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)

Recent evidence suggests that the production of nitric oxide (NO) may have important roles in the regulation of osteoblast and osteoclast metabolism. The present study was performed to investigate the effects of interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma) on the expression of inducible NO-synthase (iNOS) and to measure high-output production of NO by primary rat osteoblasts and osteoblastic cell lines ROS 17/2.8, MC3T3-E1 and MG-63. In addition, we have investigated if NO may mediate some of the effects of these cytokines on osteoblast metabolism. Northern blots and immunocytochemistry revealed time-dependent iNOS messenger RNA and protein expression in primary rat osteoblasts in response to cytokine treatment. Reverse transcription polymerase chain reaction amplified an 807-base pair (bp) product from ROS 17/2.8 cells, which had a size and restriction enzyme-cut pattern identical to that predicted for authentic rat iNOS. Nitrite accumulation in culture medium was induced by IFN-gamma in a time- and dose-dependent manner and inhibited by cotreatment with inhibitors of NOS activity and by dexamethasone. IL-1 beta, TNF-alpha, and bacterial lipopolysaccharide were found to have weak stimulatory effects on nitrite production on their own. However, IL-1 beta and TNF-alpha showed strong synergy with IFN-gamma, but, surprisingly, lipopolysaccharide was found to exert potent inhibitory effects on IFN-gamma-induced nitrite synthesis. Basal production of nitrite and induction of its synthesis was similarly observed with primary rat osteoblasts as well as ROS 17/2.8, MC3T3-E1, and MG-63 cell lines. Cytokine-induced NO production significantly reduced osteoblast activity, as was evidenced by inhibition of DNA synthesis, cell proliferation, alkaline phosphatase activity, and osteocalcin production. The results provide evidence for a basal expression of iNOS activity and show that the iNOS messenger RNA, protein, and enzyme activity are all induced by cytokines across the species. The data further suggest that osteoblast-derived NO may have an important role in mediation of localized bone destruction associated with inflammatory bone diseases such as rheumatoid arthritis.
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PMID:Cytokine-stimulated expression of inducible nitric oxide synthase by mouse, rat, and human osteoblast-like cells and its functional role in osteoblast metabolic activity. 758 94

Although the role of intraneuronal neurofilamentous aggregates in the pathogenesis of ALS is unknown, their presence forms a key neuropathological hallmark of the disease process. Conversely, the experimental induction of neurofilamentous aggregates in either neurotoxic or transgenic mice gives rise to motor system degeneration. To determine whether alterations in the physiochemical properties of NF are present in sporadic ALS, we purified NF subunit proteins from cervical spinal cord of ALS and age-matched control patients. The cytoskeleton-enriched, Triton X-100 insoluble fraction was further separated into individual NF subunits using hydroxyapatite HPLC. We observed no differences between control and ALS in the characteristics of NFH, including migration patterns on 2D-IEF, sensitivity to E. coli, alkaline phosphatase mediated dephosphorylation, peptide mapping, or proteolysis (calpain, calpain/calmodulin mediated, phosphorylated or dephosphorylated NFH). NFL showed no differences in 2D-IEF migration patterns, peptide mapping, or the extent of NFL nitrotyrosine immunoreactivity in either the Triton soluble or insoluble fractions. The latter observation demonstrated that NFL nitration is a ubiquitous occurrence in neurons and suggests that NFL might function as a sink for free reactive nitrating species. In contrast to the lack of differences in the post-translational processing of NF in ALS, we did observe a selective suppression of NFL steady state mRNA levels in the limb innervating lateral motor neuron column of ALS. This occurred in the absence of modifications in NFH, NFM or neuronal nitric oxide synthase (Type I NOS; nNOS) steady state mRNA levels. Coupled with previous observations of nNOS immunoreactivity co-localizing with NF aggregates in ALS motor neurons, this suggests activation of the nNOS enzyme complex in ALS, which would be predicted to contribute directly to the generation of reactive nitrating species. Given this, the isolated suppression of NFL steady state mRNA levels in ALS may indicate that ALS motor neurons are at an intrinsic deficit in the ability to buffer free reactive nitrating species.
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PMID:Neurofilament metabolism in sporadic amyotrophic lateral sclerosis. 1054 27

