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

Immunosuppressant nephrotoxicity is among the major contributors to chronic renal allograft failure, which is the primary cause of graft loss. Because of a lack of alternatives to the inherently nephrotoxic calcineurin inhibitors for maintenance immunosuppression, long-term survival rates for renal allografts have not increased in proportion to the rise in short-term graft survival. Clinical studies have shown that mammalian target of rapamycin-based immunosuppression in combination with calcineurin inhibitors, mycophenolate mofetil, or azathioprine is safe and efficacious. These data suggest that a target of rapamycin antagonist (sirolimus/everolimus) should be used initially in combination with calcineurin antagonists in order to prevent early acute rejection. After 3-6 months, a maintenance immunosuppressive regimen can then be individually tailored to each patient on the basis of their clinical and histological status. Those patients at high immunological risk should remain on full-dose triple therapy. All other patients should receive either a calcineurin inhibitor or corticosteroid-sparing regimen, with a maintenance dose of a target of rapamycin inhibitor. This regimen should result in less immunosuppressant nephrotoxicity and a reduction in the serious side effects of steroids, such as diabetes and osteoporosis. Whether the proposed individually designed immunosuppressive regimen, based on protocol biopsies and mammalian target of rapamycin inhibition, will result in prolonged graft and patient survival remains to be determined.
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PMID:The future role of target of rapamycin inhibitors in renal transplantation. 1185 56

The regulatory benefit of apoptosis (activation-induced cell death, AICD) in T cells may be impacted by immunosuppressive agents. We examined this for mycophenolate mofetil (MMF) compared with cyclosporine (CYA). Peripheral blood leukocytes (PBL) were stimulated by either Staph enterotoxin B (SEB) or by anti-CD3 plus anti-CD28. Cell division analysis (sequential reduction in carboxyflourescein diacetate succinimidyl ester, CFSE) was used to measure proliferation and determine status of different cell generations. Apoptosis was measured by annexin V staining, and FasL expression by anti-FasL antibody staining, of activated cells using flow cytometry. CSA and mycophenolic acid (MPA, the active agent of MMF) were added in titration in 3-day cultures. We found that CSA caused diminution in apoptosis but MPA increased it with SEB stimulation. The CSA effect on apoptosis was present when a more calcineurin-dependent stimulus. anti-CD3+ anti-CD28, was used but the MPA effect was less, producing a decrease only in the undivided cells. To look more directly at the differential effect on calcineurin-dependent AICD gene induction of the two agents, we measured Fas-L expression with anti-CD-3 + CD28 stimulation, and confirmed that CYA caused a major decrement in appearance of Fas-L, whereas MPA caused a converse accumulation of it. This seems to be explained by the block more distal in cell activation, resulting in a build-up of a precursor in the activation pathways. We conclude that MMF treatment may be rationale as an adjunct to calcineurin inhibitor treatment because of its converse effect on T cell regulatory apoptosis.
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PMID:Positive effect on T-cell regulatory apoptosis by mycophenolate mofetil. 1190 84

Prolonged action potential duration (APD) and decreased transient outward K+ current (I(to)) as a result of decreased expression of K(v4.2) and K(v4.3) genes are commonly observed in heart disease. We found that treatment of cultured neonatal rat ventricular myocytes with Heteropoda Toxin3, a blocker of cardiac I(to), induced hypertrophy as measured using cell membrane capacitance and (3)H-leucine uptake. To dissect the role of specific I(to)-encoding genes in hypertrophy, I(to) was selectively reduced by overexpressing mutant dominant-negative (DN) transgenes. I(to) amplitude was reduced equally (by about 50%) by overexpression of DN K(v1.4) (K(v1.4)N) or DN K(v4.2) (either K(v4.2)N or K(v4.2)W362F), but only DN K(v4.2) prolonged APD duration (at 1 Hz) and induced myocyte hypertrophy. This hypertrophy was prevented by coexpressing wild-type K(v4.2) channels (K(v4.2)F) with the DN K(v4.2) genes, suggesting the hypertrophy is due to I(to) reduction and not nonspecific effects of transgene overexpression. The hypertrophy caused by reductions of K(v4.x)-based I(to) was associated with increased activity of the calcium-dependent phosphatase, calcineurin, and could be prevented by coinfection with Ad-CAIN, a specific calcineurin inhibitor. The hypertrophy and calcineurin activation induced by K(v4.2)N infection were prevented by blocking Ca2+ entry and excitability with verapamil or high [K+]o. Our studies suggest that reductions of K(v4.2/3)-based I(to) play a role in hypertrophy signaling by activation of calcineurin.
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PMID:Reduction of I(to) causes hypertrophy in neonatal rat ventricular myocytes. 1190 10

