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nfcorpus-corpus-MED-3621 | null | Dental X-rays and Risk of Meningioma
Context Ionizing radiation is a consistently identified and potentially modifiable risk factor for meningioma, the most frequently reported primary brain tumor in the United States. Objective To examine the association between dental x-rays, the most common artificial source of ionizing radiation, and risk of intra-cranial meningioma. Design and Setting Population-based case-control study design. Participants The study includes 1433 intra-cranial meningioma cases aged 29-79 years diagnosed among residents of the states of Connecticut, Massachusetts, North Carolina, the San Francisco Bay Area and eight Houston, Texas counties between May 1, 2006 and April 28, 2011 and 1350 controls that were frequency-matched on age, sex and geography. Main Outcome Measure The association of intra-cranial meningioma diagnosis with self-report of bitewing, full-mouth, and panorex dental x-rays. Results Over a lifetime, cases were more than twice (Odds ratio (OR) = 2.0, 95% confidence interval (CI), 1.4-2.9) as likely as controls to report having ever had a bitewing exam. Regardless of the age at which the films were received, persons who reported receiving bitewing films on a yearly or greater frequency had an elevated risk with odds ratios of 1.4 (95%CI: 1.0-1.8), 1.6 (95%CI: 1.2-2.0), 1.9 (95%CI: 1.4-2.6), and 1.5 (95%CI: 1.1-2.0) for ages <10, 10-19, 20-49, and 50+ years, respectively. Increased risk of meningioma was also associated with panorex films taken at a young age or on a yearly or greater frequency with persons reporting receiving such films under the age of 10 years at 4.9 times (95%CI: 1.8-13.2) increased risk of meningioma. No association was appreciated with location of tumor above or below the tentorium. Conclusion Exposure to some dental x-rays performed in the past, when radiation exposure was greater than in the current era, appears to be associated with increased risk of intra-cranial meningioma. As with all sources of artificial ionizing radiation, considered use of this modifiable risk factor may be of benefit to patients. |
nfcorpus-queries-PLAIN-1962 | null | pumpkin |
nfcorpus-corpus-MED-3615 | null | Evaluation of chromosomal aberrations, micronuclei, and sister chromatid exchanges in hospital workers chronically exposed to ionizing radiation.
Cytogenetic analysis was performed in peripheral blood lymphocytes from hospital workers chronically exposed to ionizing radiation in comparison to matched non-exposed individuals. The accumulated absorbed doses calculated for the radiation workers ranged from 9.5 to 209.4 mSv. The endpoints used were chromosomal aberrations (CA), micronuclei (MN), and sister chromatid exchanges (SCE). The frequencies of CA/100 cells observed for the exposed group were significantly (P=0.018) higher than in the control group: 3.2 and 2.6, respectively. Similarly, the mean numbers of SCE per cell were statistically higher (P=0.025) in the exposed group (6.2) in comparison with the control group (5.8). In the case of micronuclei analysis, no significant (P=0,06) difference between both groups was found, but these data should be cautiously interpreted since an increase in the frequencies of MN was found for radiation workers (3.0 MN/100 cells), compared to the control group (2.6 MN/100 cells) and this increase occur in parallel to CA and SCE frequencies. The difference between the results could be explained by the nature of CA and MN generation. The increased frequencies of CA and SCE in radiation workers indicate the cumulative effect of low-level chronic exposure to ionizing radiation, and the relevance of conducting cytogenetic analysis in parallel to physical dosimetry in the working place. Copyright 2001 Wiley-Liss, Inc. |
nfcorpus-queries-PLAIN-1962 | null | pumpkin |
nfcorpus-corpus-MED-3622 | null | Dietary and clastogenic factors in children who immigrated to Israel from regions contaminated by the Chernobyl accident.
The authors evaluated the possible association between dietary history and plasma clastogenic factors in children who immigrated to Israel between 1989 and 1993 from regions contaminated by the Chernobyl accident. The authors compared questionnaire data about demographic variables, dietary histories before and after immigration occurred, and health status with clastogenic factor scores for 162 immigrants. Logistic regression analysis revealed a negative association between clastogenic factor scores and frequency of consumption of fresh vegetables and fruit among children < or = 7 yr of age during the postimmigration period. Intake of eggs and fish by boys who were < or = 7 yr of age prior to immigration was associated positively with clastogenic factor scores. Consumption of fresh vegetables and fruits afforded protection to the immune systems of children who were < or = 7 yr of age. |
nfcorpus-queries-PLAIN-1962 | null | pumpkin |
nfcorpus-corpus-MED-2790 | null | A clinical review of different formulations of Vasa (Adhatoda vasica) on Tamaka Shwasa (asthma)
Vasa (Adhatoda vasica Linn.) is a well known and easily available drug in almost all the seasons. Easy availability of any drug gains popularity among physicians as well as pharmaceuticals and this is the reason why almost every Kalpana of Vasa is found described in the Ayurvedika text. The different dosage forms of Vasa like Kvatha, Avaleha, Sneha, and Sandhana have been used for the treatment of Shwasa Roga. A number of research studies have been performed on different formulations of Vasa and its effect on Shwasa Roga. Therefore, a review study has been carried out on the Vasa extract, Vasa Avaleha (prepared from Svarasa and Kvatha), Vasa Ghrita, Vasarishta, and Vasakasava on Shwasa Roga, to know which formulation is better. It was found in the review that Vasa Ghana, Vasa Ghrita (1), and Vasa Avaleha have shown good results on Tamaka Shwasa. |
nfcorpus-queries-PLAIN-1972 | null | quinine |
nfcorpus-corpus-MED-2792 | null | Cholesterol oxides in Indian ghee: possible cause of unexplained high risk of atherosclerosis in Indian immigrant populations.
