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:3.1.3.1 (alkaline phosphatase)
47,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In vitro studies have shown that 1,25 dihydroxyvitamin D3 [1,25(OH)2D3] decreases cytokine production by monocytes and lymphocytes. In addition, intravenous or oral pulse calcitriol treatment suppresses interleukin 6 (IL6) and interleukin1beta (IL1beta) in hemodialysis patients. We studied the effect of a daily 12-week course of 1000 mg calcium and 800 U cholecalciferol on circulating 25 hydroxyvitamin D [25(OH)D], PTH, cytokines, osteoprotegerin (OPG), C-reactive protein (CRP), bone markers, lipid parameters and insulin levels in 47 healthy post-menopausal women. Thirty-nine women completed the study. A significant increase in 25(OH)D and a significant decrease in PTH were observed (p=0.0043 and p<0.0001, respectively). In addition, alkaline phosphatase, osteocalcin and, to a lesser extent, urinary free deoxypiridinoline (DPD) decreased significantly (p<0.0001, p=0.0002 and p=0.026, respectively). No change in circulating IL6, tumor necrosis factor alpha (TNFalpha), CRP, OPG, triglycerides, LDL- and HDL-cholesterol, and insulin levels was observed. Correlation studies in the 47 women enrolled in the study revealed inverse significant correlations between OPG on one side and body mass index, LDL-cholesterol, IL6, CRP and insulin levels on the other (p=0.002, p=0.002, p=0.004, p=0.023 and p=0.0001). Also, IL6 was significantly correlated with insulin levels (p=0.0005). In a multivariate model, both insulin and LDL-cholesterol were independently associated with OPG, while only insulin was independently associated with IL6. Our results showed no effect of a short-term calcium-vitamin D treatment on circulating cytokines, CRP, insulin levels and lipid parameters. This could be related to the low circulating cytokine concentrations in healthy subjects or to the short duration of treatment. The interesting association we found between OPG and some cardiovascular risk markers deserves further investigation.
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PMID:Effects of a short-term calcium and vitamin D treatment on serum cytokines, bone markers, insulin and lipid concentrations in healthy post-menopausal women. 1466 30

Helper-dependent adenovirus (HD-Ad) vectors with all adenoviral genes deleted mediate very long-term expression of therapeutic transgenes in a variety of animal models of disease. These vectors are associated with reduced toxicity and improved safety relative to traditional early region 1 deletion first-generation Ad (FG-Ad) vectors. Many studies have clearly demonstrated that FG-Ad vectors induce innate and adaptive immune responses in vivo; however, a comprehensive analysis of host immune responses to HD-Ad vectors has not yet been performed. In DBA/2 mice, intravenous injection of HD-Ad vectors encoding LacZ (HD-AdLacZ) or a murine secreted alkaline phosphatase (HD-AdSEAP) induced an early expression of inflammatory cytokine and chemokine genes in the liver, including interferon-inducible protein 10, macrophage inflammatory protein 2, and tumor necrosis factor alpha, and were expressed in a pattern similar to that induced by FG-Ad vectors encoding AdSEAP. Like AdSEAP, and consistent with the pattern of cellular gene expression, HD-AdLacZ and HD-AdSEAP induced the recruitment of CD11b-positive leukocytes to the transduced liver within hours of administration. AdSEAP also induced a second phase of liver inflammation, consisting of inflammatory gene expression and CD3-positive lymphocytic infiltrates 7 days posttransduction. In contrast, beyond 24 h no infiltrates or expression of inflammatory genes was detected in the livers of mice receiving HD-AdSEAP. Despite the lack of liver inflammation at 7 days, Ad-specific cytotoxic T lymphocytes could be detected in mice receiving HD-AdSEAP. This lack of liver inflammation was not due to reduced transduction since levels of transgene expression and the amounts of vector DNA in the liver were equivalent in mice receiving HD-AdSEAP and AdSEAP. These results demonstrate that HD-Ad vectors induce intact innate but attenuated adaptive immune responses in vivo.
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PMID:Helper-dependent adenovirus vectors elicit intact innate but attenuated adaptive host immune responses in vivo. 1514 Sep 94