Immunosuppression administered in the early postoperative period following liver transplantation plays a crucial role in the survival of the graft and the patient. The introduction of cyclosporin was an important landmark in transplantation, and to this day, calcineurin inhibitors form the basis of most induction immunosuppression regimens. New drugs are being developed which are more specifically targeted to prevention of rejection, and multiple drug combinations have been proposed as a means of reducing the adverse effects of individual drugs. Azathioprine and the newer antimetabolite mycophenolate mofetil have been added to calcineurin inhibitor-based regimens with varying amounts of success. Antibody induction has evolved as a potent form of immunosuppression as well as a means of avoiding certain adverse effects, particularly nephrotoxicity. The numerous adverse effects encountered with polyclonal preparations have been reduced with the development of more specific monoclonal antibodies such as muromonab CD3 (OKT3) or interleukin (IL)-2 receptor (IL-2R) antagonists. The anti-IL-2R antibody preparations basiliximab and daclizumab have shown excellent early results due to their potent yet highly targeted immunosuppressive effect and minimal adverse effects. Further study is needed to determine the most appropriate dosage, timing and patient population for these new drugs in the setting of liver transplantation. Although a number of different induction regimens have been described, no single protocol is suitable for all liver transplant recipients. Rather, certain regimens have advantages that could favour their use in a specific subgroup of patients. A number of clinical trials are underway to identify new, more specific drugs and combinations which could be useful in induction immunosuppression.
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PMID:Options for induction immunosuppression in liver transplant recipients. 1198 87

The effect of carbachol (Cch) on intracellular calcium concentration ([Ca2+]i) in eel enterocytes was examined using the fluorescent Ca2+ indicator fura-2. Cch caused a biphasic increase in [Ca2+]i, with an initial spike followed by a progressively decreasing level (over 6 min) to the initial, pre-stimulated, level. The effect of Cch was dose-dependent with a 7.5-fold increase in [Ca2+]i over basal level induced by the maximal dose of Cch (100 microM). In Ca2+-free/EGTA buffer the effect of Cch was less pronounced and the [Ca2+]i returned rapidly to basal levels. The increment of [Ca2+]i was dose-dependently attenuated in cells pre-treated with U73122, a specific inhibitor of phospholipase C, suggesting that the Cch-stimulated increment of [Ca2+]i required inositol triphosphate formation. In the presence of extracellular Ca2+, thapsigargin (TG), a specific microsomal Ca2+-ATPase inhibitor, caused a sustained rise in [Ca2+]i whereas in Ca2+-free medium the increase in [Ca2+]i was transient; in both cases, subsequent addition of Cch was without effect. When 2 mM CaCl2 were added to the cells stimulated with TG or with Cch in Ca2+-free medium, a rapid increase in [Ca2+]i was detected, corresponding to the capacitative Ca2+ entry. Thus, both TG and Cch depleted intracellular Ca2+ stores and stimulated influx of extracellular Ca2+ consistent with capacitative Ca2+ entry. K+ depolarization obtained with increasing concentrations of KCl in the extracellular medium induced a dose-related increase in [Ca2+]i which was blocked by 2 microM nifedipine, a non-specific L-type Ca2+ channel blocker. Nifedipine also changed significantly the height of the Ca2+ transient, and the rate of decrement to the pre-stimulated [Ca2+]i level, indicating that Ca2+ entry into enterocytes also occurs through an L-type voltage-dependent calcium channel pathway. We also show that isolated enterocytes stimulated with increasing Cch concentrations (0.1-1000 microM) showed a dose-dependent inhibition of the Na+/K+-ATPase activity. The threshold decrease was at 1 microM Cch; it reached a maximum at 100 microM (50.5% inhibition) and did not decrease further with the use of higher dose. The effect of Cch on Na+/K+-ATPase activity was dependent on both protein kinase C (PKC) and protein phosphatase calcineurin activation since the PKC inhibitor calphostin C abolished Cch effects, while the calcineurin inhibitor FK506 augmented Cch effect. Collectively, these data establish a functional pathway by which Cch can modulate the activity of the Na+/K+-ATPase through a PKC-dependent (calphostin C-sensitive) pathway and a calcineurin-dependent (FK506-sensitive) pathway.
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PMID:Muscarinic acetylcholine receptor activation induces Ca2+ mobilization and Na+/K+-ATPase activity inhibition in eel enterocytes. 1201 Jun 40

