Calcineurin: A CALCIUM and CALMODULIN-dependent serine/threonine protein phosphatase that is composed of the calcineurin A catalytic subunit and the calcineurin B regulatory subunit. Calcineurin has been shown to dephosphorylate a number of phosphoproteins including HISTONES; MYOSIN LIGHT CHAIN; and the regulatory subunits of CAMP-DEPENDENT PROTEIN KINASES. It is involved in the regulation of signal transduction and is the target of an important class of immunophilin-immunosuppressive drug complexes.Tacrolimus: A macrolide isolated from the culture broth of a strain of Streptomyces tsukubaensis that has strong immunosuppressive activity in vivo and prevents the activation of T-lymphocytes in response to antigenic or mitogenic stimulation in vitro.NFATC Transcription Factors: A family of transcription factors characterized by the presence of highly conserved calcineurin- and DNA-binding domains. NFAT proteins are activated in the CYTOPLASM by the calcium-dependent phosphatase CALCINEURIN. They transduce calcium signals to the nucleus where they can interact with TRANSCRIPTION FACTOR AP-1 or NF-KAPPA B and initiate GENETIC TRANSCRIPTION of GENES involved in CELL DIFFERENTIATION and development. NFAT proteins stimulate T-CELL activation through the induction of IMMEDIATE-EARLY GENES such as INTERLEUKIN-2.Cyclosporine: A cyclic undecapeptide from an extract of soil fungi. It is a powerful immunosupressant with a specific action on T-lymphocytes. It is used for the prophylaxis of graft rejection in organ and tissue transplantation. (From Martindale, The Extra Pharmacopoeia, 30th ed).Calmodulin-Binding Proteins: Proteins which bind calmodulin. They are found in many tissues and have a variety of functions including F-actin cross-linking properties, inhibition of cyclic nucleotide phosphodiesterase and calcium and magnesium ATPases.Immunosuppressive Agents: Agents that suppress immune function by one of several mechanisms of action. Classical cytotoxic immunosuppressants act by inhibiting DNA synthesis. Others may act through activation of T-CELLS or by inhibiting the activation of HELPER CELLS. While immunosuppression has been brought about in the past primarily to prevent rejection of transplanted organs, new applications involving mediation of the effects of INTERLEUKINS and other CYTOKINES are emerging.Phosphoprotein Phosphatases: A group of enzymes removing the SERINE- or THREONINE-bound phosphate groups from a wide range of phosphoproteins, including a number of enzymes which have been phosphorylated under the action of a kinase. (Enzyme Nomenclature, 1992)Tacrolimus Binding Proteins: A family of immunophilin proteins that bind to the immunosuppressive drugs TACROLIMUS (also known as FK506) and SIROLIMUS. EC 5.2.1.-Calcium: A basic element found in nearly all organized tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes.Signal Transduction: The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway.Calmodulin: A heat-stable, low-molecular-weight activator protein found mainly in the brain and heart. The binding of calcium ions to this protein allows this protein to bind to cyclic nucleotide phosphodiesterases and to adenyl cyclase with subsequent activation. Thereby this protein modulates cyclic AMP and cyclic GMP levels.Tacrolimus Binding Protein 1A: A 12-KDa tacrolimus binding protein that is found associated with and may modulate the function of calcium release channels. It is a peptidyl-prolyl cis/trans isomerase which is inhibited by both tacrolimus (commonly called FK506) and SIROLIMUS.Cardiomegaly: Enlargement of the HEART, usually indicated by a cardiothoracic ratio above 0.50. Heart enlargement may involve the right, the left, or both HEART VENTRICLES or HEART ATRIA. Cardiomegaly is a nonspecific symptom seen in patients with chronic systolic heart failure (HEART FAILURE) or several forms of CARDIOMYOPATHIES.Amino Acid Isomerases: Enzymes that catalyze either the racemization or epimerization of chiral centers within amino acids or derivatives. EC 5.1.1.Sirolimus: A macrolide compound obtained from Streptomyces hygroscopicus that acts by selectively blocking the transcriptional activation of cytokines thereby inhibiting cytokine production. It is bioactive only when bound to IMMUNOPHILINS. Sirolimus is a potent immunosuppressant and possesses both antifungal and antineoplastic properties.Phosphoric Monoester Hydrolases: A group of hydrolases which catalyze the hydrolysis of monophosphoric esters with the production of one mole of orthophosphate. EC 3.1.3.Calcium Signaling: Signal transduction mechanisms whereby calcium mobilization (from outside the cell or from intracellular storage pools) to the cytoplasm is triggered by external stimuli. Calcium signals are often seen to propagate as waves, oscillations, spikes, sparks, or puffs. The calcium acts as an intracellular messenger by activating calcium-responsive proteins.Immunophilins: Members of a family of highly conserved proteins which are all cis-trans peptidyl-prolyl isomerases (PEPTIDYLPROLYL ISOMERASE). They bind the immunosuppressant drugs CYCLOSPORINE; TACROLIMUS and SIROLIMUS. They possess rotamase activity, which is inhibited by the immunosuppressant drugs that bind to them.Kidney Transplantation: The transference of a kidney from one human or animal to another.Transcription Factors: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process.Phosphorylation: The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety.Cells, Cultured: Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others.Peptidylprolyl Isomerase: An enzyme that catalyzes the isomerization of proline residues within proteins. EC 5.2.1.8.Muscle Proteins: The protein constituents of muscle, the major ones being ACTINS and MYOSINS. More than a dozen accessory proteins exist including TROPONIN; TROPOMYOSIN; and DYSTROPHIN.Enzyme Inhibitors: Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction.Molecular Sequence Data: Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories.DNA-Binding Proteins: Proteins which bind to DNA. The family includes proteins which bind to both double- and single-stranded DNA and also includes specific DNA binding proteins in serum which can be used as markers for malignant diseases.Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining PROTEIN CONFORMATION.Mycophenolic Acid: An antibiotic substance derived from Penicillium stoloniferum, and related species. It blocks de novo biosynthesis of purine nucleotides by inhibition of the enzyme inosine monophosphate dehydrogenase. Mycophenolic acid is important because of its selective effects on the immune system. It prevents the proliferation of T-cells, lymphocytes, and the formation of antibodies from B-cells. It also may inhibit recruitment of leukocytes to inflammatory sites. (From Gilman et al., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th ed, p1301)Nuclear Proteins: Proteins found in the nucleus of a cell. Do not confuse with NUCLEOPROTEINS which are proteins conjugated with nucleic acids, that are not necessarily present in the nucleus.Graft Rejection: An immune response with both cellular and humoral components, directed against an allogeneic transplant, whose tissue antigens are not compatible with those of the recipient.Drug Labeling: Use of written, printed, or graphic materials upon or accompanying a drug container or wrapper. It includes contents, indications, effects, dosages, routes, methods, frequency and duration of administration, warnings, hazards, contraindications, side effects, precautions, and other relevant information.Drug Repositioning: The deliberate and methodical practice of finding new applications for existing drugs.Product Labeling: Use of written, printed, or graphic materials upon or accompanying a product or its container or wrapper. It includes purpose, effect, description, directions, hazards, warnings, and other relevant information.United States Food and Drug Administration: An agency of the PUBLIC HEALTH SERVICE concerned with the overall planning, promoting, and administering of programs pertaining to maintaining standards of quality of foods, drugs, therapeutic devices, etc.Liver Transplantation: The transference of a part of or an entire liver from one human or animal to another.Research Support, U.S. Gov't, Non-P.H.S.Research Support, U.S. Gov't, P.H.S.Research Support, Non-U.S. Gov'tResearch Support, U.S. GovernmentResearch Support, American Recovery and Reinvestment ActResearch Support, N.I.H., ExtramuralSchizophrenia: A severe emotional disorder of psychotic depth characteristically marked by a retreat from reality with delusion formation, HALLUCINATIONS, emotional disharmony, and regressive behavior.Receptors, N-Methyl-D-Aspartate: A class of ionotropic glutamate receptors characterized by affinity for N-methyl-D-aspartate. NMDA receptors have an allosteric binding site for glycine which must be occupied for the channel to open efficiently and a site within the channel itself to which magnesium ions bind in a voltage-dependent manner. The positive voltage dependence of channel conductance and the high permeability of the conducting channel to calcium ions (as well as to monovalent cations) are important in excitotoxicity and neuronal plasticity.Disease Models, Animal: Naturally occurring or experimentally induced animal diseases with pathological processes sufficiently similar to those of human diseases. They are used as study models for human diseases.Schizophrenic Psychology: Study of mental processes and behavior of schizophrenics.Dizocilpine Maleate: A potent noncompetitive antagonist of the NMDA receptor (RECEPTORS, N-METHYL-D-ASPARTATE) used mainly as a research tool. The drug has been considered for the wide variety of neurodegenerative conditions or disorders in which NMDA receptors may play an important role. Its use has been primarily limited to animal and tissue experiments because of its psychotropic effects.Encyclopedias as Topic: Works containing information articles on subjects in every field of knowledge, usually arranged in alphabetical order, or a similar work limited to a special field or subject. (From The ALA Glossary of Library and Information Science, 1983)Protein Phosphatase 2: A phosphoprotein phosphatase subtype that is comprised of a catalytic subunit and two different regulatory subunits. At least two genes encode isoforms of the protein phosphatase catalytic subunit, while several isoforms of regulatory subunits exist due to the presence of multiple genes and the alternative splicing of their mRNAs. Protein phosphatase 2 acts on a broad variety of cellular proteins and may play a role as a regulator of intracellular signaling processes.Okadaic Acid: A specific inhibitor of phosphoserine/threonine protein phosphatase 1 and 2a. It is also a potent tumor promoter. (Thromb Res 1992;67(4):345-54 & Cancer Res 1993;53(2):239-41)Protein Phosphatase 1: A eukayrotic protein serine-threonine phosphatase subtype that dephosphorylates a wide variety of cellular proteins. The enzyme is comprised of a catalytic subunit and regulatory subunit. Several isoforms of the protein phosphatase catalytic subunit exist due to the presence of multiple genes and the alternative splicing of their mRNAs. A large number of proteins have been shown to act as regulatory subunits for this enzyme. Many of the regulatory subunits have additional cellular functions.

The role of immunophilins in mutant superoxide dismutase-1linked familial amyotrophic lateral sclerosis. (1/2213)

It has been reported that expression of familial amyotrophic lateral sclerosis (FALS)-associated mutant Cu/Zn superoxide dismutase-1 (SOD) induces apoptosis of neuronal cells in culture associated with an increase in reactive oxygen species. SOD recently has been shown to prevent calcineurin inactivation, initiating the present investigations examining the role of calcineurin in mutant SOD-induced cell death. Wild-type or mutant SOD was expressed in neuronal cells by infection with replication-deficient adenoviruses. PC12 cells overexpressing human wild-type SOD exhibited higher calcineurin activity than cells expressing FALS-related mutant SOD (SODV148G); however, cells expressing SODV148G had calcineurin activity equal to mock-infected cells, suggesting that cell death induced by mutant SOD was not related to a decrease in calcineurin activity. Calcineurin antagonists such as cyclosporin A and FK506, as well as nonimmunosuppressant analogs of cyclosporin A, significantly enhanced SODV148G- and SODA4V-induced cell death. Because both groups of drugs inhibit the rotamase activity of cyclophilins (CyP), but only the immunosuppressant analogs inhibit calcineurin activity, these data suggest that rotamase inhibition underlies the enhanced cell death after SODV148G expression. The importance of rotamase activity in mutant SOD-mediated apoptosis was supported by experiments showing that overexpressed wild-type cyclophilin A (CyPA), but not CyPA with a rotamase active site point mutation, protected cells from death after SODV148G expression. These data suggest that mutant SOD produces a greater need for rotamase and, also, highlights possible new therapeutic strategies in FALS.  (+info)

Differential effects of a calcineurin inhibitor on glutamate-induced phosphorylation of Ca2+/calmodulin-dependent protein kinases in cultured rat hippocampal neurons. (2/2213)

Calcium/calmodulin-dependent protein kinases (CaM kinases) are major multifunctional enzymes that play important roles in calcium-mediated signal transduction. To characterize their regulatory mechanisms in neurons, we compared glutamate-induced phosphorylation of CaM kinase IV and CaM kinase II in cultured rat hippocampal neurons. We observed that dephosphorylation of these kinases followed different time courses, suggesting different regulatory mechanisms for each kinase. Okadaic acid, an inhibitor of protein phosphatase (PP) 1 and PP2A, increased the phosphorylation of both kinases. In contrast, cyclosporin A, an inhibitor of calcineurin, showed different effects: the phosphorylation and activity of CaM kinase IV were significantly increased with this inhibitor, but those of CaM kinase II were not significantly increased. Cyclosporin A treatment of neurons increased phosphorylation of Thr196 of CaM kinase IV, the activated form with CaM kinase kinase, which was recognized with an anti-phospho-Thr196 antibody. Moreover, recombinant CaM kinase IV was dephosphorylated and inactivated with calcineurin as well as with PP1, PP2A, and PP2C in vitro. These results suggest that CaM kinase IV, but not CaM kinase II, is directly regulated with calcineurin.  (+info)

Reduction of calcineurin activity in brain by antisense oligonucleotides leads to persistent phosphorylation of tau protein at Thr181 and Thr231. (3/2213)

Phosphorylation of tau protein promotes stability of the axonal cytoskeleton; aberrant tau phosphorylation is implicated in the biogenesis of paired helical filaments (PHF) seen in Alzheimer's disease. Protein kinases and phosphatases that modulate tau phosphorylation have been identified using in vitro techniques; however, the role of these enzymes in vivo has not been determined. We used intraventricular infusions of antisense oligodeoxynucleotides (ODNs) directed against the major brain isoforms of the Ca2+/calmodulin-dependent phosphatase calcineurin to determine how reduced activity of this enzyme would affect tau dephosphorylation. Five-day infusions of antisense ODNs (5 and 10 nmol/day) in rats decreased immunoreactive levels and activity of calcineurin throughout the brain; sense ODNs, scrambled ODNs, and infusion vehicle alone had no effect. When neocortical slices were prepared from antisense ODN-treated rats and incubated for 1 to 2 h in vitro, tau protein remained phosphorylated as determined by using the phosphorylation-sensitive monoclonal antibodies AT-180 (Thr231) and AT-270 (Thr181). In contrast, AT-180 and AT-270 sites were completely dephosphorylated during incubation of neocortical slices from vehicle-infused controls and sense ODN-treated rats. Neocortical slices from antisense-treated rats were incubated with the phosphatase inhibitors okadaic acid (100 nM; 10 microM) and FK-520 (5 microM); these preparations showed enhanced tau phosphorylation, consistent with a significant loss of calcineurin activity. Thus, we conclude that phosphorylation of at least two sites on tau protein, namely, Thr181 and Thr231, is regulated by calcineurin.  (+info)

