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 administration of branched-chain amino acids (BCAAs) to cirrhosis patients increases serum albumin levels and improves the blood Fischer's ratio. Although it has been reported that albumin synthesis in rat primary hepatocytes is diminished under lower Fisher's ratio conditions compared to normal Fischer's ratio conditions, the mode of action at the molecular level for these effects is still uncertain. It has been reported recently that the triggering signal for protein synthesis is transmitted through mTOR (mammalian target of rapamycin). We have had an interest in the mTOR signal transduction system. In the present study, we analyzed the mode of action of BCAA-induced albumin synthesis using rat primary hepatocytes. The BCAA mixture dose-dependently promoted the production of albumin, with leucine being the major effector half of which was inhibited by the mTOR inhibitor rapamycin. We also showed that only leucine induces P70 S6 kinase activation and 4E-BP1 phosphorylation which are mTOR's downstream translational effectors. These activations were completely inhibited by rapamycin. Our results suggest that BCAAs, especially leucine, promote the production of albumin in rat primary hepatocytes through an mTOR signal transduction system.
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PMID:Branched-chain amino acids promote albumin synthesis in rat primary hepatocytes through the mTOR signal transduction system. 1264 66

Branched-chain amino acid (BCAA: Leu, Ile, and Val) mixture has been used for treatment of hypoalbuminemia in patients with decompensated liver cirrhosis in Japan. It has been known that BCAA, especially leucine, activates mTOR signals and inhibition of protein degradation results in promoting protein synthesis in vitro. Furthermore, leucine activates glycogen synthase via mTOR signals in L6 cell, but not hepatocyte, and it has been shown that leucine improved glucose metabolism in normal and cirrhosis model rats. In this review, it will be proposed about the pharmacological activity of branched-chain amino acids, mainly leucine, on tissue specificity of cirrhotic disease.
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PMID:Pharmacological activities of branched-chain amino acids: specificity of tissue and signal transduction. 1468 73

It is well established that impaired glucose metabolism is a frequent complication in patients with hepatic cirrhosis. We previously showed that leucine, one of the branched-chain amino acids (BCAA), promotes glucose uptake under insulin-free conditions in isolated skeletal muscle from normal rats. The aim of the present study was to evaluate the effects of BCAA on glucose metabolism in a rat model of CCl(4)-induced cirrhosis (CCl(4) rats). Oral glucose tolerance tests were performed on BCAA-treated CCl(4) rats. In the CCl(4) rats, treatment with leucine or isoleucine, but not valine, improved glucose tolerance significantly, with the effect of isoleucine being greater than the effect of leucine. Glucose uptake experiments using isolated soleus muscle from the CCl(4) rats revealed that leucine and isoleucine, but not valine, promoted glucose uptake under insulin-free conditions. To clarify the mechanism of the blood glucose-lowering effects of BCAA, we collected soleus muscles from BCAA-treated CCl(4) rats with or without a glucose load. These samples were used to determine the subcellular location of glucose transporter proteins and glycogen synthase (GS) activity. Oral administration of leucine or isoleucine without a glucose load induced GLUT4 and GLUT1 translocation to the plasma membrane. GS activity was augmented only in leucine-treated rats and was completely inhibited by rapamycin, an inhibitor of mammalian target of rapamycin. In summary, we found that leucine and isoleucine improved glucose metabolism in CCl(4) rats by promoting glucose uptake in skeletal muscle. This effect occurred as a result of upregulation of GLUT4 and GLUT1 and also by mammalian target of rapamycin-dependent activation of GS in skeletal muscle. From these results, we consider that BCAA treatment may have beneficial effects on glucose metabolism in cirrhotic patients.
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PMID:Branched-chain amino acids improve glucose metabolism in rats with liver cirrhosis. 1559 Nov 58

LIVACT granules, which is a branched-chain amino acid (BCAA) preparation, was developed for the purpose of improving hypoalbuminemia in patients with uncompensated liver cirrhosis in Japan. Recent clinical studies have shown that BCAA supplementation not only improves hypoalbuminemia, but also reduces the occurrence frequency of various complications of liver cirrhosis, which considerably affect mortality. In order to comprehend the significance of BCAA supplementation in patients with liver cirrhosis and to suggest better treatments, we conducted basic non-clinical studies mainly using animal models, clarified the molecular mechanism of the curative effect on hypoalbuminemia and emphasized the importance of mTOR signal transduction. Moreover, we found a new pharmacological action of BCAA, which improves glucose metabolism in skeletal muscles.
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PMID:Pharmacological activities of branched-chain amino acids: augmentation of albumin synthesis in liver and improvement of glucose metabolism in skeletal muscle. 1560 34

