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)

NEW KNOWLEDGE: 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. NEW MOLECULES: The review focuses on new immunosuppressive drugs that have been developed for clinical use in renal transplantation and mechanism of action, advantages and side effects will be discussed for each of them. Neoral is a cyclosporin microemulsion, characterized by more consistent absorption. Tacrolimus shares with cyclosporin an ability to inhibit calcineurin but presents some differences. Mycophenolate mofetyl selectively inhibits purine synthesis and lymphocyte proliferation; it is easy to use and has been found effective in large clinical trials. Rapamycin and RAD are two related molecules that inhibit signal transduction by cytokines to T-cells, their use in transplant therapy remains to be determined. Anti-interleukin-2 receptor antibodies are also reviewed; they are easy to use and have been found effective. NEW STRATEGIES: These new immunosuppressive drugs provide new approaches in transplant therapy to improve their efficacy and safety.
...
PMID:[The benefits of new immunosuppressive treatments in adult kidney transplantation]. 1193 40

The FKBP-12-binding ligand FK506 has been successfully used to stimulate nerve regeneration and prevent the rejection of peripheral nerve allografts. The immunosuppressant rapamycin, another FKBP-12-binding ligand, stimulates axonal regeneration in vitro, but its influence on nerve regeneration in peripheral nerve isografts or allografts has not been studied. Sixty female inbred BALB/cJ mice were randomized into six tibial nerve transplant groups, including three isograft and three allograft (C57BL/6J) groups. Grafts were left untreated (groups I and II), treated with FK506 (groups III and IV), or treated with rapamycin (groups V and VI). Nerve regeneration was quantified in terms of histomorphometry and functional recovery, and immunosuppression was confirmed with mixed lymphocyte reactivity assays. Animals treated with FK506 and rapamycin were immunosuppressed and demonstrated significantly less immune cell proliferation relative to untreated recipient animals. Although every animal demonstrated some functional recovery during the study, animals receiving an untreated peripheral nerve allograft were slowest to recover. Isografts treated with FK506 but not rapamycin demonstrated significantly increased nerve regeneration. Nerve allografts in animals treated with FK506, and to a lesser extent rapamycin, however, both demonstrated significantly more nerve regeneration and increased nerve fiber widths relative to untreated controls. The authors suggest that rapamycin can facilitate regeneration through peripheral nerve allografts, but it is not a neuroregenerative agent in this in vivo model. Nerve regeneration in FK506-treated peripheral nerve isografts and allografts was superior to that found in rapamycin-treated animals. Rapamycin may have a role in the treatment of peripheral nerve allografts when used in combination with other medications, or in the setting of renal failure that often precludes the use of calcineurin inhibitors such as FK506.
...
PMID:The effects of rapamycin in murine peripheral nerve isografts and allografts. 1204 68

Sirolimus and cyclosporine (CsA) prevent acute rejection in man when used as primary therapies in triple drug regimens. Sirolimus does not act via the calcineurin pathway and therefore is not expected to produce the same renal side-effects. This paper presents the pooled 2-year data analysis of renal function parameters from two open-label, randomized, multicenter studies. Patients (18-68 years) receiving a primary renal allograft were randomized to receive concentration-controlled sirolimus (n = 81) or CsA (n = 80), in combination with azathioprine and steroids (n = 83), or mycophenolate mofetil (MMF) and steroids (n = 78). From week 10 through year 2, calculated glomerular filtration rate (GFR) was significantly higher in sirolimus--than in CsA-treated patients (69.3 vs. 56.8 mL/min, at 2 years, p = 0.004). Serum uric acid was significantly higher in the CsA-treated patients and magnesium was significantly lower; these parameters were more likely to be within normal limits in the sirolimus group. Mean serum potassium and phosphorus were lower in sirolimus-treated patients. In conclusion, sirolimus, when administered as primary therapy in combination with azathioprine or MMF, has a favorable safety profile compared to CsA with regards to renal function.
...
PMID:Sirolimus does not exhibit nephrotoxicity compared to cyclosporine in renal transplant recipients. 1212 9

