Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42345 (mTOR)
 26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The development of immunosuppressive agents reflects the progress in understanding the cellular and molecular mechanisms which mediate allograft rejection. Six paradigms represent the evolution of immunosuppressive strategies for organ transplantation. The proliferation paradigm advances agents which interrupt lymphocyte cell division (azathioprine, cyclophosphamide, mycophenolic acid). The depletion paradigm conscripts drugs that bind to lymphocyte cell surface markers, thereby producing cell lysis and/or inactivation (polyclonal ATGAM and thymoglobulin, and monoclonal OKT3 antilymphocyte antibodies). The cytokine paradigm uses agents that interrupt lymphocyte maturational events; eg, synthesis (calcineurin inhibitors: cyclosporine/tacrolimus), binding to surface receptors (anti-CD25 mAbs), or signal transduction phases of cytokine stimulation (sirolimus). The introduction of calcineurin inhibitors markedly reduces the rate of acute rejection episodes and increases short-term graft survival rates; nephrotoxicity and chronic allograft attrition remain as unanswered challenges. The cyclosporine A (CsA) sparing property of sirolimus permits the use of lower exposure to calcineurin agents, allows for early withdrawal of steroid therapy, and may delay allograft senescence. Furthermore, the combination of SRL with anti-IL-2R mAbs proffers an induction approach which allows prolonged periods of holiday from calcineurin inhibitors. To address the tissue nonselectivity of the calcineurin and mTOR inhibitors, which presumably causes the drug toxicities, new agents are being developed to selectively inhibit the T cell target Janus Kinase 3. In the costimulation paradigm, the accessory signals generated by antigen-presenting cells are interrupted by distinct agents: the receptor conjugate CTLA4-immunoglobulin and anti-B7 or anti-CD40 ligand mAbs. Another set of drugs (selectin blocking agents, anti-ICAM-1 antisense deoxy oligonucleotides, and the lymphocyte homing inhibitor FTY720) seeks to modulate the ischemia-reperfusion injury, which exacerbates cytokine-mediated events in the donor and the subsequent procurement injury and may also accelerate the progression of transplant senescence. Finally, the transplantation tolerance paradigm is based on the development of strategies which distort alloimmune recognition by antigen reactive cells (MHC peptides or proteins), produce anergy (costimulation blockers), functional inactivation, or deletion of antigen-reactive cells (donor bone marrow infusions and gene therapy). Presently, the optimal immunosuppressive strategy uses combinations of agents that act in synergistic fashion to provide the potency, freedom from toxic reactions, convenience of administration, and cost appropriate for the individual patient.
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PMID:Immunosuppressive agents in organ transplantation: past, present, and future. 1074 55

Ischaemia was obtained in vitro by subjecting nerve-growth-factor-differentiated PC12 cells to glucose deprivation plus anoxia. During ischaemia the rate of protein synthesis was significantly inhibited, and eIF4E-binding protein (4E-BP1) and eukaryotic initiation factor 4E (eIF4E) were significantly dephosphorylated in parallel. In addition, ischaemia induced an enhancement of the association of 4E-BP1 to eIF4E, which in turn decreased eIF4F formation, whereas no degradation of initiation factor 4G was observed. The treatment of PC12 cells with the specific p38 mitogen-activated protein kinase inhibitor SB203580 induced eIF4E dephosphorylation but did not cause any effect on protein synthesis rate. Rapamycin, the inhibitor of mammalian target of rapamycin ('mTOR'), but not PD98059, the inhibitor of extracellular signal-regulated protein kinases ('ERK1/2'), induced similar effects on 4E-BP1 phosphorylation to ischaemia; nevertheless, 4E-BP1-eIF4E complex levels were higher in ischaemia than in rapamycin-treated cells. In addition, both protein synthesis rate and eIF4F formation were lower in ischaemic cells than in rapamycin-treated cells.
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PMID:Ischaemia induces changes in the association of the binding protein 4E-BP1 and eukaryotic initiation factor (eIF) 4G to eIF4E in differentiated PC12 cells. 1102 17

