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)

Recent data on the molecular mechanism of some immunosuppressive drugs provide strong support for the fascinating postulate that CSA and FK506 work by binding to immunophilins and then, as a drug-immunophilin complex, inhibiting the calcium-activated protein phosphatase, calcineurin. This inhibition could result in an altered modification pattern of the cytoplasmic components of transcription factors, thereby disturbing their nuclear translocation, which is a prerequisite for proper IL-2 transcription. It looks as if, with the immunosuppressive microbial metabolites as molecular probes, the pieces of this complex signal transduction puzzle are starting to fit together! Once the details of the chain of events along the T-cell signaling pathways are known, the molecular structures involved will provide new tools to be used in the search for and the rational design of new and improved therapeutic agents.
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PMID:Molecular mechanisms of immunosuppressive agents. 753 Oct 51

Mammalian mitochondria possess an inner membrane channel, the permeability transition pore (MTP), which can be inhibited by nanomolar concentrations of cyclosporin (CS) A. The molecular basis for MTP inhibition by CSA remains unclear. Mitochondria also possess a matrix cyclophilin (CyP) with a unique N-terminal sequence (CyP-M). To test the hypothesis that it interacts with the MTP, we have studied the interactions of CyP-M with rat liver mitochondria by Western blotting with a specific antibody against its unique N terminus. Although sonication in isotonic sucrose at pH 7.4 refraction sediments with submitochondrial particles at 150,000 x g. We show that the interactions of this CyP-M pool with submitochondrial particles are disrupted (i) by the addition of CSA, which inhibits the pore, but not of CSH, which does not, and (ii) by acidic pH condition, which also leads to selective inhibition of the MTP; furthermore, we show that the effect of acidic pH on CyP-M fully prevents the inhibitory effect of H+ on the MTP (Nicolli, A., Petronilli, V., and Bernardi, P. (1993) Biochemistry 32, 4461-4465). These data suggest that CyP-M inhibition by CSA and protons may be due to unbinding of CyP-M from its putative binding site on the MTP. A role for CyP-M in MTP regulation is also supported by a study with a series of CSA derivatives with graded affinity for CyP. We show that with each derivative the isomerase activity of CyP-M purified to homogeneity is similar to that displayed at inhibition of MTP opening, CyP-M (but not CyP-A) and decreased efficiency at MTP inhibition is obtained by substitution in position 8 while a 4-substituted, nonimmunosuppressive derivative is a as effective as the native CSA molecule, indicating that calcineurin is not involved in MTP inhibition by CSA.
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PMID:Interactions of cyclophilin with the mitochondrial inner membrane and regulation of the permeability transition pore, and cyclosporin A-sensitive channel. 856 77

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

It is estimated that there are greater than 100000 kidney transplant recipients with a functioning graft in the United States. Recent advances in immunosuppression have improved short-term graft survival rates and decreased early mortality by decreasing the incidence and therapy for acute rejection episodes. For those accepted on the waiting list, transplant prolongs patient survival compared with remaining on dialysis. During the 1990s, 3 new immunosuppressive drugs were introduced in clinical kidney transplantation. All were approved for use by the Food and Drug Administration after large, controlled, randomized trials. Mycophenolate mofetil (MMF), when combined with cyclosporine (CSA) and prednisone, lowered acute rejection rates by nearly 50% compared with control. Tacrolimus compared with CSA also significantly reduced acute rejection rates in kidney transplant recipients, but was associated with a significant increase in posttransplant diabetes mellitus (PTDM) in the early trials. When evaluated in combination with MMF, the incidence of PTDM was much lower. At the end of the decade, sirolimus was shown in several randomized trials to lower acute rejection rates and is believed to be less nephrotoxic compared with calcineurin inhibitors. All of the randomized trials were not statistically powered to assess long-term superiority. Registry analyses have been performed that appear to show some long-term benefit of immunosuppressive therapy with MMF. Other outcome assessments in kidney transplant recipients include risk factors for chronic allograft nephropathy, hypertension, hyperlipidemia, and bone disease. Although there are few randomized trials, understanding of the significance of these common complications has progressed and strategies for therapy and intervention have been developed. This article focuses on the randomized trials of immunosuppressive therapy and complications associated with use of these drugs. In addition, we review the current management and intervention for the comorbidities associated with the long-term clinical management of the kidney transplant recipient.
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PMID:Outcomes in kidney transplantation. 1283 99