Rapamycin (RAP), tacrolimus (FK506), cyclosporin A, and glucocorticoids represent modern and classic immunosuppressive agents being used clinically. Although these agents have distinct molecular mechanisms of action and exhibit different immunoregulatory profiles, their direct influences on Ag presentation processes remain relatively unknown. Here we report quantitative and qualitative differences among the above four immunosuppressants in their impact on Ag-specific, bidirectional interaction between dendritic cells (DC) and CD4(+) T cells. In the presence of relevant Ag, bone marrow-derived DC delivered activation signals to CD4(+) T cells isolated from the DO11.10 TCR transgenic mice, leading to clonal expansion; secretion of IFN-gamma, IL-2, and IL-4; and surface expression of CD69. Conversely, DO11.10 T cells delivered maturation signals to DC, leading to IL-6 and IL-12 production and CD40 up-regulation. FK506 (10(-10)-10(-8) M) and cyclosporin A (10(-9)-10(-7) M) each blocked efficiently and uniformly all the changes resulting from intercellular signaling in both DC-->T cell and T cell-->DC directions. Dexamethasone (10(-9)-10(-6) M) suppressed all changes, except for CD69 up-regulation, rather incompletely. Remarkably, RAP (10(-10)-10(-8) M) efficiently inhibited DC-induced T cell proliferation and T cell-mediated CD40 up-regulation by DC without abrogating other changes. Interestingly, T cell-independent DC maturation triggered by LPS stimulation was inhibited by dexamethasone, but not by other agents. Our results demonstrate contrasting pharmacological effects of RAP vs calcineurin inhibitors on Ag presentation, thus forming a conceptual framework for rationale-based selection (and combination) of immunosuppressive agents for clinical application.
...
PMID:Contrasting impacts of immunosuppressive agents (rapamycin, FK506, cyclosporin A, and dexamethasone) on bidirectional dendritic cell-T cell interaction during antigen presentation. 1224 45

The immunosuppressor cyclosporin A inhibits the peptidyl-prolyl-cis/trans-isomerase activity of cyclophilins and the resulting complex inhibits the phosphatase activity of calcineurin. Both enzymes were detected in peripheral nerve endings isolated from the electric organ of Torpedo and shown to be affected by 10 micro m cyclosporin A. Among the cholinergic properties studied, choline uptake was specifically inhibited by cyclosporin A to a maximum of 40%. Cyclosporin A decreased the rate of choline transport but not the binding of the non-transportable choline analogue hemicholinium-3, indicating that the number of membrane transporters was not affected. Through the use of two other immunosuppressors, FK506, which also inhibits calcineurin, and rapamycin, which does not, two different mechanisms of choline uptake inhibition were uncovered. FK506 inhibited the rate of choline transport, whereas rapamycin diminished the affinity for choline. The Torpedo homologue of the high affinity choline transporter CHT1 was cloned and its activity was reconstituted in Xenopus oocytes. Choline uptake by oocytes expressing tCHT1 was inhibited by all three immunosuppressors and also by microinjection of the specific calcineurin autoinhibitory domain A457-481, indicating that the phosphatase calcineurin regulates CHT1 activity and could be the common target of cyclosporin and FK506. Rapamycin, which changed the affinity of the transporter, may have acted through an immunophilin on the isomerization of critical prolines that are found in the tCHT1 sequence.
...
PMID:The neuronal choline transporter CHT1 is regulated by immunosuppressor-sensitive pathways. 1235 93

