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)

Over the course of 15 years the use of sirolimus, a macrocyclic lactone, has evolved from an adjunct to calcineurin inhibitors (CNI) to the foundation of therapy due to the drug's unique properties: First, it displays synergistic pharmacodynamic interactions with CNI. Even among high immunologic risk patients, this regimen attenuates the risk of acute allograft rejection episodes when used in combination with cyclosporine or tacrolimus. Indeed >80% reduction in CNI exposure de novo yields better long-term renal function than full cyclosporine (CsA) doses, a useful tradeoff, despite the augmented occurrence of lymphoceles and impaired wound healing. Second, by inhibiting mammalian target of rapamycin (mTOR), it exerts profound anti-neoplastic effects reducing the incidence and mediating the regression of tumors displaying PTEN-deletions and/or Akt-activations in transplant and non-transplant patients. Third, it is relatively non-nephrotoxic although it may exacerbate that property of CNI agents. Fourth, it allows prompt withdrawal of steroid therapy. Fifth, it displays reduced rates of cytomegalovirus, and BK virus infections. The major adverse reactions can generally be controlled with countermeasure therapy. Myelosuppressive effects, which tend to be transient (unless sirolimus is combined with mycophenolic acid), are readily amenable to treatment with granulocyte colony stimulating factor for leukopenia, interleukin 11 for thrombocytopenia and erythropoietin for anemia. Combinations of statins and fibrates represent effective countermeasure therapy for hypercholesterolemia and hypertriglyceridemia, respectively. Idiosyncratic reactions include hypoxemic pulmonary toxicity, refractory edema and diarrhea. Thus, sirolimus represents the vanguard of a new class of maintenance agents for immunosuppression.
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PMID:Fifteen years of clinical studies and clinical practice in renal transplantation: reviewing outcomes with de novo use of sirolimus in combination with cyclosporine. 1910 Aug 99

Renal transplant patients lose their grafts most frequently from chronic allograft nephropathy and their lives from cardiac disease, malignancy, and infection. These are thus the challenges for renal transplant programs for this decade, just as acute rejection was the challenge of the last two decades. Most immunosuppressive protocols aim to minimize acute allograft rejection through heavy induction strategies and powerful but toxic maintenance therapies, counterbalanced by powerful and expensive infection prophylaxis. However, while the short-term results have improved steadily from the 1980s, and despite all the current efforts, the long-term success rates of renal transplants have not improved. Future aims include controlling both rejection and the long-term consequences of toxicity and infection risk. The biological facts that have determined our approach to the use of immunosuppressants have required us to try to balance the conflicting need for control of the allograft response and the inevitable toxicities of our drugs. The early period after transplantation requires maximum immunosuppressive efficacy with minimal ischemia reperfusion and good surgical-related wound healing. The latter period after transplantation requires less immunosuppressive efficacy and avoidance of chronic nephrotoxicity, cardiovascular, and malignancy risk factors. This usually leads to an induction strategy using a biological agent; a calcineurin inhibitor; an antiproliferative agent; and variable use of corticosteroids. In the long term, there are a variety of strategies for dose reduction or elimination of calcineurin inhibitors, incorporation of mammalian target of rapamycin inhibitors, and variable approaches to the risks of continued low-dose corticosteroids. The multiplicity of alternative strategies available testifies to the absence of evidence for a single dominant protocol and the urgent need to determine the relevant early indicators for measuring long-term success.
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PMID:Addressing the challenges for improving long-term outcomes in renal transplantation. 1910 Sep

Recent improvements in immunosuppressive therapies have reduced the incidence of acute rejection and increased patient survival. These agents may however contribute to higher rates of mortality due to an increased risk of cardiovascular disease or malignancy. Transplant patients are immunocompromised with a reduced ability to combat the development of malignancy. The higher risk for the activity of oncoviruses may also contribute to the higher incidence and determine specific tumor types. Some immunosuppressants seem to have direct oncogenic effects. In vitro data have demonstrated that calcineurin inhibitors (CNIs) may show direct effects on tumor growth and the development of metastases. In contrast, mTOR inhibitors have demonstrated anti-tumoral properties in vitro and perhaps potent anti-angiogenic effects thereby. Recent studies and registry analyses have confirmed that mTOR inhibitors are associated with a reduced incidence of malignancies. UNOS data demonstrated that an mTOR inhibitor, with or without a CNI, is associated with a reduced incidence of tumors compared to regimens without mTOR inhibitors. The Rapamune Maintenance Regimen study demonstrated that patients receiving sirolimus-based, CNI-free therapy after CsA withdrawal at 3 months showed a reduced incidence of malignancy at 5 years posttransplant, compared with those who continued on a regimen that included CsA. In the CONVERT study, patients converted to sirolimus revealed a significantly lower malignancy rate at 24 months (3.1%) compared with those who continued CNI-based therapy (9.8%, P < .001). The elimination of CNIs and the introduction of sirolimus may, therefore, have a role to reduce the risk of cancer among posttransplant patients.
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PMID:Minimizing the risk of posttransplant malignancy. 1910 Sep 6