Two populations of immigrants to London and to the West Indies from the Indian subcontinent have higher than expected morbidity and mortality from atherosclerosis but do not show the commonly accepted major risk factors. This study investigated the hypothesis that ghee, a clarified butter product prized in Indian cooking, contains cholesterol oxides and could therefore be an important source of dietary exposure to cholesterol oxides and an explanation for the high atherosclerosis risk. Substantial amounts of cholesterol oxides were found in ghee (12.3% of sterols), but not in fresh butter, by thin-layer and high-performance-liquid chromatography. Dietary exposure to cholesterol oxides from ghee may offer a logical explanation for the high frequency of atherosclerotic complications in these Indian populations. |
nfcorpus-queries-PLAIN-1972 | null | quinine |
nfcorpus-corpus-MED-2793 | null | Biochemical basis of enhanced drug bioavailability by piperine: evidence that piperine is a potent inhibitor of drug metabolism.
Piperine, a major active component of black and long peppers, has been reported to enhance drug bioavailability. The present studies were aimed at understanding the interaction of piperine with enzymatic drug biotransforming reactions in hepatic tissue in vitro and in vivo. Piperine inhibited arylhydrocarbon hydroxylation, ethylmorphine-N-demethylation, 7-ethoxycoumarin-O-deethylation and 3-hydroxy-benzo(a)pyrene glucuronidation in rat postmitochondrial supernatant in vitro in a dose-dependent manner. Piperine inhibition of these reactions in postmitochondrial supernatant from 3-methylcholanthrene- and phenobarbital-treated rats was similar to the controls. Inhibition by piperine of arylhydrocarbon hydroxylase (AHH) from 3-methylcholanthrene-treated rats was comparable to that observed with 7,8-benzoflavone. Piperine caused noncompetitive inhibition of hepatic microsomal AHH from the untreated and 3-methylcholanthrene-treated rats with a Ki of 30 microM which was close to the apparent Km of AHH observed in the controls. Similarly, the kinetics of inhibition of ethylmorphine-N-demethylase from control rat liver microsomes exhibited noncompetitive inhibition with an apparent Km of 0.8 mM and Ki of 35 microM. These studies demonstrated that piperine is a nonspecific inhibitor of drug metabolism which shows little discrimination between different cytochrome P-450 forms. Oral administration of piperine in rats strongly inhibited the hepatic AHH and UDP-glucuronyltransferase activities. The maximal inhibition of AHH observed within 1 hr restored to normal value in 6 hr. Pretreatment with piperine prolonged hexobarbital sleeping time and zoxazolamine paralysis time in mice at half the dose of SKF-525A. These results demonstrate that piperine is a potent inhibitor of drug metabolism. |
nfcorpus-queries-PLAIN-1972 | null | quinine |
nfcorpus-corpus-MED-2794 | null | Dietary turmeric potentially reduces the risk of cancer.
Turmeric, a plant rhizome that is often dried, ground and used as a cooking spice, has also been used medicinally for several thousand years. Curcumin, the phytochemical that gives turmeric its golden color, is responsible for most of the therapeutic effects of turmeric. In recent years curcumin has been studied for its effects on chronic diseases such as diabetes, Alzheimer's, and cancer. Though many researchers are investigating turmeric/curcumin in cancer therapy, there is little epidemiologic information on the effects of turmeric consumption. With limited availability of pharmacologic interventions in many areas of the world, use of turmeric in the diet may help to alleviate some of the disease burden through prevention. Here we provide a brief overview of turmeric consumption in different parts of the world, cancer rates in those regions, possible biochemical mechanisms by which turmeric acts and practical recommendations based on the information available. |
nfcorpus-queries-PLAIN-1972 | null | quinine |
nfcorpus-corpus-MED-4390 | null | Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers.
The medicinal properties of curcumin obtained from Curcuma longa L. cannot be utilised because of poor bioavailability due to its rapid metabolism in the liver and intestinal wall. In this study, the effect of combining piperine, a known inhibitor of hepatic and intestinal glucuronidation, was evaluated on the bioavailability of curcumin in rats and healthy human volunteers. When curcumin was given alone, in the dose 2 g/kg to rats, moderate serum concentrations were achieved over a period of 4 h. Concomitant administration of piperine 20 mg/kg increased the serum concentration of curcumin for a short period of 1-2 h post drug. Time to maximum was significantly increased (P < 0.02) while elimination half life and clearance significantly decreased (P < 0.02), and the bioavailability was increased by 154%. On the other hand in humans after a dose of 2 g curcumin alone, serum levels were either undetectable or very low. Concomitant administration of piperine 20 mg produced much higher concentrations from 0.25 to 1 h post drug (P < 0.01 at 0.25 and 0.5 h; P < 0.001 at 1 h), the increase in bioavailability was 2000%. The study shows that in the dosages used, piperine enhances the serum concentration, extent of absorption and bioavailability of curcumin in both rats and humans with no adverse effects. |
nfcorpus-queries-PLAIN-1972 | null | quinine |
nfcorpus-corpus-MED-2800 | null | Curcumin: a new paradigm and therapeutic opportunity for the treatment of osteoarthritis: curcumin for osteoarthritis management
The management of osteoarthritis represents a real challenge. This complex and multi-factorial disease evolves over decades and requires not only the alleviation of symptoms, i.e. pain and joint function but also the preservation of articular structure without side effects. Nutraceuticals are good candidates for the management of OA due to their safety profile and potential efficacy. However, they are not part of the treatment guidelines and published recommendations. Curcumin is the yellow pigment isolated from the rhizomes of Curcuma longa, commonly known as turmeric. Curcumin is a highly pleiotropic molecule with an excellent safety profile. Strong molecular evidence has been published for its potency to target multiple inflammatory diseases. However, naturally occurring curcumin cannot achieve its optimum therapeutic outcomes due to its low solubility and poor bioavailability. Nevertheless, curcumin presents great potential for treating OA and has been categorized as having preclinical evidence of efficacy. This review aimed at gathering most of the available information to document the potential efficacy of curcumin based on the results obtained in in vitro models of cartilage and osteoarthritis and in other diseases. |
nfcorpus-queries-PLAIN-1972 | null | quinine |
nfcorpus-corpus-MED-2791 | null | Bioavailability of curcumin: problems and promises.
