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)

Extravasation is a critical process for the physiological lymphocyte traffic as well as the hematogenous spread of malignant hemopoietic cells. Here we report that abrogation of calcineurin activity leads to in vitro transendothelial migration and in vivo infiltration of human lymphoma Nalm-6 cells, which are associated with the abrogation of the VLA-4/VCAM-1 mediated pathway. Rapamycin, which can antagonize FK506 but not CsA to inhibit calcineurin, abrogates FK-506 mediated but not CsA mediated inhibition of in vitro transendothelial migration. FK506 may exert its potent immunosuppressive action partly by inhibiting VLA-4/VCAM-1 mediated transendothelial migration or insinuation of lymphoid cells to tissues.
...
PMID:FK506 (tacrolimus) inhibits extravasation of lymphoid cells by abrogating VLA-4/VCAM-1 mediated transendothelial migration. 968 83

The neuroprotective properties of drugs binding to FKBP12, with and without subsequent inhibition of calcineurin, were investigated in rat models of ischemic embolic stroke. Drug effects on brain infarct volumes evoked by transient middle cerebral artery occlusion (MCAO) and by permanent MCAO were determined in vivo by T2-weighted magnetic resonance imaging and post mortem by triphenyltetrazolium chloride staining and histology. Drugs binding to FKBP12 and inhibiting calcineurin, such as FK506 and SDZ ASM 981, dose dependently reduced the infarct volumes, determined 48 h after MCAO by both magnetic resonance imaging and triphenyltetrazolium chloride staining but only in the transient MCAO model. In vivo potencies to reduce brain infarcts paralleled the in vitro potencies to inhibit calcineurin. Histological staining after 6 days of survival showed that the neuroprotective effects were permanent. Rapamycin, known to bind with similar affinity to FKBP12 but not to inhibit calcineurin, was not neuroprotective but abolished the neuroprotective effects of FK506 when coadministered. In the permanent MCAO models, FK506 showed no effect when injected before and little effect when injected after MCAO. Measurements of core temperatures after MCAO in controls and drug-treated rats do not support hypothermia being the mechanism responsible for neuroprotection. We conclude that drugs inhibiting calcineurin activity are neuroprotective in focal cerebral ischemia/reperfusion but not in permanent ischemia models, possibly by preventing reperfusion injury.
...
PMID:Calcineurin inhibitors FK506 and SDZ ASM 981 alleviate the outcome of focal cerebral ischemic/reperfusion injury. 991 71

To elucidate the effect of FK506 on Ca2+ oscillations in airway epithelium, we investigated cultured cow tracheal epithelial cells with a Ca2+ image-analysis system. ATP (1 microM) induced long-lasting Ca2+ oscillations, having nearly constant peak values (300-400 nM) and intervals (20-40 s) in subconfluent cells but not in confluent cells. These responses were gradually attenuated and abolished by the addition of FK506. Rapamycin, which binds the FK506-binding protein (FKBP), likewise inhibited Ca2+ oscillations, whereas cyclosporin A, a calcineurin inhibitor, did not. Treatment of cells with FK506 decreased Ca2+ content in thapsigargin-sensitive stores, suggesting that the partial depletion of the stores causes the inhibition of Ca2+ oscillations. Immunocytochemistry revealed the existence of cytoplasmic FKBP-like immunoreactivities. The expression of a 12-kDa FKBP was greater in subconfluent cells than in confluent cells as determined by Western blotting, suggesting that the 12-kDa FKBP may be one of the factors that regulates Ca2+ oscillations. Therefore, FK506 possesses an inhibitory action on the Ca2+ response via intracellular FKBP but not via calcineurin, which may result in modification of airway epithelial functions.
...
PMID:Effect of FK506 on ATP-induced intracellular calcium oscillations in cow tracheal epithelium. 1036 12

S100betabeta is a calcium binding, neurotrophic protein produced by nonneuronal cells in the nervous system. The pathway by which it enhances neuronal survival is unknown. Here we show that S100betabeta enhances survival of embryonic chick forebrain neurons in a dose-dependent manner. In the presence of suboptimal amounts of S100betabeta, neuronal survival is enhanced by the immunosuppressants FK506 and cyclosporin A at concentrations that inhibit calcineurin, which is present in these cells. Rapamycin, an immunosuppressant that does not inhibit calcineurin, did not enhance cell survival. Cypermethrin, a direct and highly specific calcineurin inhibitor, mimicked the immunophilin ligands in its neurotrophic effect. None of the drugs stimulated neuronal survival in the absence of S100betabeta. In the presence of suboptimal amounts of S100betabeta, FK506, cyclosporin A, and cypermethrin (but not rapamycin) also increased NF-kappaB activity, as measured by immunofluorescence of cells stained with antibody to the active subunit (p65) and by immunoblotting of nuclear extracts. Antioxidant and glucocorticoid inhibitors of NF-kappaB decreased both the amount of active NF-kappaB and the survival of neurons caused by S100betabeta alone or in the presence of augmenting drugs. We conclude that S100betabeta enhances the survival of chick embryo forebrain neurons through the activation of NF-kappaB.
...
PMID:Neuronal survival activity of s100betabeta is enhanced by calcineurin inhibitors and requires activation of NF-kappaB. 1046 53

