Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.1 (alkaline phosphatase)
 47,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have compared the effects of BW755C, a dual inhibitor of the arachidonic acid cyclo-oxygenase and lipoxygenase, with the effects of colchicine and indomethacin on the reversion of the biochemical and histochemical signs of rat liver cirrhosis. This was induced by i.p. administration of CCl4 for 11 weeks. At this point the rats were divided into four groups (10 animals each). CCl4 administration was continued for one month along with either colchicine, BW755C or indomethacin. No additional treatment was given to the control group. BW755C consistently improved all the parameters studied. Although colchicine also improved all but two markers (serum ALT activity and serum proteins) it ranked lower than BW755C in most of them. Indomethacin only modified favourably serum alkaline phosphatase activity, serum proteins, cholesterol and bilirubins and liver collagen content. The effects of BW755C could be mainly attributed to the inhibition of the lipoxygenase pathway. A common feature of colchicine, adrenal steroids and BW755C was the ability to inhibit the formation of leukotriene and other lipoxygenase products. The possibility that this property might contribute to their anti-cirrhotic actions is discussed.
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PMID:Reduction of apparent indicators of liver cirrhosis in rats by the arachidonate lipoxygenase inhibitor BW755C. 288 11

Recombinant human interleukin 1 (rhIL-1)alpha and rhIL-1 beta were examined for their effects on DNA synthesis, cell growth and alkaline phosphatase activity of the mouse osteoblastic cell line MC3T3-E1. The relative activity of rhIL-1 alpha and rhIL-1 beta was compared in terms of the units which induced half-maximal [3H]thymidine uptake into mouse thymocyte cultures exposed to IL-1. Both rhIL-1 alpha and rhIL-1 beta significantly inhibited DNA synthesis and division of the cells in a concentration- and cultivation time-dependent fashion. In contrast, rhIL-1 alpha and rhIL-1 beta markedly increased alkaline phosphatase activity, which is a marker of osteoblastic differentiation. This activity in cells treated with rhIL-1 alpha and rhIL-1 beta increased about 2.0- and 1.7-fold, respectively, compared with that of control cultures. Inhibition of the DNA synthesis and stimulation of alkaline phosphatase activity by both types of rhIL-1 were completely neutralized by treatment with their respective polyclonal antisera. Also, inhibition of DNA synthesis was unaffected by the addition of cyclooxygenase and lipoxygenase inhibitors, and stimulation of alkaline phosphatase activity was unaffected by the addition of indomethacin. These results indicate that both rhIL-1 alpha and rhIL-1 beta have qualitatively similar biological effects on osteoblastic cells. They also suggest that IL-1 is an important modulator of the growth and differentiation of osteoblasts.
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PMID:Effects of recombinant human interleukin 1 alpha and interleukin 1 beta on cell growth and alkaline phosphatase of the mouse osteoblastic cell line MC3T3-E1. 328 95

Timegadine is a tri-substituted guanidine derivative which inhibits both arachidonate cyclo-oxygenase and lipoxygenase activity. In a 24-week randomized double-blind controlled trial, timegadine 500 mg/day was compared with naproxen 750 mg/day in two groups of 20 patients with active rheumatoid arthritis. In the timegadine group, significant improvements were seen in both biochemical and clinical markers of disease activity, i.e. ESR, serum IgG and IgM, leukocyte and platelet counts, duration of morning stiffness, Ritchie index, number of swollen joints, pain, and general condition. In the naproxen group, only the Ritchie index improved. Differences between treatments, when present, were always in favour of timegadine. Serum alkaline phosphatase rose during the first 8 weeks of treatment in the timegadine group. A transient rise was also seen in the naproxen group. The side effects reported were mainly gastrointestinal and allergic, the latter being more frequently found in the timegadine group. Timegadine is superior to naproxen in controlling disease activity in rheumatoid arthritis, and appears to possess disease-modifying properties.
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PMID:Timegadine: more than a non-steroidal for the treatment of rheumatoid arthritis. A controlled, double-blind study. 329 Oct 99