In a search for new inhibitors of the IFN-gamma mediated signal transduction in HeLa S3 cells using secreted alkaline phosphatase (SEAP) as reporter gene, the novel pyran-dione trichodion was isolated from fermentations of the imperfect fungus Trichosporiella sp. 20-95. The compound inhibits the IFN-gamma mediated expression of the reporter gene with IC(50) values of 21-42 microM (5-10 microgram/ml). The NF-kappaB and AP-1 mediated expression of the reporter gene are inhibited with IC(50) values of 42-84 microM (10-20 microgram/ml) and 21 microM (5 microgram/ml) respectively. Western blotting with COX-2 and NOS II antibodies showed that the expression of both proinflammatory enzymes is almost completely inhibited at 21-42 microM (5-10 microgram/ml) in LPS/IFN-gamma stimulated J774 mouse macrophages. Studies on the mode of action of the compound revealed that the inhibition of the NF-kappaB dependent pathway is due to the stabilization of the IkappaB protein and the inhibition of the IFN-gamma dependent signaling is caused by an inhibition of the phosphorylation of the STAT1alpha transcription factor.
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PMID:Trichodion, a new inhibitor of inflammatory signal transduction pathways from a Trichosporiella species. 1090 24

Oestradiol can stimulate osteoblast activity. Osteoblast function is thought to be regulated by nitric oxide (NO). We hypothesised that the effect of 17beta-oestradiol (17beta-E(2)) on osteoblast activity is mediated by NO. This hypothesis was tested using osteoblasts isolated from human trabecular bone, calvariae of rats, endothelial NO synthase (eNOS) gene-deficient mice, and their wild-type counterparts. Our results show that 17beta-E(2) dose-dependently stimulated proliferation and differentiation of primary human, rat and wild-typeosteoblasts. The presence of N(G)-monomethyl-l-arginine (10(-3) M), an inhibitor of NOS activity, blocked the 17beta-E(2)-(10(-7) M)-induced increases in thymidine incorporation (P < 0.01), alkaline phosphatase activity (P < 0.01) and bone nodule formation (P < 0.01) of wild-type, human and rat osteoblasts, respectively. Moreover, 17beta-E(2) did not induce a response in eNOS gene-deficient osteoblasts. 17beta-E(2) also increased total eNOS enzyme expression in rat osteoblasts. These findings indicate 17beta-E(2) modulates osteoblast function by NO-dependent mechanisms mediated via the eNOS isoform.
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PMID:Nitric oxide mediates 17beta-estradiol-stimulated human and rodent osteoblast proliferation and differentiation. 1106 1

Nitric oxide (NO) is a pleiotropic signaling molecule that is produced by bone cells constitutively and in response to diverse stimuli such as proinflammatory cytokines, mechanical strain, and sex hormones. Endothelial nitric oxide synthase (eNOS) is the predominant NOS isoform expressed in bone, but its physiological role in regulating bone metabolism remains unclear. Here we studied various aspects of bone metabolism in female mice with targeted disruption of the eNOS gene. Mice with eNOS deficiency (eNOS KO) had reduced bone mineral density, and cortical thinning when compared with WT controls and histomorphometric analysis of bone revealed profound abnormalities of bone formation, with reduced osteoblast numbers, surfaces and mineral apposition rate. Studies in vitro showed that osteoblasts derived from eNOS KO mice had reduced rates of growth when compared with WT and were less well differentiated as reflected by lower levels of alkaline phosphatase activity. Mice with eNOS deficiency lost bone normally following ovariectomy but exhibited a significantly blunted anabolic response to high dose exogenous estrogen. We conclude that the eNOS pathway plays an essential role in regulating bone mass and bone turnover by modulating osteoblast function.
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PMID:Defective bone formation and anabolic response to exogenous estrogen in mice with targeted disruption of endothelial nitric oxide synthase. 1115 48