Failure of calcineurin inhibitors to prevent pressure-overload left ventricular hypertrophy in rats. (4/2213)

A rapidly emerging body of literature implicates a pivotal role for the Ca2+-calmodulin-dependent phosphatase calcineurin as a cellular target for a variety of Ca2+-dependent signaling pathways culminating in left ventricular hypertrophy (LVH). Most of the recent experimental support for this hypothesis is derived from in vitro studies or in vivo studies in transgenic mice expressing activated calcineurin or mutant sarcomeric proteins. The aim of the present study was to test whether calcineurin inhibitors, cyclosporin A (CsA) and FK 506, prevent pressure-overload LVH using 2 standard rat models: (1) the spontaneously hypertensive rat (SHR) and (2) aortic banding. The major new findings are 2-fold. First, in SHR, LVH (left ventricular weight to body weight ratio) was unaffected by a dose of CsA (5 mg. kg-1. d-1) that was sufficient to raise blood pressure and to inhibit calcineurin-mediated transcriptional activation in skeletal muscle. Second, in rats with aortic banding, LVH was unaffected by FK 506 (0.3 mg. kg-1. d-1) or even higher doses of CsA (10 and 20 mg. kg-1. d-1) that were sufficient to inhibit 90% of total calcineurin phosphatase activity in the hypertrophied myocardium. In the latter experiments, CsA blocked neither the elevated left ventricular end-diastolic pressures, a measure of diastolic function, nor the induction in atrial natriuretic peptide mRNA in the hypertrophic ventricles. Thus, in numerous experiments, systemic administration of potent calcineurin inhibitors did not prevent the development of LVH in 2 classic models of pressure-overload hypertrophy. These results demonstrate that pressure-overload hypertrophy can arise through calcineurin-independent pathways.  (+info)

Pressure overload induces severe hypertrophy in mice treated with cyclosporine, an inhibitor of calcineurin. (5/2213)

Cardiac hypertrophy is the fundamental adaptation of the adult heart to mechanical load. Recent work has shown that inhibition of calcineurin activity with cyclosporine suppresses the development of hypertrophy in calcineurin transgenic mice and in in vitro systems of neonatal rat cardiocytes stimulated with peptide growth factors. To test the hypothesis that the calcineurin signaling pathway is critical for load-induced hypertrophy in vivo, we examined the effects of cyclosporine treatment on left ventricular hypertrophy induced by experimental ascending aortic stenosis for 4 weeks in mice. Left ventricular systolic pressure was elevated to a similar level in aortic stenosis mice that were treated with cyclosporine versus no drug. Left ventricular mass and myocyte size were similar in treated and untreated aortic stenosis animals and significantly greater than control animals, showing that cyclosporine treatment does not suppress hypertrophic growth. Both treated and untreated animals showed increased left ventricular expression of the load-sensitive gene atrial natriuretic factor. Calcineurin activity was measured in the left ventricle and the spleen from control mice and aortic stenosis mice treated with cyclosporine versus no drug. Levels of calcineurin activity were similar in the spleens of control and untreated aortic stenosis mice. However, calcineurin activity was severely depressed in left ventricular tissue of untreated aortic stenosis mice compared with control mice and was further reduced by cyclosporine treatment. Thus, pathological hypertrophy and cardiac-restricted gene expression induced by pressure overload in vivo are not suppressed by treatment with cyclosporine and do not appear to depend on the elevation of left ventricular calcineurin activity.  (+info)

Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD. (6/2213)

The Ca2+-activated protein phosphatase calcineurin induces apoptosis, but the mechanism is unknown. Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis. The Ca2+-induced dephosphorylation of BAD correlated with its dissociation from 14-3-3 in the cytosol and translocation to mitochondria where Bcl-xL resides. In hippocampal neurons, L-glutamate, an inducer of Ca2+ influx and calcineurin activation, triggered mitochondrial targeting of BAD and apoptosis, which were both suppressible by coexpression of a dominant-inhibitory mutant of calcineurin or pharmacological inhibitors of this phosphatase. Thus, a Ca2+-inducible mechanism for apoptosis induction operates by regulating BAD phosphorylation and localization in cells.  (+info)

Yeast calcineurin regulates nuclear localization of the Crz1p transcription factor through dephosphorylation. (7/2213)

Calcineurin, a Ca2+/calmodulin dependent protein phosphatase, regulates Ca2+-dependent processes in a wide variety of cells. In the yeast, Saccharomyces cerevisiae, calcineurin effects Ca2+-dependent changes in gene expression through regulation of the Crz1p transcription factor. We show here that calcineurin dephosphorylates Crz1p and that this results in translocation of Crz1p to the nucleus. We identify a region of Crz1p that is required for calcineurin-dependent regulation of its phosphorylation, localization, and activity, and show that this region has significant sequence simlarity to a portion of NF-AT, a family of mammalian transcription factors whose localization is also regulated by calcineurin. Thus, the mechanism of Ca2+/calcineurin-dependent signaling shows remarkable conservation between yeast and mammalian cells.  (+info)

A selective role of calcineurin aalpha in synaptic depotentiation in hippocampus. (8/2213)

Pharmacological studies have suggested that long-term potentiation (LTP) and long-term depression (LTD) and depotentiation, three forms of synaptic plasticity in the hippocampus, require the activity of the phosphatase calcineurin. At least two different isoforms of calcineurin are found in the central nervous system. To investigate whether all of these forms of synaptic plasticity require the same isoforms of calcineurin, we have examined LTD, depotentiation, and LTP in mice lacking the predominant calcineurin isoform in the central nervous system, Aalpha-/- mice. Depotentiation was abolished completely whereas neither LTD nor LTP were affected. These studies provide genetic evidence that the Aalpha isoform of calcineurin is important for the reversal of LTP in the hippocampus and indicate that depotentiation and LTD operate through somewhat different molecular mechanisms.  (+info)

