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)

To explore the possible vasoregulatory role of renal prostaglandins during liver disease, excretory rates of PGE2, PGF2 alpha, and a metabolite of PGI2, 6k-PGF1 alpha, were determined before and after chronic ligation of the common bile duct in 23 dogs. Bile duct ligation for 50 +/- 3.7 days (mean +/- SEM) significantly increased serum bilirubin and alkaline phosphatase. PGE2, PGF2 alpha, and 6k-PGF1 alpha excretion rates were significantly (p less than 0.01) increased following chronic bile duct ligation, by approximately 100%, 80%, and 500%, respectively, with similar increments in both ascitic and nonascitic animals. In 10 sham-ligated animals, PGE2, PGF2 alpha, and 6k-PGF1 alpha excretion rates were unchanged. In 6 dogs sequential measurements of urine prostaglandins indicated that PGE2 and 6k-PGF1 alpha excretion were significantly increased at 2, 4, and 6 weeks after ligation, whereas the increase in PGF2 alpha excretion was not significant until 6 weeks. Indomethacin (2 mg/kg) reduced prostaglandin excretion by 65% to 90% and significantly increased arterial pressure, decreased glomerular filtration rate and renal blood flow, and increased renal vascular resistance from 0.53 +/- 0.09 to 0.90 +/- 0.13 mm Hg/ml/min. Fractional renal blood flow, assessed by microspheres, was disproportionately reduced in the inner cortex after prostaglandin inhibition in the chronic bile duct ligation group. Indomethacin did not significantly alter renal function in sham animals, despite comparable reductions in prostaglandin excretion. These data demonstrate that, in dogs with experimental liver disease produced by chronic bile duct ligation, renal prostaglandin synthesis is increased, and the enhanced synthesis of vasodilatory prostaglandins serves to maintain renal blood flow and glomerular filtration rate.
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PMID:Importance of renal prostaglandins in control of renal function after chronic ligation of the common bile duct in dogs. 654 81

The effect of epidermal growth factor (EGF) on clone MC3T3-El cells that have osteoblastic activity was examined by phase-contrast microscopy and electron microscopy; hydroxyproline content, collagen synthesis, collagen pattern, and alkaline phosphatase (ALP) activity were also determined. We found that EGF (0.4 ng/ml) transformed the cells from their normal polygonal shape to a spindle-like morphology by 8 h. This hormone also caused dose-related suppression of hydroxyproline content and ALP activity which was detectable 2 days and 1 day, respectively, after EGF addition. Indomethacin did not affect hydroxyproline content and ALP activity, suggesting that the effect of EGF on the cells may not be mediated by prostaglandins. Epidermal growth factor at concentrations of 2 to 50 ng/ml significantly decreased collagen synthesis in the cells, whereas protein synthesis was stimulated. Electron microscopy demonstrated that collagen fiber formation was also reduced by EGF; an immature type of fibril was observed compared with the typical cross-striated one in the controls. Moreover, the hormone treatment also resulted in the appearance of type III collagen in addition to the type I already present in the cells. These suppressive effects of EGF on MC3T3-El cells in vitro suggest that this hormone may be involved in bone remodelling in vivo as well.
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PMID:Effects of epidermal growth factor on osteoblastic cells in vitro. 660 67

We present evidence for the presence of specific, high-affinity binding sites for tritiated phorbol 12,13-dibutyrate on osteosarcoma-derived (HT-3) cells. Activation of protein kinase C by a phorbol ester resulted in an inhibition of alkaline phosphatase activity and the accumulation of prostaglandin E2. Indomethacin blocked prostaglandin E2 production and enhanced alkaline phosphatase activity. These data suggest that prostaglandin E2 is enhanced by activation of protein kinase C, and in turn, alkaline phosphatase activity is reduced.
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PMID:Activation of protein kinase C and the involvement of prostaglandin E2 in the inhibition of osteosarcoma-derived cell alkaline phosphatase activity. 766 74

