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)

This study was carried out to establish the effects of therapeutic and toxic doses of levamisole on thyroid hormone levels and some biochemical parameters in sheep. Twelve Akkaraman ewes were used. Levamisole was given orally at doses of 7.5 mg kg(-1) (group 1) and 40 mg kg(-1) (group 2) to the animals. Blood samples were taken from the jugular vein at 2, 4, 8, 24, 48, 96 and 144 h after the administrations. Serum thyroid hormones and some biochemical parameters were determined on these samples. When compared with the control levels, no significant changes were observed in triiodothyronine (T3) and thyroxin (T4) levels in group 1. Although levamisole was found to increase the levels of total T3, it decreased the levels of total T4 in group 2. On the other hand, free T3 and free T4 levels were not changed in either group. While serum alkaline phosphatase (ALP) activities were decreased, aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH) and creatinine kinase (CK) activities were increased significantly by levamisole. However, it increased the serum albumin and cholesterol levels, but decreased the inorganic phosphate levels in groups 1 and 2. On the other hand, when compared with the control levels, no significant changes were detected in serum sodium, potassium and calcium levels. In conclusion, therapeutic and toxic doses of levamisole were determined to affect thyroid metabolism and some biochemical parameters in sheep.
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PMID:Effects of therapeutic and toxic doses of levamisole on thyroid hormones and some biochemical parameters in sheep. 1533 66

The expression of D1 dopamine (DA) receptor gene is regulated during development, aging, and pathophysiology. The extracellular factors and signaling mechanisms that modulate the expression of D1 DA receptor have not been well characterized. Here, we present novel evidence that endogenous D1 DA receptor expression is inhibited by extracellular cAMP in the Cath.A Derived (CAD) catecholaminergic neuronal cell line. CAD cells express the multi-drug resistance protein 5 transporters and secrete cAMP. Addition of exogenous cAMP decreases D1 receptor mRNA and protein greater than fourfold in 24 h. The cAMP-induced decrease of D1 receptor mRNA levels is blocked by cGMP and by 1,3-dipropyl-8-(p-sulfo-phenyl)xanthine, an inhibitor of ecto-phosphodiestrase. Extracellular AMP, a metabolite of cAMP, also independently decreased D1 receptor mRNA levels. Inhibitors of ecto-nucleotidases, alpha,beta-methyleneadenosine 5'-di-phosphate and GMP, completely blocked the decrease of D1 receptor mRNA by extracellular cAMP, but only partially blocked the decrease induced by extracellular AMP. Levamisole, an inhibitor of tissue non-specific alkaline phosphatase, completely blocked the AMP-induced decrease of D1 receptor mRNA. The extracellular cAMP, AMP, and adenosine (ADO)-induced decrease in D1 receptor mRNA expression are mediated by A2a ADO receptor subtype. The results suggest a novel molecular mechanism linking activation of A2a ADO receptors with inhibition of D1 DA receptor expression.
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PMID:Extracellular cAMP inhibits D1 dopamine receptor expression in CAD catecholaminergic cells via A2a adenosine receptors. 1725 22

Physiological functions of organic cation transporters (OCTs) in the placenta include transporting essential nutrients from the maternal to fetal circulations. OCTN2 transports carnitine with high affinity, and the transport of several drugs has also been shown to be mediated by this transporter. In this work, the role of phosphorylation and dephosphorylation mechanisms in regulating OCTN2 was investigated by observing the effects of various activators and inhibitors of kinases and phosphatases on the uptake of carnitine in BeWo cells, a human choriocarcinoma trophoblast cell line frequently used as an in vitro model of the rate-limiting barrier for maternal-fetal exchange. Preincubation with genistein resulted in significant increases in both alkaline phosphatase (ALP) activity and carnitine uptake. Levamisole, an ALP inhibitor, caused a more substantial decrease in carnitine uptake than expected from its corresponding decrease in ALP activity. It was determined that levamisole competitively inhibits carnitine uptake, with a K(i) value of 1.01+/-0.05mM, and this effect has a greater role in decreasing carnitine uptake than any indirect effects of ALP inhibition upon OCTN2 function. Progesterone also competitively inhibited carnitine uptake (K(i)=48.6+/-5.0muM), but had no effect on ALP activity in BeWo cells.
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PMID:Contributions of phosphorylation to regulation of OCTN2 uptake of carnitine are minimal in BeWo cells. 1797 16