The antilymphocytic and antiphlogistic agent cyclosporin A (CsA) inhibits in vivo various effects induced by the tumor promoting phorbol ester 12-0-tetradecanoylphorbol-13-acetate (TPA). These include the edema of the mouse ear, the alkaline phosphatase (AP) activity and the ornithine decarboxylase (ODC) activity in mouse epidermis as well as the generation of a specific arachidonic acid (AA) metabolite in mouse epidermis. AA metabolism in an epidermal cell-free system of mouse epidermis was not suppressed by CsA. According to thin layer chromatography the TPA-induced and as yet unidentified AA metabolite exhibits a polarity between that of 5-HETE and 12-/15-HETE. Studies with inhibitors indicate it to be a lipoxygenase product.
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PMID:Cyclosporin A inhibits biological effects of tumor promoting phorbol esters. 391 31

We studied arachidonic acid (AA) metabolism by a cell suspension containing principally cells of the thick ascending limb of the loop of Henle (TALH) obtained from the inner stripe of the outer medulla of the rabbit kidney. Based on comparison of specific activities of enzymes before and after separation, alkaline phosphatase, Na+-K+-adenosine triphosphatase, as well as Tamm-Horsfall glycoprotein and electron microscopic appearance, 80% of these cells were estimated to be TALH in origin. TALH cells had low activity of cyclooxygenase and did not show evidence of lipoxygenase activity. However, they selectively converted exogenous AA to oxygenated metabolites by a cytochrome P-450 related mechanism. AA metabolites were produced in large amounts (30-40% conversion of [14C]AA, 1 to 5 micrograms/mg of protein/30 min) and were increased 5-fold after separation of TALH cells from a suspension of outer medullary cells, suggesting that TALH cells synthesized these metabolites. Induction of cytochrome P-450 by pretreatment of rabbits with beta-naphthoflavone and 3-methylcholanthrene increased formation of the AA metabolites by almost 2-fold in the separated cells and correlated with cytochrome P-450 content of the renal outer medulla. Additionally, SKF 525A and carbon monoxide inhibited product formation in these renomedullary cells, supporting a role for a cytochrome P-450-like monooxygenase in TALH cell function.
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PMID:Arachidonic acid metabolism in a cell suspension isolated from rabbit renal outer medulla. 643 72

1. The inhibitory effects of arachidonic acid (AA) and a number of structurally related fatty acids on cyclic AMP-dependent protein kinase activity have been investigated in brush border membranes (BBM) prepared from human placental vesicles. 2. BBM vesicles were characterized by electron microscopy and displayed enrichment of the appropriate marker enzymes, alkaline phosphatase and gamma-glutamyltranspeptidase; BBM were prepared by vesicles lysis in hypotonic medium. 3. Cyclic AMP-dependent protein kinase (PKA) activity was measured in BBM. At 1 microM, cyclic AMP stimulated a 4.2 +/- 0.06 fold increase over basal levels of [32P]-phosphate incorporation into the synthetic substrate kemptide and this effect was abolished by a selective PKA inhibitor. By use of synergistic pairs of site-selective cyclic AMP analogues, the kinase was identified as the type II enzyme. 4. Cyclic AMP-stimulated PKA activity was inhibited by 10 microM AA and this effect was significantly enhanced by nordihydroguaiaretic acid (NDGA) + indomethacin (Indo), inhibitors of the lipoxygenase and cyclo-oxygenase pathways of AA metabolism respectively. 5. Oleic acid, elaidic acid, but not caprylic or palmitic acids, also significantly inhibited PKA activity and this effect was again enhanced by NDGA + Indo. While arachidonyl alcohol alone was not inhibitory, in the presence of the metabolic inhibitors a significant reduction in stimulated activity was observed. 6. The commercially available PKA type II holoenzyme (activated by cyclic AMP), but not the free catalytic subunit, was inhibitable by AA, oleic or elaidic acids. 7. These results suggest that PKA localized to the brush border membrane of human placental vesicles is inhibited by fatty acids which may compete with cyclic AMP for binding to the kinase regulatory subunit. The reported inhibition by fatty acids of cyclic AMP-dependent Cl- secretion in epithelial cells may therefore be due in part to negative regulation of a Cl- channel-associated PKA.
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PMID:Inhibition by fatty acids of cyclic AMP-dependent protein kinase activity in brush border membranes isolated from human placental vesicles. 800 95