The ability of endometrial stromal cells from nonsensitized rat uteri to undergo decidualization in vitro was investigated. Cells were obtained by enzymatic dispersion from uteri of ovariectomized, steroid-treated rats at the equivalent of day 4, 5 or 6 of pseudopregnancy, or on day 5 from rats treated with 0, 0.3 or 1.0 microgram oestradiol (low, intermediate or high doses of oestradiol, respectively) on day 4, and cultured for 24, 48 or 72 h. Decidualization in vivo, as assessed by uterine mass 5 days after the unilateral intrauterine injection of 100 microliters sesame oil, was maximal for rats receiving the deciduogenic stimulus on day 5 and treated with the intermediate dose of oestradiol. Under control conditions in vitro, alkaline phosphatase (ALP) activity, the increase in ALP activity with time, and prostaglandin E2 (PGE2) accumulation in the medium were greatest for cells from maximally sensitized uteri. Indomethacin, an inhibitor of PG synthesis, reduced PGE2 accumulation to barely detectable amounts, and decreased ALP activity, especially in cells from maximally sensitized uteri, indicating that endogenous PG production contributed to the increase in ALP activity in these cells. The addition of PGE2 with indomethacin increased ALP activities. However, ALP activities were lower for cells derived from nonsensitized uteri when compared with cells from maximally sensitized uteri. These results suggest that endometrial stromal cells from nonsensitized uteri have a reduced capacity to undergo decidualization in vitro, and that this reduced capacity is not explained by differences in PGE2 production.
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PMID:Temporal- and hormone-dependent changes in uterine sensitization for the decidual cell reaction and decidualization in vitro of rat endometrial stromal cells. 906 24

Prostaglandin (PG) E2 is thought to be a mediator of the effect of mechanical stress on bone formation, but its effects on osteoblasts have not yet been fully described. Here, the effects of the continuous application of PGE2 and indomethacin, an inhibitor of prostaglandin G/H synthase (cyclo-oxygenase), on the proliferation, differentiation and mineralization of a clonal osteoblastic cell line, MC3T3-E1, were investigated. The cells were cultured in media with either a high (1 microg/ml) or a low (1 ng/ml) concentration of PGE2, with indomethacin (1 microg/ml) and, as a control, with neither agent. The effects of PGE2 and indomethacin were assessed quantitatively. Indomethacin and a high concentration of PGE2 increased the total protein compared to the control and low-PGE2 cultures. 7 days after confluence, alkaline phosphatase (ALP) activity within the cells and extracellular matrices increased. This increase was highest with indomethacin and lowest with a high concentration of PGE2. ALP activity also increased in the medium, but only 21 days after confluence; the effects of the agents were similar to those on the cells and matrices. The accumulation of calcium, inorganic phosphate and hydroxyproline was highest with indomethacin. PGE2 production was at its maximum when the cells were at confluence and was inhibited by indomethacin. Specific [3H]PGE2 binding to the microsomal fraction of the cell was also measured to examine the expression of the PGE2 receptor. The amount of [3H]PGE2 binding per mg of protein was highest at confluence, then decreased and again increased in the mineralizing stage. These results suggest that indomethacin increases ALP activity and the accumulation of mineralized tissue in MC3T3-E1 cells, presumably by inhibiting the production of PGE2. PGE2 could signal the suppression of mineralization as early as confluence.
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PMID:Long-term effects of prostaglandin E2 on the mineralization of a clonal osteoblastic cell line (MC3T3-E1). 1021 14

1. Capillary proliferation and microvessel diameters were studied in rat ankle flexors subjected to chronic electrical stimulation by implanted electrodes (10 Hz, 0.3 ms pulse width, up to 6 V, 8 h day-1) for 2 or 7 days with or without concurrent indomethacin treatment ( approximately 2 mg day-1 in drinking water) to study the role of prostaglandins in the microcirculation in relation to capillary growth. 2. Diameters of terminal arterioles, capillaries and confluent venules were measured in epi-illuminated muscles, together with capillary red cell velocity, to evaluate whether changes in capillary pressure and/or shear stress participate in capillary growth via release of prostaglandins. 3. Cell proliferation was detected following bromodeoxyuridine (BrdU) incorporation and immuno-staining of frozen sections. Labelling was assessed as the percentage of all interstitial nuclei (Haematoxylin-stained) that were BrdU positive. By comparison with serial sections stained for alkaline phosphatase, from which the capillary-to-fibre ratio (C:F) was obtained, labelling was derived for nuclei colocalised either to capillaries or to other non-capillary interstitial cells. 4. C:F increased to 1.89 +/- 0.06 from 1.47 +/- 0.04 in controls only after 7 days stimulation; indomethacin reduced this to 1.55 +/- 0.07. Capillary labelling increased from 2.9 +/- 0.5 % in controls to 11.3 +/- 2.2 % after 2 days stimulation and 10.6 +/- 0.8 % after 7 days. The increase was attenuated by indomethacin at both time points (to 5.8 +/- 1.6 % and 4.2 +/- 0.5 %, respectively). 5. Non-capillary interstitial labelling (2.0 +/- 0.4 % in controls) increased to 9.5 +/- 2.7 % after 2 days stimulation and was back to normal after 7 days (3.2 +/- 0.7 %). Indomethacin depressed the increase at 2 days to 4.0 +/- 1.3 % and had no effect at 7 days (2.9 +/- 0.13 %). Labelling in sham-operated rats with or without indomethacin or in vehicle-treated animals was no different from controls. 6. Arteriolar and venular diameters were increased by 2 days of stimulation but unchanged after 7 days. Indomethacin increased diameters of arterioles after 2 days and venules after 7 days in sham-operated animals, but had no effect on diameters of either vessel type in stimulated muscles. 7. Capillary diameters did not change during acute muscle contractions whereas red cell velocity did. Calculated shear stress in capillaries was thereby increased by 75 %. 8. Thus during chronic electrical stimulation both capillary growth and the cell proliferation that precedes it were attenuated by indomethacin. Transient stimulation-induced increases in arteriolar and venular diameters, which were unaffected by indomethacin, do not implicate increased capillary pressure as a factor in prostaglandin release and capillary growth. Estimations of increases in capillary shear stress during muscle contractions and of a 45 % higher value even at rest after chronic stimulation for 7 days suggest that shear stress is a more likely stimulus for prostaglandin release in chronically stimulated muscles.
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PMID:Effect of indomethacin on capillary growth and microvasculature in chronically stimulated rat skeletal muscles. 1089 32