Protein phosphorylation and dephosphorylation are important regulators of cellular and extracellular events. The purpose of this study was to define how these events regulate cartilage matrix calcification in a cell culture system that mimics endochondral ossification. The presence of casein kinase II (CK2), an enzyme known to phosphorylate matrix proteins, was confirmed by immunohistochemistry. The importance of phosphoprotein phosphorylation and dephosphorylation was examined by comparing effects of inhibiting CK2 or phosphoprotein phosphatases on mineral accretion relative to untreated mineralizing controls. Specific inhibitors were added to differentiating chick limb-bud mesenchymal cell micromass cultures during the development of a mineralized matrix at the times of cell differentiation, proliferation, formation of the mineralized matrix, or proliferation of the mineral crystals. The mineralizing media for these cultures contained 4 mM inorganic phosphate and no organic-phosphate esters; control cultures had 1 mM inorganic phosphate. Mineralization was monitored based on (45)Ca uptake and infrared characterization of the mineral; cell viability was assessed by three independent methods. Treatments that caused cell toxicity were excluded from the analysis. Inhibition of CK2 activity with apigenin or CK2 inhibitor II reduced the rate of mineral deposition, but did not block mineral accretion. Effects were greatest during the time of mineralized matrix formation. Inhibition of phosphoprotein phosphatase activities with okadaic acid, calyculin A, and microcystin-LR, at early time points also markedly inhibited mineral accretion. Inhibition after mineralization had commenced increased the mineral yield. Levamisole, an alkaline phosphatase inhibitor, had no effect on mineral accretion in this system, suggesting the involvement of other phosphatases. Adding additional inorganic phosphate to the inhibited cultures after mineralization had started, but not earlier, reversed the inhibition indicating that the phosphatases were, in part, providing a source of inorganic phosphate. To characterize the roles of specific phosphoproteins blocking studies were performed. Blocking with anti-osteopontin antibody confirmed osteopontin's previously reported role as a mineralization inhibitor. Blocking antibodies to bone sialoprotein added from day 9 or on days 9 and 11 retarded mineralization, supporting its role as a mineralization nucleator. Antibodies to osteonectin slightly stimulated early mineralization, but had no effect after the time that initial mineral deposition occurs. Taken together, the results of this study demonstrate the importance of the phosphorylation state of extracellular matrix proteins in regulating mineralization in this culture system.
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PMID:Modulation of extracellular matrix protein phosphorylation alters mineralization in differentiating chick limb-bud mesenchymal cell micromass cultures. 1839 25

During endochondral and desmal osteogenesis, mineralization of bone and cartilage matrix requires an appropriate solubility product of calcium and phosphate, collagen as a nucleator and deactivation of inhibitors, in order to prevent heterotopic calcification. In the 1960s, Fleisch and coworkers detected pyrophosphate (PPi) as an inhibitor of hydroxyapatite crystal growth, which should be removed by cleavage to tissue non-specific alkaline phosphatase (TNAP) activity. This theory had been established by basic experiments performed with collagen gels and demineralized matrices. In order to investigate the effect of PPi on matrix mineralization in bone and cartilage, calcium content and TNAP activity were measured in organoid cultures of mouse calvarial osteoblasts and limb bud cartilage after treatment with PPi and/or levamisole. In organoid cultures, bone and cartilage develop in a clear histotypical manner. PPi did not induce mineralization. Beta-glycerophosphate (beta-GP) and inorganic phosphate (Pi) induced mineralization which could be significantly reduced by PPi. Levamisole, an inhibitor of TNAP, also reduced mineralization; the combination with PPi was additive. TNAP activity was increased after treatment with PPi and levamisole in both osteoblast and cartilage cultures. Mineralization induced by beta-GP and Pi decreased TNAP activity in the osteoblast but not in cartilage organoid culture. In this culture system, PPi reduced mineralization as predicted by Fleisch's theory. Indications of cleavage of PPi were indirectly found because inhibition of hydrolysis of PPi by levamisole further reduced mineralization, probably due to the higher amounts of PPi available for binding to hydroxyapatite.
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PMID:Effects of pyrophosphate on desmal and endochondral mineralization and TNAP activity in organoid culture. 1841 70