Modulatory calcineurin-interacting proteins (MCIPs), also known as the Down syndrome critical region 1 (DSCR1) and DSCR1-like proteins, are a recently described family of small, structurally related proteins that are preferentially expressed in heart, skeletal muscle, and brain. MCIP proteins can bind to and inhibit calcineurin, a calcium/calmodulin-regulated serine/threonine protein phosphatase that is activated during cardiac hypertrophy and failure. Transcription of the mammalian MCIP1 gene is induced by calcineurin, suggesting that it functions as an endogenous feedback regulator of calcineurin signal transduction. Forced expression of human MCIP1 protein in the hearts of transgenic mice attenuates the hypertrophic response to a broad range of stimuli. This review summarizes work from a number of laboratories on the structure, regulation, and function of MCIP proteins.
TY - JOUR. T1 - A novel calcineurin-interacting protein, CNP-3, modulates calcineurin deficient phenotypes in Caenorhabditis elegans. AU - Kim, Yun Hee. AU - Song, Hyun Ok. AU - Ko, Kyung Min. AU - Singaravelu, Gunasekaran. AU - Jee, Chang Hoon. AU - Kang, Junsu. AU - Ahnn, Joohong. PY - 2008/6/30. Y1 - 2008/6/30. N2 - Calcineurin (Cn) is a calcium/calmodulin-dependent serine/threonine protein phosphatase that has diverse functions in different cell types and organisms. We screened proteins interacting with the C. elegans CnA homolog, TAX-6, by the yeast two-hybrid system. CNP-3 (Calcineurin interacting protein-3) is a novel protein that physically interacts with the catalytic domain of TAX-6. It is strongly expressed in the nuclei of intestine, hypodermis, dorsal uterine regions and spermatheca. Expression begins around the 60-cell stage and proceeds during all larval stages and the adult. To elucidate the biological function of cnp-3 we isolated a cnp-3 deletion mutant. Since CNP-3 binds CnA, ...
Background: Activation of the protein phosphatase calcineurin is a fundamental signaling event promoting hypertrophic growth and pathological remodeling of the heart. The modulatory calcineurin-interacting protein 1 (MCIP1) is an endogenous feedback inhibitor of calcineurin. We have previously shown that increasing the level of MCIP1 protein protects the heart from unrestrained activation of calcineurin, suggesting that strategies to increase MCIP1 protein in the heart may be a viable therapeutic approach. To this end we have undertaken genetic and biochemical studies to decipher mechanisms that regulate degradation of MCIP1 proteins.. Methods and Results: There are two major isoforms of MCIP1 (MCIP1.1 and MCIP1.4). MCIP1.1 levels are extremely stable with a half-life of over 8 hours in cultured cardiomyocytes. In contrast, MCIP1.4 levels are very low in an unstressed heart but increase precipitously in response to stress and calcineurin activation. Unlike MCIP1.1, the MCIP1.4 protein is ...
The PMC1 gene in Saccharomyces cerevisiae encodes a vacuolar Ca2+ ATPase required for growth in high-Ca2+ conditions. Previous work showed that Ca2+ tolerance can be restored to pmc1 mutants by inactivation of calcineurin, a Ca2+/calmodulin-dependent protein phosphatase sensitive to the immunosuppressive drug FK506. We now report that calcineurin decreases Ca2+ tolerance of pmc1 mutants by inhibiting the function of VCX1, which encodes a vacuolar H+/Ca2+ exchanger related to vertebrate Na+/Ca2+ exchangers. The contribution of VCX1 in Ca2+ tolerance is low in strains with a functional calcineurin and is high in strains which lack calcineurin activity. In contrast, the contribution of PMC1 to Ca2+ tolerance is augmented by calcineurin activation. Consistent with these positive and negative roles of calcineurin, expression of a vcx1::lacZ reporter was slightly diminished and a pmc1::lacZ reporter was induced up to 500-fold by processes dependent on calcineurin, calmodulin, and Ca2+. It is likely ...
Calcineurin-mediated dephosphorylation of Drp1 contributes to mitochondrial phenotypes related to loss of PINK1.(A) Calcineurin enzyme activity was measured in
Calcineurin (CaN) is a calcium and calmodulin dependent serine/threonine protein phosphatase (also known as protein phosphatase 3, and calcium-dependent serine-threonine phosphatase). It activates the T cells of the immune system and can be blocked by drugs. Calcineurin activates nuclear factor of activated T cell, cytoplasmic (NFATc), a transcription factor, by dephosphorylating it. The activated NFATc is then translocated into the nucleus, where it upregulates the expression of interleukin 2 (IL-2), which, in turn, stimulates the growth and differentiation of T cell response. Calcineurin is the target of a class of drugs called calcineurin inhibitors, which includes cyclosporin, voclosporin, pimecrolimus and tacrolimus. Calcineurin is a heterodimer of a 61-kD calmodulin-binding catalytic subunit, calcineurin A and a 19-kD Ca2+-binding regulatory subunit, calcineurin B. There are three isozymes of the catalytic subunit, each encoded by a separate gene (PPP3CA, PPP3CB, and PPP3CC) and two ...
ADAPT78, Adapt78, calcium and oxidant-inducible mRNA, calcipressin-1, Down syndrome candidate region 1, Down syndrome critical region gene 1, Down syndrome critical region protein 1, DSC1, modulatory calcineurin-interacting protein 1, Myocyte-enriched calcineurin-interacting protein 1, near DSCR proline-rich protein, regulator of calcineurin ...
A less likely alternative hypothesis is that calcineurin is not part of a signal transduction pathway required for virulence, but is instead required to maintain activity of components required for growth at high temperature and CO2 and pH resistance. Such a model would require that some proteins differ in phosphorylation state at 37 and 24°C, or that activity at 37°C requires dephosphorylation whereas activity at 24°C does not. One means to test these and other models, and to identify downstream effectors of calcineurin, would be to characterize suppressor mutations that restore growth to calcineurin mutants at 37°C. In summary, our studies reveal that calcineurin is required for virulence and may delineate the first elements of a signal transduction cascade required for fungal pathogenesis.. By analogy with other systems, the targets of calcineurin might include ion pumps or transcription factors, which could regulate expression of other proteins required for virulence. The role of ...
After been conditioned, rats were divided into two groups: light-alone and context control. Immunoblotting for phosphorylated Akt (P-Akt) was performed immediately after extinction training (Fig. 2C). Figure 2D indicates that the degree of Akt phosphorylation was significantly reduced in the light-alone group (t(10) = 3.75;p , 0.01). In contrast, Akt phosphorylation in the context control group was comparable with and not significantly different from the preextinction test (t(10) = 0.32; p = 0.75). These results suggest that memory testing-induced Akt phosphorylation was abrogated after light-alone trials. Given that synaptic plasticity may be governed by the balance between protein kinase and phosphatase activity (ODell and Kandel, 1994; Winder and Sweatt, 2001), a decrease in the phosphorylated state of Akt after extinction trials led us consider the possible involvement of calcium-dependent phosphatase calcineurin. We determined the involvement of calcineurin by infusing FK-506, a ...
The goal of these experiments was to measure the activity of calcineurin in the PBMC of patients with SLE. The major results are as follows. Firstly, there is no difference in the calcineurin activities of PBMC in the GCS-free patients with SLE and healthy control subjects. Secondly, as far as we know, this is the first experimental evidence of decreased calcineurin activity of PBMC induced by GCS used for the treatment of patients with SLE.. Unfractionated PBMC-that is, suspensions of T and B lymphocytes, NK cells, and monocytes, were used in this study because the calcineurin activity assays required a large number of cells. As patients with SLE are lymphopenic it would have been difficult to obtain a sufficient volume of blood for the separation of various purified subsets of the cells. As the subsets of PBMC were characterised by flow cytometry, and as it was found that 69.4% of the cells were T cells, these preparations could be regarded as "T cell-rich suspensions". There was no ...
AID fragments, derived from the autoinhibitory domain of the calcineurin A subunit were the first examined inhibitory peptides for calcineurin. These peptides, containing the residues 424-521 (AID 424-521 ), are potent inhibitors of the phosphatase activity by blocking the access of protein substrates to the catalytic centre of calcineurin [164]. A peptide spanning the residues 457-482 (AID 457-482 ) of calcineurin represents the core inhibitory motif [165, 166]. This peptide is already able to suppress the dephosphorylation of the RII phosphopeptide in phosphatase assays. However, additional autoinhibitory elements are present within the calcineurin region 420-457. Therefore, the peptides containing the extended AID region AID420-511 and AID328-511 were three- to fourfold more potent to inhibit RII phosphopeptide dephosphorylation compared to the AID457-482 peptide [167]. The 11R-AID457-482 peptide, containing eleven arginine residues, is reported to be indeed cell-permeable for selected cell ...
Inp53 is a calcineurin substrate. (A) Domain structure of yeast synaptojanins and creation of Inp53ARAQAA allele. IP5P, inositol-polyphosphate 5-phosphatase dom
Study to Evaluate the Value of the Follow-up of CALCIneurin Activity to MOdulate Calcineurin Inhibitors-induced Immunosuppression in Lung Transplantation
Heart transplant is a recognized therapeutic strategy in refractory heart failure. Its success is however hampered by severe cancer occurrence and recurrence. The new m-tor inhibiting drugs Sirolimus and Everolimus have shown potential for reducing the incidence of cancer in animal models. They are potent immunosuppressant, antiproliferative and antiangiogenic drugs. This open labelled randomized multicenter study aims at evaluating the beneficial antineoplastic effect of Everolimus in 159 heart transplant patients suffering of recurrent skin cancer. Primary objective is to demonstrate a reduction in the number of new skin cancers. Secondary end point will be time of recurrence, incidence of non skin cancer, graft function following switch (including death), renal function evolution following calcineurin inhibitors reduction or withdrawal, Everolimus tolerance profile, schemes of calcineurin inhibitors reduction management in centers ...
Heart transplant is a recognized therapeutic strategy in refractory heart failure. Its success is however hampered by severe cancer occurrence and recurrence. The new m-tor inhibiting drugs Sirolimus and Everolimus have shown potential for reducing the incidence of cancer in animal models. They are potent immunosuppressant, antiproliferative and antiangiogenic drugs. This open labelled randomized multicenter study aims at evaluating the beneficial antineoplastic effect of Everolimus in 159 heart transplant patients suffering of recurrent skin cancer. Primary objective is to demonstrate a reduction in the number of new skin cancers. Secondary end point will be time of recurrence, incidence of non skin cancer, graft function following switch (including death), renal function evolution following calcineurin inhibitors reduction or withdrawal, Everolimus tolerance profile, schemes of calcineurin inhibitors reduction management in centers ...
Schizophrenia, a form of mental illness that affects about 1% of the population, is believed to depend on a complex and incompletely understood interplay of genetic and environmental factors. Two related articles provide evidence suggesting that alterations in signaling from the serine-threonine phosphatase calcineurin may contribute to the pathogenesis of this severe and disabling disease. Miyakawa et al. subjected a strain of mutant mice that lacked forebrain calcineurin to a battery of tests and observed a spectrum of behavioral abnormalities reminiscent of those found in individuals with schizophrenia. The authors, who had previously noted deficits in working memory in these mice, observed decreased social interaction, impaired attention, and impaired nesting behavior. The mice also displayed increased hyperactivity, which is characteristic of other animal models of schizophrenia, and enhanced susceptibility to N-methyl-D-aspartate receptor blockade. In an accompanying article, Gerber et al. ...
In this study, we used whole-genome array analysis and pharmacological reagents to identify PROCR as a potential Cn/NFAT-dependent gene in vascular smooth muscle. We corroborate the only report to date that vascular SMCs do express the protein C receptor (PROCR).15 More importantly, we validate our informatics approach and are the first to report Cn/NFAT signaling as a regulator of PROCR activation. We show PDGF-BB stimulation induced PROCR expression in a Cn/NFAT-dependent manner at both the transcriptional and translational levels. Mutation of a highly conserved NFAT binding motif significantly attenuated PROCR promoter activation, supporting the NFAT-dependent property of PROCR activity. In addition, PROCR expression is upregulated in vivo as a result of acute vascular injury, highlighting the potential role of PROCR in vessel restenosis.. Until the recent detection of PROCR in vascular SMCs, PROCR was believed to be expressed predominantly in ECs. Studies to date on PROCR transcription focus ...
Sustained calcium signaling induces a state of anergy or antigen unresponsiveness in T cells, mediated through calcineurin and the transcription factor NFAT. We show here that Ca(2+)-induced anergy is a multistep program that is implemented at least partly through proteolytic degradation of specific signaling proteins. Calcineurin increased mRNA and protein of the E3 ubiquitin ligases Itch, Cbl-b and GRAIL and induced expression of Tsg101, the ubiquitin-binding component of the ESCRT-1 endosomal sorting complex. Subsequent stimulation or homotypic cell adhesion promoted membrane translocation of Itch and the related protein Nedd4, resulting in degradation of two key signaling proteins, PKC-theta and PLC-gamma1. T cells from Itch- and Cbl-b-deficient mice were resistant to anergy induction. Anergic T cells showed impaired calcium mobilization after TCR triggering and were unable to maintain a mature immunological synapse, instead showing late disorganization of the outer ring containing lymphocyte
CDK5 and Calcineurin Regulate Synaptic Ca2+ Influx. Sung Hyun Kim and Timothy A. Ryan. (see pages 8937-8950). The cyclin-dependent kinase CDK5 has numerous targets and helps regulate nearly every aspect of neuron development and function, including migration, neurite outgrowth, synaptic vesicle release and recycling, synaptic plasticity, and neuron death. At synaptic terminals, CDK5 and the Ca2+-dependent phosphatase calcineurin work in opposition to regulate the distribution of synaptic vesicles between resting and recycling pools, thus regulating release during sustained activity. Kim and Ryan report that these molecules also regulate release probability in response to single action potentials by modulating influx through N-type voltage gated Ca2+ channels (CaV2.2) in rat hippocampal neurons. Specifically, knocking down the α isoform of calcineurin subunit A (CANα) reduced, whereas knocking down CDK5 increased Ca2+ influx and exocytosis evoked by single spikes. Blocking CaV2.2 occluded the ...
In most models of pathological hypertrophy studied to date, inhibition of calcineurin-NFAT signaling has yielded either a reduction in the hypertrophic response and/or a delay in the progression from hypertrophy to heart failure.9,38 The data presented in this study extend this paradigm to demonstrate that calcineurin-NFAT signaling is activated in a sustained manner during both TAC-induced pressure overload and myocardial infarction-induced heart failure. However, very little is presently known regarding the role of calcineurin-NFAT signaling in regulating physiological hypertrophy or adaptive growth of the myocardium. Our results indicate that calcineurin-NFAT is not activated after either voluntary wheel-running or swimming, despite the observation of significant cardiac hypertrophy. In fact, swimming exercise even produced a significant and reproducible reduction in NFAT-luciferase activity in the heart at certain time points. Also of note, direct infusion of GH-IGF-1, which is thought to ...
Sustained hemodynamic stress, e.g. due to hypertension or valvular defects, ultimately results in pathological remodeling of the myocardium, characterized by hypertrophy, fibrosis and progressive contractile dysfunction. The phosphatase calcineurin plays a key role in the molecular pathogenesis of these processes. In previous experiments, we could show the mice deficient for the calcineurin-interacting protein calsarcin-1 (CS1) were sensitized to cardiomyopathic stimuli. Conversely, transgenic mice with a cardiac restricted overexpression of CS1 were protected against prohypertophic stimuli. To further explore the therapeutic potential of calsarcin-1, we now generated an adeno-associated virus serotype 9 (CS1-AAV9) expressing CS1 under the control of a cardiac-specific MLC2-CMV promoter. CS1-AAV9 or a control AAV9 encoding for luciferase (Luc-AAV9) were systemically injected into adult male C57Bl/6 mice (2x1011 genomes/mouse). After one week, osmotic minipumps were implanted for another two ...