Quercitrin was tested for acute and chronic anti-inflammatory activity in trinitrobenzenesulfonic acid-induced rat colitis. The inflammatory status was evaluated by myeloperoxidase, alkaline phosphatase and total glutathione levels, leukotriene B4 synthesis, in vivo colonic fluid absorption, macroscopical damage and occurrence of diarrhea and adhesions. Treatment with 1 or 5 mg/kg of quercitrin by the oral route reduced myeloperoxidase and alkaline phosphatase levels, preserved normal fluid absorption, counteracted glutathione depletion and ameliorated colonic damage at 2 days. Increasing or lowering the dose of the flavonoid resulted in marked loss of effect. The acute anti-inflammatory effect of quercitrin is unrelated to impairment of neutrophil function or lipoxygenase inhibition, and it may be caused by mucosal protection or enhancement of mucosal repair secondary to increased defense against oxidative insult and/or preservation of normal colonic absorptive function. When tested in chronic colitis (2 and 4 weeks), quercitrin treatment (1 or 5 mg/kg.day) decreased colonic damage score and the incidence of diarrhea, and normalized the colonic fluid transport. All other parameters were unaffected. The chronic effect of the flavonoid is apparently related to its action on colonic absorption, although it can be partly secondary to its acute beneficial effect.
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PMID:Effect of quercitrin on acute and chronic experimental colitis in the rat. 876 30

Prior studies have shown that 24,25-dihydroxyvitamin D3 [24,25-(OH)2D3] plays a major role in resting zone chondrocyte differentiation and that this vitamin D metabolite regulates both phospholipase A2 and protein kinase C (PKC) specific activities. Arachidonic acid is the product of phospholipase A2 action and has been shown in other systems to affect a variety of cellular functions, including PKC activity. The aim of the present study was to examine the interrelationship between arachidonic acid and 24,25-(OH)2D3 on markers of proliferation, differentiation, and matrix production in resting zone chondrocytes and to characterize the mechanisms by which arachidonic acid regulates PKC, which was shown previously to mediate the rapid effects of 24,25-(OH)2D3 and arachidonic acid on these cells. Confluent, fourth passage resting zone cells from rat costochondral cartilage were used to evaluate these mechanisms. The addition of arachidonic acid to resting zone cultures stimulated [3H]thymidine incorporation and inhibited the activity of alkaline phosphatase and PKC, but had no effect on proteoglycan sulfation. In contrast, 24,25-(OH)2D3 inhibited [3H]thymidine incorporation and stimulated alkaline phosphatase, proteoglycan sulfation, and PKC activity. In cultures treated with both agents, the effects of 24,25-(OH)2D3 were reversed by arachidonic acid. The PKC isoform affected by arachidonic acid was PKCalpha; cytosolic levels were decreased, but membrane levels were unaffected, indicating that translocation did not occur. Arachidonic acid had a direct effect on PKC in isolated plasma membranes and matrix vesicles, indicating a nongenomic mechanism. Plasma membrane PKCalpha was inhibited, and matrix vesicle PKCzeta was stimulated; these effects were blocked by 24,25-(OH)2D3. Studies using cyclooxygenase and lipoxygenase inhibitors indicate that the effects of arachidonic acid are due in part to PG production, but not to leukotriene production. This is supported by the fact that H8-dependent inhibition of protein kinase A, which mediates the effects of PGE2, had no effect on the direct action of arachidonic acid but did mediate the role of arachidonic acid in the cell response to 24,25-(OH)2D3. Diacylglycerol does not appear to be involved, indicating that phospholipase C and/or D do not play a role. Gamma-linolenic acid, an unsaturated precursor of arachidonic acid, elicited a similar response in matrix vesicles but not plasma membranes, whereas palmitic acid, a saturated fatty acid, had no effect. These data suggest that arachidonic acid may act as a negative regulator of 24,25-(OH)2D3 action in resting zone chondrocytes.
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PMID:Arachidonic acid directly mediates the rapid effects of 24,25-dihydroxyvitamin D3 via protein kinase C and indirectly through prostaglandin production in resting zone chondrocytes. 1038 91