Tissue-nonspecific alkaline phosphatase (TNAP) plays a key role in mineralization by degrading inorganic pyrophosphate and providing free inorganic phosphate. We have previously reported that TNAP is induced by beta-glycerophosphate and NaH(2)PO(4) in short-term cultures of SaOS-2 human osteoblast-like cells and that PHEX (phosphate-regulating gene with homologies to endopeptidase on the X chromosome) mRNA is also induced after TNAP induction. In the present study, we have investigated the effects of levamisole, a TNAP inhibitor, and phosphonoformic acid (PFA), a type III sodium-phosphate cotransporter inhibitor, on the phosphate-induced expression of TNAP and mineralization. Levamisole inhibited beta-glycerophosphate-induced mineralization, TNAP and PHEX expression, and the increase in enzymatic activity of NPP1 (5'-nucleotide pyrophosphatase phosphodiesterase 1), but did not inhibit NaH(2)PO(4)-induced mineralization. PFA completely inhibited NaH(2)PO(4)-induced mineralization and NPP1 enzymatic activation, and partly inhibited beta-glycerophosphate-induced mineralization, but did not affect the increase in TNAP activity. These results suggest that phosphate derived from TNAP-induced hydrolysis of beta-glycerophosphate yields signals that induce TNAP expression and mineralization, and that PHEX expression may be linked to TNAP expression. However, luciferase assays failed to detect any transcriptional activation of the promoter region of the human TNAP gene by beta-glycerophosphate or NaH(2)PO(4), suggesting that the effects of these phosphates may be indirect.
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PMID:The role of tissue-nonspecific alkaline phosphatase in the phosphate-induced activation of alkaline phosphatase and mineralization in SaOS-2 human osteoblast-like cells. 1850 Jun 57

Presence of basic calcium phosphate in knee joints of osteoarthritis patients could be prevented by inhibiting tissue non-specific alkaline phosphatase (TNAP) activity. Levamisole or the L stereoisomer of tetramisole (a known TNAP inhibitor) has been used as a treatment for curing rheumatoid arthritis but its therapeutical use is limited due to side effects. We report the synthesis and the TNAP inhibition property of benzo[b]thiophene derivatives, among which benzothiopheno-tetramisole and benzothiopheno-2,3-dehydrotetramisole, which could be involved in a drug therapy for osteoarthritis. Two water soluble racemic benzothiopheno-tetramisole and -2,3-dehydrotetramisole with apparent inhibition constants K(i)=85+/-6 microM and 135+/-3 microM (n=3) comparable to that of enantiomeric levamisole 93+/-4 microM were found. Several novel derivatives showed more pronounced inhibition properties towards intestinal alkaline phosphatase than TNAP.
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PMID:Synthesis and evaluation of benzo[b]thiophene derivatives as inhibitors of alkaline phosphatases. 1978 51

Levamisole has previously been identified as an inhibitor of angiogenesis in vitro and in vivo, but the mechanism behind the anti-angiogenic behavior has not yet been established. However, one known effect of levamisole is the inhibition of alkaline phosphatase, and this fact encouraged us to test other phosphatase inhibitors for their anti-angiogenic effects by using the same method as used to identify levamisole: an ELISA-based co-culture angiogenesis assay giving quantitative and qualitative results. Historically, intracellular phosphatases have been associated with the downregulation of signaling pathways, and kinases with their upregulation, but lately, the phospatases have also been coupled to positive signaling, which is why inhibition of phosphatases has become associated with anti-tumorigenic and anti-angiogenic effects. The results obtained in this work reveal several agents with anti-angiogenic potential and give a strong indication that phosphatase inhibition is linked to anti-angiogenic activity. An apparent disruption of endothelial tube formation was seen for seven of eight phosphatase inhibitors tested in the angiogenesis assay. By looking at the morphological results, it was seen that most of the inhibitors impaired proliferation and elongation of the endothelial cells, which still had a differentiated appearance. One inhibitor, PTP inhibitor IV, seemed to impair endothelial cell differentiation and induced the same morphology as when cells were treated with levamisole, although at a 200 times lower concentration than that of levamisole. Hence, our work points out compounds with a potential that may be of use in the search for new medical products for the treatment of malignant tumors, or other conditions where angiogenesis plays a central role.
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PMID:Phosphatase inhibitors with anti-angiogenic effect in vitro. 2004 71