Curcumin, a polyphenolic compound derived from dietary spice turmeric, possesses diverse pharmacologic effects including anti-inflammatory, antioxidant, antiproliferative and antiangiogenic activities. Phase I clinical trials have shown that curcumin is safe even at high doses (12 g/day) in humans but exhibit poor bioavailability. Major reasons contributing to the low plasma and tissue levels of curcumin appear to be due to poor absorption, rapid metabolism, and rapid systemic elimination. To improve the bioavailability of curcumin, numerous approaches have been undertaken. These approaches involve, first, the use of adjuvant like piperine that interferes with glucuronidation; second, the use of liposomal curcumin; third, curcumin nanoparticles; fourth, the use of curcumin phospholipid complex; and fifth, the use of structural analogues of curcumin (e.g., EF-24). The latter has been reported to have a rapid absorption with a peak plasma half-life. Despite the lower bioavailability, therapeutic efficacy of curcumin against various human diseases, including cancer, cardiovascular diseases, diabetes, arthritis, neurological diseases and Crohn's disease, has been documented. Enhanced bioavailability of curcumin in the near future is likely to bring this promising natural product to the forefront of therapeutic agents for treatment of human disease. |
nfcorpus-queries-PLAIN-1972 | null | quinine |
nfcorpus-corpus-MED-2825 | null | Curcumin-free turmeric exhibits anti-inflammatory and anticancer activities: Identification of novel components of turmeric.
Turmeric, a dried powder derived from the rhizome of Curcuma longa, has been used for centuries in certain parts of the world and has been linked to numerous biological activities including antioxidant, anti-inflammatory, anticancer, antigrowth, anti-arthritic, anti-atherosclerotic, antidepressant, anti-aging, antidiabetic, antimicrobial, wound healing, and memory-enhancing activities. One component of turmeric is curcumin, which has been extensively studied, as indicated by more than 5600 citations, most of which have appeared within the past decade. Recent research has identified numerous chemical entities from turmeric other than curcumin. It is unclear whether all of the activities ascribed to turmeric are due to curcumin or whether other compounds in turmeric can manifest these activities uniquely, additively, or synergistically with curcumin. However, studies have indicated that turmeric oil, present in turmeric, can enhance the bioavailability of curcumin. Studies over the past decade have indicated that curcumin-free turmeric (CFT) components possess numerous biological activities including anti-inflammatory, anticancer, and antidiabetic activities. Elemene derived from turmeric is approved in China for the treatment of cancer. The current review focuses on the anticancer and anti-inflammatory activities exhibited by CFT and by some individual components of turmeric, including turmerin, turmerone, elemene, furanodiene, curdione, bisacurone, cyclocurcumin, calebin A, and germacrone. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. |
nfcorpus-queries-PLAIN-1972 | null | quinine |
nfcorpus-corpus-MED-4539 | null | Natural products as sources of new drugs over the last 25 years.
This review is an updated and expanded version of two prior reviews that were published in this journal in 1997 and 2003. In the case of all approved agents the time frame has been extended to include the 251/2 years from 01/1981 to 06/2006 for all diseases worldwide and from 1950 (earliest so far identified) to 06/2006 for all approved antitumor drugs worldwide. We have continued to utilize our secondary subdivision of a "natural product mimic" or "NM" to join the original primary divisions. From the data presented, the utility of natural products as sources of novel structures, but not necessarily the final drug entity, is still alive and well. Thus, in the area of cancer, over the time frame from around the 1940s to date, of the 155 small molecules, 73% are other than "S" (synthetic), with 47% actually being either natural products or directly derived therefrom. In other areas, the influence of natural product structures is quite marked, with, as expected from prior information, the antiinfective area being dependent on natural products and their structures. Although combinatorial chemistry techniques have succeeded as methods of optimizing structures and have, in fact, been used in the optimization of many recently approved agents, we are able to identify only one de novo combinatorial compound approved as a drug in this 25 plus year time frame. We wish to draw the attention of readers to the rapidly evolving recognition that a significant number of natural product drugs/leads are actually produced by microbes and/or microbial interactions with the "host from whence it was isolated", and therefore we consider that this area of natural product research should be expanded significantly. |
nfcorpus-queries-PLAIN-1972 | null | quinine |
nfcorpus-corpus-MED-4540 | null | Marked variability of monacolin levels in commercial red yeast rice products: buyer beware!