Previous studies suggest that the enhanced expression of the osteoblastic phenotype exhibited by MG63 osteoblast-like cells on rough Ti surfaces (R(a) 4-5 microm) involves increased production of prostaglandin. Inhibition of prostaglandin synthesis by indomethacin blocks surface-roughness-dependent decreases in cell proliferation and increases in alkaline phosphatase activity and the production of osteocalcin and TGF-beta1. This study examined the hypothesis that the increase in expression of the osteoblastic phenotype noted in MG63 cells cultured on rough Ti surfaces is mediated by inducible cyclooxygenase-2 (Cox-2) whereas Cox-1 modulates prostaglandin production and phenotypic expression of the cells under standard conditions and on smooth Ti surfaces. MG63 cells were cultured on tissue culture plastic, smooth Ti (PT, R(a) = 0.60 microm), and two rough Ti surfaces with differing morphologies (SLA, R(a) = 3.97 microm and TPS, R(a) = 5.21 microm). At 24 h after plating, media were replaced with media containing the general Cox inhibitor indomethacin (10(-7)M), the Cox-1 inhibitor resveratrol (1 or 10 microM), or the Cox-2 inhibitor NS-398 (1 or 10 microM). Media were changed again after 48 h. Five days after plating, osteocalcin, PGE(2), and TGF-beta1 content of the conditioned media were determined. Cell numbers were assessed in the same cultures used for determination of osteocalcin production. Cell layer protein and alkaline phosphatase specific activity were assessed in cultures used to measure PGE(2) and TGF-beta1. Indomethacin, resveratrol, and NS-398 had no effect on cell number. Indomethacin blocked the surface-roughness-dependent increase in PGE(2) production by up to 80%. Similarly, resveratrol inhibited up to 50% of the PGE(2) production on smooth surfaces and up to 80% on rough surfaces. In contrast, NS-398 had no effect on PGE(2) production by cells on smooth surfaces but caused a 60% reduction in cultures on rough surfaces. Indomethacin reduced alkaline phosphatase on all surfaces below basal levels. However, neither resveratrol nor NS-398 had an effect. Indomethacin blocked the stimulatory effect of surface roughness on osteocalcin production while resveratrol only partially reduced osteocalcin production, and NS398 completely blocked the surface-dependent increase. TGF-beta1 production on rough surfaces was blocked by indomethacin. The effects of resveratrol and NS-398 were dose dependent, but neither agent caused total inhibition of the increase noted on SLA, and only resveratrol blocked the increase on TPS. These results indicate that both Cox-1 and Cox-2 are involved in the response of osteoblasts to surface roughness with respect to production of PGE(2), TGF-beta1, and osteocalcin. While prostaglandin mediates the effects of surface roughness on alkaline phosphatase, neither Cox-1 nor Cox-2 appears to be involved, at least with respect to the two inhibitors used.
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PMID:Both cyclooxygenase-1 and cyclooxygenase-2 mediate osteoblast response to titanium surface roughness. 1125 88