Calcineurin A; One Isoform (the Other Is Cmp2p) Of The Catalytic Subunit Of Calcineurin, A Ca++/calmodulin-regulated Protein Phosphatase Which Regulates Crz1p (a Stress-response Transcription Factor), The Other Calcineurin Subunit Is CNB1; Regulates The Function Of Aly1p Alpha-arrestin; CNA1 Has A Paralog, CMP2, That Arose From The Whole Genome Duplication
gene. Loss of α-actinin-3 is associated with reduced power and enhanced endurance capacity in elite athletes and nonathletes due to "slowing" of the metabolic and physiological properties of fast fibers. Here, we have shown that α-actinin-3 deficiency results in increased calcineurin activity in mouse and human skeletal muscle and enhanced adaptive response to endurance training. α-Actinin-2, which is differentially expressed in α-actinin-3-deficient muscle, has higher binding affinity for calsarcin-2, a key inhibitor of calcineurin activation. We have further demonstrated that α-actinin-2 competes with calcineurin for binding to calsarcin-2, resulting in enhanced calcineurin signaling and reprogramming of the metabolic phenotype of fast muscle fibers. Our data provide a mechanistic explanation for the effects of the ...
Aim: To determine whether Ca2+/calcineurin mediated the inhibitory effects of nitric oxide /cGMP-dependent protein kinase (NO/PKG) on the proliferation of vascular smooth muscle cells (VSMC). Methods: Proliferation and viability of primary VSMC from rat aorta were measured using [3-(4,5-dimethyl thiazol-2-yl)-2, 5-diphenyl tetrazolium bromide] (MTT) assay and acridine orange and ethidium bromide staining, respectively. Cytosolic Ca2+ was determined by Fluo-3/AM. Calcineurin protein and its activity were assayed using immunoblotting and free inorganic phosphate analysis, respectively. Results: (+/-)-S-nitroso-N-acetylpenicillamine (SNAP) and Sp-8-(4-chlorophenylthio)-guanosine-3′,5′-cyclic monophosphorothioate (Sp-8-pCPT-cGMPS) decreased phenylephrine (PE)-induced proliferation of VSMC by 27.3% and 36.6%, respectively, but Rp-8-[4-chlorophenyl)thio]-guanosine-3′,5′-cyclic monophosphorothioate (Rp-8-pCPT-cGMPS) increased PE-induced proliferation of VSMC. SNAP, Sp-8-pCPT-cGMPS, and ...
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This study is investigating the efficacy of maintaining standard immunosuppressive therapy with calcineurin inhibitors (tacrolimus + ciclosporin) + mycophenolic
Exposure of the yeast Saccharomyces cerevisiae to alkaline stress resulted in adaptive changes that involved remodeling the gene expression. Recent evidence suggested that the calcium-activated protein phosphatase calcineurin could play a role in alkaline stress signaling. By using an aequorin luminescence reporter, we showed that alkaline stress resulted in a sharp and transient rise in cytoplasmic calcium. This increase was largely abolished by addition of EGTA to the medium or in cells lacking Mid1 or Cch1, components of the high affinity cell membrane calcium channel. Under these circumstances, the alkaline response of different calcineurin-sensitive transcriptional promoters was also blocked. Therefore, exposure to alkali resulted in entry of calcium from the external medium, and this triggered a calcineurin-mediated response. The involvement of calcineurin and Crz1/Tcn1, the transcription factor activated by the phosphatase, in the transcriptional response triggered by alkalinization has ...
Myocyte application models cardiac myocyte (heart muscle cell) and simulates its behavior according to the work by Saucerman and Bers [8]. The model integrates cardiac myocyte electrical activity with the calcineurin pathway, which is a key aspect of the development of heart failure. The model spans large number of temporal scales to reflect how changes in heart rate as observed during exercise or stress contribute to calcineurin pathway activation, which ultimately leads to the expression of numerous genes that remodel the hearts structure. It can be used to identify potential therapeutic targets that may be useful for the treatment of heart failure. Biochemical reactions, ion transport and electrical activity in the cell are modeled with 91 ordinary differential equations (ODEs) that are determined by more than 200 experimentally validated parameters. The model is simulated by solving this group of ODEs for a specified time interval. The process of ODE solving is based on the causal ...
Myocyte application models cardiac myocyte (heart muscle cell) and simulates its behavior according to the work by Saucerman and Bers [1]. The model integrates cardiac myocyte electrical activity with the calcineurin pathway, which is a key aspect of the development of heart failure. The model spans large number of temporal scales to reflect how changes in heart rate as observed during exercise or stress contribute to calcineurin pathway activation, which ultimately leads to the expression of numerous genes that remodel the hearts structure. It can be used to identify potential therapeutic targets that may be useful for the treatment of heart failure. Biochemical reactions, ion transport and electrical activity in the cell are modeled with 91 ordinary differential equations (ODEs) that are determined by more than 200 experimentally validated parameters. The model is simulated by solving this group of ODEs for a specified time interval. The process of ODE solving is based on the causal ...
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Inadequate pancreatic β cell function underlies type 1 and type 2 diabetes mellitus. Strategies to expand functional cells have focused on discovering and controlling mechanisms that limit the proliferation of human β cells. Here, we developed an engraftment strategy to examine age-associated human islet cell replication competence and reveal mechanisms underlying age-dependent decline of β cell proliferation in human islets. We found that exendin-4 (Ex-4), an agonist of the glucagon-like peptide 1 receptor (GLP-1R), stimulates human β cell proliferation in juvenile but not adult islets. This age-dependent responsiveness does not reflect loss of GLP-1R signaling in adult islets, since Ex-4 treatment stimulated insulin secretion by both juvenile and adult human β cells. We show that the mitogenic effect of Ex-4 requires calcineurin/nuclear factor of activated T cells (NFAT) signaling. In juvenile islets, Ex-4 induced expression of calcineurin/NFAT signaling components as well as target genes ...
Inadequate pancreatic β cell function underlies type 1 and type 2 diabetes mellitus. Strategies to expand functional cells have focused on discovering and controlling mechanisms that limit the proliferation of human β cells. Here, we developed an engraftment strategy to examine age-associated human islet cell replication competence and reveal mechanisms underlying age-dependent decline of β cell proliferation in human islets. We found that exendin-4 (Ex-4), an agonist of the glucagon-like peptide 1 receptor (GLP-1R), stimulates human β cell proliferation in juvenile but not adult islets. This age-dependent responsiveness does not reflect loss of GLP-1R signaling in adult islets, since Ex-4 treatment stimulated insulin secretion by both juvenile and adult human β cells. We show that the mitogenic effect of Ex-4 requires calcineurin/nuclear factor of activated T cells (NFAT) signaling. In juvenile islets, Ex-4 induced expression of calcineurin/NFAT signaling components as well as target genes ...
Inadequate pancreatic β cell function underlies type 1 and type 2 diabetes mellitus. Strategies to expand functional cells have focused on discovering and controlling mechanisms that limit the proliferation of human β cells. Here, we developed an engraftment strategy to examine age-associated human islet cell replication competence and reveal mechanisms underlying age-dependent decline of β cell proliferation in human islets. We found that exendin-4 (Ex-4), an agonist of the glucagon-like peptide 1 receptor (GLP-1R), stimulates human β cell proliferation in juvenile but not adult islets. This age-dependent responsiveness does not reflect loss of GLP-1R signaling in adult islets, since Ex-4 treatment stimulated insulin secretion by both juvenile and adult human β cells. We show that the mitogenic effect of Ex-4 requires calcineurin/nuclear factor of activated T cells (NFAT) signaling. In juvenile islets, Ex-4 induced expression of calcineurin/NFAT signaling components as well as target genes ...
SD nephrotic syndrome carries a high risk of toxicity from steroids or standard steroid-sparing agents. Therefore, alternative treatment options are needed. Although recent studies support the use of rituximab as a steroid-sparing and CNI-sparing agent in SD-INS, benefits may be suboptimal, especially in complicated forms of the disease. The new anti-CD20 ofatumumab may be more effective than rituximab in controlling the disease, due to its stronger affinity for the CD20. Moreover, due to its fully humanised structure, it may be used in larger doses with minimal risk of side effects. These considerations motivated the use of an active comparator to test the effects of different agents blocking the CD20 antigen pathway.. This is the first randomised controlled trial comparing the effects of two anti-CD20 antibodies on the risk of relapse of INS following steroid and CNI withdrawal. Strengths in the design of this trial include: objective and clinical important outcomes, identification of a ...
Tumor angiogenesis is a hallmark of cancer, and plays a critical role in tumor growth, expansion, and metastasis. Both physiological and pathological angiogenesis is assumed to be regulated by the balance between pro and anti-angiogenic factors. One of the best characterized and most potent pro-angiogenic regulators is vascular endothelial growth factor, or VEGF. Calcineurin signaling is an important mediator of VEGF signaling in endothelial cells. Negative regulation of calcineurin by increased expression of its endogenous inhibitor, Down Syndrome Candidate Region-1 (DSCR1), suppresses tumor growth and angiogenesis. However, a potent pharmacological calcineurin inhibitor, the commonly used immunosuppressant cyclosporin A (CsA), significantly increases the incidence of cancer in organ transplant recipients. The mechanism by which CsA promotes cancer in this patient population is not well understood and despite the significance of calcineurin signaling in endothelial cells, the consequences of CsA on
Calcineurin has functions in T cell activation, activation-induced cell death (AICD), T cell tolerance, ion channel regulation, cardiac myocyte hypertrophy, sperm motility, synaptic endocytosis, and Alzheimers disease (17-20). In lymphocytes, antigen engagement of lymphocyte receptors promotes the activation of phospholipase C-γ (PLC-γ) (Figure 10). Activated PLC-γ hydrolyzes phosphatidylinositol-4,5-bisphosphate into inositol-1,4,5-trisphosphate (IP3) and diacylglycerol. IP3 then binds to receptors on the endoplasmic reticulum and drives Ca2+ release from the endoplasmic reticulum into the cytoplasm, which triggers opening of Ca2+ release-activated Ca2+ channels. Calcineurin is activated by binding of CaM in response to sustained increased levels of intracellular calcium (11;21). Upon calcineurin activation, it dephosphorylates members of the nuclear factor of activated T cells (NFAT) family, promoting their translocation from the cytosol to the nucleus and subsequent induction of the ...
Pancreatic β-cells are highly regulated by certain nutrients, peptide hormones, neurotransmitters, and pharmacological compounds, but the most physiologically relevant of these is glucose (31). Glucose metabolism is required to generate secondary signals that in turn control many of the normal functions of β-cells including insulin secretion, (pro)insulin production, adaptive β-cell growth, and survival (31). IRS-2 also is key to β-cell survival and compensatory growth in response to an increased metabolic load (4,6,7). IRS-2 turns over relatively rapidly in β-cells (10), but this is compensated for by IRS-2 expression being highly regulated at the transcriptional level, especially by glucose (10) and a glucose-dependent potentiation by incretins like GLP-1 (12). This glucose-mediated regulation of IRS-2 expression in islet β-cells occurs in vivo and is possibly unique to β-cells, since it is not found in other nutrient-sensing organs such as the liver (Fig. 1).. Here we show that the ...
Wnt-5a signaling may activate PKC and intracellular Ca2+ mobilization to trigger a series of downstream effects including activation of NF-AT and CaMKII (Kuhl et al., 2000a; Saneyoshi et al., 2002). During early Xenopus development, Wnt-5a activates calcineurin, which leads to NF-AT nuclear localization and increased β-catenin degradation (Saneyoshi et al., 2002). To address how Wnt-5a transduces its signal in mammalian cells, we checked whether Wnt-5a activates NF-AT transcriptional activity and whether such activation is required for Wnt-5a-induced β-catenin degradation. We found that NF-AT transcriptional activity was only weakly activated by Wnt-5a (∼50%), whereas it was strongly up-regulated by activated calcineurin (∼300%; Fig. 3 A). In addition, we found that although activated calcineurin was able to inhibit the TOPFLASH activity up-regulated by β-catenin S37A, Wnt-5a had an additive effect in its presence (Fig. 3 B). Moreover, specific inhibition of calcineurin by Cyclosporin A ...
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Non-compliance of immunosuppression after lung-transplantation provokes rejection, infection and renal insufficiency. This study was carried out to determine whether tablet-pc education is non-inferior to conventional, face-to-face, education by a specialist for improvement of immunosuppression levels after lung-transplantation.. A single-centre (Medical School of Hannover), randomised controlled trial with 6 months follow-up, including patients with less than 50% of calcineurin inhibitor trough levels in target range in last 6 months was initiated.. 64 patients were randomised, stratified only by underlying disease of cystic fibrosis. 6 months after inclsuion, mean improvement of a single education was 26% of calcineurin inhibitor trough levels in target range. Primary end-point of non-inferiority was reached, a two-sided t-test revealed no difference between types of education (p = 0.17, see figure 1). Trough level variability decreased (tablet-pc: 22.9% and 17.9% conservative, p = 0.13), ...
View mouse Nfatc3 Chr8:106058840-106130537 with: phenotypes, sequences, polymorphisms, proteins, references, function, expression
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Lapin Calcineurin B Polyclonal anticorps pTyr106 pour IHC (p), WB. Commandez anti-Calcineurin B anticorp. | Numéro de produit ABIN1712443
Rabbit polyclonal Calcipressin 1 antibody validated for WB, ELISA and tested in Human. Immunogen corresponding to synthetic peptide
A potent immunosuppresant and in vitro T cell proliferation blocker. It disrupts calcineurin-mediated signal transduction in T-lymphocytes. It interacts with its FK506-bi
I would like to know. What is the difference between HHA and CNA and which would give you a have a better overview and understanding of what being a LPN is all about.
台裔美國學者湯猛雄最新研究發現,電子煙霧會引起小鼠罹患肺癌,且有膀胱尿路上皮細胞增生,增癌變風險。台灣專家指出,此研究首度證實電子菸會致癌,拆穿電子菸「減害」謊言。
folliculitis more commonly caused by ointment.. #4 Topical immunomodulants. There is strong evidence that TCIs have a steroid-sparing effect and long-term use up to 12 months can prevent flares. Topical calcineurin inhibitors are particularly useful for sensitive sites including the face, neck, and skin flexures. Its now studied that there is no statistically significant cancer risk.. #5 Proactive approach with topical anti-inflammatory therapy. The results suggested that for a patient with moderate-to-severe eczema and chronic relapsing lesions, maintenance treatment with topical anti-inflammatory therapy twice a week may be a better strategy to prevent eczema flares and topical corticosteroids more effective than topical calcineurin inhibitors. The rationale is that there is inflammation in the underneath layer of skin that is not visible, ie has not presented itself as rash.. #6 Antimicrobials and antiseptics. Bacteria count was reduced and there was significant improvement in mean eczema ...
