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)

Diabetes mellitus results in chronic hyperglycemia, a serious metabolic disorder associated with a markedly increased risk of cardiovascular disease. However, the effects of high glucose (HG) on cardiac myocyte growth have not been fully clarified. In this study, the effect of glucose on cardiac myocyte growth was examined using leucine incorporation as an index of protein synthesis. High glucose (HG, 25 mmol/L) increased leucine incorporation (167% +/- 0.2% over normal glucose, n=4, P<.01) compared with a physiological glucose concentration (5.5 mmol/L, normal glucose). The HG-induced increase in leucine incorporation was time- and dose-dependent and was not due to osmotic changes because 25 mmol/L mannitol did not change leucine incorporation. High glucose also significantly reduced elongation factor 2 phosphorylation, an effect known to result in increased protein synthesis at the elongation step. Western blot analysis showed that HG-activated protein kinase B (PKB), also called Akt (PKB/Akt), at 18 hours. High glucose-induced leucine incorporation was attenuated with phosphatidylinositol 3-kinase (PI3K) inhibition using wortmannin and LY294002 and by rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, 72%, 64%, and 65% (P<.05), respectively. High glucose also activated extracellular signal-regulated kinase 1/2 activity with peak stimulation at 5 minutes. In addition, PD98059, an inhibitor of mitogen-activated protein kinase kinase, attenuated HG-induced leucine incorporation. These data show for the first time that elevated glucose increases protein synthesis in cardiac myocytes. The increase appears to be mediated by activation of PI3K-PKB/Akt and/or PI3K-mTOR as well as extracellular signal-regulated kinase 1/2. These results provide new evidence for a direct effect of glucose independent of insulin on cardiac myocyte growth.
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PMID:Elevated glucose activates protein synthesis in cultured cardiac myocytes. 1625 33

Over the last decade, there has been a decrease in acute graft rejection rates following renal transplantation; however, this has not corresponded with an improvement in long-term outcomes of transplantation. One of the major causes of long-term morbidity and mortality in renal transplant recipients is cardiovascular disease. Immunosuppressive regimens, especially those including steroids and calcineurin inhibitors, have a negative role in the induction of cardiovascular risk factors. The proliferation signal inhibitors (PSIs)/mammalian target of rapamycin (mTOR) inhibitors sirolimus and everolimus have shown considerable promise in reducing acute rejection in renal transplant recipients. Although PSIs are associated with an increase in hyperlipidaemia (hypercholesterolaemia and hypertriglyceridaemia), which is a major risk factor for atherosclerosis and associated cardiovascular disease, recent studies with sirolimus have demonstrated protection from atheroma progression in hyperlipidaemic apolipoprotein E-deficient mice. Here, we summarize the results of pre-clinical and clinical studies with sirolimus and everolimus, with particular emphasis on the beneficial and adverse effects that these drugs exert on the cardiovascular system, and the underlying molecular mechanisms.
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PMID:Potential role of proliferation signal inhibitors on atherosclerosis in renal transplant patients. 1681 51

Pathological fetal growth is associated with perinatal morbidity and the development of diabetes and cardiovascular disease later in life. Placental nutrient transport is a primary determinant of fetal growth. In human intrauterine growth restriction (IUGR) the activity of key placental amino acid transporters, such as systems A and L, is decreased. However the mechanisms regulating placental nutrient transporters are poorly understood. We tested the hypothesis that the mammalian target of rapamycin (mTOR) signalling pathway regulates amino acid transport in the human placenta and that the activity of the placental mTOR pathway is reduced in IUGR. Using immunohistochemistry and culture of trophoblast cells, we show for the first time that the mTOR protein is expressed in the transporting epithelium of the human placenta. We further demonstrate that placental mTOR regulates activity of the l-amino acid transporter, but not system A or taurine transporters, by determining the mediated uptake of isotope-labelled leucine, methylaminoisobutyric acid and taurine in primary villous fragments after inhibition of mTOR using rapamycin. The protein expression of placental phospho-S6K1 (Thr-389), a measure of the activity of the mTOR signalling pathway, was markedly reduced in placentas obtained from pregnancies complicated by IUGR. These data identify mTOR as an important regulator of placental amino acid transport, and provide a mechanism for the changes in placental leucine transport in IUGR previously demonstrated in humans. We propose that mTOR functions as a placental nutrient sensor, matching fetal growth with maternal nutrient availability by regulating placental nutrient transport.
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PMID:Mammalian target of rapamycin in the human placenta regulates leucine transport and is down-regulated in restricted fetal growth. 1746 46