Efforts have been made to reduce the undesirable side effects of cisplatin, mainly nephro- and neurotoxicity, but their reduction is usually accompanied by a concomitant inhibition of antitumor activity. The local anesthetic procaine hydrochloride (P.HCl) improves the therapeutic index of cisplatin not only by the reduction of its nephro- and hemotoxicity, but also by an increase of its antitumor activity. We therefore investigated the effects of a combined treatment of cisplatin and P.HCl on rat kidneys and compared this to kidneys from rats treated with a toxic dose of cisplatin or P.HCl alone. Treatment with a saline solution was used as control. Dehydrogenase activities [succinate dehydrogenase (SDH) and NADPH diaphorase reaction demonstrating nitric oxide synthase (NOS/NADPHd)] and phosphatase activities [K -nitrophenyl phosphatase (K pNPPase), alkaline phosphatase (AlPase) and acid phosphatase (AcPase)] were studied on cryostatic sections of kidneys from controls and treated rats. Evidence of heavy morphological damage and altered AlPase and AcPase activities induced by cisplatin were observed in the S3 segment of the proximal tubules. In addition, SDH and K pNPPase activities showed some changes in the distal tubule cells. The NOS/NADPHd activity in macula densa was drastically reduced. Combined treatment of cisplatin and P.HCl greatly attenuated morphological alterations of the rat kidney and reduced the changes in enzyme activities, except for NOS/NADPHd activity, compared to the cisplatin-treated group of animals. The study indicates that, in cisplatin-induced nephrotoxicity, a significant role is played by enzyme activities, in particular K pNPPase and NOS/NADPHd, and that P.HCl can mitigate the nephrotoxicity of cisplatin, possibly by influencing some enzyme activities involved in important renal metabolic pathways.
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PMID:Protective effect of procaine hydrochloride on cisplatin-induced alterations in rat kidney. 1243 38

In a search for new inhibitors of the IFN-gamma mediated signal transduction in HeLa S3 cells using secreted alkaline phosphatase (SEAP) as reporter gene, a novel compound, designated as S14-95 was isolated from fermentations of the imperfect fungus Penicillium sp. 14-95. The compound inhibits the IFN-gamma mediated expression of the reporter gene with IC50 values of 2.5 to approximately 5 microg/ml (5.4 to approximately 10.8 microM). Furthermore the compound inhibited the expression of the proinflammatory enzymes COX-2 and NOS II at 5 microg/ml (10.8 microM) in LPS/IFN-gamma stimulated J774 mouse macrophages. Studies on the mode of action of the compound revealed that the inhibition of the IFN-gamma dependent signaling pathway is caused by an inhibition of the phosphorylation of the STAT1alpha transcription factor. In addition, S14-95 inhibited the activation of the p38 MAP kinase, which is involved in the inducible expression of many proinflammatory genes.
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PMID:S14-95, a novel inhibitor of the JAK/STAT pathway from a Penicillium species. 1281 6

This experimental study was designed to examine the effect of nitric oxide (NO) on bone metabolism in ovariectomized rats following chronic ethanol treatment. Chronic ethanol intake was produced by gradual substitution (within 3 weeks) of tap water in diet with 5,10,15 and finally 20% of ethanol. Thereafter, the rats were maintained under these conditions for a duration of 4 months. The rats were divided into two groups. The first group received sham operation (SHAM) and the rats in Group II were ovariectomized (OVX). Five weeks after the SHAM and ovariectomy, the rats were treated with ethanol for 4 months. After this period of ethanol administration, the NOS inhibitor N(W)-nitro-L-arginine methyl ester (L-NAME) was given for three weeks along with ethanol to the same rats. Serum interleukin (IL)-1beta, IL-6, tumor necrosis factor (TNF)-alpha, NO, calcium (Ca), phosphorous (P), parathyroid hormone (PTH), 25 HydroxyvitaminD3 [25(OH)D3], alkaline phosphatase (ALP), bone alkaline phosphatase (b-ALP), alanine amino transferase (ALT), aspartate amino transferase (AST), gamma-glutamyltransferase (GGT) levels were measured in different stages of the experiment. IL-1beta, IL-6, TNFalpha and NO levels increased after ethanol administration in SHAM and OVX rats. The decrease in serum Ca was significant while the changes in P, PTH and 25 (OH)D3 levels were not. ALP and b-ALP levels were significantly decreased; ALT, AST and GGT levels were significantly increased. In ovariectomized and SHAM rats, administration of L-NAME together with ethanol, produced a significant increase in IL-1beta, IL-6 and TNFalpha levels. In this group, Ca and P levels were significantly increased, PTH and 25 (OH)D3 levels were significantly decreased. Also, there was a significant decrease in ALT, AST, ALP, b-ALP, and GGT levels. NO increase due to alcohol intake may function as a protective mechanism preventing bone resorption in cases of estrogen insufficiency.
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PMID:The role of nitric oxide on bone metabolism in ovariectomized rats following chronic ethanol intake. 1570 79

