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

---

Query: EC:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of cyclosporin A on induction of nitric oxide synthase in rat aortic smooth muscle cells was examined. A combination of interleukin-1 alpha (100 U/mL) and tumor necrosis factor--alpha (5000 U/mL) induced accumulation of nitrite/nitrate, the stable end products of nitric oxide, in culture media within 48 hours. Cyclosporin A inhibited this nitrite/nitrate accumulation in a concentration-dependent manner with an IC50 of 4 x 10(-7) mol/L when applied simultaneously with the cytokines. The expression of inducible nitric oxide synthase messenger RNA (mRNA) induced by the combination of interleukin-1 alpha and tumor necrosis factor-alpha was inhibited by the cyclosporin A cotreatment. Cyclosporin A did not decrease inducible nitric oxide synthase mRNA stability in the presence of transcription inhibitor actinomycin D (5 micrograms/mL). Induction of nitrite/nitrate production by the combination of tumor necrosis factor-alpha and bacterial lipopolysaccharide or that of interleukin-1 alpha and interferon gamma (100 U/mL) was also inhibited by cyclosporin A cotreatment. Another inhibitor of calcineurin, FK506 (up to 10(-6) mol/L), had no effect on the induction of nitrite/nitrate production, suggesting the possibility that the inhibitory effect of cyclosporin A may be exerted by means of a novel pathway other than inhibition of calcineurin. These results indicate that cyclosporin A inhibits inducible nitric oxide synthase induction at the mRNA level and that inducible nitric oxide synthase in vascular smooth muscle cells can be a target for cyclosporin A, providing a possible mechanism for the interference of the drug with the balance of vasoactive substances.
...
PMID:Cyclosporin A inhibits nitric oxide synthase induction in vascular smooth muscle cells. 753 14

Leishmania parasites, transmitted by phlebotomine sand flies, are obligate intracellular parasites of macrophages. The sand fly Phlebotomus papatasi is the vector of Leishmania major, a causative agent of cutaneous leishmaniasis in the Old World, and its saliva exacerbates parasite proliferation and lesion growth in experimental cutaneous leishmaniasis. Here we show that P. papatasi saliva contains a potent inhibitor of protein phosphatase 1 and protein phosphatase 2A of murine macrophages. We further demonstrate that P. papatasi saliva down regulates expression of the inducible nitric oxide synthase gene and reduces nitric oxide production in murine macrophages. Partial biochemical characterization of the protein phosphatase and nitric oxide inhibitor indicated that it is a small, ethanol-soluble molecule resistant to boiling, proteolysis, and DNase and RNase treatments. We suggest that the P. papatasi salivary protein phosphatase inhibitor interferes with the ability of activated macrophages to transmit signals to the nucleus, thereby preventing up regulation of the induced nitric oxide synthase gene and inhibiting the production of nitric oxide. Since nitric oxide is toxic to intracellular parasites, the salivary protein phosphatase inhibitor may be the mechanism by which P. papatasi saliva exacerbates cutaneous leishmaniasis.
...
PMID:Phlebotomus papatasi saliva inhibits protein phosphatase activity and nitric oxide production by murine macrophages. 952 78