Although considerable progress has been achieved using immunosuppressive drugs that inhibit lymphocyte activation and T-cell cytokine signal transduction pathways, the widespread tissue distribution of the molecular targets exploited to date, calcineurin, mammalian target of rapamycin, and inosine monophosphate dehydrogenase, engenders a constellation of collateral toxicities. One strategy to develop new immunosuppressants seeks to identify targets that are critical for and specific to the adaptive immune response. Three approaches have been used to guide this enterprise; molecular design based on steric resemblance of the antagonist to the natural ligand; construction of complementary DNA oligonucleotides that hybridize with the leader sequence of messenger RNA encoding the synthesis of the specific target, thereby preventing production of that protein; and functional comparisons based on similar inhibitory profiles of candidate compounds and a probe that blocks the target nonselectively. Use of these 3 technologies has led to identification of antagonists blocking selectins, intercellular adhesion molecule-1, or Janus kinase 3, respectively. These lead compounds have been tested for their effects on the alloimmune response and/or the ischemia-reperfusion injuries.
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PMID:New approaches to transplant immunosuppression. 1296 33

The AMP-activated protein kinase (AMPK) exists as a heterotrimetric complex comprising a catalytic alpha subunit and non-catalytic beta and gamma subunits. Under conditions of hypoxia, exercise, ischemia, heat shock, and low glucose, AMPK is activated allosterically by rising cellular AMP and by phosphorylation of the catalytic alpha subunit. The mammalian target of rapamycin (mTOR) controls cellular functions in response to amino acids and growth factors. Recent reports including our study have demonstrated the possible interplay between mTOR and AMPK signaling pathways, supporting a model in which mitochondrial dysfunction caused by the mitochondrial inhibitors or ATP depletion inhibits activation of p70 S6 kinase alpha (p70alpha), a downstream effector of mTOR, by activating AMPK. Leucine may stimulate p70alpha phosphorylation via mTOR pathway, in part, by serving both as a mitochondrial fuel through oxidative carboxylation and an allosteric activation of glutamate dehydrogenase. This hypothesis may support an idea in which leucine modulates mTOR function, in part by regulating mitochondrial function and AMPK. Further understanding of the role of mTOR in coordinating amino acid- and energy-sensing pathways would provide new insights into relationship between nutrients and cellular functions.
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PMID:mTOR integrates amino acid- and energy-sensing pathways. 1468 82

Ischemia-reperfusion (I-R) injury in transplanted kidney, a key pathogenic event of delayed graft function (DGF), is characterized by tubular cell apoptosis and interstitial inflammation. Akt-mammalian target of rapamycin-S6k and NF-kappaB-inducing kinase (NIK)-NF-kappaB axis are the two main signaling pathways regulating cell survival and inflammation. Rapamycin, an immunosuppressive drug inhibiting the Akt axis, is associated with a prolonged DGF. The aim of this study was to evaluate Akt and NF-kappaB axis activation in patients who had DGF and received or not rapamycin and in a pig model of I-R and the role of coagulation priming in this setting. In graft biopsies from patients who were not receiving rapamycin, phosphorylated Akt increased in proximal tubular, interstitial, and mesangial cells with a clear nuclear translocation. The same pattern of activation was observed for S6k and NIK. However, in rapamycin-treated patients, a significant reduction of S6k but not Akt and NIK activation was observed. A time-dependent activation of phosphatidylinositol 3-kinase, Akt, S6k, and NIK was observed in the experimental model with the same pattern reported for transplant recipients who did not receive rapamycin. Extensive interstitial and glomerular fibrin deposition was observed both in pig kidneys upon reperfusion and in DGF human biopsies. It is interesting that the activation of both Akt and NIK-NF-kappaB pathways was induced by thrombin in cultured proximal tubular cells. In conclusion, the data suggest that (1) coagulation may play a pathogenic role in I-R injury; (2) the Akt axis is activated after I-R, and its inhibition may explain the prolonged DGF observed in rapamycin-treated patients; and (3) NIK activation in I-R and DGF represents a proinflammatory, rapamycin-insensitive signal, potentially leading to progressive graft injury.
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PMID:Ischemia-reperfusion induces glomerular and tubular activation of proinflammatory and antiapoptotic pathways: differential modulation by rapamycin. 1546 72