Background. Benefits of conversion from calcineurin inhibitor (CNI) to mammalian target of rapamycin inhibitor-based immunosuppression in long-term kidney transplant patients remain uncertain. Methods. ASCERTAIN was a 24-month, open-label, multicenter study. Kidney transplant patients more than 6 months posttransplant receiving CNI (baseline glomerular filtration rate [GFR] 30-70 mL/min/1.73 m(2)) were randomized to everolimus with CNI elimination (n = 127) or CNI minimization (n = 144), or continued CNI unchanged (controls, n = 123) to assess the effect on measured GFR at month 24 after randomization. Results. Renal function was stable in all groups to month 24. Mean measured GFR at month 24, the primary endpoint, was 48.0 +/- 22.0 mL/min/1.73 m(2), 46.6 +/- 21.1 mL/min/1.73 m(2), and 46.0 +/- 20.4 mL/min/1.73 m(2) in the CNI elimination, CNI minimization, and control groups, respectively. Differences between CNI elimination (1.12 mL/min/1.73 m(2), 95% confidence interval [CI] -3.51 to 5.76, ...
Results] We were able to observe 3,622 genes modulated in at least one timepoint in the mutant when compared to the wild type strain (3,211 and 411 at 10 and 30 minutes, respectively). Decreased mRNA abundance in the ΔcrzA was seen for genes encoding calcium transporters, transcription factors and genes that could be directly or indirectly involved in calcium metabolism. Increased mRNA accumulation was observed for some genes encoding proteins involved in stress response. AfCrzA overexpression in A. fumigatus increases the expression of several of these genes. The deleted strain of one of these genes, AfRcnA, belonging to a class of endogenous calcineurin regulators, calcipressins, had more calcineurin activity after exposure to calcium and was less sensitive to menadione 30 μM, hydrogen peroxide 2.5 mM, EGTA 25 mM, and MnCl2 25 mM. We constructed deletion, overexpression, and GFP fusion protein for the closely related A. nidulans AnRcnA. GFP::RcnA was mostly detected along the germling, did ...
Purpose: Calcineurin orchestrates growth, stress responses and virulence in major pathogenic fungi including Aspergillus fumigatus responsible for life-threatening fungal infections worldwide. While these cellular regulatory functions of calcineurin make it an attractive antifungal target, the immunosuppressive effects of the currently available calcineurin inhibitors, FK506 and CsA, make it difficult to exploit the antifungal potential due to conservation of calcineurin in the host and the fungal pathogen. Critical molecular understanding of calcineurin-immunophilin-immunosuppressor complexes would facilitate the design of novel non-immunosuppressive CsA and FK506 analogs for fungal-specific targeting of calcineurin.. Methods: We solved the crystal structure of calcineurin-FK506-FKBP12 complex in A. fumigatus and using site-directed mutagenic approaches, we constructed several mutations in the CnaA catalytic subunit of calcineurin and FKBP12. To identify differences between the A. fumigatus ...
Calcineurin (CN), a calcium- and calmodulin-dependent protein phosphatase, plays a significant role in the central nervous system. Previously, we reported that forebrain-specific CN knockout mice (CN mutant mice) have impaired working memory. To further analyze the behavioral effects of CN deficiency, we subjected CN mutant mice to a comprehensive behavioral test battery. Mutant mice showed increased locomotor activity, decreased social interaction, and impairments in prepulse inhibition and latent inhibition. In addition, CN mutant mice displayed an increased response to the locomotor stimulating effects of MK-801. Collectively, the abnormalities of CN mutant mice are strikingly similar to those described for schizophrenia. We propose that alterations affecting CN signaling could comprise a contributing factor in schizophrenia pathogenesis.. ...
Eczema, or atopic dermatitis, is a common inflammatory disease of the skin. The condition often has its start in childhood and follows a variable and sometimes unremitting course.
New and emerging trends in the treatment of atopic dermatitis Christina M Gelbard1, Adelaide A Hebert1,21Departments of Dermatology; 2Pediatrics, University of Texas-Houston, Houston, TX, USAAbstract: Atopic dermatitis is a chronic, inflammatory skin condition that affects 10% to 20% of children and 1% to 3% of adults in the US. Symptoms often result in sleeplessness, psychological stress, poor self-esteem, anxiety, and poor school or work performance. The cost of atopic dermatitis is estimated to be US$0.9 to 3.8 billion every year. Topical steroids are first-line treatment for atopic dermatitis, and recent advances in vehicle technologies have resulted in improved patient tolerability and compliance. Topical calcineurin inhibitors are also safe and effective topical treatments for atopic dermatitis, and provide an additional therapeutic option for patients with this disease. Systemic immunomodulators are used in the treatment of severe refractory disease. Cyclosporine, methotrexate, azathioprine,
Pulmonary surfactant proteins and lipids are required for lung function after birth. Lung immaturity and resultant surfactant deficiency cause respiratory distress syndrome, a common disorder contributing to morbidity and mortality in preterm infants. Surfactant synthesis increases prior to birth in association with formation of the alveoli that mediate efficient gas exchange. To identify mechanisms controlling perinatal lung maturation, the Calcineurin b1 (Cnb1) gene was deleted in the respiratory epithelium of the fetal mouse. Deletion of Cnb1 caused respiratory failure after birth and inhibited the structural maturation of the peripheral lung. Synthesis of surfactant and a lamellar body-associated protein, ABC transporter A3 (ABCA3), was decreased prior to birth. Nuclear factor of activated T cells (Nfat) calcineurin-dependent 3 (Nfatc3), a transcription factor modulated by calcineurin, was identified as a direct activator of Sftpa, Sftpb, Sftpc, Abca3, Foxa1, and Foxa2 genes. The ...
Calcineruin control over hyphal septation and cell wall biosynthesis. Septa are crucial in hyphal growth as they are the natural dividers in the growing hyphae, critical for continued growth and compartmentalization of cellular function. We were the first group to establish that both calcineurin subunits are stably present in the developing A. fumigatus hyphal septum, sitting as disks on each side of the septum. Calcineurin deletion mutants create septal defects and miscues in cellular metabolism. The hyphal septa is also a prime example of how important cell wall biosynthesis is for the organism. The cell wall serves as the leading point for the growing and invading hyphae as well as the first contact point with the host. The cell wall functions as both a structural component to hold the cell together as well as a scaffold for countless cellular functions. We have shown that calcineurin controls cell wall metabolism, and now we are working on uncovering the exact molecular mechanisms of ...
Certain immune-suppressing drugs, such as those taken by patients who have had organ transplants, greatly increase the risk of developing diabetes. These drugs are known to put a stranglehold on a protein called calcineurin.. So its not exactly a surprise that Seung Kim, MD, PhD, assistant professor of developmental biology at the Stanford University School of Medicine, chose to study why calcineurin inhibition leads to the disease. What is surprising is just how central calcineurin turns out to be in the health and happiness of the insulin-producing pancreatic beta cells. His findings, to be published in the Sept. 21 issue of Nature, could shake up diabetes research, lead to new classes of diabetes drugs and aid in efforts to develop stem cell treatments for diabetes.. "This work has the potential to be big," said Scott Campbell, PhD, vice president of research for the American Diabetes Association. He said that drugs based on this research could potentially expand the numbers of the few beta ...
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TMEM110, also designated as STIMATE (for STIM-activating enhancer), is an ER-resident multi-transmembrane protein identified through a proteomic study on the ER-PM junctions. The ER-PM junctions are defined as specialized junctional sites, also known as membrane contact sites, that connect the endoplasmic reticulum (ER) and the plasma membrane (PM), and are closely implicated in controlling lipid and calcium homeostasis in mammalian cells. TMEM110 is a positive modulator of calcium flux mediated by the STIM-ORAI signaling in vertebrates. STIMATE can physically associate with STIM1 to promote conformational switch of STIM1 from inactive toward an activated state, thereby coupling to and gating the ORAI calcium channels on the plasma membrane. Depletion of TMEM110 with RNAi knockdown or Cas9-mediated gene disruption substantially reduces the puncta formation of STIM1 at ER-PM junctions and remarkably inhibits the calcium/calcineurin/NFAT signaling axis. More genetic and biochemical studies are ...
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|i|Background/Aims:|/i| A potential risk of lymphoma associated with the use of topical calcineurin inhibitors is debated. We assessed the risk of lymphoma among patients treated with topi
Drs Krakowski and Eichenfeld pointed out that based on these new understandings of AD pathogenesis, an emphasis of therapy has been on barrier repair. Novel barrier repair creams can be used as adjuncts to conventional topical therapies, such as corticosteroids and topical calcineurin inhibitors, or as long-term maintenance therapy. One of the most promising agents…
In this study, it was shown that IL-4-mediated signals were strikingly but transiently inhibited by TCR engagement of naive T cells. This inhibition involved triggering of both the PKC-MAPK and calcineurin pathways. It has recently been reported by Ivashkiv and colleagues that the IL-2 signal was inhibited by TCR engagement in preactivated T cells and the inhibition was mediated by the PKC-MAPK pathway (35). We have also checked the IL-4 signal in activated cells and observed results quite similar to those described above for naive T cells (data not shown). In addition, we found that the IL-2 signal was also inhibited by TCR engagement in naive T cells. McMahon and colleagues have shown that sustained activation of the Raf-MEK-ERK pathway elicited cytokine unresponsiveness in T cells (46). These results are consistent in indicating that MAPK plays an important role in the cross-talk between TCR and cytokine signals. Our data further show that although MAPK activation is necessary, it is not ...
GATA-3 is necessary for the development of MHC class II-restricted CD4 T cells, and its expression is increased during positive selection of these cells. TCR signals drive this upregulation, but the signaling pathways that control this process are not well understood. Using genetic and pharmacological approaches, we show that GATA-3 upregulation during thymocyte-positive selection is the result of additive inputs from the Ras/MAPK and calcineurin pathways. This upregulation requires the presence of the transcription factor c-Myb. Furthermore, we show that TH-POK can also upregulate GATA-3 in double-positive thymocytes, suggesting the existence of a positive feedback loop that contributes to lock in the initial commitment to the CD4 lineage during differentiation. ...
Tehrani N., Anoushiravani A., Bhakta A., Petrov R., Tafen M., Samuels S. Non-operative Management of Water Injection Injury to the Neck. J of Pediatric Surgical Cases. In press.. Petrov R, Elbahloul O, Gallichio MH, Stellrecht K, Conti D. Monthly screening for polyoma virus eliminates BK nephropathy and preserves renal function. Surg Infect. 2009 Feb;10(1):85-90. PMID: 19298172.. Conti D, Petrov R, Elbalhoul O, Gallichio M. Sirolimus-based, calcineurin-inhibitor sparing immunotherapy, long-term (6-year) results. Transpl Immunol. 2008 Nov; 20(1-2): 12-3. PMID: 18793727.. Friedrich J, Petrov R, Askay S, Clark M, Foy H, Isik F, Dellinger P, Klein M, Engrav L. Resection of panniculus morbidus: a salvage procedure with a steep learning curve.. Plast Reconstr Surg.. 2008 Jan; 121(1): 108-14. Cited in PubMed; PMID: 18176212.. ...
The NFAT family of transcription factors include the cytoplasmic NFAT transcription factors [NFATc1 (NFATc), NFATc2 (NFATp), NFATc3 (NFAT4, NFATx), NFATc4 (NFAT3), NFATc5] and nuclear NFAT (NFATn ...
The NFAT family of transcription factors include the cytoplasmic NFAT transcription factors [NFATc1 (NFATc), NFATc2 (NFATp), NFATc3 (NFAT4, NFATx), NFATc4 (NFAT3), NFATc5] and nuclear NFAT (NFATn ...
However, depending on the amplitude of the Ca2+ signal as well as the condition of the cell, Ca2+ can also initiate apoptosis as a consequence of organelle disruption, free radical production, and the activation of Ca2+-dependent phosphatases and proteases such as calcineurin and calpain (96).. The release of Ca2+ from the ER is a critical early event for the initiation of apoptosis induced by many apoptotic signals (115). The sensitivity of a cell to such apoptotic stimuli appears to be largely dependent on the ER Ca2+ load, with a high resting ER Ca2+ concentration sensitizing cells to apoptotic stimuli and a low ER Ca2+ concentration conferring resistance. Once released into the cytosol, Ca2+ is rapidly adsorbed by mitochondria that can trigger apoptotic responses by disrupting the mitochondrial respiratory chain and generating reactive oxygen species or by opening the PTP (122).. The original finding that Bcl-2 affected Ca2+ signaling was discovered over a decade ago. In these studies, Bcl-2 ...
ES increased expression of Hey1 and Pitx2 suggesting increased Notch and Wnt signaling, respectively, but did not normalize RCAN1.4, a measure of calcineurin/NFAT signaling, or PGC-1ß mRNA levels. ES increased PGC-1α expression but not that of slow myofibrillar genes. Microarray analysis showed that after ES, genes coding for calcium binding proteins and nicotinic acetylcholine receptors were increased, and the expression of genes involved in blood vessel formation and morphogenesis was altered. Of the 165 genes altered by ES only 16 were also differentially expressed after GA, of which 12 were altered in the same direction by ES and GA. In contrast to ES, GA induced expression of genes related to oxidative phosphorylation ...
Ustilago maydis is a dimorphic basidiomycete and the causal agent of corn smut disease. It serves as a genetic model for understanding dimorphism, pathogenicity, and mating response in filamentous fungi ...
Screening for a gene deletion mutant whose temperature sensitivity is suppressed by FK506 in budding yeast and its application for a positive screening for drugs inhibiting calcineurin, BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY, 79巻, 5号, pp.790-pp.794, MAY 4 ...
In this issue of JAMA Dermatology, Speeckaert and colleagues report that levels of the soluble CD25 and CD27 molecules (sCD25 and sCD27) are elevated in the serum of patients with active vitiligo compared with patients with stable disease. In addition, sCD25 levels were found to be significantly lower in the serum of patients being treated with topical immunosuppressants (including steroids and calcineurin inhibitors) and the serum level of sCD27 was significantly lower in patients with recent repigmentation, suggesting a potential to use these as biomarkers to monitor treatment responses. Interestingly, the authors continued to prospectively study a relatively large number of participants and demonstrated that serum levels of both sCD25 and sCD27 were associated with disease progression during follow-up. These important findings suggest that monitoring of these markers in the serum of patients with vitiligo may provide a glimpse into what is happening in the skin, a process that is not obvious by
Emory scientists have identified troublemaker cells-present in some patients before kidney transplantation-that are linked to immune rejection after transplant. Their results could guide transplant specialists in the future by helping to determine which drug regimens would be best for different groups of patients. Eventually, the findings could lead to new treatments that improve short- and long-term outcomes.. Transplant patients used to have no choice but to take non-specific drugs to prevent immune rejection of their new kidneys. While these drugs, called calcineurin inhibitors, are effective at preventing early rejection, they lack specificity for the immune system and ironically can damage the very kidneys they are intended to protect. In addition, their side effects lead to higher rates of high blood pressure, diabetes, and cardiovascular disease, ultimately shortening the life of the transplant recipient. This changed with the advent of costimulation blockers, which avoid these harmful ...
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Ppp3r2 - Ppp3r2 (untagged ORF) - Rat protein phosphatase 3, regulatory subunit B, alpha isoform (calcineurin B, type II) (Ppp3r2), (10 ug) available for purchase from OriGene - Your Gene Company.