The purpose of this study was to determine whether calcineurin inhibitor (CNI)-induced chronic nephrotoxicity in liver transplant patients is reversible by replacement of the CNI with rapamycin as the primary immunosuppressive agent. CNIs, while providing potent immunosuppression for liver transplant patients, exhibit nephrotoxicity as a major side-effect. Whereas acute CNI-induced nephrotoxicity is reversible by withdrawal of the CNI, chronic nephrotoxicity due to CNIs is a progressive process thought to be irreversible. Eight liver transplant patients with CNI-induced chronic nephrotoxicity were converted to rapamycin as the primary immunosuppressive agent. The CNI was either discontinued (four patients) or the dosage lowered to maintain a subtherapeutic level (four patients). Renal function as assessed by serum creatinine was measured before and after conversion to rapamycin. Two patients progressed to dialysis dependence following conversion to rapamycin. These two patients had been on CNIs for a mean of 112 months (range 93-131 months) prior to conversion to rapamycin. Five patients experienced improvement in renal function. These patients had been on calcineurin inhibitors for a mean of 60 months (range 42-75 months) prior to conversion. One patient with chronic nephrolithiasis as a contributing factor to his renal dysfunction has progressed to dialysis dependence despite conversion to rapamycin following exposure to a CNI for 24 months. In the five patients with improved renal function, serum creatinine levels decreased significantly (2.4 +/- 0.3 mg/dL to 1.5 +/- 0.1 mg/dL, p < 0.05) by a mean of 7.2 months (range 5-10 months) after conversion from CNI to rapamycin-based immunosuppression. Liver function remained stable after conversion to rapamycin. CNI-induced chronic nephrotoxicity can be reversed upon withdrawal of the CNI. Rapamycin is an effective replacement agent as primary immunosuppressive therapy following withdrawal of CNIs in liver transplant patients with CNI-induced chronic nephrotoxicity.
...
PMID:Calcineurin inhibitor-induced chronic nephrotoxicity in liver transplant patients is reversible using rapamycin as the primary immunosuppressive agent. 1237 44

There has been a necessary change in attitude to transplantation; there is much less concern with short-term outcome and more concern with long-term kidney function, overall health and quality of life. Nephrotoxicity is an invariable consequence of long-term treatment with calcineurin antagonists and it is one of the most underestimated causes of late graft loss; it has been reported as a serious threat to both patient and graft survival following heart, liver and bone marrow transplantation. Sirolimus has been shown in many recent studies to be of great value in allowing patients to be weaned from cyclosporine with excellent patient and graft survival at 24 months a significant improvement in renal function with resolution of hirsutism and gum hyperplasia. Patients maintained on the combined regime of cyclosporine and sirolimus had significantly higher blood pressure, much more cyclosporine nephrotoxicity and hyperuricaemia at 12 months. The experimental studies have found cyclosporine and sirolimus potentiate with each other's good and adverse effects. Cyclosporine therefore augments hyperlipidaemia caused by sirolimus, and sirolimus augments nephrotoxicity caused by cyclosporine. The results of these studies indicate that sirolimus is a suitable replacement for cyclosporine or tacrolimus for long-term maintenance therapy. By contrast the use of sirolimus in combination with cyclosporine results in potentiation of side effects. The principal disadvantages being increased cyclosporine associated nephrotoxicity and sirolimus associated hyperlipidaemia
...
PMID:Sirolimus (Rapamune) in renal transplantation. 1239 5

We recently developed a murine protocol for the induction of allogeneic mixed chimerism and tolerance employing nonmyeloablative total body irradiation (TBI), standard-dose bone marrow transplantation (BMT), and costimulation blockade (cobl) with an anti-CD154 monoclonal antibody (mAb) plus CTLA4Ig. We now evaluated whether a short course (1 month) of immunosuppressive drugs, which would be ethically required in the clinical setting of organ transplantation to prevent graft loss in case tolerance is not achieved, interferes with tolerance induced with this regimen. Our results show that calcineurin inhibitors (cyclosporin A [CyA] or tacrolimus [FK]) inhibit development of long-term chimerism and abrogate tolerance induction in this model. Rapamycin (rapa), methylprednisolone (MP), FTY720, and mycophenolate mofetil (MMF), in contrast, have no negative effect on chimerism or tolerance development. Peripheral deletion of donor-reactive T cells, which usually occurs in the weeks following BMT in this model, is blocked by CyA and FK, but not by the other drugs tested. Furthermore, we found that the additional use of compatible immunosuppressive drugs (rapa plus MMF plus MP) allows the dose of TBI to be reduced, so that mixed chimerism and donor skin-graft acceptance can be achieved with 1 Gy using clinically feasible cell numbers. Thus, this protocol of BMT with costimulation blockade can be safely combined with a clinically tested immunosuppressive regimen to permit success with a lower dose of irradiation. These results should facilitate clinical application of this tolerance strategy.
...
PMID:The influence of immunosuppressive drugs on tolerance induction through bone marrow transplantation with costimulation blockade. 1243 77