1. Microglial cells represent the first line of defence in the brain against infection and damage. However, under conditions of chronic inflammation and neurodegeneration, excessive activation of microglia can contribute to the neurodegenerative process by releasing a cornucopia of potentially cytotoxic substances including the cytotoxic free radical nitric oxide (NO). Although the cell signalling events implicated in NO formation in peripheral macrophages are well defined, events occurring in the phenotypically homologous cerebral microglial cell are not yet fully characterized. 2. In the present study, a cloned murine microglial cell line (N9), stimulated with combined lipopolysaccharide/interferon-gamma (LPS/IFN) incubation, was shown to produce a significant increase in NO formation, as measured by medium nitrite levels, during 8-72 h exposure. 3. LPS/IFN-stimulated NO production was partially inhibited with the nitric oxide synthase (NOS) competitive antagonists; N(omega)-nitro-L-arginine methyl ester and N(omega)-nitro-L-arginine. The ability of the selective inducible (iNOS) inhibitor, aminoguanidine, but not the selective 'neuronal-type' constitutive (cNOS) inhibitor 7-nitroindazole, to inhibit NO production suggested a primary role of iNOS in this response and was confirmed by immunolabelling of activated cells with a specific iNOS antibody. 4. A series of tyrosine kinase inhibitors, herbimycin A, genestein, tyrphostins, AG-126, AG-556 and the tyrosine phosphatase inhibitors, sodium orthovanadate and phenylarsine oxide, significantly attenuated LPS/IFN-mediated NO production. The serine/threonine kinase inhibitors, staursporine (protein kinase C), H-9 (cyclic GMP/cyclic AMP-dependent kinase) or serine/threonine phosphatase inhibitors, cyclosporin A (phosphatase 2B) and okadaic acid (phosphatase 1/2A), reduced NO formation by an apparent cytostatic mechanism, as determined by cellular reduction of 3-(4,5-dimethylthiazol-2-yi)-2,5-diphenyl-tetrazolium bromide (MTT). 5. The present results suggest that the co-ordinated activation of protein tyrosine kinases/phosphatases, and proximal signalling events implicating the interplay between serine-threonine kinases/phosphatases, is intricately linked with inflammatory mediated mechanisms of iNOS activation in microglial cells by regulating the activation of the transcription factor NFkappaB.
...
PMID:Suppression of nitric oxide formation by tyrosine kinase inhibitors in murine N9 microglia. 953 16

Imidazoline compounds have been considered for the treatment of type 2 diabetes. We have now investigated the effects of imidazolines on interleukin (IL)-1beta-induced beta-cell apoptosis and the signal transduction pathways involved. Inhibition of Ca2+ influx into beta-cells by D-600, a blocker of voltage-gated L-type Ca2+ channels, suppressed IL-1beta-induced apoptosis. Our data show that calcineurin, Ca2+/calmodulin-dependent serine/threonine protein phosphatase 2B, is responsible for the effect of Ca2+ on beta-cell apoptosis. We also demonstrate that IL-1beta-mediated apoptosis correlates with expression of inducible nitric oxide synthase (iNOS) and the increase in intracellular production of nitric oxide. An inhibitor of cGMP-dependent protein kinase (PKG), KT5823, suppressed IL-1beta-induced apoptosis, suggesting the involvement of a PKG-dependent pathway in the apoptotic process. One of the major findings in this study is that imidazoline compounds RX871024 and efaroxan, suggested as prototypes of a new generation of drugs against type 2 diabetes, can protect against IL-1beta-induced apoptosis in pancreatic beta-cells, possibly by their inhibition of the expression of iNOS, a key element in the IL-1beta-induced apoptotic pathway in pancreatic beta-cells. These data suggest that imidazoline compounds should be explored as a potential therapeutic agent for the treatment of both type 1 and type 2 diabetes.
...
PMID:Imidazoline compounds protect against interleukin 1beta-induced beta-cell apoptosis. 1127 6

C(60)-Fullerene trisamine adducts inhibit neuronal nitric oxide synthase and calcineurin phosphatase activities in a manner completely reversible by calmodulin. As measured by difference spectroscopy, D(3)-trisamine and C(3)-semiamine fullerene adducts displace trifluoperazine bound to calmodulin coincident with their binding. These binding events are complete at a molar ratio of 4 mol added fullerene per mole calmodulin. Trisamine fullerene adducts alter the native electrophoretic mobility of calmodulin, producing a heterogeneity of bands with associated fullerene. D(3)- and C(3)-trisamine fullerene adducts interact with dansylated calmodulin, producing a 50% loss of maximal fluorescence at concentrations of 30 nM. At higher concentrations than those required to inhibit neuronal nitric oxide synthase, trisamine fullerene adducts inhibit nitric oxide formation by the cytokine-inducible nitric oxide synthase isoform. These inhibitions are fully reversible by calmodulin and skeletal muscle troponin C but not by skeletal muscle parvalbumin. Of the trisamine fullerene adducts tested only the C(3)- and D(3)-semiamine adducts inhibit Ca(2+)-dependent nitric oxide production in GH(3) pituitary cells. These observations support the proposal that trisamine C(60)-fullerene adducts are potent calmodulin antagonists, some of which display activity in intact cellular systems.
...
PMID:Trisamine C(60)-fullerene adducts inhibit neuronal nitric oxide synthase by acting as highly potent calmodulin antagonists. 1188 98