Andere Agenzien enthalten aktuelle calcineurin Hibitoren wie Protopic tacrolimus und Elidel pimecrolimus. Aktuelle psoriatic Behandlungen sollten nie an den heiklen Gebieten der Haut, wie den Augen, Mund, Genitalien Psoriasis-Behandlung mit Fett anderen Bereichen angewendet werden.. Cancel reply to comment. Unfortunately, studies show that only about 5 million people living with OAB seek care from a doctor, and only half of those patients seek a specialist like a urologist or urogynecologist for treatment. Antibiotic resistance is happening in hospitals quite Psoriasis-Behandlung mit Fett. Probably the main place where resistant organisms and pathogens are acquired is in intensive care units ICUs.. The mTOR pathway is probably the main pathway in humans and other animals that drives growth. That is, the accumulation of mass and adding mass to make an organism bigger by both making more cells, and making cells grow and become bigger. Psoriasis-Behandlung mit Fett provides this medical information ...
Inflammation, in excess, was believed to be an underlying factor in the pathogenesis of proliferative cardiovascular diseases such as atherosclerosis and resten...
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TY - JOUR. T1 - Effects of calcineurin inhibitors on sodium excretion in recipients of allogeneic hematopoietic stem cell transplantation. AU - Saburi, Masuho. AU - Kohashi, Sumiko. AU - Kato, Jun. AU - Koda, Yuya. AU - Sakurai, Masatoshi. AU - Toyama, Takaaki. AU - Kikuchi, Taku. AU - Karigane, Daiki. AU - Yuda, Sayako. AU - Yamane, Yusuke. AU - Hashida, Risa. AU - Abe, Ryohei. AU - Nakazato, Tomonori. AU - Hirahashi, Junichi. AU - Ogata, Masao. AU - Okamoto, Shinichiro. AU - Mori, Takehiko. PY - 2017/5/17. Y1 - 2017/5/17. N2 - Calcineurin inhibitors (CIs) such as cyclosporine A (CSA) and tacrolimus often cause renal dysfunction, resulting in increased serum creatinine, hyperkalemia, and hyperuricemia. However, the effects of CIs on sodium excretion have not been fully elucidated. We retrospectively evaluated the effects of CI administration on sodium excretion in recipients of allogeneic hematopoietic stem cell transplantation (HSCT). Fifty consecutive recipients each of allogeneic HSCT ...
Free Radic Biol Med. 2005 Sep 15;39(6):719-27. Research Support, N.I.H., Extramural; Research Support, Non-U.S. Govt; Research Support, U.S. Govt, P.H.S.
Sirolimus is a compound produced by the bacteria Streptomyces hygroscopicus. Sirolimus inhibits the response to interleukin-2 (IL-2) and thereby blocks activation of T- and B-cells. In contrast, tacrolimus inhibits the production of IL-2. Sirolimus limits the immune response and helps to prevent organ rejection by inhibiting immune cell activation and proliferation, and antibody production.. The chief advantage sirolimus has over calcineurin inhibitors is that it has low renal toxicity. Transplant patients maintained on calcineurin inhibitors long-term tend to develop impaired kidney function or even chronic renal failure; this can be avoided by using sirolimus instead. It is particularly advantageous in patients with kidney transplants for hemolytic-uremic syndrome, as this disease is likely to recur in the transplanted kidney if a calcineurin-inhibitor is used.. Sirolimus can be taken orally and it is absorbed from the gastrointestinal tract, concentrations peak in the blood within 1 - 2 hours ...
Journal of Drugs in Dermatology, March, 2006 by Lindsey Warino, James Libecco Abstract Cancer is a major cause of death in immunosuppressed transplant patients. Therefore, sirolimus is frequently used in these patients for its immunosuppressive and antineoplastic properties. However, a variety of cutaneous side effects have resulted from sirolimus therapy. Consequently, dermatologists must be aware of such adverse events and understand the risks and benefits of discontinuing therapy. Introduction Sirolimus (Rapamycin) is an immunosuppressive agent often used in combination with cyclosporine and corticosteroids in renal transplant patients. In contrast to the calcineurin inhibitors, sirolimus, a macrocyclic lactone isolated from Streptomyces Hygroscopicus, has no effect on calcineurin activity. (1-15) Rather, it acts to suppress cytokine-driven T cell proliferation and inhibits the progression from G1 to the S phase of the cell cycle. Not only is sirolimus used for its immunosuppressive ...
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The safety profile and clinical efficacy of caspofungin (CAS) has raised questions as to whether its effectiveness could be further improved by administering higher dosages. However, in vitro studies as well as some dosage escalation studies in animals have reported a paradoxical attenuation of CAS activity at higher drug concentrations (5, 17, 21, 23). These concentrations are comparable to plasma CAS levels achieved in humans at recommended doses (22). The mechanism of the attenuated CAS activity at higher concentrations and its clinical relevance are unknown. Studies of the genetically amenable yeast Saccharomyces cerevisiae have suggested links with both the intracellular protein kinase C (PKC) cell wall integrity and calcineurin pathways (1, 4, 7, 13, 18, 20). In view of the evolutionary conservation of several key cellular processes, including homeostatic responses toward drug-induced damage of the fungal cell wall (2, 19), we hypothesized that the cell wall integrity and calcineurin ...
For the first time, an immunosuppressive agent has shown better organ survival in kidney transplant recipients than a calcineurin inhibitor, the current standard of care, according to a worldwide study led by UC San Francisco and Emory University investigators.. The study of the drug belatacept, which carries short-term risks that include an increased possibility for a certain cancer, appears in the Jan. 28 issue of the New England Journal of Medicine.. "Belatacept is potentially a transformational drug in kidney transplantation because unlike the currently used calcineurin inhibitor drugs cyclosporine and tacrolimus, it is not toxic to the kidney," said lead author Flavio Vincenti, MD, a UCSF Health kidney and pancreas transplant specialist. "In fact, it helps preserve the function of the kidney over the long term and is more effective in suppressing antibodies against the kidney, which are important causes of late graft loss.". Kidney transplant recipients need to take drugs to prevent their ...
For the first time, an immunosuppressive agent has shown better organ survival in kidney transplant recipients than a calcineurin inhibitor, the current standard of care, according to a worldwide study led by UC San Francisco and Emory University investigators.. The study of the drug belatacept, which carries short-term risks that include an increased possibility for a certain cancer, appears in the Jan. 28 issue of the New England Journal of Medicine.. "Belatacept is potentially a transformational drug in kidney transplantation because unlike the currently used calcineurin inhibitor drugs cyclosporine and tacrolimus, it is not toxic to the kidney," said lead author Flavio Vincenti, MD, a UCSF Health kidney and pancreas transplant specialist. "In fact, it helps preserve the function of the kidney over the long term and is more effective in suppressing antibodies against the kidney, which are important causes of late graft loss.". Kidney transplant recipients need to take drugs to prevent their ...
Keywords: IgA nephropathy, Calcineurin inhibitor, Cyclosporine A, Tacrolimus Background IgA nephropathy is the most common main glomerular disease worldwide. A wide variety of treatments have attempted to reduce kidney burden and the high risk of kidney failure events in this populace. IgAN is an autoimmune kidney disease, indicating that immunosuppressive therapy may be helpful. Immunosuppressive therapy is supposed to reduce the deterioration in kidney function as well as a reduction in proteinuria. The core I 3-Gal-T-specific molecular chaperone (Cosmc) gene expression was decreased in IgAN patients. Immunosuppressive therapy can up-regulate the Cosmc expression in peripheral lymphocytes of IgAN patients. It might be the underlying mechanism of immunosuppressive therapy used in treating IgAN [1, 2]. It has been proven that calcineurin inhibitors (CNIs) which include cyclosporine A (CsA) and tacrolimus (TAC), can suppress the immune response by downregulating the transcription of various genes ...
OBJECTIVE: Physical activity and circadian rhythms are well-established determinants of human health and disease, but the relationship between muscle activity and the circadian regulation of muscle genes is a relatively new area of research. It is unknown whether muscle activity and muscle clock rhythms are coupled together, nor whether activity rhythms can drive circadian gene expression in skeletal muscle. METHODS: We compared the circadian transcriptomes of two mouse hindlimb muscles with vastly different circadian activity patterns, the continuously active slow soleus and the sporadically active fast tibialis anterior, in the presence or absence of a functional skeletal muscle clock (skeletal muscle-specific Bmal1 KO). In addition, we compared the effect of denervation on muscle circadian gene expression. RESULTS:We found that different skeletal muscles exhibit major differences in their circadian transcriptomes, yet core clock gene oscillations were essentially identical in fast and slow ...
TY - JOUR. T1 - Pharmacotherapy options for membranous nephropathy. AU - Schieppati, Arrigo. AU - Remuzzi, Giuseppe. PY - 2016/2/1. Y1 - 2016/2/1. N2 - Introduction: Membranous nephropathy (MN) is a rare, antibody-mediated glomerular disease that causes nephrotic syndrome in adults. It is a chronic disease with spontaneous remissions in approximately 30% of patients. The reminder, however, experience long periods of nephrotic syndrome and progress toward end-stage renal diseases. The ideal treatment for patients with MN is still matter of debate.Areas covered: The PubMed database was searched for original articles and reviews published up to August 2015. The search terms were: membranous nephropathy, prognosis, pathogenesis, and treatment.Expert opinion: Steroids in association with alkylating agents and calcineurin inhibitors are currently used and recommended by international guidelines as treatment of choice in MN. However the treatment benefits are uncertain, and often offset by adverse ...
The results of these studies demonstrate that calcineurin inhibitors cause endothelial cells to increase the number of microparticles released into the circulation from the cell surface. Calcineurin inhibitors also alter the composition of the microparticles such that they become complement activating. We found that alternative pathway-deficient mice are protected from CsA-induced renal and vascular injury. We also found that endothelial microparticles cause injury of unmanipulated endothelial cells in vitro, and they cause mesangial proliferation and complement activation when passively transferred into wild-type mice in vivo. These results demonstrate that CsA-induced endothelial microparticles can cause bystander injury of endothelial cells, and they promote glomerular complement activation and mesangial expansion. Furthermore, preliminary data from human transplant patients indicate that treatment of these patients with tacrolimus is also associated with generation of endothelial ...
Down syndrome (MIM 190685) is the most common genetic form of mental retardation. It is caused by trisomy of all or a portion of chromosome 21. The 2.5-Mb region [3, 4] between DNA markers D21S17 and ERG (MIM 165080) is associated with the main features of Down syndrome and is termed the Down syndrome critical region. As part of the human genome project, our laboratory is studying the physical structure of human chromosome 21. To identify the genes and functional units mapped on chromosome 21, we are focusing on the physical mapping and sequencing of several regions. One region we have sequenced is the distal 1.6-Mb end of the Down syndrome critical region. The 4-Mb region from the SOD1 gene (MIM 147450) to the AML1 (MIM 151385) gene will soon be completely sequenced. This study describes the detailed sequence analysis of these two regions of chromosome 21.
Cyclosporine and tacrolimus, calcineurin inhibitors (CNIs), are commonly used as immunosuppressive therapy in patients who have undergone kidney transplantation. According to Josep M. Grinyó, MD, PhD, and colleagues in Buenos Aires, Argentina, those agents may be associated with patient comorbidity via nephrotoxicity and cardiovascular risk (hypertension, hypercholesterolemia, and diabetes mellitus), as well as transplant loss via chronic transplant injury. The researchers contend that there is a need for immunosuppressive agents that control the alloimmune response as effectively as CNIs, but do not have the possible renal and cardiovascular adverse effects.. Some immunosuppressive regimens that avoid or minimize CNI involve the mammalian target of rapamycin (mTOR) inhibitors sirolimus or everolimus; those have been evaluated in earlier prospective studies of recipients of kidney transplant. In those studies, patients who switched from therapy based on CNIs to one based on a mTOR inhibitor had ...
TY - JOUR. T1 - Cyclosporine elimination in the presence of TOR inhibitors. T2 - Effects on renal function, acute rejection, and safety. AU - Velosa, Jorge A.. AU - Larson, Timothy S.. AU - Gloor, James M.. AU - Stegall, Mark D. PY - 2001. Y1 - 2001. N2 - Sirolimus in combination with cyclosporine reduces the incidence of acute rejection in renal transplant recipients when administered in double- or triple-therapy immunosuppressive regimens. Sirolimus administered as primary therapy has a beneficial effect on renal function, and the frequency of rejection episodes is similar to that of primary immunosuppression with cyclosporine. A strategy that may result in a more benign immunologic course with a substantially beneficial effect on renal function is to administer sirolimus and a calcineurin inhibitor early after transplantation, thereby promoting immunologic adaptation, and then to withdraw the calcineurin inhibitor at some point after transplantation to prevent nephrotoxicity. This article ...
TY - JOUR. T1 - Variable magnitude of drug interaction between oral voriconazole and cyclosporine A in recipients of allogeneic hematopoietic stem cell transplantation. AU - Kikuchi, Taku. AU - Mori, Takehiko. AU - Yamane, Akiko. AU - Kato, Jun. AU - Kohashi, Sumiko. AU - Okamoto, Shinichiro. PY - 2012/9/1. Y1 - 2012/9/1. N2 - Drug interaction between voriconazole and calcineurin inhibitors is often problematic after allogeneic hematopoietic stem cell transplantation (HSCT) or solid organ transplantation. We previously demonstrated an unpredictable inter-individual variability in the magnitude of this drug interaction; however, the route of drug administration was not taken into account. In this study, the drug interaction between voriconazole and calcineurin inhibitors was further analyzed under the condition that both agents were administered orally. Twenty adult recipients of HSCT who had already been on a steady dose of oral cyclosporine A (CsA) and were started on oral voriconazole (400 ...
calcineurin inhibitor. unknown. D-penicillamine (seldom used today). Reducing numbers of T-lymphocytes etc.. unknown. ...
... which acts via calmodulin to activate calcineurin. Calcineurin then dephosphorylates the transcription factor nuclear factor of ... ISBN 0-07-144040-2. Liu J, Farmer J, Lane W, Friedman J, Weissman I, Schreiber S (1991). "Calcineurin is a common target of ... Tacrolimus is a macrolide calcineurin inhibitor. In T-cells, activation of the T-cell receptor normally increases intracellular ... This FKBP12-FK506 complex interacts with and inhibits calcineurin, thus inhibiting both T-lymphocyte signal transduction and IL ...
Calcineurin inhibitors and azathioprine have been linked with post-transplant malignancies and skin cancers in organ transplant ... It is a macrolide lactone and acts by inhibiting calcineurin. The drug is used primarily in liver and kidney transplantations, ... It binds to the immunophilin FKBP1A, followed by the binding of the complex to calcineurin and the inhibition of its ... Like tacrolimus, ciclosporin (Novartis' Sandimmune) is a calcineurin inhibitor (CNI). It has been in use since 1983 and is one ...
Naesens M, Kuypers DR, Sarwal M (2009). "Calcineurin inhibitor nephrotoxicity". Clin. J. Am. Soc. Nephrol. 4 (2): 481-509. doi: ...
In molecular biology, the calcipressin family of proteins negatively regulate calcineurin by direct binding. They are essential ... Calcipressin 1 is a phosphoprotein that increases its capacity to inhibit calcineurin when phosphorylated at the conserved ... Calcipressin 1 is also known as modulatory calcineurin-interacting protein 1 (MCIP1), Adapt78 and Down syndrome critical region ... Parry RV, June CH (September 2003). "Calcium-independent calcineurin regulation". Nat. Immunol. 4 (9): 821-3. doi:10.1038/ ...
... which acts via calmodulin to activate calcineurin. Calcineurin then dephosphorylates the transcription factor NF-AT (nuclear ... Ciclosporin's main effect is to lower the activity of T-cells; it does so by calcineurin-phosphatase pathway and preventing the ... This ciclosporin-cyclophilin complex inhibits calcineurin, which is normally responsible for activating the transcription of ... CsA also inhibits the phosphatase calcineurin pathway (14).[24][25][59] Inhibition of this pathway has been shown to decrease ...