Tristetraprolin (TTP) is a hyperphosphorylated protein that destabilizes mRNA by binding to an AU-rich element (ARE). Mice deficient in TTP develop a severe inflammatory syndrome. The biochemical properties of TTP have not been adequately characterized, due to the difficulties in protein purification and lack of a high-titer antiserum. Full-length human TTP was expressed in human HEK293 cells and purified to at least 70% homogeneity. The purified protein was free of endogenous ARE binding activity, and was used for investigating its size, zinc dependency, and binding kinetics for tumor necrosis factor alpha mRNA ARE. A high-titer rabbit antiserum was raised against the MBP-hTTP fusion protein expressed in Escherichia coli. Cellular localization studies of the transfected cells indicated that approximately 80% of the expressed TTP was in the cytosol, with 20% in the nuclei. TTP from both locations bound to the ARE and formed similar complexes. The purified TTP was shown to be intact by N-terminal His-tag purification, C-terminal peptide sequencing, and mass spectrometry analysis. Results from size exclusion chromatography are consistent with the predominant form of active TTP being a tetramer. TTP's ARE binding activity was increased by 10 microM Zn(2+). The half-maximal binding of TTP from HEK293 cells was approximately 30 nM in assays containing 10 nM ARE. This value was about twice that of TTP from E. coli. TTP from HEK293 cells was highly phosphorylated, and its electrophoretic mobility was increased by alkaline phosphatase treatment and somewhat by T271A mutation, but not by PNGase F or S186A mutation. The gel mobility of TTP from E. coli was decreased by in vitro phosphorylation with p42/ERK2 and p38 mitogen-activated protein kinases. These results suggest that TTP's zinc-dependent ARE binding affinity is reduced by half by posttranslational modifications, mainly by phosphorylation but not by glycosylation, in mammalian cells. The results support a model in which each subunit of the TTP tetramer binds to one of the five overlapping UUAUUUAUU sequences of the ARE, resulting in a stable TTP-ARE complex.
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PMID:Expression, purification, and biochemical characterization of the antiinflammatory tristetraprolin: a zinc-dependent mRNA binding protein affected by posttranslational modifications. 1550 35

The first epithelial surface encountered by inhaled materials is the epithelium of the respiratory tract. The epithelium is lined by a fluid (ELF) that can be sampled by a saline wash (lavage) of the area of interest. This technique, known as bronchoalveolar lavage (BAL), provides a means of sampling a body fluid that can provide valuable information on the reaction of the lung to inhaled materials. The most common responses measured are indicators of an inflammatory response, the most sensitive of which is an influx of neutrophils. In the extracellular fluid, levels of beta-glucuronidase activity indicate activation of macrophages, and lactate dehydrogenase activity indicates cytotoxicity. Other pro- and anti-inflammatory soluble factors that can be measured in BAL fluid include secretory products of macrophages and epithelial cells, such as tumor necrosis factor alpha, fibronectin, interleukin-1, various chemotactic factors (including IL-8, MIP-2), growth factors, proteases, and antiproteases. Oxidative stress can be measured by the levels of reduced glutathione in ELF, and increased levels of alkaline phosphatase indicate increased Type II cell secretions. Allergic responses are indicated by increased eosinophils and factors such as histamine and arachidonate metabolites in BAL fluid. BAL analysis can be used as a complementary technique with more traditional measures of lung injury, such as histopathology or radiology. The advantage of BAL analysis is that one can pick up early indicators of biochemical changes leading to later morphological changes in a disease process. A second advantage is that the BAL fluid analyses are quantitative, and dose-response measures can be obtained. In large animals, one can do repeated lavages to follow a disease process; in small animals, one can use serial sacrifices in similarly exposed rodents to achieve the same goal. Research related to the use of BAL fluid analyses to detect lung damage has been conducted at the Lovelace Respiratory Research Institute with funding from various sources including the US Department of Energy and the US Environmental Protection Agency.
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PMID:Use of bronchoalveolar lavage to detect respiratory tract toxicity of inhaled material. 1609 23

Vertebral fractures due to osteoporosis are a common but frequently unrecognized complication in established ankylosing spondylitis (AS). It is known that inflammatory activity in rheumatic diseases (i.e., proinflammatory cytokines) itself plays a possible role in the pathophysiology of bone loss. The aim of this study was to analyze whether inflammatory activity and an alteration of the vitamin D metabolism play a substantial role in the loss of bone mass in AS. In this cross-sectional study, 58 patients with established AS and an age- and sex-matched control group were examined. The vitamin D status was investigated, as was, in parallel, the relationship to disease activity (erythrocyte sedimentation rate [ESR], C-reactive protein [CRP], Bath Ankylosing Spondylitis Disease Activity Index [BASDAI]), markers of bone metabolism (parathyroid hormone [PTH], 1.25 vitamin D3, 25 vitamin D3), calcium, bone alkaline phosphatase (bone-AP), urine cross-links, and plasma tumor necrosis factor alpha (TNFalpha). Bone mineral density was measured by quantitative computed tomography (QCT) of the lumbar spine. Osteoporosis was diagnosed in early as well as in progressive stages of AS (23/58=39.6%). Furthermore, serum levels of 1.25 vitamin D3 and PTH were negatively correlated with disease activity and TNFalpha. The excretion of cross-links showed a positive correlation with disease activity and TNFalpha, and 1.25 vitamin D3 and PTH were positively correlated with bone-AP. TNFalpha also positively correlated with disease activity. AS patients with osteoporosis showed significantly increased CRP, ESR, cross-links and PTH and a significantly decreased 1.25 D3. Osteoporosis is frequent in AS and high disease activity is associated with an alteration in vitamin D metabolites and increased levels of bone resorption in active AS. Our findings propose a close association of BMD, bone metabolism and inflammatory activity, possibly related to vitamin D inflammation interactions.
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PMID:Association of 1.25 vitamin D3 deficiency, disease activity and low bone mass in ankylosing spondylitis. 1617