The goal of this investigation was to explore the mechanism by which NOS and NO serve to regulate events linked to chondrocyte terminal differentiation. NOS isoform expression and NO adducts in chick growth cartilage were detected by immunohistochemistry and Western blot analysis. All NOS isoforms were expressed in chick growth plate chondrocytes with the highest levels present in the hypertrophic region. The enzymes were active since nitrosocysteine and nitrotyrosine residues were detected in regions of the epiphysis with the highest levels of NOS expression. Maturing chick sternal chondrocytes evidenced an increase in NO release and a rise in NOS protein levels. When treated with NOS inhibitors, there was a decrease in the alkaline phosphatase activity of the hypertrophic cells. On the other hand, NO donors caused a small but significant elevation in alkaline phosphatase activity. Transient transfections of chondrocytes with an endothelial NOS isoform caused an increase in collagen type X promoter activity. Induction of both collagen type X expression and alkaline phosphatase activity was blocked by inhibitors of the cGMP pathway. These findings indicate that NO is generated by three NOS isoforms in terminally differentiated chondrocytes. The expression of NOS and the generation of NO enhanced maturation by upregulating alkaline phosphatase and collagen type X expression. Since expression of these two determinants was blocked by inhibitors of the cGMP pathway, it is concluded that NO metabolism is required for development of the mature chondrocyte phenotype.
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PMID:Nitric oxide-nitric oxide synthase regulates key maturational events during chondrocyte terminal differentiation. 1586 14

Among the different scorpion species, Buthus martensi Karsch, a widely distributed scorpion species in Asia especially in Korea, has received a lot of attention. Indeed, over the past decade, more than 70 different peptides, toxins, or homologues have been isolated. It may prove a valuable resource for identifying potential anti-inflammatory and analgesic drugs. The recent observation has suggested that the aromatase is a possible local modulator of bone remodeling in osteoarthritis and osteoporosis. In the present study, therefore, the effect of Buthus martensi Karsch (BMK) extract, traditional immunosuppressive Korean aqua-acupuncture water, on the bone function of human osteoblastic cells was studied. To provide insights into the effect of BMK on aromatase activity in bone-derived cells, we examined the human leukaemic cell line FLG 29.1, which is induced to differentiate toward the osteoclastic phenotype by 12-O-tetradecanoyl-phorbol-13-acetate (TPA) and transforming growth factor (TGF)-beta1, and the primary first-passage osteoblastic cells (hOB). Gene expression of the aromatase was not affected by Buthus martensi Karsch in FLG 29.1 and hOB cells. However, enzyme activity was stimulated in a time-dependent fashion by 10.0 microg/ml BMK and by either 1-50 nM TPA or 0.01-0.5 ng/ml TGF-beta1, with maximal responses after 2-3 hr exposure. On the other hand, BMK strongly inhibited interleukin-1beta (IL-1beta)- and tumor necrosis factor (TNF)alpha-induced Nitricoxide (NO) synthase expression with little effect on constitutive NO synthase expression. BMK extracts (10 microg/ml) inhibited cytokine-induced iNOS and nNOS expression. BMK (10 microg/ml) did not affect the ecNOS expression, indicating the extracts are not working on the constitutive NOS expression. BMK strongly inhibited the cytokine-induced NO production (p < 0.01). BMK also showed significant inhibition on NO production in both induced by TNF-alpha+IL-1beta. NO donors, sodium nitroprusside, and NONOate dose-dependently elevated alkaline phosphatase activity. These results suggest that NO directly facilitates osteoblastic differentiation. This result also suggests that BMK is effective for bone resorptive action in bone cells.
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PMID:Effect of Buthus martensi Karsch on aromatase activity and cytokine-inducted NOS and NO production in osteoblasts and leukaemic cell line FLG 29.1. 1687 93


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