Hepatocellular carcinoma is often diagnosed at an advanced stage, when it is not amenable to curative therapies. There is no effective chemotherapy. Advances in cancer biology suggest that a limited number of pathways are responsible for initiating and maintaining dysregulated cell proliferation, which is the major cellular alteration responsible for the cancer phenotype. New treatments in development target several of these critical pathways, including agents targeting the receptor tyrosine kinase pathways, the Wnt/beta-catenin signaling pathway, the ubiquitin/proteasome degradation pathway, the epigenetic DNA methylation and histone deacetylation pathways, the PI3 kinase/AKT/mTOR pathway, angiogenic pathways, and telomerase. Several of these approaches hold significant promise for improving the long-term outcome of patients with advanced hepatocellular carcinoma. Because of the high prevalence of liver cirrhosis in hepatocellular carcinoma patients, these approaches must be coupled with new strategies for halting or reversing the progression of chronic liver disease.
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PMID:Hepatocellular carcinoma: molecular pathways and new therapeutic targets. 1591 49

Hepatocellular carcinoma is often diagnosed at an advanced stage, when potentially curative surgical or local ablative therapies are not feasible. There is no effective chemotherapy for hepatocellular carcinoma. Recent advances in cancer biology suggest that a limited number of signalling pathways may be responsible for uncontrolled cell proliferation, the major cellular alteration responsible for the cancer phenotype. Novel anticancer agents target these critical pathways, including the receptor tyrosine kinase pathways, the Wnt/beta-catenin signalling pathway, the ubiquitin/proteasome degradation pathway, the DNA methylation and histone deacetylation pathways, the PI3 kinase/AKT/mTOR pathway, angiogenic pathways, telomerase and the cell cycle. These agents hold promise for improving the outcome of patients with intermediate and advanced hepatocellular carcinoma. Because of the high prevalence of liver cirrhosis in hepatocellular carcinoma patients, to achieve long-term survival of the majority of patients, targeted anticancer therapies will need to be coupled with strategies aimed at reversing the progression of chronic liver disease.
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PMID:Emerging drugs for hepatocellular carcinoma. 1693 86

Long-term supplementation of branched-chain amino acids (BCAA) improves hypoalbuminemia in patients with cirrhosis. Our previous findings have suggested that the binding of polypyrimidine-tract-binding protein (PTB) to rat albumin mRNA attenuates its translation. The aim of the present study was to investigate the role of PTB in the regulation of albumin synthesis by BCAA in human hepatoma cells. HepG2 cells were cultured in a medium containing no amino acids (AA-free medium), a medium containing only 1 amino acid (a BCAA: valine, leucine or isoleucine) or a medium containing all 20 amino acids (AA-complete medium). HepG2 cells cultured in AA-complete medium secreted much more albumin than cells cultured in AA-free medium, with no difference in albumin mRNA levels. In cells cultured in AA-free medium, nuclear export of PTB was observed, and the level of the albumin mRNA-PTB complex was greater than in cells cultured in AA-complete medium. Addition of amino acids stimulated nuclear import of PTB. However, addition of amino acids with rapamycin inhibited the nuclear import of PTB. The addition of leucine, but not of valine or isoleucine, to AA-free medium increased albumin secretion and stimulated the nuclear import of PTB. These data indicate that the mammalian target of rapamycin is involved in the regulation of PTB localization and that leucine promotes albumin synthesis by inhibiting the formation of the albumin mRNA-PTB complex.
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PMID:Localization of polypyrimidine-tract-binding protein is involved in the regulation of albumin synthesis by branched-chain amino acids in HepG2 cells. 1770 30