Valvular calcification during calcific aortic stenosis is associated with morphological features of bone formation and expression of various bone-associated proteins, which are both associated with marked leukocyte infiltration of the calcified valve areas. The pro-inflammatory cytokine tumor necrosis factor alpha (TNF-alpha) is abundantly present in areas of leukocyte infiltration in stenotic aortic valves. We therefore hypothesized that valvular calcification might be actively regulated by an inflammatory process involving TNF-alpha. Upon stimulation with TNF-alpha, human aortic valve myofibroblasts cultured under mineralizing conditions showed an increased formation of calcified, alkaline phosphatase (ALP)-enriched cell nodules, ALP activity, concentration of the bone-type ALP isoenzyme, and concentration of osteocalcin, all of which are markers of an osteoblast-like cellular phenotype. By electrophoretic mobility shift assay, DNA binding of the essential osteoblastic transcription factor Cbfa-1 was increased compared to untreated controls. These results support the concept that aortic valve calcification is associated with an osteoblast-like phenotype of local myofibroblasts. In addition, the data demonstrate direct mechanistic evidence that aortic valve calcification may be actively regulated by an inflammatory process involving TNF-alpha.
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PMID:Tumor necrosis factor alpha promotes an osteoblast-like phenotype in human aortic valve myofibroblasts: a potential regulatory mechanism of valvular calcification. 1621 Dec 57

Expression of intracellular adhesion molecule-1 (ICAM-1) in an obstructive jaundice model and the potential protective role of platelet activating factor antagonist over small intestine and liver together with its effects on bacterial translocation are examined in this study. Forty-eight male Wistar albino rats were assigned into four equal groups of 12. In groups I and II, animals were sham operated. In groups III and IV, common bile duct ligation and division were performed. In group I and group III, 0.5 ml/day normal saline was applied intraperitoneally daily from day 2 to 6 of the study; in group II and group IV, 1 mg/kg/day BN 52021 was applied intraperitoneally daily from day 2 to 6 of the study. All animals were sacrificed on postoperative day 7. ICAM-1 expression (CD54 positivity) was analyzed in the liver and ileum tissue by immunohistochemical method. Samples from blood, liver mesenteric lymph nodes, and spleen were cultured under aerobic conditions. It is revealed that ICAM-1 expression was statistically higher in group III, with highest bacterial translocation and liver and spleen injury when compared to other groups. Serum alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), gamma-glutamyltranspeptidase (GGT), bilirubin, tumor necrosis factor alpha (TNFalpha), and interleukin 1beta(IL-1beta) values were at the highest level in group III, and there was a statistical decrease in group IV compared to group III. The administration of BN52021 in experimental obstructive jaundice is a useful way to reduce liver and intestinal mucosal villi damage by inhibiting bacterial translocation and systemic inflammatory response.
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PMID:The effect of platelet activating factor antagonist BN 52021 on bacterial translocation and ICAM-I expression in experimental obstructive jaundice. 1624 68