Calcineurin-binding protein cabin-1 is a protein that in humans is encoded by the CABIN1 gene. Calcineurin plays an important ... "Entrez Gene: CABIN1 calcineurin binding protein 1". Lai MM, Luo HR, Burnett PE, Hong JJ, Snyder SH (Nov 2000). "The calcineurin ... The protein encoded by this gene binds specifically to the activated form of calcineurin and inhibits calcineurin-mediated ... Esau C, Boes M, Youn HD, Tatterson L, Liu JO, Chen J (Nov 2001). "Deletion of calcineurin and myocyte enhancer factor 2 (MEF2) ...
OCLC 48435597 Klumpp, S.; Krieglstein, J. (2003). "Regulation of Calcineurin by Oxidative Stress". Protein Phosphatases. ...
Calcineurin activates TAK1 and NLK kinase, which can interfere with TCF/ß-Catenin signaling in the canonical Wnt pathway. ... Increased calcium also activates calcineurin and CaMKII. CaMKII induces activation of the transcription factor NFAT, which ...
Calcineurin subunit B type 2 is a protein that in humans is encoded by the PPP3R2 gene. Among its related pathways are MAPK ... 2007). "The calcineurin activity profiles of cyclosporin and tacrolimus are different in stable renal transplant patients". ... 2007). "Calcineurin potentiates the activation of procaspase-3 by accelerating its proteolytic maturation". J. Biol. Chem. 282 ... Jang H, Cho EJ, Youn HD (2007). "A new calcineurin inhibition domain in Cabin1". Biochem. Biophys. Res. Commun. 359 (1): 129-35 ...
When intracellular calcium reaches a threshold, it will activate the calcineurin /NFAT pathway. DAG activates the calcineurin/ ... The mechanism of how TRPC channels promote cardiac hypertrophy is through activation of the calcineurin pathway and the ... canonical transient receptor potential channels promote cardiomyocyte hypertrophy through activation of calcineurin signaling ...
These complexes inhibit calcineurin, block dephosphorylation of the transcription factor NFAT of activated T-cells and its ... Liu, J; Farmer JD, Jr; Lane, WS; Friedman, J; Weissman, I; Schreiber, SL (23 August 1991). "Calcineurin is a common target of ... Cyclosporine and tacrolimus are inhibitors of calcineurin. Both substances are structurally different but have the same ...
PGC-1α leads to calcineurin activation. Akt and calcineurin are both activators of NF kappa B (p65). Through their activation ...
It is thought to mediate calcineurin inhibition. It also interacts functionally with mature corticoid receptor hetero-complexes ... a novel T-cell-specific immunophilin capable of calcineurin inhibition". Mol. Cell. Biol. 15 (8): 4395-402. doi:10.1128/mcb. ... and FK506-binding protein that can mediate calcineurin inhibition". Biochem. Biophys. Res. Commun. 232 (2): 437-43. doi:10.1006 ...
Graef IA, Chen F, Chen L, Kuo A, Crabtree GR (Jun 2001). "Signals transduced by Ca(2+)/calcineurin and NFATc3/c4 pattern the ... Molkentin JD, Lu JR, Antos CL, Markham B, Richardson J, Robbins J, Grant SR, Olson EN (Apr 1998). "A calcineurin-dependent ... Crabtree GR (Mar 1999). "Generic signals and specific outcomes: signaling through Ca2+, calcineurin, and NF-AT". Cell. 96 (5): ... "Entrez Gene: NFATC4 nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 4". Fougère M, Gaudineau B, Barbier ...
Graef IA, Chen F, Chen L, Kuo A, Crabtree GR (June 2001). "Signals transduced by Ca(2+)/calcineurin and NFATc3/c4 pattern the ... Esau C, Boes M, Youn HD, Tatterson L, Liu JO, Chen J (November 2001). "Deletion of calcineurin and myocyte enhancer factor 2 ( ... Mukerjee N, McGinnis KM, Gnegy ME, Wang KK (August 2001). "Caspase-mediated calcineurin activation contributes to IL-2 release ... Crabtree GR (March 1999). "Generic signals and specific outcomes: signaling through Ca2+, calcineurin, and NF-AT". Cell. 96 (5 ...
The protein encoded by this gene interacts with calcineurin A and inhibits calcineurin-dependent signaling pathways of genetic ... DSCR1 in human is located at the centromeric border of the DSCR and encodes an inhibitor of calcineurin/ NFAT (nuclear factor ... DSCR1 Consist of putative functional motifs and calcineurin binding domain. DSCR1 contains two proline-rich SH3 binding domain ... Ermak G, Morgan TE, Davies KJ (Oct 2001). "Chronic overexpression of the calcineurin inhibitory gene DSCR1 (Adapt78) is ...
A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell 93, 215-228. McKinsey, T.A., Zhang, C.L., Lu, J ...
21, 4066-4073, "Calcineurin Links Ca++ Dysregulation with Brain Aging"( Chen L, Willis SN, Wei A, Smith BJ, Fletcher JI, Hinds ... BAD phosphorylation is thus anti-apoptotic, and BAD dephosphorylation (e.g., by Ca2+-stimulated Calcineurin) is pro-apoptotic. ... "Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD". Science. 284 (5412): 339-43. doi:10.1126/science.284.5412 ...
Paterson JM, Smith SM, Harmar AJ, Antoni FA (1995). "Control of a novel adenylyl cyclase by calcineurin". Biochem. Biophys. Res ...
This phosphorylation can be reversed by the phosphatase, calcineurin. The phosphorylation of the isozymes is accompanied by a ...
It has been shown in vitro that pimecrolimus binds to macrophilin-12 (also referred to as FKBP-12) and inhibits calcineurin.[ ... CS1 maint: Multiple names: authors list (link) Spergel JM, Leung DY (2006). "Safety of topical calcineurin inhibitors in atopic ... Pimecrolimus is an immunomodulating agent of the calcineurin inhibitor class used in the treatment of atopic dermatitis (eczema ... Stern RS (2006). "Topical calcineurin inhibitors labeling: putting the "box" in perspective". Archives of Dermatology. 142 (9 ...
1998). "A calcineurin-dependent transcriptional pathway for cardiac hypertrophy". Cell. 93 (2): 215-28. doi:10.1016/S0092-8674( ...
Frey N, Richardson JA, Olson EN (2001). "Calsarcins, a novel family of sarcomeric calcineurin-binding proteins". Proc. Natl. ...
It also reversibly inhibits calcineurin and binds to calmodulin. It inhibits replication of the HIV-1 virus. It is an effective ...
Mice lacking the MYOZ2 gene (MYOZ2-/-) are generally sensitized to calcineurin signaling in both muscle types. In slow-skeletal ... Calsarcin-1 binds to alpha-actinin, gamma-filamin, telethonin, ZASP/Cypher and calcineurin. The binding region of calsarcin-1 ... However, upon calcineurin activation or pressure overload-induced pathologic hypertrophy, MYOZ2-/- exhibited exaggerated ... Frey N, Richardson JA, Olson EN (December 2000). "Calsarcins, a novel family of sarcomeric calcineurin-binding proteins". ...
Calcineurin is a heterodimer of a 61-kD calmodulin-binding catalytic subunit, calcineurin A and a 19-kD Ca2+-binding regulatory ... Calcineurin/NFAT signaling is required for perinatal lung maturation and function. Calcineurin has been shown to interact with ... Calcineurin is the target of a class of drugs called calcineurin inhibitors, which includes cyclosporin, voclosporin, ... Wang MG, Yi H, Guerini D, Klee CB, McBride OW (1996). "Calcineurin A alpha (PPP3CA), calcineurin A beta (PPP3CB) and ...
Inhibiting the calcineurin-NFAT (nuclear factor of activated T cells) signaling pathway with a regulator of calcineurin-derived ... Calcineurin signaling and muscle remodeling. Cell. 2000;101:689-92.PubMedPubMedCentralCrossRefGoogle Scholar ... Future studies showed that the DSCR1 gene product is a calcineurin regulator, and the new name "regulator of calcineurin (RCAN ... Renaming the DSCR1/Adapt78 gene family as RCAN: regulators of calcineurin. FASEB J. 2007;21:3023-8.PubMedPubMedCentralCrossRef ...
The calcineurin-like phosphoesterases are a family of enzymes related to calcineurin. It includes a diverse range of ...
Calcineurin inhibitors/everolimus/methylprednisolone. Post-transplant diabetes mellitus and diabetic nephropathy: case report ...
Calcineurin activation is central to α-syn toxicity in yeast. (A) Control and HiTox strains lacking calcineurin (cnb1Δ) were ... calcineurin A, CNA) and an activating regulatory subunit (calcineurin B, CNB). As intracellular Ca2+ levels rise, Ca2+ binds to ... Calcineurin is critical for α-synuclein toxicity. Gabriela Caraveo, Pavan K. Auluck, Luke Whitesell, Chee Yeun Chung, Valeriya ... Calcineurin is critical for α-synuclein toxicity. Gabriela Caraveo, Pavan K. Auluck, Luke Whitesell, Chee Yeun Chung, Valeriya ...
SEARCH RESULTS for: Calcineurin Inhibitors [Drug Class] (69 results) * Share : JavaScript needed for Sharing tools. Bookmark & ...
We also found that M. circinelloides encodes three calcineurin catalytic A subunits (CnaA, CnaB, and CnaC) and one calcineurin ... Disruption of the cnbR gene encoding the sole calcineurin B subunit necessary for calcineurin activity yielded mutants locked ... Calcineurin Plays Key Roles in the Dimorphic Transition and Virulence of the Human Pathogenic Zygomycete Mucor circinelloides. ... Lee, S. C., Li, A., Calo, S., & Heitman, J. (2013). Calcineurin Plays Key Roles in the Dimorphic Transition and Virulence of ...
Posttransplantation hypertension related to calcineurin inhibitors. Liver Transpl, 6: 521-530. doi: 10.1053/jlts.2000.9737 ...
Redox response of the endogenous calcineurin inhibitor Adapt 78.. Narayan AV1, Stadel R, Hahn AB, Bhoiwala DL, Cornielle G, ... Adapt 78 (DSCR 1/calcipressin/MCIP 1) is a potent natural inhibitor of calcineurin, an important intracellular phosphatase that ... which may contribute to its known calcineurin-regulating and cytoprotective activities, and further suggest that Adapt 78 plays ... and accompanied by induction of the classic immune response mediator and calcineurin-pathway-stimulated interleukin-2. These ...
A Role for Calcineurin Dysfunction in Schizophrenia? Message Subject. (Your Name) has forwarded a page to you from Science ... Miyakawa et al. subjected a strain of mutant mice that lacked forebrain calcineurin to a battery of tests and observed a ... In an accompanying article, Gerber et al. demonstrated that the PPP3CC gene, which encodes the calcineurin γ catalytic subunit ... The authors discuss possible mechanisms whereby abnormalities in calcineurin signaling could predispose to the pathogenesis of ...
... Manabu Kubokawa, Kazuyoshi ... Roles of calcineurin (CaN), a Ca2+/calmodulin- (CaM-) dependent protein phosphatase, and Ca2+/CaM-dependent protein kinase-II ( ...
Overactivation of calcineurin induced by amyloid-beta and prion proteins.. Agostinho P1, Lopes JP, Velez Z, Oliveira CR. ... The Ca2+/calmodulin-dependent phosphatase calcineurin (CaN), through the dephosphorylation of the proapoptotic protein BAD, may ...
Galactokinase Is a Novel Modifier of Calcineurin-Induced Cardiomyopathy in Drosophila. Teresa E. Lee, Lin Yu, Matthew J. Wolf ... Galactokinase Is a Novel Modifier of Calcineurin-Induced Cardiomyopathy in Drosophila. Teresa E. Lee, Lin Yu, Matthew J. Wolf ... Galactokinase Is a Novel Modifier of Calcineurin-Induced Cardiomyopathy in Drosophila. Teresa E. Lee, Lin Yu, Matthew J. Wolf ... Galactokinase Is a Novel Modifier of Calcineurin-Induced Cardiomyopathy in Drosophila Message Subject (Your Name) has forwarded ...
Compare calcineurin binding protein 1 ELISA Kits from leading suppliers on Biocompare. View specifications, prices, citations, ... calcineurin binding protein 1 ELISA Kits. The ELISA (enzyme-linked immunosorbent assay) is a well-established antibody-based ... Your search returned 101 calcineurin binding protein 1 ELISA ELISA Kit across 8 suppliers. ...
Maybe yeast will help develop new strategies for calcineurin-related diseases!. Youve gotta "hand" it to calcineurin! (from ... Yeast calcineurin is so similar to human calcineurin that it too is affected by these drugs! ... Remember that the Cnb1 protein is the regulatory subunit of calcineurin, and calcineurin activates a transcription factor by ... Calcineurin is actually made up of two different proteins that bind together. One is a catalytic protein subunit (called CNA) ...
Calcineurin / antagonists & inhibitors*. Cholesterol / blood. Cyclosporine / therapeutic use. Drug Therapy, Combination. Female ... CONCLUSION: Calcineurin-inhibiting drugs, CsA and tacrolimus, have pro-oxidant activity and they increase the susceptibility of ...
Calcineurin inhibitor withdrawal or tapering for kidney transplant recipients. What is the issue? ... Calcineurin inhibitors (CNI) can reduce acute transplant rejection and immediate graft loss but are associated with significant ... Calcineurin inhibitors (CNI, cyclosporin and tacrolimus) are an important part of treatment to suppress the immune system to ... Calcineurin inhibitor withdrawal or tapering for kidney transplant recipients. Cochrane Database of Systematic Reviews 2017, ...
Topical calcineurin inhibitors increase the risk of viral, bacterial, fungal, and protozoal infections, including opportunistic ...
Ausgesuchte Qualitäts-Hersteller für Calcineurin A Antikörper. Hier bestellen. ... Monoklonale und polyklonale Calcineurin A Antikörper für viele Methoden. ... Bezeichner auf Proteinebene für anti-Calcineurin A (CAN) Antikörper calcineurin A , Calcineurin A , protein phosphatase-2B , ... Fruit Fly (Drosophila melanogaster) Calcineurin A (CAN) Interaktionspartner * results suggest a key role for calcineurin in ...
Invitrogen Anti-Calcineurin B Polyclonal, Catalog # PA5-29939. Tested in Western Blot (WB), Immunofluorescence (IF), ... Cite Calcineurin B Polyclonal Antibody. The following antibody was used in this experiment: Calcineurin B Polyclonal Antibody ... Calcineurin (also referred to as protein phosphatase 2B) is composed of two subunits; calcineurin A (CnA), a 60 kDa catalytic ... Knockdown of Calcineurin B was achieved by transfecting HeLa with Calcineurin B specific siRNAs (Silencer® select Product # ...
More significantly, genetic disruption of the calcineurin Aβ gene rescued hypertrophic cardiomyopathy and depressed functional ... Targeted inhibition of p38 MAPK promotes hypertrophic cardiomyopathy through upregulation of calcineurin-NFAT signaling. ... Targeted inhibition of p38 MAPK promotes hypertrophic cardiomyopathy through upregulation of calcineurin-NFAT signaling. ... indicate that reduced p38 signaling in the heart promotes myocyte growth through a mechanism involving enhanced calcineurin- ...
Transcriptomic Analysis Reveals Genes Mediating Salt Tolerance through Calcineurin/CchA-Independent Signaling in Aspergillus ...
2010) Calcineurin and its regulation by Sra/RCAN is required for completion of meiosis in Drosophila. Dev Biol 344:957-967. ... Calcineurin and Its Regulator Sra/DSCR1 Are Essential for Sleep in Drosophila. Yasuhiro Nakai, Junjiro Horiuchi, Manabu Tsuda, ... 2006) The calcineurin regulator sra plays an essential role in female meiosis in Drosophila. Curr Biol 16:1435-1440. ... Calcineurin regulates sleep and locomotor activity. Why do sra mutants sleep less than wild-type flies? Sras role as a CN ...
Home » Topics » Kidney Transplantation » Research » Spironolactone and Prevention of Calcineurin Inhibitor Toxicity in Kidney ... More From BioPortfolio on "Spironolactone and Prevention of Calcineurin Inhibitor Toxicity in Kidney Transplant Recipients". * ... Spironolactone and Prevention of Calcineurin Inhibitor Toxicity in Kidney Transplant Recipients. 2014-08-27 03:17:39 , ... kidney transplant recipients receiving calcineurin inhibitors. Study Design. Allocation: Randomized, Control: Placebo Control, ...
In the present thesis, I tried to vary the central nitrogen-heterocyclic cores, the functionalised side chains and its position of attachment. As a synthetic strategy, palladium-catalyzed coupling reactions were used to introduce side chains and aryl substituents into the central heterocycle. In this way the utility of such reactions to heterocyclic systems, which were neglected so far, could be figured out. Halogen substituted diaryl heterocycles are important intermediates in the synthesis of general structures. The introduction of the desired side chains by Carbon-Carbon bond formation reactions was achieved by Sonogashira coupling and Heck coupling. Buchwald-Hartwig amination and nucleophilic substitution were used to establish side chains which are connected to the core heterocycle by heteroatom-Carbon bonds. Sonogashira reaction turned out to be the most effective and convenient method to introduce functionalized alkynyl group into the heterocyclic cores. In the present work, more than 180 ...
  • These results suggest that dysfunction of cnp-3 enhances certain calcineurin loss-of-function phenotypes in C. elegans. (elsevier.com)
  • Since CNP-3 binds CnA, we looked at factors associated with calcineurin loss-of-function mutants, such as brood size, body size, serotonin- and levamisole-mediated egg-laying behavior. (elsevier.com)
  • One role of calcineurin under these conditions is to activate gene expression through its regulation of the Crz1p transcription factor. (asm.org)
  • The in vivo role of calcineurin, however, is not fully understood. (embopress.org)
  • To understand the role of calcineurin in cellular signaling, we undertook to identify the gene products which interact with Ppb1, re‐examining phenotypes of the calcineurin disruption mutant (Δ ppb1 ). (embopress.org)
