected SWCNTs in the main organs (such as liver, lung and spleen) in mice were carefully studied. Although SWCNTs stayed in mice over 3 months, they showed low toxicity to mice. The long-term accumulation of SWCNTs in the main organs was evidenced by using Raman spectroscopy and TEM technique. Statistically significant changes in organ indices and serum biochemical parameters (LDH, ALT and AST) were observed. The histological observations demonstrate that slight inflammation and inflammatory cell infiltration occurred in lung, but the serum immunological indicators (CH 50 level and TNF-alpha level) remained unchanged. No apoptosis was induced in the main organs. The decreasing glutathione (GSH) level and increasing malondialdehyde (MDA) level suggest that the toxicity of SWCNTs might be due to the oxidative stress.
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PMID:Long-term accumulation and low toxicity of single-walled carbon nanotubes in intravenously exposed mice. 1876 Mar 40

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

The pathophysiological mechanisms of thioacetamide (TAA)-induced hepatic fibrogenesis are not yet fully understood. In particular, the role of hepatic stellate cells (HSCs) remains unclear. We therefore examined proliferation and transdifferentiation of HSC as well as the underlying molecular mechanisms in TAA-induced fibrosis. Hepatic fibrogenesis was induced in mice by addition of TAA to drinking water. Liver damage was determined by assessment of alanine aminotransferase and aspartate aminotransferase levels, and measurement of collagen deposition. Additionally, expression patterns of alpha-smooth muscle actin, glial fibrillary acidic protein (GFAP, specific hepatic biomarker for HSC), cysteine- and glycine-rich protein 2 (CRP2, specific marker of HSC transdifferentiation), tissue inhibitor of metalloproteinases-1, matrix metalloproteinase-9 (MMP-9), interleukins (IL-1beta, IL-6), platelet-derived growth factors (PDGF-B, PDGF-D) , tumor necrosis factor (TNF)-alpha, and (transforming growth factor (TGF)-beta1 were assessed by real-time PCR. Transcription of GFAP and CRP2 were transiently upregulated during TAA-induced fibrogenesis (punctum maxima (p.m.) week 10 for GFAP and week 14 for CRP2). Similar transient expression patterns were demonstrated for IL-1beta, IL-6, TGF-beta1, and PDGF-B (p.m. week 12) whereas TNF-alpha and PDGF-D continuously increased with ongoing liver injury. In particular, not only neutrophil granulocytes, but also macrophages and leukocytes served as a major source for MMP-9 expression. GFAP and CRP2 expression patterns demonstrated transiently increased HSC-activation during TAA-induced hepatic fibrogenesis. The rate of increase of transcription of GFAP correlated best with PDGF-B, whereas CRP2 levels correlated with PDGF-B, PDGF-D, and IL-1beta expression. This study demonstrates for the first time that transiently increased activation patterns of HSC are observed in toxically induced hepatic fibrosis. Thus, TAA in drinking water is an effective and elegant model to induce reproducible states of liver fibrosis without parenchymal damage in mice.
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PMID:Activation of hepatic stellate cells is associated with cytokine expression in thioacetamide-induced hepatic fibrosis in mice. 1879 50


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