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1.
BackgroundLiver transplantation (LT) is an effective treatment option for end-stage liver disease. Mammalian target of rapamycin (mTOR) inhibitors, such as rapamycin, are widely used post LT.Data sourcesIn this review, we focused on the anti-cancer activities and metabolic side effects of rapamycin after LT. The literature available on PubMed for the period of January 1999-September 2022 was reviewed. The key words were rapamycin, sirolimus, liver transplantation, hepatocellular carcinoma, diabetes, and lipid metabolism disorder.ResultsRapamycin has shown excellent effects and is safer than other immunosuppressive regimens. It has exhibited excellent anti-cancer activity and has the potential in preventing hepatocellular carcinoma (HCC) recurrence post LT. Rapamycin is closely related to two long-term complications after LT, diabetes and lipid metabolism disorders.ConclusionsRapamycin prevents HCC recurrence post LT in some patients, but it also induces metabolic disorders. Reasonable use of rapamycin benefits the liver recipients.  相似文献   

2.
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that plays an important role in cell growth and metabolism. mTOR has been postulated as a nutrient sensor, but its role in the regulation of fatty acid and glucose metabolism is poorly understood. For the first time, we show that mTOR inhibition in skeletal muscle cells has pronounced effects on intermediary metabolism. Rapamycin, a uniquely specific mTOR inhibitor with clinical applications, increased fatty acid oxidation by 60% accompanied by increased activities of carnitine palmitoyltransferases I and II, the former believed to be the primary intracellular regulatory enzyme of the fatty acid oxidation pathway. Furthermore, glucose transport capacity, glycogen synthesis, and glycolysis were reduced by approximately 40% under the same conditions. In addition, in the presence of rapamycin, hyperinsulinemic conditions (100 nmol/L insulin, 24 hours) were unable to suppress fatty acid oxidation in L6 myotubes. Rapamycin treatment also decreased baseline phosphorylation of mTOR residues S2448 and S2481 by 30% and almost completely abolished p70 S6 kinase phosphorylation. These results show that rapamycin causes a metabolic shift from glucose utilization to fatty acid oxidation in model muscle cells in the presence of nutrient abundance and underline the importance of mTOR as a key regulator in glucose and lipid metabolism.  相似文献   

3.
The chronic and systemic administration of rapamycin extends life span in mammals. Rapamycin is a pharmacological inhibitor of mTOR. Metformin also inhibits mTOR signaling but by activating the upstream kinase AMPK. Here we report the effects of chronic and systemic administration of the two mTOR inhibitors, rapamycin and metformin, on adult neural stem cells of the subventricular region and the dendate gyrus of the mouse hippocampus. While rapamycin decreased the number of neural progenitors, metformin-mediated inhibition of mTOR had no such effect. Adult-born neurons are considered important for cognitive and behavioral health, and may contribute to improved health span. Our results demonstrate that distinct approaches of inhibiting mTOR signaling can have significantly different effects on organ function. These results underscore the importance of screening individual mTOR inhibitors on different organs and physiological processes for potential adverse effects that may compromise health span.  相似文献   

4.
Rapamycin is an immunosuppressive agent used after organ transplantation, but its molecular effects on glucose metabolism needs further evaluation. We explored rapamycin effects on glucose uptake and insulin signalling proteins in adipocytes obtained via subcutaneous (n=62) and omental (n=10) fat biopsies in human donors. At therapeutic concentration (0.01 μM) rapamycin reduced basal and insulin-stimulated glucose uptake by 20-30%, after short-term (15 min) or long-term (20 h) culture of subcutaneous (n=23 and n=10) and omental adipocytes (n=6 and n=7). Rapamycin reduced PKB Ser473 and AS160 Thr642 phosphorylation, and IRS2 protein levels in subcutaneous adipocytes. Additionally, it reduced mTOR-raptor, mTOR-rictor and mTOR-Sin1 interactions, suggesting decreased mTORC1 and mTORC2 formation. Rapamycin also reduced IR Tyr1146 and IRS1 Ser307/Ser616/Ser636 phosphorylation, whereas no effects were observed on the insulin stimulated IRS1-Tyr and TSC2 Thr1462 phosphorylation. This is the first study to show that rapamycin reduces glucose uptake in human adipocytes through impaired insulin signalling and this may contribute to the development of insulin resistance associated with rapamycin therapy.  相似文献   