Recent studies have shown that 24R,25-(OH)(2)D(3) mediates its effects on growth plate chondrocytes via membrane receptors. This study examined the roles of phospholipase A(2) (PLA(2)) and cyclooxygenase (Cox) in the mechanism of action of 24R, 25-(OH)(2)D(3) in resting zone chondrocytes in order to determine whether the activity of one or both enzymes provides a regulatory checkpoint in the signaling pathway resulting in increased protein kinase C (PKC) activity. We also determined whether constitutive or inducible Cox is involved. Cultures were incubated with 24R, 25-(OH)(2)D(3) for 90 min to measure PKC or for 24 h to measure physiological responses ([(3)H]-thymidine incorporation, alkaline phosphatase-specific activity, [(35)S]-sulfate incorporation). Based on RT-PCR and Northern blot analysis, resting zone chondrocytes express mRNAs for both Cox-1 and Cox-2. Levels of mRNA for both proteins were unchanged from control levels after a 24-h incubation with 24R,25-(OH)(2)D(3). To examine the role of Cox, the cultures were also treated with resveratrol (a specific inhibitor of Cox-1), NS-398 (a specific inhibitor of Cox-2), or indomethacin (a general Cox inhibitor). Cox-1 inhibition resulted in effects on proliferation, differentiation, and matrix production typical of 24R, 25-(OH)(2)D(3). In contrast, inhibition of Cox-2 had no effect, indicating that 24R,25-(OH)(2)D(3) exerts its effects via Cox-1. Inhibition of Cox-1 also blocked 24R,25-(OH)(2)D(3)-dependent increases in PKC. Activation of PLA(2) with melittin inhibited 24R, 25-(OH)(2)D(3)-dependent stimulation of PKC, and inhibition of PLA(2) with quinacrine stimulated PKC in response to 24R, 25-(OH)(2)D(3). Inclusion of resveratrol reduced the melittin-dependent inhibition of PLA(2) and caused an increase in quinacrine-stimulated PLA(2) activity. Metabolism of arachidonic acid to leukotrienes is not involved in the response to 24R, 25-(OH)(2)D(3) because inhibition of lipoxygenase had no effect. The effect of 24R,25-(OH)(2)D(3) was specific because 24S,25-(OH)(2)D(3), the biologically inactive stereoisomer, failed to elicit a response from the cells. These results support the hypothesis that 24R, 25-(OH)(2)D(3) exerts its effects via more than one signaling pathway and that these pathways are interrelated via the modulation of PLA(2). PKC regulation may occur at multiple stages in the signal transduction cascade.
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PMID:24R,25-(OH)(2)D(3) mediates its membrane receptor-dependent effects on protein kinase C and alkaline phosphatase via phospholipase A(2) and cyclooxygenase-1 but not cyclooxygenase-2 in growth plate chondrocytes. 1065 6

Sandhika is a polyherbal formulation, (water soluble fraction of Commiphora mukul, Boswellia serrata, Semecarpus anacardium and Strychnos nux vomica), which has been in clinical use in India for last 20 years. Its modified formulation BHUx has shown specific inhibition of cyclooxygenase (COX)-2 and lipoxygenase (LOX)-15 and has prevented diet-induced atherosclerosis in rabbits. In order to explore the possibility of the use of Sandhika for the management of osteoporosis, we have examined its influence on MC3T3-E1 osteoblast-like cells in presence of lipopolysaccharide (1 microg/ml) in terms of calcium nodule formation and alkaline phosphatase activity. MC3T3-E1 osteoblast-like cells (80% confluence in 6-well plates) were treated with water extract of Sandhika, for 10 days, in the concentration range of 0.5 to 16 mg/ml final concentration, in presence of LPS. Media was changed on every third day and culture supernatant was collected after every change to assess the alkaline phosphatase activity and on the tenth day, cells were washed and stained with "Alizarin S" for visualization of calcium nodules by using Meta Morph software (Universal Imaging, Downingtown, PA). The results showed significant enhancement in calcium nodule formation in the dose dependent manner up to 2 mg/ml, followed by gradual decrease at higher concentrations. This change was accompanied with the increase in the alkaline phosphatase activity in these plates, indicating a potential anabolic effect of this polyherbal formulation on osteoblast-like cells under inflammatory conditions induced by LPS.
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PMID:Role of Sandhika: a polyherbal formulation on MC3T3-E1 osteoblast-like cells. 1768 34


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