12-O-Tetradecanoylphorbol-13-acetate (TPA) caused strong suppression of gap junctional intercellular communication, altered phosphorylation status of the gap junction protein, connexin43, and disappearance of immunorecognizible connexin43-containing gap junction plaques in V79 fibroblasts. When TPA was removed, all parameters normalized during a 3- to 4-h period. The normalizations were independent of protein synthesis, suggesting the possible involvement of phosphatases. None of the phosphatase inhibitors okadaic acid, calyculin A, cyclosporin A, or FK506 affected intercellular communication or connexin43 phosphorylation status on their own. In sequential exposures to TPA and phosphatase inhibitors, only the protein-phosphatase 2B (PP2B) inhibitors cyclosporin A and FK506 delayed the recovery of the studied parameters. Rapamycin binds to the same set of proteins as does FK506, but without inhibiting PP2B. Rapamycin did not affect the recovery of intercellular communication, but it delayed the normalization of connexin43 band pattern and immunorecognition of gap junction plaques. Dephosphorylation of immunoprecipitated connexin43 was studied using PP1, 2A, 2B, and 2C. PP2A was the most efficient (by 100-fold on a molar basis). Connexin43 immunoprecipitated from TPA-exposed cells was a poor substrate for PP1, 2B, and 2C. Thus, PP2B appeared to play a role in normalization of intercellular communication, but not necessarily in direct dephosphorylation of connexin43. Peptidyl-prolyl isomerase activity of cyclosporin/FK506/rapamycin-binding proteins may promote the dephosphorylation of connexin43 in cells.
...
PMID:Phosphatases involved in modulation of gap junctional intercellular communication and dephosphorylation of connexin43 in hamster fibroblasts: 2B or not 2B? 1052 35

Over the last few years, improved knowledge of the immunological mechanisms underlying transplant rejection have resulted in the development of new immunosuppressive agents capable of selectively blocking various steps of the immune response. It is anticipated that these agents will prove useful in the treatment of autoimmune disease and graft-versus-host disease. Neoral is a cyclosporin microemulsion characterized by better and more consistent absorption as compared to the conventional galenic form. Tacrolimus shares with cyclosporin an ability to inhibit calcineurin and may have similar indications. Rapamycin and RAD are two related molecules that inhibit signal transduction by cytokines to T-cells, although they have not yet been proved clinically effective in large studies of solid organ transplant recipients. Mycophenolate mofetil selectively inhibits purine synthesis and lymphocyte proliferation; it is easy to use and has been found effective in a number of autoimmune disorders. Further clinical work is needed to determine the therapeutic indications for each of these new drugs. Elucidation of their mechanisms of action may help to identify drug combinations providing both enhanced efficacy and improved safety.
...
PMID:[New immunosuppressive agents]. 1057 3

During the past 50 years, many immunosuppressive drugs have been described. Often their mechanisms of action were established long after their discovery. Eventually these mechanisms were found to fall into five groups: (i) regulators of gene expression; (ii) alkylating agents; (iii) inhibitors of de novo purine synthesis; (iv) inhibitors of de novo pyrimidine synthesis; and (v) inhibitors of kinases and phosphatases. Glucocorticoids exert immunosuppressive and anti-inflammatory activity mainly by inhibiting the expression of genes for interleukin-2 and other mediators. Cyclophosphamide metabolites alkylate DNA bases and preferentially suppress immune responses mediated by B-lymphocytes. Methotrexate and its polyglutamate derivatives suppress inflammatory responses through release of adenosine; they suppress immune responses by inducing the apoptosis of activated T-lymphocytes and inhibiting the synthesis of both purines and pyrimidines. Azathioprine metabolites inhibit several enzymes of purine synthesis. Mycophenolic acid and mizoribine inhibit inosine monophosphate dehydrogenase, thereby depleting guanosine nucleotides. Mycophenolic acid induces apoptosis of activated T-lymphocytes. A leflunomide metabolite and Brequinar inhibit dihydroorotate dehydrogenase, thereby suppressing pyrimidine nucleotide synthesis. Cyclosporine and FK-506 (Tacrolimus) inhibit the phosphatase activity of calcineurin, thereby suppressing the production of IL-2 and other cytokines. In addition, these compounds have recently been found to block the JNK and p38 signaling pathways triggered by antigen recognition in T-cells. In contrast, rapamycin inhibits kinases required for cell cycling and responses to IL-2. Rapamycin also induces apoptosis of activated T-lymphocytes. Immunosuppressive and anti-inflammatory compounds in development include inhibitors of p38 kinase and of the type IV isoform of cyclic AMP phosphodiesterase which is expressed in lymphocytes and monocytes.A promising future application of immunosuppressive drugs is their use in a regime to induce tolerance to allografts. The role of leukocytes in grafts, and the induction of apoptosis of clones of responding T-lymphocytes, is discussed.
...
PMID:Immunosuppressive drugs: the first 50 years and a glance forward. 1087 84