Protein turnover represents the balance between protein synthesis and degradation. It can be controlled quantitatively, for instance by an activation of protein synthesis during cardiac hypertrophy or by activating protein degradation during ventricular unloading. It can also be regulated qualitatively by changing the steady state concentration of specific proteins and enzymes. The recent literature points to an emerging role for the mammalian target of rapamycin (mTOR) and for the ubiquitin-proteasome system (UPS) in this process, and both pathways interact in the regulation of cell growth and survival. We highlight the critical role played by such interaction in different cellular functions, including insulin signaling, stress response to hypoxia, adaptation to variations in workload, regulation of protein phosphatase activity, apoptosis and post-ischemic recovery. A deregulation of these pathways participates in the mechanisms of cardiac ischemia, hypertrophy and failure, and controlling their activity represents an opportunity for novel therapeutic avenues.
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PMID:Protein turnover in cardiac cell growth and survival. 1606 Dec 15

Although bradykinin has been demonstrated to protect the heart at reperfusion, the detailed cellular and molecular mechanisms that mediate the protection remain elusive. Here we aimed to determine whether bradykinin protects the heart at reperfusion by modulating the mitochondrial permeability transition pore (mPTP) opening through glycogen synthase kinase 3beta (GSK-3beta). Bradykinin given at reperfusion reduced infarct size in isolated rat hearts subjected to 30 min regional ischemia followed by 2 h of reperfusion. The infarct-limiting effect of bradykinin was reversed by atractyloside, an opener of the mPTP, suggesting that bradykinin may protect the heart at reperfusion by modulating the mPTP opening. In support of this observation, bradykinin prevented the collapse of mitochondrial membrane potential (DeltaPsi(m)), an index of the mPTP opening. Bradykinin increased GSK-3beta phosphorylation at reperfusion, and the selective inhibitor of GSK-3beta SB216763 reduced infarct size and prevented the loss of DeltaPsi(m) by mimicking the effect of bradykinin. The effect of bradykinin on GSK-3beta phosphorylation was blocked by wortmannin and LY294002, and bradykinin increased Akt phosphorylation at reperfusion. Further experiments showed that the MEK inhibitor PD98059 prevented the effect of bradykinin on GSK-3beta. However, the mTOR/p70s6K pathway inhibitor rapamycin did not alter bradykinin-induced GSK-3beta phosphorylation and bradykinin failed to alter phosphorylation of either mTOR or p70s6K at reperfusion. Taken together, these data suggest that bradykinin protects the heart at reperfusion by modulating the mPTP opening through inhibition of GSK-3beta. The PI3-kinase/Akt pathway and ERK, but not the mTOR/p70s6K pathway account for the suppression of GSK-3beta by bradykinin.
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PMID:Bradykinin prevents reperfusion injury by targeting mitochondrial permeability transition pore through glycogen synthase kinase 3beta. 1651 18

The A1/A2 adenosine agonist 5'-(N-ethylcarboxamido) adenosine (NECA) limits infarction when administered at reperfusion. The present study investigated whether p70S6 kinase is involved in this anti-infarct effect. Adult rat ventricular myocytes were isolated and incubated in tetramethylrhodamine ethyl ester (TMRE, 100 nM), which causes cells to fluoresce in proportion to their mitochondrial membrane potential. A reduction in TMRE fluorescence serves as an indicator of collapse of the mitochondrial transmembrane potential. Cells were subjected to H2O2 (200 microM), which like ischemia induces loss of mitochondrial membrane potential. Fluorescence was measured every 3 min and to facilitate quantification membrane potential was arbitrarily considered as collapsed when fluorescence reached less than 60% of the starting value. Adding NECA (1 mM) to the cells prolonged the time to fluorescence loss (48.0+/-3.2 min in the NECA group versus 29.5+/-2.2 min in untreated cells, P<0.001) and the mTOR/p70S6 kinase inhibitor rapamycin (5 nM) abolished this protection (31.3+/-3.4 min). Since cyclosporine A offered similar protection, mitochondrial permeability transition pore formation is a likely cause of the H2O2-induced loss of potential. The direct GSK-3beta inhibitor SB216763 (3 microM) also prolonged the time to fluorescence loss (49.2+/-2.1 min, P<0.001 versus control), and its protection could not be blocked by rapamycin (42.2+/-2.3 min, P<0.001 versus control). NECA treatment (100 nM) of intact isolated rabbit hearts at reperfusion after 30 min of regional ischemia decreased infarct size from 33.0+/-3.8% of the risk zone in control hearts to 11.8+/-2.0% (P<0.001), and rapamycin blocked this NECA-induced protection (38.3+/-3.7%). A comparable protective effect was seen for SB216763 (1 microM) with infarct size reduction to 13.5+/-2.3% (P<0.001). NECA treatment (200 nM) of intact rabbit hearts at reperfusion also resulted in phosphorylation of p70S6 kinase more than that seen in untreated hearts. This NECA-induced phosphorylation was blocked by rapamycin. These experiments reveal a critical role for p70S6 kinase in the signaling pathway of NECA's cardioprotection at reperfusion.
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PMID:NECA at reperfusion limits infarction and inhibits formation of the mitochondrial permeability transition pore by activating p70S6 kinase. 1660 38