BACKGROUND: Red yeast rice (RYR) is a widely available dietary supplement used by millions of patients as an alternative therapy for hyperlipidemia. It contains 14 active compounds called monacolins that inhibit hepatic cholesterol synthesis. Although studies have suggested that some formulations of RYR may be effective and safe for lipid lowering, monacolin levels are not standardized among marketed products and are generally not published on labels. We evaluated monacolin levels in 12 commercial RYR formulations and tested for citrinin, a mycotoxin that is nephrotoxic in animals. METHODS: Each formulation of RYR was labeled "600 mg/capsule" of active product. Analyses for monacolins and citrinin were performed between August 2006 and June 2008 using high-performance liquid chromatography with mass spectroscopy-mass spectroscopy detection. Laboratory analyses of RYR products were conducted by ConsumerLab.com, White Plains, New York. RESULTS: There was marked variability in the 12 RYR products in total monacolins (0.31-11.15 mg/capsule), monacolin K (lovastatin) (0.10-10.09 mg/capsule), and monacolin KA (0.00-2.30 mg/capsule). Four products had elevated levels of citrinin. CONCLUSIONS: We found striking variability in monacolin content in 12 proprietary RYR products and the presence of citrinin in one-third of the formulations tested. Although RYR may have potential as an alternative lipid-lowering agent, our findings suggest the need for improved standardization of RYR products and product labeling. Until this occurs, physicians should be cautious in recommending RYR to their patients for the treatment of hyperlipidemia and primary and secondary prevention of cardiovascular disease. |
nfcorpus-queries-PLAIN-1972 | null | quinine |
nfcorpus-corpus-MED-4541 | null | Comparative cardiovascular effects of thiazolidinediones: systematic review and meta-analysis of observational studies
Objective To determine the comparative effects of the thiazolidinediones (rosiglitazone and pioglitazone) on myocardial infarction, congestive heart failure, and mortality in patients with type 2 diabetes. Design Systematic review and meta-analysis of observational studies. Data sources Searches of Medline and Embase in September 2010. Study selection Observational studies that directly compared the risk of cardiovascular outcomes for rosiglitazone and pioglitazone among patients with type 2 diabetes mellitus were included. Data extraction Random effects meta-analysis (inverse variance method) was used to calculate the odds ratios for cardiovascular outcomes with thiazolidinedione use. The I2 statistic was used to assess statistical heterogeneity. Results Cardiovascular outcomes from 16 observational studies (4 case-control studies and 12 retrospective cohort studies), including 810 000 thiazolidinedione users, were evaluated after a detailed review of 189 citations. Compared with pioglitazone, use of rosiglitazone was associated with a statistically significant increase in the odds of myocardial infarction (n=15 studies; odds ratio 1.16, 95% confidence interval 1.07 to 1.24; P<0.001; I2=46%), congestive heart failure (n=8; 1.22, 1.14 to 1.31; P<0.001; I2=37%), and death (n=8; 1.14, 1.09 to 1.20; P<0.001; I2=0%). Numbers needed to treat to harm (NNH), depending on the population at risk, suggest 170 excess myocardial infarctions, 649 excess cases of heart failure, and 431 excess deaths for every 100 000 patients who receive rosiglitazone rather than pioglitazone. Conclusion Among patients with type 2 diabetes, use of rosiglitazone is associated with significantly higher odds of congestive heart failure, myocardial infarction, and death relative to pioglitazone in real world settings. |
nfcorpus-queries-PLAIN-1972 | null | quinine |
nfcorpus-corpus-MED-2513 | null | Insights into the beneficial effect of caloric/ dietary restriction for a healthy and prolonged life
Over the last several years, new evidence has kept pouring in about the remarkable effect of caloric restriction (CR) on the conspicuous bedfellows- aging and cancer. Through the use of various animal models, it is now well established that by reducing calorie intake one can not only increase life span but, also, lower the risk of various age related diseases such as cancer. Cancer cells are believed to be more dependent on glycolysis for their energy requirements than normal cells and, therefore, can be easily targeted by alteration in the energy-metabolic pathways, a hallmark of CR. Apart from inhibiting the growth of transplantable tumors, CR has been also shown to inhibit the development of spontaneous, radiation, and chemically induced tumors. The question regarding the potentiality of the anti-tumor effect of CR in humans has been in part answered by the resistance of a cohort of women, who had suffered from anorexia in their early life, to breast cancer. However, human research on the beneficial effect of CR is still at an early stage and needs further validation. Though the complete mechanism of the anti-tumor effect of CR is far from clear, the plausible involvement of nutrient sensing pathways or IGF-1 pathways proposed for its anti-aging action cannot be overruled. In fact, cancer cell lines, mutant for proteins involved in IGF-1 pathways, failed to respond to CR. In addition, CR decreases the levels of many growth factors, anabolic hormones, inflammatory cytokines, and oxidative markers that are deregulated in several cancers. In this review, we discuss the anti-tumor effect of CR, describing experiments done in vitro in tumor models and in vivo in mouse models in which the tumor was induced by means of radiation or chemical exposure, expressing oncogenes or deleting tumor suppression genes. We also discuss the proposed mechanisms of CR anti-tumor action. Lastly, we argue the necessity of gene expression studies in cancerous versus normal cells upon CR. |
nfcorpus-queries-PLAIN-1983 | null | rapamycin |
nfcorpus-corpus-MED-2502 | null | Macronutrient balance and lifespan
Dietary restriction (DR) without malnutrition is widely regarded to be a universal mechanism for prolonging lifespan. It is generally believed that the benefits of DR arise from eating fewer calories (termed caloric restriction, CR). Here we argue that, rather than calories, the key determinant of the relationship between diet and longevity is the balance of protein to non-protein energy ingested. This ratio affects not only lifespan, but also total energy intake, metabolism, immunity and the likelihood of developing obesity and associated metabolic disorders. Among various possible mechanisms linking macronutrient balance to lifespan, the nexus between the TOR and AMPK signaling pathways is emerging as a central coordinator. |
nfcorpus-queries-PLAIN-1983 | null | rapamycin |
nfcorpus-corpus-MED-2498 | null | Dietary Restriction, Growth Factors and Aging: from yeast to humans
Dietary restriction (DR) and reduced growth factor signaling both elevate resistance to oxidative stress, reduce macromolecular damage, and increase lifespan in model organisms. In rodents, both DR and decreased growth factor signaling reduce the incidence of tumors and slow down cognitive decline and aging. DR reduces cancer and cardiovascular disease and mortality in monkeys, and reduces metabolic traits associated with diabetes, cardiovascular disease and cancer in humans. Neoplasias and diabetes are also rare in humans with loss of function mutations in the growth hormone receptor. DR and reduced growth factor signaling may thus slow aging by similar, evolutionarily conserved, mechanisms. We review these conserved anti-aging pathways in model organisms, discuss their link to disease prevention in mammals, and consider the negative side effects that might hinder interventions intended to extend healthy lifespan in humans. |
nfcorpus-queries-PLAIN-1983 | null | rapamycin |
nfcorpus-corpus-MED-2504 | null | Nutrient control of TORC1, a cell-cycle regulator.