The introduction of cyclosporine (CSA) into organ transplantation was a landmark achievement leading to a substantial improvement of the early transplant results. It was particularly the reduction in early severe acute rejections that accounted for this improvement. However, on a long-term basis development of chronic transplant nephropathy did not seem to become counteracted by CSA. Conversely, CSA may cause both acute and chronic nephrotoxicity, with reduced renal transplant function along with arteriolopathy and interstitial fibrosis. This is the shortcoming of CSA as well as other calcineurin inhibitors (CNIs) such as tacrolimus (TAC). Other immunosuppressive agents were developed subsequently, including Target of Rapamycin (ToR) blockers and mycophenolate mofetil (MMF), which were not nephrotoxic. Current strategies to overcome CNI toxicity include reduction or even stopping administration of CSA or TAC along with switching to a sirolimus, everolimus or MMF based regimen. This strategy has been documented (and there are currently additional ongoing studies) to cause an improvement in renal transplant function or to reduce the deterioration rate. These measures to deal with CSA toxicity need further documentation, since a preserved good renal function seems to not only have an important impact on graft survival but also on patient survival.
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PMID:Cyclosporine nephrotoxicity. 1504 41

Posttransplant diabetes mellitus (PTDM) is a disturbing side effect of immunosuppression. The aim of this study was to evaluate the effect of different immunosuppressive agents on the development of PTDM in renal transplant recipients (KTx). The incidence of PTDM was evaluated in 538 consecutive KTx. Baseline immunosuppression was azathioprine (AZA), cyclosporine (CSA), or tacrolimus (TAC), or sirolimus in combination with calcineurin inhibitors (SIR). All patients received steroids for both induction and maintenance therapy during the first 6 months posttransplantation. Mean follow-up after KTx was 73 +/- 53.5 months (range 6 months to 16 years). PTDM was defined as two consecutive blood glucose determinations above 126 mg/dL. Thirty-six of 538 (6.7%) recipients experienced PTDM, 31 of whom required insulin treatment and five oral antidiabetic medications. PTDM occurred at 25.3 +/- 38 months posttransplantation in 4.8% of KTx treated with AZA, 4.8% of CSA, 6.5% of KTx treated with TAC and 12.5% of KTx treated with SIR. The time of onset of PTDM was significantly shorter (P =.003) among TAC (2.1 +/- 1.7 months posttransplantation) versus CSA (27.8 +/- 34 months). PTDM disappeared in 6 of 36 patients. We conclude that with current levels of immunosuppression, there is no difference in the incidence of PTDM between TAC- and CSA-treated KTx.
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PMID:Posttransplant diabetes mellitus after kidney transplantation with different immunosuppressive agents. 1511 Jun 32

Calcineurin was found as a positive regulator of chondrogenesis in chondrifying chicken micromass cultures (HDCs), as cyclosporine A (CsA) reduced both the amount of cartilage and the expression of mRNAs of aggrecan and the chondrogenic transcription factor Sox9. Cartilage formation was inhibited by H(2)O(2) in a concentration-dependent manner without loss of cellular viability or severe decrease of cell number. Expression of both the mRNA and the unphosphorylated protein Sox9 was decreased, while its phosphorylation was stimulated by either H(2)O(2) or CsA. Oxidative stress decreased the activity of calcineurin but the phosphorylation of the member of MAPK family ERK1/2 was extremely elevated either by 1 mM H(2)O(2) or 2 muM CSA. The ERK inhibitor PD098059 attenuated the depletion of cartilage matrix as well as decreased the expression and phosphorylation of Sox9 in cultures treated with H(2)O(2) or CsA. Our results suggest that the chondrogenesis-inhibiting effect of H(2)O(2) is mediated, at least partly, by inhibition of calcineurin and by activation of ERK1/2. We also propose a regulatory role of calcineurin in the phosphorylation level of either ERK1/2 or Sox9 and a positive role of ERK1/2 in regulating both the expression level and the phosphorylation state of Sox9 in chicken HDCs.
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PMID:Hydrogen peroxide inhibits formation of cartilage in chicken micromass cultures and decreases the activity of calcineurin: implication of ERK1/2 and Sox9 pathways. 1577 99