Nitric oxide (NO) production is increased in inflammatory bowel disease and selective inducible nitric oxide synthase (iNOS) inhibitors have proved to be anti-inflammatory in experimentally induced colitis. The aim of the present study was to test if drugs used in the treatment of inflammatory bowel disease effect on NO production in colon epithelial and macrophage cell lines. We tested the effects of cyclosporin A, tacrolimus (FK-506), methotrexate, sulfasalazine, 5-aminosalicylic acid and two novel TNF-alpha antagonists etanercept and infliximab on endotoxin-induced NO production in human T84 colon epithelial cells and in murine J774 macrophages. Cyclosporin A and FK-506 inhibited iNOS expression, and subsequent NO production, in a dose-dependent manner at therapeutically achievable drug concentrations in both cell lines. The effect was most pronounced when cyclosporin A was given 1 h prior to 4 h after endotoxin, and declined thereafter, indicating that cyclosporin A does not inhibit iNOS activity. Neither cyclosporin A nor FK-506 altered the activation of nuclear factor-kappaB (NF-kappaB) that is a critical transcription factor for iNOS. Sulfasalazine inhibited NO production slightly only when given at high (100 microM) drug concentrations. Methotrexate, 5-aminosalicylic acid and TNF-alpha antagonists infliximab and etanercept were practically ineffective. Two inhibitors of phosphatase calcineurin, cyclosporin A and FK-506, inhibited iNOS expression and NO production in human T84 colon epithelial cells and in murine J774 macrophages by an NF-kappaB independent manner. These findings are implicated in the anti-inflammatory action of these compounds.
...
PMID:Calcineurin inhibitors, cyclosporin A and tacrolimus inhibit expression of inducible nitric oxide synthase in colon epithelial and macrophage cell lines. 1214 47

Estimation of post-mortem interval (PMI) remains an elusive issue in forensic investigations. In this study, we examined the possible use of calmodulin (CaM) binding proteins (CaMBPs) as indicators of PMI. Whole CaMBP populations from homogenized rat lung and rat skeletal muscle removed at 0, 24, 48 and 96 h post-mortem at 21 degrees C were detected by the calmodulin binding overlay technique (CaMBOT) using 35S-VU1-CaM and visualized by autoradiography. CaMBOT showed that, in both tissues, the CaMBP population remained relatively stable for up to 96 h post-mortem with the exception of a single approximately 200 kDa CaMBP that increased in 24 h post-mortem samples then showed decreasing amounts at subsequent times. Immunoblot analysis of the specific CaMBPs, Ca(2+)/CaM-dependent kinase II (CaMKII), calcineurin A (CNA), myristoylated alanine-rich C-kinase substrate (MARCKS) and inducible nitric oxide synthase (iNOS) were done on lung tissue samples. CaMKII levels did not change appreciably over the 96 h PMI examined. In contrast to iNOS levels, which varied from sample to sample, CNA and MARCKS showed predictable patterns of change: the level of MARCKS decreased steadily in the 0-96 h post-mortem lung samples while CNA underwent a shift in mobility on SDS-PAGE by 24 h post-mortem before slowly decreasing in amount. The stability of CaMKII levels over 96 h was also seen in skeletal muscle tissue while CNA showed variable levels at 0, 48 and 96 h with the presence of the rapidly migrating band at 24 h. These patterns of change in CaMBPs provide some insight into the post-mortem changes in calmodulin-mediated signaling components in lung and skeletal muscle and support the further study of CNA and CaMKII as potential markers for estimating short- and long-term PMIs.
...
PMID:Post-mortem changes in calmodulin binding proteins in muscle and lung. 1259 53