Sirolimus (SRL) provides effective immunosuppression for kidney transplantation and may be useful in patients with delayed allograft function after kidney transplantation. We review our experience with SRL in liver transplant recipients for whom calcineurin inhibitors are undesirable. Fourteen patients with renal insufficiency or acute mental status impairment were administered SRL after liver transplantation (5- to 10-mg load, 1 to 4 mg/d). Immunosuppression also consisted of mycophenolate mofetil and corticosteroids. On resolution of neurological or renal dysfunction (return to baseline mental status or serum creatinine level), tacrolimus (TAC) therapy was initiated. Twelve patients received primary transplants, 1 patient received a combined liver-kidney transplant, and 1 patient received a third transplant. Follow-up was 2 to 7 months. Calcineurin inhibitors were initially withheld in 9 patients, and therapy was aborted because of toxicity in the remaining 5 patients. Mean times to the initiation of SRL and TAC therapy were 5.4 +/- 4.6 and 26.8 +/- 24.4 days, respectively. Serum trough levels of SRL did not correlate with dose or other patient variables. Two patients died after prolonged pretransplantation hospital courses in the intensive care unit. Six patients experienced acute rejection, but only 1 patient required antilymphocyte therapy. Serum creatinine levels at the start of SRL therapy were 2.2 +/- 1.1 and 1.2 +/- 0.6 mg/dL at 3 months. All 3 patients with neurological indications for SRL had a return to their baseline mental status. All patients had improved liver function chemistry test results and prothrombin times. No patients developed leukopenia or thrombocytopenia. SRL is safe after liver transplantation in patients with acute neurological or renal impairment. SRL is an attractive alternative when calcineurin inhibitors are undesirable, but serum trough levels of SRL should be monitored. A prospective randomized study of an SRL-based calcineurin inhibitor-avoiding regimen compared with standard therapy in patients with renal insufficiency will further evaluate the role for SRL in liver transplantation.
...
PMID:Experience with the use of sirolimus in liver transplantation--use in patients for whom calcineurin inhibitors are contraindicated. 1108 60

Delayed graft function (DGF) after renal transplantation is a significant risk factor for early acute rejection and graft loss. Sirolimus (SRL) can be administered in the setting of DGF without exacerbating the impaired renal function after transplantation. We examined a calcineurin-sparing regimen using SRL during the early post-operative period in renal transplant patients with delayed or impaired graft function. A retrospective review of 14 consecutive kidney transplant recipients with delayed or impaired graft function who received SRL was performed. The immunosuppressive regimen consisted of daclizumab induction (2 mg/kg), SRL (5-15 mg load followed by 2 5 mg daily maintenance therapy), corticosteroids, and mycophenolate mofetil (MMF, 1.5-3 g/d). Patients were monitored for allograft function, acute rejection, graft survival, thrombocytopenia, and leukopenia. Serum levels of SRL were determined by high-performance liquid chromatography performed at an independent commercial laboratory. Donors were cadaveric in 13 cases and living related in one. The duration of follow-up was 0.5-5.2 months. Nine patients required hemodialysis after transplantation. The mean time to initiation of calcineurin inhibitors was 21 +/- 13 d. Average serum creatinine levels at the initiation of SRL and at 1 month after transplantation were 8.4 +/- 2.7 and 2.1 +/- 1.2 mg/dL, respectively. There were 2 patients (14%) who experienced acute rejection within the first month after transplantation -1 with type I (steroid therapy) and 1 with type II (anti-thymocyte therapy). Serum levels of SRL were initially undetectable in the 2 patients with acute rejection. No grafts were lost during the period of follow-up. Three patients developed thrombocytopenia (platelets < 100 x 10(9)) and no patients developed leukopenia. The combination of SRL with anti-CD25 mAb, MMF, and corticosteroids appears to provide effective non-nephrotoxic immunosuppression for kidney transplantation without the need for a lymphocyte-depleting regimen. However, it is important to monitor serum SRL levels to determine the optimal dosing regimen. Furthermore, long-term follow-up of these patients will be helpful to determine whether improved immunosuppression can be achieved with a fully calcineurin-sparing regimen using SRL.
...
PMID:A calcineurin inhibitor-sparing regimen with sirolimus, mycophenolate mofetil, and anti-CD25 mAb provides effective immunosuppression in kidney transplant recipients with delayed or impaired graft function. 1112 7

Rapamycin in transplantation: A review of the evidence. The calcineurin inhibitors have been the mainstays of immunosuppression for solid organ transplantation over the last two decades, but nephrotoxicity limits their therapeutic benefit. Rapamycin is a new drug with both immunosuppressant and antiproliferative properties that has a unique mechanism of action distinct from that of the calcineurin inhibitors. It has a role as a maintenance immunosuppressant either alone or in combination with a calcineurin inhibitor and can also be used to treat refractory acute rejection. Theoretical evidence suggests that it may limit the development and progression of chronic rejection in transplant recipients, but this has yet to be confirmed. This review examines the current in vitro animal and human work underlying the use of rapamycin and, in addition, comments on the pharmacokinetics and side-effect profile of this promising new agent.
...
PMID:Rapamycin in transplantation: a review of the evidence. 1113 52


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---