Cyclosporine (CSA) is a widely used immunosuppressive agent, predominantly for transplant patients. It is well recognized that transplant patients are prone to develop squamous carcinoma of the skin and mucosa, and this high incidence of squamous carcinoma in the transplant population cannot be explained by immunosuppression alone. We hypothesize that CSA may play a significant role in the transformation of normal epidermal squamous cells to carcinoma. CSA is a specific ligand for calcineurin, a ubiquitously expressed cellular serine/threonine phosphatase, that plays important roles in the immune system and cardiac muscles. Using global gene-profiling methods, we studied the short-time CSA effect on the squamous cell line (SCC-015) using Affymetrix human gene chips (Human U133, 2.0 plus chip). Multiple groups of genes were identified to be responsive to CSA treatment, including many genes of unknown functions. We then used reverse transcriptase-polymerase chain reaction and immunoblot analyses to selectively confirm the results from the chips analyses with emphasis on the regulatory molecules important for cellular functions of apoptosis, DNA damage repair, and cellular transformation. This global gene-profiling study indicated that CSA not only functions as an immunosuppressant on the immune system, but also activates/inhibits a wide array of genes important for cell-cycle regulation, apoptosis, and oncogene/tumor-suppressor activation. These functions of CSA on skin and mucosa systems at the molecular level are likely important in the pathogenesis of squamous carcinoma in transplant patients.
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PMID:Molecular basis of posttransplant squamous cell carcinoma: the potential role of cyclosporine a in carcinogenesis. 1665 84

Frequency and clinical significance of cerebrospinal fluid (CSF) pleocytosis in hemopoietic stem cell (HSC) transplantation were surveyed. Cyclosporine (CSA)- or tacrolimus (FK506)-based regimens were used as graft-vs-host disease (GVHD) prophylaxis in allogeneic HSC transplantation. CSF pleocytosis with or without neurologic symptoms was detected in 12 of 25 patients receiving allogeneic HSC transplants but in none of 11 patients receiving autologous HSC transplants. Of the 12 patients with CSF pleocytosis, only one patient developed leukoencephalopathy later. There was a correlation between CSF cell numbers and trough levels of CSA but not with those of FK506. In patients receiving allogeneic HSC transplants, CSF pleocytosis may be relatively common and may reflect neurologic damage associated with calcineurin inhibitors.
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PMID:Pleocytosis after hemopoietic stem cell transplantation. 1696 74

New immunosuppressive regimens have decreased acute rejection rates after kidney transplant. However, the use of these new agents has modified the profile of surgical complications. We compared the incidence of surgical complications in relation with the use of three types of drugs: calcineurin inhibitors, antiproliferative agents, and mammalian target of rapamycin (mTOR) inhibitors. This retrospective study included 359 cadaveric recipients who received an allograft between 1997 and 2004. The mean age was 54 years. The prevalence of diabetes was 8.5% and that of obesity (body mass index > 30 kg/m(2)) was 15.4%. The mean follow-up time was 44 +/- 5.6 months. The regimen most frequently used was tacrolimus (TACRO), mycophenolate mofetil (MMF), and prednisone (PRED) (n = 172), followed by TACRO-PRED (n = 49), cyclosporine (CSA) and MMF and PRED (n = 41), and CSA-azathioprine (AZA) and PRED (n = 24). A surgical complication was considered to be any type of event during the first year, although minimal, directly related to surgery. The rate of surgical complications was 34.8% (122/350). Collections and bleeding were higher in CSA than in TACRO regimens, 12% versus 3.8% (P < .05) and 11.5% versus 3% (P = .002), respectively. The incidence of lymphoceles was higher in regimens with than without mTOR inhibitors: 16% versus 3.7% (P = .012). The incidence of surgical complications was not influenced by the use of MMF or diabetes. In conclusion, the use of mTOR inhibitor-based immunosuppressive regimens leads to a higher incidence of lymphoceles, while the use of MMF does not increase the incidence of surgical complications.
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PMID:Post-kidney transplant surgical complications under new immunosuppressive regimens. 1709 62


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