The purpose of the present study was to assess the therapeutic effect of hypothermic retrograde jugular vein flush (HRJVF) on heatstroke. HRJVF was accomplished by infusion of 4 degrees C isotonic sodium chloride solution via the external jugular vein (1.7 mL/100 g of body weight over 5 min). Immediately after the onset of heatstroke, anesthetized rats were divided into 2 major groups and given the following: 36 degrees C or 4 degrees C isotonic sodium chloride solution, i.v. They were exposed to ambient temperature of 43 degrees C to induce heatstroke. Another group of rats was exposed to room temperature (24 degrees C) and used as normothermic controls. When the 36 degrees C saline-treated rats underwent heat exposure, their survival time values were found to be 23 to 28 min. Immediately after the onset of heatstroke, resuscitation with an i.v. dose of 4 degrees C saline significantly improved survival during heatstroke (208-252 min). All heat-stressed animals displayed systemic inflammation and activated coagulation, evidenced by increased tumor necrosis factor alpha, prothrombin time, activated partial thromboplastin time, and d-dimer, and decreased platelet count and protein C. Biochemical markers evidenced cellular ischemia and injury/dysfunction: plasma levels of blood urea nitrogen, creatinine, glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, and alkaline phosphatase; and striatal levels of glycerol, glutamate, and lactate/pyruvate; dihydroxy benzoic acid, lipid peroxidation, oxidized-form glutathione reduced-form glutathione, dopamine, and serotonin were all elevated during heatstroke. Core and brain temperatures and intracranial pressure were also increased during heatstroke. In contrast, the values of mean arterial pressure, cerebral perfusion pressure, and striatal levels of local blood flow, partial pressure of oxygen, superoxide dismutase, catalase, glutathione peroxidase, and glutathions reductase activities were all significantly lower during heatstroke. The circulatory dysfunction, systemic inflammation, hypercoagulable state, and cerebral oxidative stress, ischemia, and damage during heatstroke were all significantly suppressed by HRJVF. These findings demonstrate that brain cooling caused by HRJVF therapy may resuscitate persons who had a stroke by attenuating cerebral oxidative stress, systemic inflammation, activated coagulation, and tissue ischemia/injury during heatstroke.
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PMID:Brain cooling causes attenuation of cerebral oxidative stress, systemic inflammation, activated coagulation, and tissue ischemia/injury during heatstroke. 1687 31

The present study was performed to assess the prophylactic effect of platonin, a cyanine photosensitizing dye and an inhibitor of proinflammatory cytokines, in an animal model of heatstroke. Anesthetized rats were immediately divided into 2 major groups after the start of heat stress and administered either isotonic sodium chloride solution (dose, 1 mL/kg of body weight i.v.) or platonin (dose, 12.5-50 microg/mL per kilogram of body weight i.v.). They were exposed to ambient temperature of 43 degrees C to induce heatstroke. Another group of rats were exposed to room temperature (26 degrees C) and used as normothermic controls. Their physiological and biochemical parameters were continuously monitored. When the isotonic sodium chloride solution-pretreated rats underwent heat stress, their survival time values were found to be from 20 to 24 min. Pretreatment with intravenous doses of platonin (12.5-50 microg/mL per kilogram of body weight) immediately after the start of heat exposure significantly improved survival time during heatstroke (duration, 63-185 min). As compared with normothermic controls, all vehicle-pretreated heatstroke animals displayed higher levels of creatinine, serum urea nitrogen, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, tumor necrosis factor alpha, prothrombin time, activated partial thromboplastin time and D-dimer in the plasma, cellular ischemia and injury markers in striatum, and intracranial pressure. In contrast, all vehicle-pretreated heatstroke animals had lower levels of mean arterial pressure, cerebral perfusion pressure, cerebral blood flow, brain Po2, and platelet count and protein C in the plasma. Immediately after the start of heat exposure, the previous administration of platonin significantly improved survival time by reducing the systemic inflammation, hypercoagulable state, and tissue ischemia and damage during heatstroke. The results demonstrate that platonin is effective for attenuation of heatstroke reactions.
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PMID:Platonin, a cyanine photosensitizing dye, is effective for attenuation of heatstroke in rats. 1711 36

This study investigated the effects of rimonabant (SR141716), an antagonist of the cannabinoid receptor type 1 (CB1), on obesity-associated hepatic steatosis and related features of metabolic syndrome: inflammation (elevated plasma levels of tumor necrosis factor alpha [TNFalpha]), dyslipidemia, and reduced plasma levels of adiponectin. We report that oral treatment of obese (fa/fa) rats with rimonabant (30 mg/kg) daily for 8 weeks abolished hepatic steatosis. This treatment reduced hepatomegaly, reduced elevation of plasma levels of enzyme markers of hepatic damage (alanine aminotransferase, gamma glutamyltransferase, and alkaline phosphatase) and decreased the high level of local hepatic TNFalpha currently associated with steatohepatitis. In parallel, treatment of obese (fa/fa) rats with rimonabant reduced the high plasma level of the proinflammatory cytokine TNFalpha and increased the reduced plasma level of the anti-inflammatory hormone adiponectin. Finally, rimonabant treatment also improved dyslipidemia by both decreasing plasma levels of triglycerides, free fatty acids, and total cholesterol and increasing the HDLc/LDLc ratio. All the effects of rimonabant found in this study were not or only slightly observed in pair-fed obese animals, highlighting the additional beneficial effects of treatment with rimonabant compared to diet. These results demonstrate that rimonabant plays a hepatoprotective role and suggest that this CB1 receptor antagonist potentially has clinical applications in the treatment of obesity-associated liver diseases and related features of metabolic syndrome.
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PMID:Rimonabant reduces obesity-associated hepatic steatosis and features of metabolic syndrome in obese Zucker fa/fa rats. 1759 67


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