Sirolimus (SRL) is an mTOR inhibitor that has been shown, in contrast to calcineurin inhibitors (CNI), to inhibit cancers in experimental models. Since February 2005, we introduced SRL in liver transplant patients in group a, in whom the primary disease was hepatocellular carcinoma (HCC) associated with hepatitis B virus (HBV), hepatitis C virus (HCV), alcoholic or autoimmune liver cirrhosis, and group b, HCC-negative patients who developed posttransplantation cancers de novo. Of 18 patients in group a, 11 received SRL ab initio (subgroup a1), starting for 10 patients at 66.1+/-29.2 days after surgical healing and after 10 days in 1 case; the remaining 7 patients (subgroup a2) received SRL at 31.2+/-24.2 months. Three patients in group b, included 1 with Kaposi's sarcoma, 1 with bladder cancer, and 1 with thyroid cancer. In this group, SRL was introduced at 80.8+/-40.4 months. In all patients but one, who received a single 5 mg loading dose, SRL was started at 2 mg/d and adjusted to 6 to 8 ng/mL blood levels. CNI drugs, present as primary therapy, were gradually tapered to low levels and eventually stopped. The following observations were drawn from this initial experience: (1) 4/21 (19.0%) patients had to discontinue SRL because of early and late side effects: thrombocytopenia (n=2) and headache with leukopenia and leg edema associated with knee joint arthralgia (n=2); (2) 14 patients (11 in group a and 3 in group b) are still on SRL monotherapy; (3) 1 HCC recurrence and 1 de novo pancreatic adenocarcinoma were observed at 14 and 16 months, respectively (at the time of transplantation, both patients were beyond the MIlan HCC criteria), and (4) 1 patient, from subgroup a1, died after 99 days due to pneumonitis and possible relation to SRL lung toxicity. In conclusion, SRL appeared to be an effective immunosuppressant that could be used as monotherapy in liver transplant patients. Any conclusion on SRL anticancer effects can only come from randomized large studies after long follow-up.
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PMID:Sirolimus therapy in liver transplant patients: an initial experience at a single center. 1867 98

The first liver transplantation (LT) was conducted in 1963. After a two-decade development phase with the improvement of surgical and anesthesia-resuscitation techniques, and a better control of allograft rejection, LT has become the benchmark treatment for the majority of end-stage liver diseases. Since the 1980s, indications of LT have gradually expanded and the current main indications in adults are hepatocellular carcinoma at an early stage (15 to 30% of indications), C cirrhosis (15 to 40% of indications) and alcoholic cirrhosis (20 to 25% of indications). Five thousand LTs are performed yearly in Europe, including 1000 LTs in France, with, over the 2000-2006 period, survival rates of 86, 75 and 68% at one, five and 10 years, respectively. Several advances have accompanied the increasing number of indications and these excellent results: (a) the development of more specific immunosuppressive drugs to prevent rejection, the incidence of which is currently less than 20%: tacrolimus, mycophenolic acid, anti-IL2 receptor antibodies, mTOR inhibitors, (b) a policy of active recruitment of organs together with surgical innovations (split liver, domino LT, living donor transplantation) contributing to the expansion of the pool of organs, (c) standardization of organ allocation policies, based on the sickest first policy. The applicability of LT, however, remains limited by the shortage of organs and the occurrence of long-term complications of immunosuppression. Due to the lack of effective alternative perspectives to LT for the treatment of end-stage liver diseases, the two major challenges for the liver transplant community should be the optimization of organ recruitment and the development of innovative immunosuppressive regimens able to overcome the side effects of current immunosuppressive drugs. The development of non heart beating donation and appropriate use of intrafamilial donation could partly compensate for the organ shortage in the midterm. The identification of molecular signatures in tolerant patients in whom immunosuppression could be stopped, and induction of tolerance, trough lymphocyte depletion or T lymphocyte costimulation blockade, are the most advanced research ways to reduce complications of immunosuppression.
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PMID:[Hepatic transplantation]. 1955 84

MicroRNA (miRNAs) are negative regulators of gene expression and can function as tumor suppressors or oncogenes. Expression patterns of miRNAs and their role in the pathogenesis of hepatocellular carcinoma (HCC) are still poorly understood. We profiled miRNA expression in tissue samples (104 HCC, 90 adjacent cirrhotic livers, 21 normal livers) as well as in 35 HCC cell lines. A set of 12 miRNAs (including miR-21, miR-221/222, miR-34a, miR-519a, miR-93, miR-96, and let-7c) was linked to disease progression from normal liver through cirrhosis to full-blown HCC. miR-221/222, the most up-regulated miRNAs in tumor samples, are shown to target the CDK inhibitor p27 and to enhance cell growth in vitro. Conversely, these activities can be efficiently inhibited by an antagomiR specific for miR-221. In addition, we show, using a mouse model of liver cancer, that miR-221 overexpression stimulates growth of tumorigenic murine hepatic progenitor cells. Finally, we identified DNA damage-inducible transcript 4 (DDIT4), a modulator of mTOR pathway, as a bona fide target of miR-221. Taken together, these data reveal an important contribution for miR-221 in hepatocarcinogenesis and suggest a role for DDIT4 dysregulation in this process. Thus, the use of synthetic inhibitors of miR-221 may prove to be a promising approach to liver cancer treatment.
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PMID:miR-221 overexpression contributes to liver tumorigenesis. 2001 59


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