It has become apparent that galanin as well as proopiomelanocortin-derived peptides, such as beta-endorphin, play an important role in the hypothalamic circuitry that regulates neuroendocrine functions and appetite behavior. We have recently shown that GalR1 and GalR2 galanin receptor mRNAs are expressed in proopiomelanocortin neurons of the arcuate nucleus, suggesting a direct modulatory action of galanin on the proopiomelanocortin neuronal system. In the present study, we investigated the effect of galanin on beta-endorphin release and proopiomelanocortin mRNA expression from male rat mediobasal hypothalamic fragments incubated ex vivo. Galanin induced a decrease of spontaneous beta-endorphin release within the first 30-60 min of incubation and this effect was blocked by the galanin receptor antagonist galantide. Co-incubation of galanin with FK-506 (tacrolimus), a calcineurin inhibitor, suppressed the inhibitory effect of galanin on beta-endorphin release, suggesting that calcineurin is involved in the galanin-evoked decrease in beta-endorphin release. Measurement of beta-endorphin levels in the tissues at the end of the incubation period (120 min) revealed that galanin caused a two-fold increase of beta-endorphin peptide concentration in the mediobasal hypothalamic tissues. Concurrently, galanin induced an increase in the mean density of silver grains overlying proopiomelanocortin neurons after 60 min of incubation, an effect antagonized by galantide. Finally, reverse transcription-polymerase chain reaction analysis revealed that the mRNAs for the three galanin receptor subtypes (i.e. GalR1, GalR2, and GalR3) were expressed in the incubated mediobasal hypothalamic fragments. Taken as a whole, our results indicate that galanin plays a modulatory role on proopiomelanocortin neurons and this interrelation contributes to the elucidation of the neural circuitry that controls, among others, gonadotropin-releasing hormone function.
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PMID:Galanin modulates the activity of proopiomelanocortin neurons in the isolated mediobasal hypothalamus of the male rat. 1204 65

The effect of synthetic LVV-hemorphin-4 (LVV-H4) on human blood and tonsils lymphocytes total phosphatase activity was studied by a spectrofluorimetric assay using 4-methylumbelliferyl phosphate (4-MUP) as a substrate. It has been established that LVV-H4 at concentrations of 10(-9) to 10(-7) M induces the inhibition of human blood (12-24%) and tonsils (42-45%) lymphocytes total phosphatase activity as 1 mM EGTA. The same peptide at concentrations of 10(-5) to 10(-4) M induces activation of human blood (48-57%) and tonsils (20-25%) lymphocytes total phosphatase activity. LVV-H4 is able to neutralize the inhibitory effect of calmodulin (CaM) antagonist and calcineurin inhibitor trifluoperazine (TFP) on human blood lymphocyte total phosphatase activity. It is suggested that a dose-dependent activation/inhibition of lymphocytes total phosphatase activity is due to activation/inhibition of lymphocyte calcineurin activity. Using enzyme-linked immunosorbentassay (ELISA) it was found that LVV-H4 neutralized the inhibitory effect of cyclosporin A (CsA) and TFP on interleukin-2 (IL-2) synthesis by activated blood lymphocytes. LVV-H4 also affects the lymphocytes proliferation, suppressed in pathophysiological condition, and restores their function by enhancement of DNA synthesis, as determined by measuring of [3H] thymidine incorporation into lymphocytes. It has been proposed that CaM is an essential component in starting up the molecular mechanism of hemorphins action and that calcineurin is a key enzyme underlying the molecular mechanism of hemorphins action on the brain and immune system.
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PMID:LVV-hemorphin-4 modulates Ca2+/calmodulin-dependent pathways in the immune system by the same mechanism as in the brain. 1205 38