It is well established that the target of rapamycin (TOR) protein kinase has pivotal roles in controlling cell functions (including protein synthesis, cell growth and cell proliferation) and is implicated in numerous human diseases. Mammalian TOR complex 1 (mTORC1) signalling is activated by hormones and growth factors, and is also stimulated by intracellular amino acids. Recent research has provided important new insight into the poorly understood mechanism by which amino acids activate mTORC1 signalling, showing that the protein kinase MAP4K3 and Rag GTPases have important roles in this. mTORC1 is known to control the G1/S transition of the cell cycle: new data show that (m)TORC1 also controls G2/M progression in yeast and mammals, albeit in contrasting ways. |
nfcorpus-queries-PLAIN-1983 | null | rapamycin |
nfcorpus-corpus-MED-2505 | null | Ten years of life: Is it a matter of choice?
BACKGROUND: Relative risk estimates suggest that effective implementation of behaviors commonly advocated in preventive medicine should increase life expectancy, although there is little direct evidence. OBJECTIVE: To test the hypothesis that choices regarding diet, exercise, and smoking influence life expectancy. METHODS: A total of 34 192 California Seventh-Day Adventists (75% of those eligible) were enrolled in a cohort and followed up from 1976 to 1988. A mailed questionnaire provided dietary and other exposure information at study baseline. Mortality for all subjects was ascertained by matching to state death tapes and the National Death Index. RESULTS: California Adventists have higher life expectancies at the age of 30 years than other white Californians by 7.28 years (95% confidence interval, 6.59-7.97 years) in men and by 4.42 years (95% confidence interval, 3.96-4.88 years) in women, giving them perhaps the highest life expectancy of any formally described population. Commonly observed combinations of diet, exercise, body mass index, past smoking habits, and hormone replacement therapy (in women) can account for differences of up to 10 years of life expectancy among Adventists. A comparison of life expectancy when these factors take high-risk compared with low-risk values shows independent effects that vary between 1.06 and 2.74 years for different variables. The effect of each variable is assessed with all others at either medium- or high-risk levels. CONCLUSIONS: Choices regarding diet, exercise, cigarette smoking, body weight, and hormone replacement therapy, in combination, appear to change life expectancy by many years. The longevity experience of Adventists probably demonstrates the beneficial effects of more optimal behaviors. |
nfcorpus-queries-PLAIN-1983 | null | rapamycin |
nfcorpus-corpus-MED-2507 | null | mTORC1 activity as a determinant of cancer risk--rationalizing the cancer-preventive effects of adiponectin, metformin, rapamycin, and low-protein ...
Increased plasma levels of adiponectin, metformin therapy of diabetes, rapamycin administration in transplant patients, and lifelong consumption of low-protein plant-based diets have all been linked to decreased risk for various cancers. These benefits may be mediated, at least in part, by down-regulated activity of the mTORC1 complex, a key regulator of protein translation. By boosting the effective availability of the translation initiator eIF4E, mTORC1 activity promotes the translation of a number of "weak" mRNAs that code for proteins, often up-regulated in cancer, that promote cellular proliferation, invasiveness, and angiogenesis, and that abet cancer promotion and chemoresistance by opposing apoptosis. Measures which inhibit eIF4E activity, either directly or indirectly, may have utility not only for cancer prevention, but also for the treatment of many cancers in which eIF4E drives malignancy. Since eIF4E is overexpressed in many cancers, strategies which target eIF4E directly--some of which are now being assessed clinically--may have the broadest efficacy in this regard. Many of the "weak" mRNAs coding for proteins that promote malignant behavior or chemoresistance are regulated transcriptionally by NF-kappaB and/or Stat3, which are active in a high proportion of cancers; thus, regimens concurrently targeting eIF4E, NF-kappaB, and Stat3 may suppress these proteins at both the transcriptional and translational levels, potentially achieving a very marked reduction in their expression. Copyright © 2011 Elsevier Ltd. All rights reserved. |
nfcorpus-queries-PLAIN-1983 | null | rapamycin |
nfcorpus-corpus-MED-5239 | null | Leucine signaling in the pathogenesis of type 2 diabetes and obesity
Epidemiological evidence points to increased dairy and meat consumption, staples of the Western diet, as major risk factors for the development of type 2 diabetes (T2D). This paper presents a new concept and comprehensive review of leucine-mediated cell signaling explaining the pathogenesis of T2D and obesity by leucine-induced over-stimulation of mammalian target of rapamycin complex 1 (mTORC1). mTORC1, a pivotal nutrient-sensitive kinase, promotes growth and cell proliferation in response to glucose, energy, growth factors and amino acids. Dairy proteins and meat stimulate insulin/insulin-like growth factor 1 signaling and provide high amounts of leucine, a primary and independent stimulator for mTORC1 activation. The downstream target of mTORC1, the kinase S6K1, induces insulin resistance by phosphorylation of insulin receptor substrate-1, thereby increasing the metabolic burden of β-cells. Moreover, leucine-mediated mTORC1-S6K1-signaling plays an important role in adipogenesis, thus increasing the risk of obesity-mediated insulin resistance. High consumption of leucine-rich proteins explains exaggerated mTORC1-dependent insulin secretion, increased β-cell growth and β-cell proliferation promoting an early onset of replicative β-cell senescence with subsequent β-cell apoptosis. Disturbances of β-cell mass regulation with increased β-cell proliferation and apoptosis as well as insulin resistance are hallmarks of T2D, which are all associated with hyperactivation of mTORC1. In contrast, the anti-diabetic drug metformin antagonizes leucine-mediated mTORC1 signaling. Plant-derived polyphenols and flavonoids are identified as natural inhibitors of mTORC1 and exert anti-diabetic and anti-obesity effects. Furthermore, bariatric surgery in obesity reduces increased plasma levels of leucine and other branched-chain amino acids. Attenuation of leucine-mediated mTORC1 signaling by defining appropriate upper limits of the daily intake of leucine-rich animal and dairy proteins may offer a great chance for the prevention of T2D and obesity, as well as other epidemic diseases of civilization with increased mTORC1 signaling, especially cancer and neurodegenerative diseases, which are frequently associated with T2D. |
nfcorpus-queries-PLAIN-1983 | null | rapamycin |
nfcorpus-corpus-MED-2509 | null | Amino acid sensing in dietary-restriction-mediated longevity: roles of signal-transducing kinases GCN2 and TOR
DR (dietary restriction), or reduced food intake without malnutrition, is associated with extended longevity, improved metabolic fitness and increased stress resistance in a wide range of organisms. DR is often referred to as calorie restriction, implying that reduced energy intake is responsible for its widespread and evolutionarily conserved benefits. However, recent data indicate dietary amino acid restriction as a key mediator of DR benefits. In fruitflies, an imbalance in essential amino acid intake is thought to underlie longevity benefits of DR. In mammals, reduced dietary protein or essential amino acid intake can extend longevity, improve metabolic fitness and increase stress resistance. In the present paper we review two evolutionarily conserved signal transduction pathways responsible for sensing amino acid levels. The eIF2α (eukaryotic initiation factor 2α) kinase GCN2 (general amino acid control non-derepressible 2) senses the absence of one or more amino acids by virtue of direct binding to uncharged cognate tRNAs. The presence of certain amino acids, such as leucine, permits activation of the master growth regulating kinase TOR (target of rapamycin). These two signal transduction pathways react to amino acid deprivation by inhibiting general protein translation while at the same time increasing translation of specific mRNAs involved in restoring homoeostasis. Together, these pathways may contribute to the regulation of longevity, metabolic fitness and stress resistance. |
nfcorpus-queries-PLAIN-1983 | null | rapamycin |
nfcorpus-corpus-MED-2519 | null | Caloric restriction in humans: potential pitfalls and health concerns.