Cyclosporine A (CsA) is associated with the development of cardiovascular toxicity in transplant patients but can exert myocardial protection against ischemia/reperfusion damages. We examined in a rat model of chronic CsA administration whether subtle variations in the NO pathway could account for these opposite effects. CsA treatment rapidly led to an increase in myocardial Hsp90 expression promoting the recruitment of Akt and calcineurin, thereby promoting eNOS activation through Ser1177 phosphorylation and Thr495 dephosphorylation, respectively. This was associated with an increase in myocardial VEGF expression and led to anti-apoptotic effects in isolated cardiac myocytes. Upon longer CsA exposure, cardiac toxicity developed, as documented by the infiltration of connective tissue and the increase in iNOS expression. These later effects were associated with a dramatic decrease in the abundance and scaffold function of Hsp90, thereby unraveling the key role of Hsp90 in governing CsA effects.
...
PMID:Changes in Hsp90 expression determine the effects of cyclosporine A on the NO pathway in rat myocardium. 1452 73

Ca(2+) and Ca(2+)/calmodulin-dependent protein phosphatase calcineurin (CN) have been known to play crucial roles in immune response and inflammation. Using mouse peritoneal macrophages and RAW 264.7 macrophage cells, we demonstrated that LPS mobilized intracellular free Ca(2+) and induced CN phosphatase activity. iNOS expression and NO secretion in response to LPS were suppressed by Ca(2+) antagonists (TMB-8, BAPTA/AM, and nifedipine) and CN inhibitor (cyclosporin A). Transient expression of constitutively active CN in mouse peritoneal macrophages and RAW 264.7 macrophages strongly activated NF-kappaB, a key mediator of iNOS expression. We also found that CN mediates NF-kappaB activation via IkappaB-alpha hyperphosphorylation and degradation. Overexpression of dominant negative mutant of IKKalpha and -beta demonstrates that only IKKbeta is the target for CN. These results indicate that CN is required for full iNOS expression and the effective activation of NF-kappaB in RAW 264.7 and peritoneal macrophages.
...
PMID:Ca2+/calmodulin-dependent protein phosphatase calcineurin mediates the expression of iNOS through IKK and NF-kappaB activity in LPS-stimulated mouse peritoneal macrophages and RAW 264.7 cells. 1474 91

Astrocyte infection in HIV has been associated with rapid progression of dementia in a subset of HIV/AIDS patients. Astrogliosis and microglial activation are observed in areas of axonal and dendritic damage in HIVD. In HIV-infected astrocytes, the regulatory gene tat is over expressed and mRNA levels for Tat are elevated in brain extracts from individuals with HIV-1 dementia. Tat can be detected in HIV-infected astrocytes in vivo. The HIV-1 protein Tat transactivates viral and cellular gene expression, is actively secreted mainly from astrocytes, microglia and macrophages, into the extracellular environment, and is taken up by neighboring uninfected cells such as neurons. The HIV-1 protein Tat released from astrocytes reportedly produces trimming of neurites, mitochondrial dysfunction and cell death in neurons, while protecting its host, the astrocyte. We utilized proteomics to investigate protein expression changes in human astrocytes intracellularly expressing Tat (SVGA-Tat). By coupling 2D fingerprinting and identification of proteins by mass spectrometry, we identified phosphatase 2A, isocitrate dehydrogenase, nuclear ribonucleoprotein A1, Rho GDP dissociation inhibitor alpha, beta-tubulin, crocalbin like protein/calumenin, and vimentin/alpha-tubulin to have decreased protein expression levels in SVGA-Tat cells compared to the SVGA-pcDNA cells. Heat shock protein 70, heme oxygenase-1, and inducible nitric oxide synthase were found to have increased protein expression in SVGA-Tat cells compared to controls by slotblot technique. These findings are discussed with reference to astrocytes serving as a reservoir for the HIV virus and how Tat promotes survival of the astrocytic host.
...
PMID:Proteomics analysis of human astrocytes expressing the HIV protein Tat. 1571 Feb 48


1 2 3 Next >>

---