Establishment of Entamoeba histolytica infection is facilitated through macrophage effector disruption by a prostaglandin E2 (PGE2)-mediated mechanism. Infection severity may be measured by weight of abscess formed. Indomethacin (Indo) treatment of infected hamsters reduced abscess weight by 30% at 7 days post-infection presumably by inhibition of PGE2. To explain reductions in abscess development by Indo treatment, we determined liver functionality in Indo-treated or untreated animals, either healthy or infected. Determinations of serum glutamic oxaloacetic (SGOT) and glutamic pyruvic (SGPT) transaminases, serum alkaline phosphatase (SAP), total serum protein (TSP), and bilirubinemia were done. SGOT, SGPT, and SAP activities showed a significant increase in their values by 600% at seven days post-infection in infected animals in both conditions; nonstatistical differences were found between animals treated or not. This increase did not correlate with the percentage of damage. Infected nontreated hamsters showed TSP levels 30% below normal group (P < 0.05). Infected Indo-treated hamsters had no significant differences compared to normal values. Infected nontreated animals showed an increase in bilirubin, particularly in indirect bilirubin, whereas infected Indo-treated hamsters showed total bilirubin values lower than normals (P < 0.05), with a decrease in direct bilirubin levels. Our results demonstrated that E. histolytica infection in hamsters produces similar abnormalities in liver function as it does in humans, and that the beneficial effect of Indo treatment on amoebic abscess development is not related with an improvement of liver functionality.
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PMID:Liver function tests during amoebic liver abscess formation in indomethacin-treated hamsters. 1147 99

This study sought to assess the role of several signaling pathways in the fluid flow shear stress-induced proliferation and differentiation of normal human osteoblasts. We evaluated the effects of an effective dose of selective inhibitors of the extracellular signal-regulated kinases (ERK) pathway (PD98059 and U0126), the nitric oxide synthase pathway (N(omega)-nitro-L-arginine methyl ester), the cyclo-oxygenase pathway (indomethacin), or the Gi/o pathway (pertussis toxin [PTX]) on the flow-mediated effects. A 30-min steady flow shear stress at 20 dynes/cm(2) increased significantly [(3)H]thymidine incorporation (an indicator of proliferation), alkaline phosphatase activity (an index of osteoblast differentiation), phosphorylation of ERK, and expression of integrin beta1. PD98059, U0126, and N(omega)-nitro-L-arginine methyl ester completely blocked the shear stress-induced increases in ERK phosphorylation, [(3)H]thymidine incorporation, and alkaline phosphatase, but without an effect on integrin beta1 expression, indicating that the ERK and nitric oxide synthase pathways are essential for the shear stress-induced proliferation and differentiation of normal human osteoblasts and that each involves ERK activation but not integrin beta1 upregulation. Indomethacin blocked the shear stress-induced osteoblast proliferation and differentiation and integrin beta1 upregulation but not ERK activation, suggesting that the cyclo-oxygenase pathway (i.e., prostacyclin and/or prostaglandin E(2)) mediates the shear stress-induced osteoblast proliferation in an ERK-independent manner. In contrast, PTX completely blocked the flow-induced increase in integrin beta1 expression but had no effect on the increase in the ERK phosphorylation or [(3)H]thymidine incorporation. PTX not only did not inhibit but also significantly enhanced the stimulatory effect of shear stress on alkaline phosphatase activity, suggesting that a PTX-sensitive signaling pathway may have an inhibitory role in osteoblast differentiation. In summary, this study shows, for the first time, that the signal transduction mechanism of shear stress in osteoblasts is complex and involves multiple ERK-dependent and independent pathways, and provides circumstantial evidence that there may be a PTX-sensitive pathway that has completing effects with an unknown pathway on the differentiation of normal human osteoblasts.
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PMID:Fluid flow shear stress stimulates human osteoblast proliferation and differentiation through multiple interacting and competing signal transduction pathways. 1266 51

There is increasing evidence that non-steroidal anti-inflammatory drugs (NSAIDs) can adversely affect bone repair. We have, therefore, studied the in vitro effects of NSAIDs, which differentially inhibit cyclooxygenases (COX), the prostaglandin/thromboxane synthesising enzymes, on human osteoblasts. Indomethacin and the new nitric oxide (NO)-donating NSAIDs block the activity of both COX-1 and COX-2. Indomethacin and 5,5-dimethyl-3-(3 fluorophenyl)-4-(4 methylsulphonal) phenyl-2 (5H)-furanone (DFU) reduced osteoblast numbers in a dose-dependant manner and increased collagen synthesis and alkaline phosphatase activity. The reduction in osteoblast numbers was not caused by loss of adhesion and was reversible. Neither NSAID influenced DNA synthesis. There was no difference between the effects of indomethacin and DFU. NO-NSAIDs did not affect cell numbers. These results suggest that care should be taken when administering NSAIDs to patients with existing skeletal problems and that NO-NSAIDs may be safer.
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PMID:The influence on human osteoblasts in vitro of non-steroidal anti-inflammatory drugs which act on different cyclooxygenase enzymes. 1512 36


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