To date, the only intervention that has consistently been shown to slow the rate of aging, and to increase mean and maximum lifespan in short-lived species, is life-long calorie restriction. It is yet unclear whether long-term calorie restriction in longer lived species (i.e. primates and humans) will have a similar effect. In humans, several studies investigating short-term calorie restriction or "weight loss" programs suggest beneficial outcomes on parameters of cardiovascular disease. Studies on long-term calorie restriction are performed on a self-selected group of human subjects and show similar effects. However, few studies are currently investigating the quality of life and potential pitfalls of long-term calorie restriction in humans. It is likely that some of the physiological and psychological effects of caloric restriction that occur in animals may impact the human life very differently. For certain, calorie restriction has a plethora of health benefits in mammals, such as a reduction in age-related diseases such as cancer. However, despite the "magic" of CR, this intervention in humans may present itself with a number of health concerns, which may not be applicable to or impact the life of experimental animals, but may do so in humans. These potential pitfalls and "side effects" are not clearly addressed in the literature and will be a focus of this review. |
nfcorpus-queries-PLAIN-1983 | null | rapamycin |
nfcorpus-corpus-MED-2510 | null | Comparative and meta-analytic insights into life extension via dietary restriction.
Dietary restriction (DR) extends the lifespan of a wide range of species, although the universality of this effect has never been quantitatively examined. Here, we report the first comprehensive comparative meta-analysis of DR across studies and species. Overall, DR significantly increased lifespan, but this effect is modulated by several factors. In general, DR has less effect in extending lifespan in males and also in non-model organisms. Surprisingly, the proportion of protein intake was more important for life extension via DR than the degree of caloric restriction. Furthermore, we show that reduction in both age-dependent and age-independent mortality rates drives life extension by DR among the well-studied laboratory model species (yeast, nematode worms, fruit flies and rodents). Our results suggest that convergent adaptation to laboratory conditions better explains the observed DR-longevity relationship than evolutionary conservation although alternative explanations are possible. © 2012 The Authors. Aging Cell © 2012 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland. |
nfcorpus-queries-PLAIN-1983 | null | rapamycin |
nfcorpus-corpus-MED-2511 | null | The Okinawan diet: health implications of a low-calorie, nutrient-dense, antioxidant-rich dietary pattern low in glycemic load.
Residents of Okinawa, the southernmost prefecture of Japan, are known for their long average life expectancy, high numbers of centenarians, and accompanying low risk of age-associated diseases. Much of the longevity advantage in Okinawa is thought to be related to a healthy lifestyle, particularly the traditional diet, which is low in calories yet nutritionally dense, especially with regard to phytonutrients in the form of antioxidants and flavonoids. Research suggests that diets associated with a reduced risk of chronic diseases are similar to the traditional Okinawan diet, that is, vegetable and fruit heavy (therefore phytonutrient and antioxidant rich) but reduced in meat, refined grains, saturated fat, sugar, salt, and full-fat dairy products. Many of the characteristics of the diet in Okinawa are shared with other healthy dietary patterns, such as the traditional Mediterranean diet or the modern DASH (Dietary Approaches to Stop Hypertension) diet. Features such as the low levels of saturated fat, high antioxidant intake, and low glycemic load in these diets are likely contributing to a decreased risk for cardiovascular disease, some cancers, and other chronic diseases through multiple mechanisms, including reduced oxidative stress. A comparison of the nutrient profiles of the three dietary patterns shows that the traditional Okinawan diet is the lowest in fat intake, particularly in terms of saturated fat, and highest in carbohydrate intake, in keeping with the very high intake of antioxidant-rich yet calorie-poor orange-yellow root vegetables, such as sweet potatoes, and green leafy vegetables. Deeper analyses of the individual components of the Okinawan diet reveal that many of the traditional foods, herbs, or spices consumed on a regular basis could be labeled "functional foods" and, indeed, are currently being explored for their potential health-enhancing properties. |
nfcorpus-queries-PLAIN-1983 | null | rapamycin |
nfcorpus-corpus-MED-5237 | null | mTOR: from growth signal integration to cancer, diabetes and ageing
Preface In all eukaryotes, the target of rapamycin (TOR) signaling pathway couples energy and nutrient abundance to the execution of cell growth and division, owing to the ability of TOR protein kinase to simultaneously sense energy, nutrients and stress, and, in metazoan, growth factors. Mammalian TOR complexes 1 and 2 (mTORC1 and mTORC2) exert their actions by regulating other important kinases, such as S6K and Akt. In the last few years, a significant advance in our understanding of the regulation and functions of mTOR has revealed its critical involvement in the onset and progression of diabetes, cancer and ageing. |
nfcorpus-queries-PLAIN-1983 | null | rapamycin |
nfcorpus-corpus-MED-2517 | null | mTOR is a key modulator of ageing and age-related disease
Many experts in the biology of ageing believe that pharmacological interventions to slow ageing are a matter of ‘when’ rather than ‘if’. A leading target for such interventions is the nutrient response pathway defined by the mechanistic target of rapamycin (mTOR). Inhibition of this pathway extends lifespan in model organisms and confers protection against a growing list of age-related pathologies. Characterized inhibitors of this pathway are already clinically approved, and others are under development. Although adverse side effects currently preclude use in otherwise healthy individuals, drugs that target the mTOR pathway could one day become widely used to slow ageing and reduce age-related pathologies in humans. |
nfcorpus-queries-PLAIN-1983 | null | rapamycin |
nfcorpus-corpus-MED-2518 | null | Aging is not programmed
Aging is not and cannot be programmed. Instead, aging is a continuation of developmental growth, driven by genetic pathways such as mTOR. Ironically, this is often misunderstood as a sort of programmed aging. In contrast, aging is a purposeless quasi-program or, figuratively, a shadow of actual programs. “The brightest flame casts the darkest shadow.” -George Martin |
nfcorpus-queries-PLAIN-1983 | null | rapamycin |
nfcorpus-corpus-MED-2520 | null | TOR-driven aging: speeding car without brakes.