Protein expression in the heart is altered following periods of myocardial ischemia. The changes in protein expression are associated with increased cell size that can be maladaptive. There is little information regarding the regulation of protein expression through the process of mRNA translation during ischemia and reperfusion in the heart. Therefore, the purpose of this study was to identify changes in signaling pathways and downstream regulatory mechanisms of mRNA translation in an in vivo model of myocardial ischemia and reperfusion. Hearts were collected from rats whose left main coronary arteries had either been occluded for 25 min or reversibly occluded for 25 min and subsequently reperfused for 15 min. Following reperfusion, both the phosphoinositide 3-kinase and mitogen-activated protein kinase pathways were activated, as evidenced by increased phosphorylation of Akt (PKB), extracellular signal-regulated kinase 1/2, and p38 mitogen-activated protein kinase. Activation of Akt stimulated signaling through the protein kinase mammalian target of rapamycin, as evidenced by increased phosphorylation of two of its effectors, the ribosomal protein S6 kinase and the eukaryotic initiation factor eIF4E binding protein 1. Ischemia and reperfusion also resulted in increased phosphorylation of eIF2 and eIF2B. These changes in protein phosphorylation suggest that control of mRNA translation following ischemia and reperfusion is modulated through a number of signaling pathways and regulatory mechanisms.
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PMID:Activation of signaling pathways and regulatory mechanisms of mRNA translation following myocardial ischemia-reperfusion. 1669 Jul 84

Rapamycin (sirolimus) is an antibiotic that inhibits protein synthesis through mammalian target of rapamycin (mTOR) signaling and is used as an immunosuppressant in the treatment of organ rejection in transplant recipients. Recently, the antigrowth properties of rapamycin have been utilized for cardiovascular benefit as stents impregnated with rapamycin effectively reduce coronary restenosis. We report here a novel role of this drug in protection against ischemia/reperfusion (I/R) injury. Adult male ICR mice were treated with rapamycin (0.25 mg/kg, IP) or volume-matched DMSO (solvent for rapamycin). The hearts were subjected to 20 min of global ischemia and 30 min of reperfusion in Langendorff mode. The blocker of mitochondrial KATP channel, 5-hydroxydecanoate (5-HD, 100 microM) was given 10 min before ischemia. Infarct size in the DMSO treated group was 28.2 +/- 1.3% and was reduced to 10.1 +/- 2.8% in the rapamycin-treated mice (64% decrease, P < 0.001). 5-HD blocked the protective effect (infarct area 32.2 +/- 1.8%, P < 0.001 vs. rapamycin). The infarct limiting effect of rapamycin was not associated with improved recovery of ventricular function. We further examined the effect of rapamycin in protection against necrosis and apoptosis in adult cardiomyocytes subjected to simulated ischemia and reoxygenation. Myocytes treated with rapamycin in doses from 25-100 nM demonstrated significantly lower trypan blue-positive necrotic cells and TUNEL-positive apoptotic nuclei, supporting the protective role of drug in the intact heart. These data suggest that rapamycin induces potent preconditioning-like effect against myocardial infarction through opening of mitochondrial KATP channels. We propose that rapamycin may be a novel therapeutic strategy to limit infarction, apoptosis, and remodeling following I/R injury in the heart.
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PMID:Rapamycin confers preconditioning-like protection against ischemia-reperfusion injury in isolated mouse heart and cardiomyocytes. 1678 29


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