Signaling through the protein phosphatase calcineurin may play a critical role in cardiac hypertrophy. The gene for Down Syndrome Critical Region-1 (DSCR1) encodes a protein that is an endogenous calcineurin inhibitor. This study was designed to test the hypothesis that DSCR1 is directly induced by biomechanical stimuli. Neonatal rat cardiac myocytes were exposed to biaxial cyclic mechanical strain; mechanical strain upregulated DSCR1 mRNA expression in a time- and amplitude-dependent manner (3.4 +/- 0.2-fold at 8% strain for 6 h, n = 11, P < 0.01), and this induction was angiotensin II and endothelin I independent. Biomechanical induction of DSCR1 mRNA was partially blocked by calcineurin inhibition with cyclosporine A (30 +/- 5%, n = 3, P < 0.01). DSCR1 promoter-reporter experiments showed that mechanical strain induced DSCR1 promoter activity by 2.3-fold and that this induction was completely inhibited by cyclosporin A. Furthermore, DSCR1 gene expression was increased in the left ventricles of mice with pressure-overload hypertrophy induced by transverse aortic banding. These data demonstrate that biomechanical strain directly induces gene expression for the calcineurin inhibitor DSCR1 in cardiac myocytes, indicating that mechanically induced DSCR1 may regulate the hypertrophic response to mechanical overload.
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PMID:Direct biomechanical induction of endogenous calcineurin inhibitor Down Syndrome Critical Region-1 in cardiac myocytes. 1212 98

Calcineurin plays a critical role in Ca(2+) signaling in various cell types. In fission yeast, calcineurin is required for cytokinesis and chloride ion homeostasis. However, most of its physiological functions remain obscure. A genetic screen was performed to identify genes that share an essential function with calcineurin. We screened for mutations that confer sensitivity to the calcineurin inhibitor FK506 and to a high concentration of chloride ion and isolated a mutant, cis2-1/myp2-c2, which contains a novel allele of the myp2(+)/myo3(+) gene that encodes a type 2 myosin heavy chain. The myp2-c2 mutant showed morphological defects similar to those associated with a calcineurin deletion mutant, such as multiseptated and branched cells. Consistently, myp2-null cells were hypersensitive to chloride ion and showed the multiseptated phenotype in the presence of immunosuppressants or at high chloride concentrations. Overexpression of constitutively active calcineurin suppressed the chloride ion-sensitive growth defect and cytokinesis abnormality of the myp2-c2 mutant and myp2-null cells. Interestingly, the essential myosin light chain mutant cdc4-8 failed to grow and could not form a normal contractile ring in the presence of immunosuppressants. Furthermore, calcineurin-null cells exhibited aberrant contractile rings, suggesting impaired contraction of the rings. These results indicate that calcineurin is involved in the regulation of cytokinesis and that chloride ion homeostasis is mediated by type 2 myosin.
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PMID:Genetic interaction between calcineurin and type 2 myosin and their involvement in the regulation of cytokinesis and chloride ion homeostasis in fission yeast. 1213 4

CD4/CD8 lineage commitment of thymocytes is controlled by the T cell receptor-mediated signals and is mimicked in vitro by a long-pulse stimulation of isolated CD4(+)CD8(+) thymocytes with proper combinations of phorbol myristate acetate and the calcium ionophore ionomycin. CD4 lineage commitment required higher intracellular Ca(2+) levels than CD8 lineage commitment in this culture system. The calcineurin inhibitor FK506 at 1nM inhibited the development of thymocytes to either lineage, but 0.3nM FK506 significantly switched the development from the CD4 cell fate to the CD8 cell fate. The switch in lineage commitment was also observed when 1nM FK506 was added 8h after the start of the culture. Delayed addition of 20microM U0126, an Mek (Erk kinase) inhibitor, also induced the switch. These results suggest that the intensity of calcineurin activity and the duration of both calcineurin and Erk pathway activation are crucial for thymocyte lineage commitment.
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PMID:Duration of calcineurin and Erk signals regulates CD4/CD8 lineage commitment of thymocytes. 1214 35


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