This article discusses that the traditional analogy of an aging organism with a rusting (albeit self-repairing) car is misleading. The true analogy is a speeding car that enters a low-speed zone and damages itself because it does not and cannot slow down. For such a car without brakes (and actually without a driver), aging from rusting never occurs. Using simple analogies (although turning gerontology upside down), this article discusses the origin of aging, how overactivation of the mTOR (Target of Rapamycin) pathway causes aging, why aging causes damage (organ damage) not damage causes aging, the link between aging and age-related diseases, slow aging versus aging tolerance and suppression of aging with rapamycin. |
nfcorpus-queries-PLAIN-1983 | null | rapamycin |
nfcorpus-corpus-MED-2521 | null | Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle.
A streptomycete was isolated from an Easter Island soil sample and found to inhibit Candida albicans, Microsporum gypseum and Trichophyton granulosum. The antibiotic-producing microorganism was characterized and identified as Streptomyces hygroscopicus. The antifungal principle was extracted with organic solvent from the mycelium, isolated in crystalline form and named rapamycin. Rapamycin is mainly active against Candida albicans; minimum inhibitory concentration against ten strains ranged from 0.02 to 0.2 mug/ml. Its apparent activity against Microsporum gypseum and Trichophyton granulosum is lower because of its instability in culture media on prolonged incubation required by these fungi. No activity was observed against gram-positive and gram-negative bacteria. Acute toxicity in mice is low. |
nfcorpus-queries-PLAIN-1983 | null | rapamycin |
nfcorpus-corpus-MED-2127 | null | Nutrient Signaling to mTOR and Cell Growth
The mammalian target of rapamycin (mTOR) is a conserved protein kinase involved in a multitude of cellular processes including cell growth. Increased mTOR activation is observed in multiple human cancers and inhibition of mTOR has proven efficacious in numerous clinical trials. mTOR comprises two complexes, termed mTORC1 and mTORC2. Both complexes respond to growth factors, whereas only mTORC1 is controlled by nutrients, such as glucose and amino acids. Since the discovery of mTOR, extensive studies have intricately detailed the molecular mechanisms by which mTORC1 is regulated. Somewhat paradoxically, amino acid induced mTORC1 activation—arguably the most essential stimulus leading to mTORC1 activation—is the least understood. Here we review the current knowledge of nutrient dependent regulation of mTORC1. |
nfcorpus-queries-PLAIN-1983 | null | rapamycin |
nfcorpus-corpus-MED-2128 | null | Sirolimus for Kaposi's sarcoma in renal-transplant recipients.
BACKGROUND: Recipients of organ transplants are susceptible to Kaposi's sarcoma as a result of treatment with immunosuppressive drugs. Sirolimus (rapamycin), an immunosuppressive drug, may also have antitumor effects. METHODS: We stopped cyclosporine therapy in 15 kidney-transplant recipients who had biopsy-proven Kaposi's sarcoma and began sirolimus therapy. All patients underwent an excisional biopsy of the lesion and one biopsy of normal skin at the time of diagnosis. A second biopsy was performed at the site of a previous Kaposi's sarcoma lesion six months after sirolimus therapy was begun. We examined biopsy specimens for vascular endothelial growth factor (VEGF), Flk-1/KDR protein, and phosphorylated Akt and p70S6 kinase, two enzymes in the signaling pathway targeted by sirolimus. RESULTS: Three months after sirolimus therapy was begun, all cutaneous Kaposi's sarcoma lesions had disappeared in all patients. Remission was confirmed histologically in all patients six months after sirolimus therapy was begun. There were no acute episodes of rejection or changes in kidney-graft function. Levels of Flk-1/KDR and phosphorylated Akt and p70S6 kinase were increased in Kaposi's sarcoma cells. The expression of VEGF was increased in Kaposi's sarcoma cells and even more so in normal skin cells around the Kaposi's sarcoma lesions. CONCLUSIONS: Sirolimus inhibits the progression of dermal Kaposi's sarcoma in kidney-transplant recipients while providing effective immunosuppression. Copyright 2005 Massachusetts Medical Society. |
nfcorpus-queries-PLAIN-1983 | null | rapamycin |
nfcorpus-corpus-MED-2129 | null | Amino acid sensing mechanisms: an Achilles heel in cancer?