Everolimus inhibits the mammalian target of rapamycin (mTOR) in proliferating cells. It is widely used in transplant patients and has also been exploited by drug-eluting stents for the treatment of cardiovascular disease. However, there is only limited data on the pathophysiological effects of mTOR-inhibitors on the vascular wall. We aimed to unravel the effects of everolimus on cholesterol-induced atherosclerosis and on circulating cell mediators in LDL-receptor-deficient (LDLR(-/-)) mice. Male hypercholesterolemic LDLR(-/-) mice received either solvent (group A; n=28) or everolimus at 0.05 mg/kg (group B, n=22) and 1.5 mg/kg (group C, n=29) per body weight per day by subcutaneously implanted osmotic minipumps for the study period of 12 weeks. Group B showed 44% reduction of atherosclerotic lesions at the brachiocephalic artery (BCA). In group C atherosclerotic lesions were reduced by 85% in the BCA and by 60% at the aortic root. This was associated with a significantly lower complexity of lesions in both treated groups (p<0.001) and despite a 40% increase of plasma cholesterol. Everolimus caused a significant reduction of circulating cell mediators such as interleukin-1alpha, interleukin-5, GM-CSF and interleukin-12p40. Everolimus increased the plasma levels of KC but had no effect on eighteen other circulating cell mediators studied. Everolimus strongly inhibits atherosclerosis development in LDL-receptor(-/-) mice despite severe hypercholesterolemia. Everolimus application had only small effects on circulating cell mediators. The significant reduction of atherosclerotic lesions was associated with a delayed transition from early macrophages enriched lesions to advanced atherosclerotic plaques.
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PMID:Prevention of atherosclerosis by the mTOR inhibitor everolimus in LDLR-/- mice despite severe hypercholesterolemia. 1798 Mar 69

Cardiovascular disease is the major cause of death in renal transplant recipients. Renal transplant recipients share the same cardiovascular risk factors as the general population, including hypertension, hyperlipidemia, diabetes mellitus, smoking, and positive family history. However, renal transplant recipients are also exposed to transplant-specific risk factors such as chronic immunosuppression. Most renal transplant recipients receive combinations or permutations of immunosuppressive drugs including a calcineurin inhibitor (cyclosporine or tacrolimus), a mammalian target of rapamycin (mTOR) inhibitor (sirolimus), an antiproliferative drug (mycophenolate mofetil and azathioprine), and corticosteroids. Cyclosporine and tacrolimus can induce glucose intolerance, hypertension, and hyperlipidemia. Sirolimus can induce hyperlipidemia. Corticosteroids can induce glucose intolerance, hypertension, hyperlipidemia, and weight gain. Central to the development of metabolic complications in renal transplant recipients is insulin resistance induced by immunosuppressive drugs. Insulin resistance is considered to be the central pathophysiological feature of metabolic syndrome, which is linked to increased risk of cardiovascular disease and to chronic renal failure. Therefore, metabolic syndrome likely contributes to cardiovascular disease and chronic renal allograft dysfunction in renal transplant recipients. Treatment of metabolic complications in renal transplant recipients is difficult, as conversion to an alternate immunosuppressive drug may lead to introduction of new metabolic complications, and as discontinuation of immunosuppressive therapy may lead to rejection. Future research should focus on designing immunosuppressive regimens that have minimal effects on insulin resistance and metabolic complications but that are effective in preventing acute rejection and in prolonging both allograft and patient survival.
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PMID:Immunosuppression and metabolic syndrome in renal transplant recipients. 1837 Jun 95

The incidence, pathogenesis, consequences and treatment of mammalian target of rapamycin (mTOR) inhibitor dyslipidemia are not well described. We conducted a systematic review of randomized controlled trials reporting cholesterol and triglycerides in mTOR versus non-mTOR inhibitor immunosuppressive treatment regimens in kidney transplant recipients. All but one of 17 trials reported higher levels of cholesterol and triglycerides, or an increased prevalence of treatment with lipid-lowering agents. Approximately 60% of mTOR inhibitor-treated patients received lipid-lowering agents (2-fold higher than controls). There appeared to be little difference between dyslipidemias caused by sirolimus (14 trials) versus everolimus (3 trials). It was difficult to determine the extent to which declines in lipids over time posttransplant were due to lipid-lowering therapy, changes in doses and/or discontinuations of mTOR inhibitors. From the four trials that measured lipoproteins, it appeared that at least some of the increase in total cholesterol with mTOR inhibitors was due to increased low-density lipoprotein cholesterol. What direct or indirect effects mTOR inhibitors have on atherosclerotic cardiovascular disease in kidney transplant patients are unknown. However, in the absence of the necessary clinical trials, dyslipidemia should be managed, as it would be in nontransplant patients at high risk for cardiovascular disease.
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PMID:Mammalian target of rapamycin inhibitor dyslipidemia in kidney transplant recipients. 1851 Jun 33

Leptin is both a hormone/cytokine that plays a major role in the regulation of feeding and energy expenditure. Beyond its central role in the hypothalamus, leptin modulates peripheral tissues' responses to growth and storage based on nutrient availability, and it regulates the innate and adaptive immune responses. mTOR (mammalian Target of Rapamycin) is a core component of intracellular signaling for cellular growth, mRNA translation, and metabolism. Here, we review recent findings on the cross talk between mTOR and leptin signaling. Important roles for mTOR on leptin signaling have been established both in hypothalamic centers to control food intake and in peripheral cells to regulate lipid metabolism and inflammation. Leptin directly activates resident macrophages to form ADRP-enriched lipid droplets and enhances eicosanoid production via a mechanism that is dependent on activation of the PI3K/mTOR pathway. Leptin-induced mTOR activation may have implications for obesity-related pathophysiological conditions such as diabetes, cardiovascular disease and cancer.
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PMID:Leptin and mTOR: partners in metabolism and inflammation. 1858 36