Liver transplant recipients are at increasingly high risk for suffering from impaired renal function and probable need of renal replacement therapy. Extended criteria organs and transplantation of patients with higher model for end-stage liver disease scores further increase this problem. Acute and chronic nephrotoxicity are the trade-off in immunosuppression with potent calcineurin inhibitors (CNIs). As a good renal function is associated with better graft and patient survival, CNI minimization protocols have been developed. Current strategies to overcome CNI toxicity include reduction or withdrawal of CNIs concurrently with switching over to mammalian target of rapamycin inhibitor or mycophenolate mofetil (MMF)-based regimens. This strategy caused an improvement in renal function in a significant number of liver transplantation patients according to several studies. However, total CNI avoidance seems to result in higher rejection rates. To prevent chronic renal dysfunction in patients prone to or with acute renal failure, CNI delay - with induction therapy for bridging - followed by low-dose CNI in combination with MMF are proven strategies without risking higher rejection rates. An individualized, tailor-made immunosuppressive regime, with a special focus on renal function is recommended. This review gave an overview on CNI minimization protocols in liver transplantation also focusing on recently analyzed studies.
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PMID:Calcineurin inhibitor minimization protocols in liver transplantation. 1912 Nov 46

The calcineurin inhibitors cyclosporin A and tacrolimus and the inhibitors of the mTOR, sirolimus and everolimus bind immunophilins that are required for their immunosuppressive action. In contrast to cyclosporin A, tacrolimus and the mTOR inhibitors (MTIs) share common immunophilins, the FK506-binding proteins (FKBPs). We investigated the immunosuppressive interactions of MTIs on tacrolimus based immune suppression, since insights in immunological drug-drug interactions can be very relevant for optimization of immunosuppressive regimens in allograft transplantation medicine. Isolated peripheral blood mononuclear cells from healthy volunteers were incubated with combinations of MTIs and calcineurin inhibitors and when monitored for calcineurin activity and IL-2 excretion after mitogen stimulation, tacrolimus IC(50) concentrations shifted to higher concentrations in the presence of MTIs. This antagonism was absent for cyclosporin A, reproducible for 10 healthy volunteers (p<0.001) and stronger for sirolimus than for everolimus. When cell lysate was treated with and without MTI, tacrolimus and FKBP12, FKBP12 could increase calcineurin inhibition by tacrolimus and reverse the MTI antagonism for both MTIs. These results demonstrate that FKBP12 can be rate limiting for calcineurin inhibition at high tacrolimus concentrations and that the antagonism of sirolimus and everolimus on tacrolimus based immune suppression is mediated via saturation of FKBP12.
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PMID:Everolimus and sirolimus antagonize tacrolimus based calcineurin inhibition via competition for FK-binding protein 12. 1915 28

mTOR is a central regulator of cell growth and angiogenesis. The mTOR pathway is activated in 40-50% of patients with hepatocellular cancer (HCC). In different models (i.e., hepatoma cell lines and implanted HCC tumors in rats), mTOR inhibitors (mTORIs) were effective in reducing cell growth and tumor vascularity. Synergistic effects were observed for mTORIs and chemotherapeutic agents in these studies, while other combinations involving mTORIs and inhibitors of growth hormones and angiogenesis are awaiting further clinical testing. A number of mTORIs are already clinically available (e.g., sirolimus, temsirolimus and everolimus), sharing similiar pharmacokinetic parameters (except for absorption) and side effects. Clinical data are, as yet, only preliminary and are mainly derived from retrospective studies in patients who underwent liver transplantation for HCC. Those patients had received sirolimus thereafter for immunosuppression, and a much lower rate of tumor recurrence than with calcineurin inhibitors alone was noted. Current prospective trials for treatment of advanced HCC include mTORIs alone or in combination with either transarterial chemoembolization or other systemic drugs, and will be discussed in detail in this review.
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PMID:mTOR inhibitors for hepatocellular cancer: a forward-moving target. 1919 62

Resistance training and to a lesser extent endurance training are capable of enhancing protein synthesis in skeletal muscle via various signaling pathways. Additionally, the expression of muscle fiber types responds to different regimes of training stimuli and immobilization as characterized by changes in myosin heavy chain isoforms (I<-->IIA<-->IIX). Eccentric resistance training has been shown to be highly efficient in inducing sarcomeric protein assembly in the longitudinal orientation of muscle cells. However, concentric contractions lead to a hypertrophic response (increased fiber diameter) in muscle which can still be activated in old age. The central signaling pathway to mediate the elevation of protein synthesis in response to training is the mTOR pathway, which is also stimulated by free amino acids. Moreover, adaptation to endurance training is mediated by the calcium-calcineurin-NFATc1 pathway which is strongly activated by the calcium transients involved in the muscle contraction process. High contraction frequency and long duration of training sessions are essential for activation and maintenance of fiber type I expression as well as for induction of transformation of type II into type I fibers. Endurance training sessions should therefore be longer than 30 min and dominated by periods of high frequency contractions. A further factor in the muscular response to training includes the recruitment and integration of satellite cells into muscle fibers. Satellite cells can respond to muscular stretch, activity and injury with increased proliferation and can later be integrated into muscle fibers. Therefore, new myonuclei are available to enhance mRNA synthesis and protein expression in muscle cells. New understanding of the cellular mechanisms of signal transduction in muscle in response to training, bed rest and ageing will help to optimize training and interventions in an ageing population.
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PMID:[Exercise and cellular adaptation of muscle]. 1930 45