5.
Inhibition of mTOR signaling using rapamycin has been shown to increase lifespan and healthspan in multiple model organisms; however, the precise mechanisms for the beneficial effects of rapamycin remain uncertain. We have previously reported that rapamycin delays senescence in human cells and that enhanced mitochondrial biogenesis and protection from mitochondrial stress is one component of the benefit provided by rapamycin treatment. Here, using two models of senescence, replicative senescence and senescence induced by the presence of the Hutchinson-Gilford progeria lamin A mutation, we report that senescence is accompanied by elevated glycolysis and increased oxidative phosphorylation, which are both reduced by rapamycin. Measurements of mitochondrial function indicate that direct mitochondria targets of rapamycin are succinate dehydrogenase and matrix alanine aminotransferase. Elevated activity of these enzymes could be part of complex mechanisms that enable mitochondria to resume their optimal oxidative phosphorylation and resist senescence. This interpretation is supported by the fact that rapamycin-treated cultures do not undergo a premature senescence in response to the replacement of glucose with galactose in the culture medium, which forces a greater reliance on oxidative phosphorylation. Additionally, long-term treatment with rapamycin increases expression of the mitochondrial carrier protein UCP2, which facilitates the movement of metabolic intermediates across the mitochondrial membrane. The results suggest that rapamycin impacts mitochondrial function both through direct interaction with the mitochondria and through altered gene expression of mitochondrial carrier proteins.  相似文献   

6.
The discovery of life extension in Caenorhabditis elegans treated with anticonvulsant medications has raised the question whether these drugs are prospective anti-aging candidate compounds. The impact of these compounds on neural modulation suggests that they might influence the chronic diseases of aging as well. Lamotrigine is a commonly used anticonvulsant with a relatively good adverse-effects profile. In this study, we evaluated the interaction between the impacts of lamotrigine on mortality rate, lifespan, metabolic rate and locomotion. It has been proposed in a wide range of animal models that there is an inverse relationship between longevity, metabolic rate, and locomotion. We hypothesized that the survival benefits displayed by this compound would be associated with deleterious effects on health span, such as depression of locomotion. Using Drosophila as our model system, we found that lamotrigine decreased mortality and increased lifespan in parallel with a reduction in locomotor activity and a trend towards metabolic rate depression. Our findings underscore the view that assessing health span is critical in the pursuit of useful anti-aging compounds.  相似文献   

7.
Lui SL  Yung S  Tsang R  Zhang F  Chan KW  Tam S  Chan TM 《Lupus》2008,17(4):305-313
Rapamycin is a potent immunosuppressive drug currently used mainly for rejection prophylaxis in renal transplantation. The aim of this study was to determine the effect of rapamycin treatment on the development of nephritis in lupus-prone New Zealand Black/White F1 (NZB/W F1) mice. Twelve-week-old female NZB/W F1 mice were treated with rapamycin (3 mg/kg body weight) or saline once daily by oral gavage for 20 weeks. The severity of nephritis was assessed by clinical and biochemical parameters, renal histology, immunohistochemistry and gene expression studies. Rapamycin treatment markedly reduced proteinuria, improved renal function, decreased serum anti-double stranded DNA antibody levels and diminished splenomegaly. Kidney sections from saline-treated mice showed marked mesangial proliferation, tubular dilation with protein cast deposition and interstitial inflammatory cell infiltration. Rapamycin-treated mice had near normal renal histology, with marked reduction in glomerular immune deposition and the infiltration by T cells, B cells and macrophages. Rapamycin treatment was associated with down-regulation of intra-renal expression of monocyte chemoattractant protein-1 (MCP-1) mRNA and protein. We conclude that rapamycin is highly effective in preventing the development of nephritis in NZB/W F1 mice. The beneficial effects of rapamycin are mediated through inhibition of lymphoproliferation and reduced MCP-1 expression.  相似文献   