  • This specific role of calcineurin in coordinating physical interactions with host cells highlights an ancestral mechanism for parasitism used by apicomplexans. (blogspot.com)
  • Thus, Pmca4b likely reduces the local Ca2+ signals involved in reactive cardiomyocyte hypertrophy via calcineurin regulation. (jci.org)
  • Signaling events managed by calcineurin promote cardiac hypertrophy but the degree to which such pathways are required to transduce the effects of various hypertrophic stimuli remains uncertain. (cylch.org)
  • However cardiac-specific manifestation of hMCIP1 inhibited cardiac hypertrophy reinduction of fetal gene manifestation and progression to dilated cardiomyopathy that normally result from manifestation of a constitutively active form of calcineurin. (cylch.org)
  • These results demonstrate that levels of hMCIP1 generating no apparent deleterious effects in cells of the normal heart are adequate to inhibit several forms of cardiac hypertrophy and suggest an important part for calcineurin signaling in varied forms of cardiac hypertrophy. (cylch.org)
  • Many recent studies possess wanted to determine whether calcineurin acts a significant signaling function in types of cardiac hypertrophy that are highly relevant to human being disease. (cylch.org)
  • Retroviral-mediated gene transfer of a constitutively active form of calcineurin is able to induce myogenesis only in the presence of extracellular calcium, suggesting that multiple calcium-dependent pathways are required for differentiation. (rupress.org)
  • Transgenic mice overexpressing a continuously active form of calcineurin in the heart (MHC-CnA) displayed conduction abnormalities and increased arrhythmia vulnerability relative to wildtype (WT). (ovid.com)
  • Asymmetric retraction of growth cone filopodia following focal inactivation of calcineurin. (springer.com)
  • The Ca2+/calmodulin-dependent phosphatase calcineurin (CaN), through the dephosphorylation of the proapoptotic protein BAD, may be the link between Ca2+homeostasis deregulation and apoptotic neuronal death. (nih.gov)
  • Calcineurin-mediated dephosphorylation of the nuclear factor of activated T-cells (NF-AT) is essential for NF-AT activation, nuclear translocation, and early gene expression in T-cells. (thermofisher.com)
  • Reduced action potential conduction and Gj in raised [Ca2+] are regulated by calcineurin-dependent Cx43-S365 phosphorylation, leading to Cx43-S368 dephosphorylation. (surrey.ac.uk)
  • The calcineurin action is indirect, via I1 dephosphorylation and subsequent activation of PP1. (surrey.ac.uk)
  • Mitochondrial alterations in PINK1 deficient cells are influenced by calcineurin-dependent dephosphorylation of dynamin-related protein 1. (nih.gov)
  • Calcineurin-mediated dephosphorylation of Drp1 contributes to mitochondrial phenotypes related to loss of PINK1. (nih.gov)
  • Renaming the DSCR1/Adapt78 gene family as RCAN: regulators of calcineurin. (springer.com)
  • Chronic overexpression of the calcineurin inhibitory gene DSCR1 (Adapt78) is associated with Alzheimer's disease. (springer.com)
  • Calcineurin is a heterodimer of a 61-kD calmodulin-binding catalytic subunit, calcineurin A and a 19-kD Ca2+-binding regulatory subunit, calcineurin B. There are three isozymes of the catalytic subunit, each encoded by a separate gene (PPP3CA, PPP3CB, and PPP3CC) and two isoforms of the regulatory, also encoded by separate genes (PPP3R1, PPP3R2). (wikipedia.org)
  • demonstrated that the PPP3CC gene, which encodes the calcineurin γ catalytic subunit, mapped to a chromosomal locus previously associated with susceptibility to schizophrenia and displayed a polymorphism that resulted in a nonconservative change in amino acid sequence. (sciencemag.org)
  • In our yeast friend Saccharomyces cerevisiae , the regulatory CNB protein subunit of the calcineurin complex is encoded by the CNB1 gene. (yeastgenome.org)
  • In yeast, the transcription factor regulated by calcineurin is encoded by the CRZ1 gene. (yeastgenome.org)
  • More significantly, genetic disruption of the calcineurin Aβ gene rescued hypertrophic cardiomyopathy and depressed functional capacity observed in p38-inhibited mice. (jci.org)
  • Calcineurin Aβ gene-targeted mice also showed a normal hypertrophic response after GH-IGF-1 infusion. (ahajournals.org)
  • Calcineurin (CnA) is a Ca2+-calmodulin dependent serine-threonine phosphatase, which is known to activate a signalling cascade leading to slow-twitch fibre gene expression. (uwaterloo.ca)
  • The protein phosphatase calcineurin performs a critical function in the procedures by which various kinds AT13387 cells react to extracellular indicators or environmental strains through adjustments in gene appearance. (cylch.org)
  • In mice and human beings MCIP1 can be expressed mainly in cardiac and skeletal muscle groups (16) and transcription from the MCIP1 gene can be potently activated by triggered calcineurin (17) therefore establishing a poor feedback system that presumably acts to safeguard cells from in any other case deleterious outcomes of unrestrained calcineurin activity. (cylch.org)
  • Calcineurin (Cn), also known as protein phosphatase 2B, is a unique calcium/calmodulin activated serine/threonine phosphatase that serves as a calcium effector, usually requiring prolonged Ca 2+ elevation, that alters both gene expression and cellular effectors (28). (pancreapedia.org)
  • Genetic evidence supports a model in which immunophilin-drug complexes inhibit calcineurin to prevent growth at 37°C. The gene encoding the C.neoformans calcineurin A catalytic subunit was cloned and disrupted by homologous recombination. (embopress.org)
  • Introduction of the wild‐type calcineurin A gene complemented these growth defects and restored virulence. (embopress.org)
  • Here, we show that disruption of the calcineurin gene ( ppb1 + ) in fission yeast results in a drastic chloride ion (Cl − )‐sensitive growth defect and that a high copy number of a novel gene pmp1 + suppresses this defect. (embopress.org)
  • Activation of the Calcineurin in 4 skeletal muscle myocytes selectively up-regulates slowfiber- specific gene promoters through a mechanism involving the transcription factor NFATcI. (uclan.ac.uk)
  • Our results define a complex molecular program that links gene transcription induced by calcium and calcineurin to a paradoxical impairment of signal transduction in anergic T cells. (ox.ac.uk)
  • Our findings demonstrate that calcineurin is required for C.neoformans virulence and may define signal transduction elements required for fungal pathogenesis that could be targets for therapeutic intervention. (embopress.org)
  • We find that the parasite homolog of calcineurin, a calcium-regulated phosphatase complex central to signal transduction in eukaryotes, also contributes to host cell invasion by the malaria parasite Plasmodium falciparum and related Toxoplasma gondii. (blogspot.com)
  • The authors discuss possible mechanisms whereby abnormalities in calcineurin signaling could predispose to the pathogenesis of schizophrenia. (sciencemag.org)
  • Cardiomyocyte plasma membrane Ca2+-ATPase (PMCA) extrudes Ca2+ but has little effect on excitation-contraction coupling, suggesting its potential role in controlling Ca2+-dependent signaling effectors such as calcineurin. (jci.org)
  • Is the Subject Area "Calcineurin signaling cascade" applicable to this article? (plos.org)
  • It has been assumed that the α isoform of calcineurin is the relevant isoform mediating TCR signaling. (elsevier.com)
  • We found that the β2 isoform of calcineurin is predominant in T and B lymphocytes as well as in thymus compared to the α isoform, suggesting that the β2 isoform may play a key role in TCR signaling. (elsevier.com)
  • but the exact signaling functions of calcineurin are still obscure in many cellular processes. (embopress.org)
  • In the present study we used a rat model of CIPS to test the hypothesis that CK2 contributes to increased NMDAR activity in the spinal cord and persistent pain hypersensitivity caused by calcineurin inhibitors. (exposed-skin-care.net)
  • These studies reveal new redox-related activities for Adapt 78 isoform 4, which may contribute to its known calcineurin-regulating and cytoprotective activities, and further suggest that Adapt 78 plays a role in basic T-cell response. (nih.gov)
  • Calcineurin is activated by increased Ca2+ levels caused by stress, and transduces signals by dephosphorylating protein substrates. (duke.edu)
  • Herein, we identified and characterized calcineurin substrates in C. neoformans by employing phosphoproteomic TiO2 enrichment and quantitative mass spectrometry. (duke.edu)
  • The calcineurin targets identified in this study share little overlap with known calcineurin substrates, with the exception of Crz1. (duke.edu)
  • Calcineurin activates nuclear factor of activated T cell, cytoplasmic (NFATc), a transcription factor, by dephosphorylating it. (wikipedia.org)
  • PMCA4b reduced calcineurin nuclear factor of activated T cell-luciferase activity after TAC and in cultured neonatal cardiomyocytes after agonist stimulation. (jci.org)
  • Recent evidence suggested that the nucleus of cardiac myocytes might be a Ca 2+ microdomain and that calcineurin, once translocated into the nucleus, could act as a nuclear Ca 2+ sensor. (springer.com)
  • Temporal regulation of nuclear factor one occupancy by calcineurin/NFA" by Baojin Ding, Wei Wang et al. (umassmed.edu)
  • Calcineurin induces different transcription factors (NFATs) that are important in the transcription of IL-2 genes. (wikipedia.org)
  • When these transcription factors have their phosphate group(s) chopped off by calcineurin, they travel into the cell's nucleus and turn on a specific set of genes needed to make the cell respond appropriately to the original environmental or developmental cue. (yeastgenome.org)
  • Remember that the Cnb1 protein is the regulatory subunit of calcineurin, and calcineurin activates a transcription factor by dephosphorylating it. (yeastgenome.org)
  • Ca 2+ -induced Crz1p-mediated transcription is unaffected in hph1 Δ hph2 Δ mutants, and genetic analyses indicate that HPH1/HPH2 and CRZ1 act in distinct pathways downstream of calcineurin. (asm.org)
  • These data provide an explanation how Ca 2+ and calcineurin might regulate transcription in cardiomyocytes in response to neurohumoral signals independently from their role in cardiac contraction control. (springer.com)
  • On the other hand, in patients with SLE taking various doses of GCS, decreased calcineurin activity can be measured. (bmj.com)
  • Drosophila expressing constitutively active calcineurin (CanA act ) in the heart displayed cardiac abnormalities. (genetics.org)
  • These findings support a model whereby calcineurin controls stress and virulence, at the transcriptional level via Crz1, and post-transcriptionally by localizing to PBs/SGs and acting on targets involved in mRNA metabolism. (duke.edu)
  • 10-12 Recently, oestrogen dependent, increased expression of calcineurin mRNA was found in the T cells of female patients with SLE. (bmj.com)
  • Calcineurin increased mRNA and protein of the E3 ubiquitin ligases Itch, Cbl-b and GRAIL and induced expression of Tsg101, the ubiquitin-binding component of the ESCRT-1 endosomal sorting complex. (ox.ac.uk)
  • lacZ reporter was induced up to 500-fold by processes dependent on calcineurin, calmodulin, and Ca2+. (asm.org)
  • Calcineurin Targets Involved in Stress Survival and Fungal Virulence. (duke.edu)
  • Several calcineurin targets localized to PBs/SGs, including Puf4 and Pbp1, contribute to stress resistance and virulence individually or in conjunction with Crz1. (duke.edu)
  • These findings further highlight C. neoformans as an outstanding model to define calcineurin-responsive virulence networks as targets for antifungal therapy. (duke.edu)
  • Calcineurin orchestrates growth, stress responses and virulence in major pathogenic fungi including Aspergillus fumigatus responsible for life-threatening fungal infections worldwide. (aspergillus.org.uk)
  • We recently demonstrated that the protein phosphatase calcineurin is required for growth at 37°C and virulence of C. neoformans . (asm.org)
  • Molecular cloning and characterization of porcine calcineurin-alpha subunit expression in skeletal muscle. (uchicago.edu)
  • Genetic disruption of calcineurin improves skeletal muscle pathology and cardiac disease in a mouse model of limb-girdle muscular dystrophy. (uchicago.edu)
  • 1. Strong evidence suggests that Calcineurin levels are higher in fast muscle fibers compared to slow-twitch in resting skeletal muscles. (uclan.ac.uk)
  • Background and objectives Prolonged use of calcineurin inhibitors (CNIs) in kidney transplant recipients is associated with renal and nonrenal toxicity and an increase in cardiovascular risk factors. (asnjournals.org)
  • Utilization of an EMR-biorepository to identify the genetic predictors of calcineurin-inhibitor toxicity in heart transplant recipients. (vumc.org)
  • Patients on calcineurin-inhibitors for long periods almost universally experience declines in renal function, and a subpopulation of transplant recipients ultimately develop chronic kidney disease that may progress to end stage renal disease attributable to calcineurin inhibitor toxicity (CNIT). (vumc.org)
  • Finally, other local susceptibility factors for calcineurin inhibitor nephrotoxicity are reviewed, including variability in P-glycoprotein and CYP3A4/5 expression or activity, older kidney age, salt depletion, the use of nonsteroidal anti-inflammatory drugs, and genetic polymorphisms in genes like TGF-beta and ACE. (kuleuven.be)
  • Concurrent with Bad translocation, a Ca 2+ -sensitive increase in cellular calcineurin activity was observed. (biochemj.org)
  • We show that Crz1 is a bona fide calcineurin substrate, and Crz1 localization and transcriptional activity are controlled by calcineurin. (duke.edu)
  • OBJECTIVE To compare the activity of calcineurin in the peripheral blood mononuclear cells (PBMC) of 32 patients with systemic lupus erythematosus (SLE) and 35 healthy controls. (bmj.com)
  • METHODS The activity of calcineurin was assayed in the supernatants of sonicated mononuclear cells. (bmj.com)
  • RESULTS There was no significant difference in the calcineurin activity of patients with SLE not taking glucocorticosteroids (GCS) compared with the healthy controls. (bmj.com)
  • On the other hand, the activity of calcineurin was reduced in patients with SLE taking GCS, correlating negatively with the dose of GCS. (bmj.com)
  • The stimulation of PBMC by phorbol ester and calcium ionophore decreased the calcineurin activity both in patients with SLE and in healthy controls. (bmj.com)
  • GCS could also reduce calcineurin activity in the mononuclear cells of healthy subjects in vitro. (bmj.com)
  • CONCLUSIONS In patients with SLE the decrease in the calcineurin activity of PBMC depended on the dose of GCS used for treatment, and it was not a disease specific alteration. (bmj.com)
  • In this study we show that in patients with SLE not taking any glucocorticosteroids (GCS) the calcineurin activity of peripheral blood mononuclear cells (PBMC) does not differ from that of healthy controls. (bmj.com)
  • The higher the concentration of GCS, the greater the decrease in calcineurin activity. (bmj.com)
  • The in vitro stimulation of PBMC by phorbol ester and Ca 2+ ionophore ( A23187 ) results in a pronounced decrease in the calcineurin activity of cells derived from patients with SLE or from healthy controls. (bmj.com)
  • GCS can reduce the calcineurin activity also in the mononuclear cells of healthy subjects in vitro. (bmj.com)
  • Calcineurin modifies the distribution of Hph1p within the endoplasmic reticulum and is required for full Hph1p activity in vivo. (asm.org)
  • The contribution of VCX1 in Ca2+ tolerance is low in strains with a functional calcineurin and is high in strains which lack calcineurin activity. (asm.org)
  • 2014 Even so little is well known about how vertebral NMDAR activity is certainly potentiated by calcineurin inhibitors. (exposed-skin-care.net)
  • Calcineurin inhibition may augment NMDAR activity by leading to extreme phosphorylation of NMDARs and/or NMDAR-interacting protein (Tong et al. (exposed-skin-care.net)
  • IGF-1 significantly increased CaM kinase and calcineurin activity and the cellular levels of phosphorylated CREB in a time-dependent manner. (deepdyve.com)
  • Raised [Ca2+]i also decreased I1 phosphorylation, also prevented by calcineurin inhibitors, to increase activity of the Ca2+-independent phosphatase, PPI. (surrey.ac.uk)
  • A) Calcineurin enzyme activity was measured in postnuclear supernatants of extracts from control and PINK1 shRNA lines. (nih.gov)
  • Calcineurin B antibody LS-C667722 is an unconjugated rabbit polyclonal antibody to human Calcineurin B (PPP3R1). (lsbio.com)
  • You need info about Human Calcineurin (CaN) ELISA Kit or any other Gentaur produtct? (gentaurshop.com)
  • We are hopeful that our studies will lead to clinical trials that test the use of already available calcineurin blocking drugs for the treatment of pancreatitis. (grantome.com)