For patients with end-stage kidney failure, kidney transplantation improves both their quality of life and overall life expectancy compared with dialysis, but it is not without adverse effects. Cancer is second to cardiovascular disease as one of the major causes of morbidity and mortality in renal transplant recipients. Prolonged use of modern immunosuppression, which leads to alteration of immune function and immune surveillance, is associated with increased cancer risk. There is now convincing evidence from observational studies and registry data to confirm a 3- to 5-fold increase in overall cancer incidence, with viral-related neoplasia incurring the greatest risk when compare with the general population. Despite the increased risk, little is known about the overall cancer prognosis, screening, treatment strategies, and effectiveness in this population. Cancers can recur, occur de novo, and be transmitted from donor organs posttransplantation. Uncertainties exist as to how modern immunosuppressive agents impact on cancer management and outcomes in these patients, with some agents such as calcineurin inhibitors and azathioprine, being more carcinogenic than others. The newer agents, proliferation signal/mammalian target of rapamycin inhibitors and mycophenolate mofitil, may have some antiproliferative and antitumor activities demonstrated in preclinical and clinical studies, but long-term well-powered trial data are needed to determine whether they are either protective or curative for cancers in renal transplant recipients. In this review, the incidence, etiology, prognosis, and potential approaches to cancer screening and management post-renal transplantation are discussed.
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PMID:Cancers after renal transplantation. 1863 67

Several studies indicated that people who live in the Mediterranean region have very low rates of chronic diseases such as cardiovascular disease and cancer. It is well known that Mediterranean-style diet is rich in vegetables, tomato, fruit, fish and olive oil. These important dietary components may contribute to lower risk of cancer. Lycopene, a major component in tomato, exhibited potential anticarcinogenic activity. Previous studies showed that consumption of fish containing eicosapentaenoic acid (EPA) correlated with reduced risk of cancer. However, the combined effects of lycopene and EPA on the proliferation of human colon cancer have not been studied well yet. Thus, we investigated the anticancer properties and therapeutic potential of lycopene and EPA in human colon cancer HT-29 cells. In this study, we determined the combined effects of lycopene and EPA on the proliferation of human colon cancer HT-29 cells. We demonstrated that low concentration of lycopene and EPA could synergistically inhibit the proliferation of colon cancer cells. The inhibitory mechanism was associated with suppression of phosphatidylinositol 3-kinase/Akt signaling pathway. Furthermore, treatment of lycopene and EPA also synergistically blocked the activation of downstream mTOR molecule. Immunocytochemical staining results revealed that lycopene and EPA could also up-regulate the expression of apoptotic proteins such as Bax and Fas ligand to suppress cell survival. In conclusion, our novel findings suggest that lycopene and EPA synergistically inhibited the growth of human colon cancer HT-29 cells even at low concentration. The inhibitory effects of lycopene and EPA on cell proliferation of human colon cancer HT-29 cells were, in part, associated with the down-regulation of the PI-3K/Akt/mTOR signaling pathway.
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PMID:Concomitant supplementation of lycopene and eicosapentaenoic acid inhibits the proliferation of human colon cancer cells. 1870 85

Although continuous improvements have been made in fighting rejection with immunosuppressive drugs in transplant recipients, this success story has been tempered by an associated high incidence of cancer. The latest projections are that cancer might exceed cardiovascular disease as the leading cause of death among transplant recipients. Indeed, immunosuppression reduces our natural ability to destroy cancer cells and to inhibit viral infections potentially linked to cancer development. Therefore, a strategy to counter the problem of cancer in transplantation is needed. Recently, mammalian target of rapamycin (mTOR) inhibitors have demonstrated potential as both immunosuppressive and anticancer agents. Although mTOR inhibitors prevent organ transplant rejection, this class of drugs has potential anticancer properties that may be useful in the "balance of effects" toward cancer-free survival in transplant recipients. Mechanisms of mTOR inhibitors' anticancer effects are multiple, affecting processes including angiogenesis, cell proliferation, cell survival, and molecular oncogenic signaling. Importantly, experimental work supports the view that tumor inhibition can be accomplished with mTOR inhibitors while protecting allografts against rejection. Most recently, prospective randomized clinical studies have been initiated to test the concept that mTOR inhibitors reduce cancer while simultaneously inhibiting allograft rejection. One such study, the SiLVER trial, examines hepatocellular carcinoma recurrence in mTOR inhibitor-treated liver transplant patients. More robust evidence as to whether cancer risk can be reduced in transplant recipients with mTOR inhibitors may come from such clinical trials.
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PMID:The impact of mTOR inhibitors on the development of malignancy. 1910 Sep 4


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