CD73 metabolizes extracellular 5'-AMP to adenosine; yet recent experiments in brain tissue suggest that CD73 is not required for the metabolism of 5'-AMP to adenosine because of tissue nonspecific alkaline phosphatase (TNAP), which like CD73 is a GPI-anchored ecto-enyzme with 5'-nucleotidase activity. Because adenosine importantly regulates renovascular function, we investigated whether both TNAP and CD73 are involved in the renovascular metabolism of 5'-AMP. To test this, we examined in isolated, perfused mouse kidneys the metabolism of 5'-AMP (applied to the lumen of the renal vasculature via intrarenal artery administration) to adenosine by measuring renal venous levels of 5'-AMP, adenosine, and inosine (adenosine metabolite) by mass spectrometry. In one study, we compared 5'-AMP metabolism in naive CD73+/+ (wild-type, n = 16) vs. CD73-/- (knockout, n = 16) kidneys; and in a second study, we compared 5'-AMP metabolism in CD73+/+ (n = 9) vs. CD73-/- (n = 8) kidneys pretreated with levamisole (1 mmol/l; TNAP inhibitor). In naive kidneys, 5'-AMP increased renal venous 5'-AMP, adenosine, and inosine, and these responses were similar in CD73+/+ vs. CD73-/- kidneys. Levamisole per se did not inhibit renovascular 5'-AMP metabolism; however, in the presence of levamisole, 5'-AMP increased renal venous 5'-AMP threefold more in CD73-/- vs. CD73+/+ kidneys and knockout of CD73 inhibited 5'-induced adenosine and inosine by 81 and 86%, respectively. TNAP mRNA, protein, and activity were similar in CD73+/+ vs. CD73-/- kidneys. In conclusion, CD73 and TNAP play interactive roles to metabolize luminally applied 5'-AMP in the renal vasculature such that inhibition of both is required to inhibit the production of adenosine.
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PMID:Interactive roles of CD73 and tissue nonspecific alkaline phosphatase in the renal vascular metabolism of 5'-AMP. 2499 Aug 99

Tissue non-specific alkaline phosphatase (TNAP) may be involved in the synthesis of GABA and adenosine, which are the main inhibitory neurotransmitters in cortex. We explored this putative TNAP function through electrophysiological recording (local field potential ) in slices of mouse somatosensory cortex maintained in vitro. We used tetramisole, a well documented TNAP inhibitor, to block TNAP activity. We expected that inhibiting TNAP with tetramisole would lead to an increase of neuronal response amplitude, owing to a diminished availability of GABA and/or adenosine. Instead, we found that tetramisole reduced neuronal response amplitude in a dose-dependent manner. Tetramisole also decreased axonal conduction velocity. Levamisole had identical effects. Several control experiments demonstrated that these actions of tetramisole were independent from this compound acting on TNAP. In particular, tetramisole effects were not stereo-specific and they were not mimicked by another inhibitor of TNAP, MLS-0038949. The decrease of axonal conduction velocity and preliminary intracellular data suggest that tetramisole blocks voltage-dependent sodium channels. Our results imply that levamisole or tetramisole should not be used with the sole purpose of inhibiting TNAP in living excitable cells as it will also block all processes that are activity-dependent. Our data and a review of the literature indicate that tetramisole may have at least four different targets in the nervous system. We discuss these results with respect to the neurological side effects that were observed when levamisole and tetramisole were used for medical purposes, and that may recur nowadays due to the recent use of levamisole and tetramisole as cocaine adulterants.
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PMID:Tetramisole and Levamisole Suppress Neuronal Activity Independently from Their Inhibitory Action on Tissue Non-specific Alkaline Phosphatase in Mouse Cortex. 2621 15


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