Sirolimus (SRL) is a non-nephrotoxic immunosuppressive drug blocking T-cell proliferation through mTOR inhibition. SRL can be used as (1) an early drug in a calcineurin inhibitor-free protocol in the first 3 months after transplantation, (2) in the early and late conversion protocols as suggested by the multicenter randomized CONVERT trial, and (3) in recipients from marginal donors, because calcineurin inhibitors can increase the preexisting renal damage induced by age, hypertension, and diabetes that are frequent in elderly cadaveric donors. In any case, SRL should be used in patients with a cutoff of proteinuria (<or=800 mg/24 hr) or proteinuria-to-creatinine ratio less than 0.11.
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PMID:Review of symposium. Sirolimus in kidney transplantation. 1938 85

The purpose of our study was to compare the effects of 8-week progressive strength and power training regimens on strength gains and muscle plasticity [muscle fiber hypertrophy and phenotype shift, mammalian target of rapamycin (mTOR), regulatory-associated protein of mTOR (RAPTOR), rapamycin-insensitive companion of m-TOR (RICTOR), calcineurin and calcipressin gene expression]. Twenty-nine physically active subjects were divided into three groups: strength training (ST), power training (PT) and control (C). Squat 1 RM and muscle biopsies were obtained before and after the training period. Strength increased similarly for both ST and PT groups (P<0.001). Fiber types I, IIa and IIb presented hypertrophy main time effect (P<0.05). Only type IIb percentage decreased from pre- to post-test (main time effect, P<0.05). mTOR and RICTOR mRNA expression increased similarly from pre- to post-test (P<0.01). RAPTOR increased after training for both groups (P<0.0001), but to a greater extent in the ST (P<0.001) than in the PT group. 4EBP-1 decreased after training when the ST and PT groups were pooled (P<0.05). Calcineurin levels did not change after training, while calcipressin increased similarly from pre- to post-test (P<0.01). In conclusion, our data indicate that these training regimens produce similar performance improvements; however, there was a trend toward greater hypertrophy-related gene expression and muscle fiber hypertrophy in the ST group.
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PMID:Expression of genes related to muscle plasticity after strength and power training regimens. 1942 45

Cardiomyocyte hypertrophy occurs in response to a variety of physiological and pathological stimuli. While pathological hypertrophy in heart failure is usually coupled with depressed contractile function, physiological hypertrophy associates with increased contractility. In the present study, we explored whether 8 weeks of moderate intensity exercise training would lead to a cardiac anti-remodelling effect in an experimental model of heart failure associated with a deactivation of a pathological (calcineurin/NFAT, CaMKII/HDAC) or activation of a physiological (Akt-mTOR) hypertrophy signalling pathway. The cardiac dysfunction, exercise intolerance, left ventricle dilatation, increased heart weight and cardiomyocyte hypertrophy from mice lacking alpha(2A) and alpha(2C) adrenoceptors (alpha(2A)/alpha(2C)ARKO mice) were associated with sympathetic hyperactivity induced heart failure. The relative contribution of Ca(2+)-calmodulin high-affinity (calcineurin/NFAT) and low-affinity (CaMKII/HDAC) targets to pathological hypertrophy of alpha(2A)/alpha(2C)ARKO mice was verified. While nuclear calcineurin B, NFATc3 and GATA-4 translocation were significantly increased in alpha(2A)/alpha(2C)ARKO mice, no changes were observed in CaMKII/HDAC activation. As expected, cyclosporine treatment decreased nuclear translocation of calcineurin/NFAT in alpha(2A)/alpha(2C)ARKO mice, which was associated with improved ventricular function and a pronounced anti-remodelling effect. The Akt/mTOR signalling pathway was not activated in alpha(2A)/alpha(2C)ARKO mice. Exercise training improved cardiac function and exercise capacity in alpha(2A)/alpha(2C)ARKO mice and decreased heart weight and cardiomyocyte width paralleled by diminished nuclear NFATc3 and GATA-4 translocation as well as GATA-4 expression levels. When combined, these findings support the notion that deactivation of calcineurin/NFAT pathway-induced pathological hypertrophy is a preferential mechanism by which exercise training leads to the cardiac anti-remodelling effect in heart failure.
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PMID:Cardiac anti-remodelling effect of aerobic training is associated with a reduction in the calcineurin/NFAT signalling pathway in heart failure mice. 1988 Aug 76


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