Elevated levels of free fatty acids (FFA) have been implicated in the pathogenesis of neuronal injury and death induced by cerebral ischemia. This study evaluated the effects of immunosuppressants agents, calcineurin inhibitors and blockade of endoplasmic reticulum (ER) calcium channels on free fatty acid formation and efflux in the ischemic/reperfused (I/R) rat brain. Changes in the extracellular levels of arachidonic, docosahexaenoic, linoleic, myristic, oleic and palmitic acids in cerebral cortical superfusates during four-vessel occlusion-elicited global cerebral ischemia were examined using a cortical cup technique. A 20-min period of ischemia elicited large increases in the efflux of all six FFAs, which were sustained during the 40 min of reperfusion. Cyclosporin A (CsA) and trifluoperazine, which reportedly inhibit the I/R elicited opening of a mitochondrial permeability transition (MPT) pore, were very effective in suppressing ischemia/reperfusion evoked release of all six FFAs. FK506, an immunosuppressant which does not directly affect the MPT, but is a calcineurin inhibitor, also suppressed the I/R-evoked efflux of FFAs, but less effectively than CsA. Rapamycin, a derivative of FK506 which does not inhibit calcineurin, did not suppress I/R-evoked FFA efflux. Gossypol, a structurally unrelated inhibitor of calcineurin, was also effective, significantly reducing the efflux of docosahexaenoic, arachidonic and oleic acids. As previous experiments had implicated elevated Ca(2+) levels in the activation of phospholipases with FFA formation, agents affecting endoplasmic reticulum stores were also evaluated. Dantrolene, which blocks the ryanodine receptor (RyR) channel of the ER, significantly inhibited I/R-evoked release of docosahexaenoic, arachidonic, linoleic and oleic acids. Ryanodine, which can either accentuate or block Ca(2+) release, significantly enhanced ischemia/reperfusion-elicited efflux of linoleic acid, with non-significant increases in the efflux of myristic, arachidonic, palmitic and oleic acids. Xestospongin C, an inhibitor of the inositol triphosphate (IP(3)R) channel, failed to affect I/R-evoked FFA efflux. Thapsigargin, an inhibitor of the Ca(2+)-ATPase ER uptake pump, elicited significant elevations in the efflux of myristic, arachidonic and linoleic acids, in the absence of ischemia. Collectively, the data suggest an involvement of both ER and mitochondrial Ca(2+) stores in the chain of events which lead to PLA(2) activation and FFA formation.
...
PMID:Effects of immunosuppressants, calcineurin inhibition, and blockade of endoplasmic reticulum calcium channels on free fatty acid efflux from the ischemic/reperfused rat cerebral cortex. 1244 75

Macrolides are xenobiotics, produced by soil fungi, which have immunosuppressant properties. They will probably revolutionise the treatment of inflammatory dermatoses. This article outlines the context and putative mechanisms of action of this novel class of drugs. Cyclosporin, and the structurally distinct macrolides tacrolimus and pimecrolimus (an ascomycin derivative), modulate immune-cell function by inhibiting calcineurin-dependent dephosphorylation-activation of specific nuclear factors, thus preventing transcription of pro-inflammatory cytokines. The macrolide rapamycin (sirolimus) acts by abrogating Target of Rapamycin, a key signalling protein that controls activation of a number of proteins which direct progression of the cell cycle in response to pro-inflammatory cytokines. Tacrolimus and pimecrolimus are small enough molecules to penetrate skin and are available in topical formulations. "Skin-specific" pimecrolimus seems not to cause systemic immunosuppression when given orally. Neither topical tacrolimus nor pimecrolimus are capable of producing skin atrophy. Sirolimus has anti-angiogenic properties that may be beneficial to the treatment of psoriasis and perhaps skin cancer.
...
PMID:The macrolide immunosuppressants in dermatology: mechanisms of action. 1245 45


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

---