8.
Although rapamycin (rapa) is a fungicide, it is now believed to possess the capacity to extend mammalian life span. Because rapamycin is insoluble in water, its study in the aqueous phase has been limited. We therefore solubilized rapamycin in isotonic buffer using reconstituted high-density lipoprotein containing V156K-apolipoprotein A-I (V156K-rHDL). Rapamycin (final concentration, 0.1 mg/mL) was solubilized in rHDL containing either wild-type (WT) or V156K-apoA-I (1 mg/mL of protein) prepared using the sodium cholate dialysis method. V156K-rHDL containing rapamycin (V156K-rapa-rHDL) had a slightly larger particle size than rapamycin-loaded WT-rHDL (WT-rapa-rHDL). V156K-rapa-rHDL exhibited enhanced antioxidant ability, cholesteryl ester transfer protein inhibitory activity, and anti-atherosclerotic activity. Treatment with V156K-rapa-rHDL resulted in attenuation of senescence in human cells with increased cell survival and enhancement of tissue regenerative activities in zebrafish model compared with WT-rapa-rHDL or rHDL alone.  相似文献   

9.
Studies were carried out to define the hormone-induced signal transduction pathway during maturation of Rana dybowskii oocytes. Rapamycin, a specific inhibitor of S6 kinase, blocked progesterone-induced oocyte germinal vesicle breakdown (GVBD) in a dose-dependent manner indicating that S6 kinase is required for meiotic maturation of Rana oocytes. Addition of rapamycin within 3 h, but not 6 h, of progesterone treatment inhibited GVBD. In contrast, cycloheximide, a general protein synthesis inhibitor, blocked GVBD even when added 9 h after progesterone addition. A twofold increase in S6 kinase activity occurred within 1 h of progesterone stimulation and rapamycin inhibited this activity. Rapamycin also suppressed, in a dose-dependent manner, progesterone-induced protein synthesis during the first 12 h of culture but less effectively later. Histone H1 kinase activity (maturation-promoting factor, MPF) was observed in oocyte extracts at two different times (between 6 and 9 h and at 24 h) following progesterone stimulation. Rapamycin blocked H1 kinase activity between 6 and 9 h of culture but not that observed at 24 h. In contrast, cycloheximide suppressed progesterone-induced H1 kinase activity as well as protein synthesis throughout the course of incubation. Such results indicate that rapamycin and cycloheximide have common and unique effects on oocyte maturation and suggest that progesterone-induced S6 kinase activity is closely associated with induction of protein synthesis and activation of MPF during oocyte maturation. Results in Rana contrast with those obtained in Xenopus where rapamycin inhibited S6 kinase but failed to inhibit GVBD or protein synthesis. Differences in the response of Rana and Xenopus oocytes to rapamycin are discussed in relation to seasonal, biochemical, and species variations.  相似文献   

10.
A remarkable discovery of recent years is that, despite the complexity of ageing, simple genetic interventions can increase lifespan and improve health during ageing in laboratory animals. The pathways involved have often proved to sense nutrients and to match costly activities of organisms, such as growth, metabolism and reproduction, to nutrient status. For instance, the insulin/insulin-like growth factor and Target of Rapamycin signalling network has proved to play a function in ageing, from yeast to mammals, seemingly including humans. In the fruit fly Drosophila, altered activity of several components of this network can increase lifespan and improve locomotor and cardiac function during ageing. The fly brain, fat body (equivalent of mammalian liver and white adipose tissue) and the germ line are important in determination of lifespan, with considerable communication between different tissues. Cellular detoxification pathways, increased autophagy and altered protein synthesis have all been implicated in increased lifespan from reduced IIS/TOR activity, with the role of defence against oxidative stress unresolved. Reduced IIS/TOR signalling can alter or block the response of lifespan to dietary restriction. Reduced IIS can act acutely to lower death rate, implying that it may ameliorate the effects of ageing-related damage, rather than preventing it.  相似文献   

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