The act of increasing mass, either in non-dividing cells or in dividing cells seeking to provide new material for daughter cells, depends upon the continued presence of extracellular nutrients in order to conserve mass. For amino acid nutrients, it appears that their insufficiency for new protein synthesis is actively monitored by both prokaryotic and eukaryotic cells, eliciting appropriate cellular responses that may depend not only on bulk nutrient supply, but also on the abundance of specific amino acids. © 2012 The Author Journal compilation © 2012 FEBS. |
nfcorpus-queries-PLAIN-1983 | null | rapamycin |
nfcorpus-corpus-MED-2130 | null | Deconvoluting mTOR biology
In metazoans, TOR is an essential protein that functions as a master regulator of cellular growth and proliferation. Over the past decade, there has been an explosion of information about this critical master kinase, ranging from the composition of the TOR protein complex to its ability to act as an integrator of numerous extracellular signals. Unfortunately, this plethora of information has also raised numerous questions regarding TOR function. Currently, the prevailing view is that mammalian TOR (mTOR) exists in at least two molecular complexes, mTORC1 and mTORC2, which are largely defined by the presence of either RAPTOR or RICTOR. However, additional co-factors have been identified for each complex, and their importance in mediating mTOR signals has been incompletely elucidated. Similarly, there are differences in mTOR function that reflect the tissue of origin. In this review, we present an alternative view to mTOR complex formation and function, which envisions mTOR regulation and signal propagation as a reflection of cell type- and basal state-dependent conditions. The re-interpretation of mTOR biology in this framework may facilitate the design of therapies most likely to effectively inhibit this central regulator of cell behavior. |
nfcorpus-queries-PLAIN-1983 | null | rapamycin |
nfcorpus-corpus-MED-2132 | null | mTORC1 signaling: what we still don't know.
The mammalian target of rapamycin (mTOR) is a protein kinase that plays key roles in cellular regulation. It forms complexes with additional proteins. The best-understood one is mTOR complex 1 (mTORC1). The regulation and cellular functions of mTORC1 have been the subjects of intense study; despite this, many questions remain to be answered. They include questions about the actual mechanisms by which mTORC1 signaling is stimulated by hormones and growth factors, which involves the small GTPase Rheb, and by amino acids, which involves other GTPase proteins. The control of Rheb and the mechanism by which it activates mTORC1 remain incompletely understood. Although it has been known for many years that rapamycin interferes with some functions of mTORC1, it is not known how it does this, or why only some functions of mTORC1 are affected. mTORC1 regulates diverse cellular functions. Several mTORC1 substrates are now known, although in several cases their physiological roles are poorly or incompletely understood. In the case of several processes, although it is clear that they are regulated by mTORC1, it is not known how mTORC1 does this. Lastly, mTORC1 is implicated in ageing, but again it is unclear what mechanisms account for this. Given the importance of mTORC1 signaling both for cellular functions and in human disease, it is a high priority to gain further insights into the control of mTORC1 signaling and the mechanisms by which it controls cellular functions and animal physiology. |
nfcorpus-queries-PLAIN-1983 | null | rapamycin |
nfcorpus-corpus-MED-2134 | null | mTOR and cancer therapy.
Proteins regulating the mammalian target of rapamycin (mTOR), as well as some of the targets of the mTOR kinase, are overexpressed or mutated in cancer. Rapamycin, the naturally occurring inhibitor of mTOR, along with a number of recently developed rapamycin analogs (rapalogs) consisting of synthetically derived compounds containing minor chemical modifications to the parent structure, inhibit the growth of cell lines derived from multiple tumor types in vitro, and tumor models in vivo. Results from clinical trials indicate that the rapalogs may be useful for the treatment of subsets of certain types of cancer. The sporadic responses from the initial clinical trials, based on the hypothesis of general translation inhibition of cancer cells are now beginning to be understood owing to a more complete understanding of the dynamics of mTOR regulation and the function of mTOR in the tumor microenvironment. This review will summarize the preclinical and clinical data and recent discoveries of the function of mTOR in cancer and growth regulation. |
nfcorpus-queries-PLAIN-1983 | null | rapamycin |
nfcorpus-corpus-MED-2135 | null | Fisetin regulates obesity by targeting mTORC1 signaling.
Fisetin, a flavonol present in vegetables and fruits, possesses antioxidative and anti-inflammatory properties. In this study, we have demonstrated that fisetin prevents diet-induced obesity through regulation of the signaling of mammalian target of rapamycin complex 1 (mTORC1), a central mediator of cellular growth, cellular proliferation and lipid biosynthesis. To evaluate whether fisetin regulates mTORC1 signaling, we investigated the phosphorylation and kinase activity of the 70-kDa ribosomal protein S6 kinase 1 (S6K1) and mTORC1 in 3T3-L1 preadipocytes. Fisetin treatment of preadipocytes reduced the phosphorylation of S6K1 and mTORC1 in a time- and concentration-dependent manner. To further our understanding of how fisetin negatively regulates mTORC1 signaling, we analyzed the phosphorylation of S6K1, mTOR and Akt in fisetin-treated TSC2-knockdown cells. The results suggested that fisetin treatment inhibits mTORC1 activity in an Akt-dependent manner. Recent studies have shown that adipocyte differentiation is dependent on mTORC1 activity. Fisetin treatment inhibited adipocyte differentiation, consistent with the negative effect of fisetin on mTOR. The inhibitory effect of fisetin on adipogenesis is dependent of mTOR activity, suggesting that fisetin inhibits adipogenesis and the accumulation of intracellular triglycerides during adipocyte differentiation by targeting mTORC1 signaling. Fisetin supplementation in mice fed a high-fat diet (HFD) significantly attenuated HFD-induced increases in body weight and white adipose tissue. We also observed that fisetin efficiently suppressed the phosphorylation of Akt, S6K1 and mTORC1 in adipose tissue. Collectively, these results suggest that inhibition of mTORC1 signaling by fisetin prevents adipocyte differentiation of 3T3-L1 preadipocytes and obesity in HFD-fed mice. Therefore, fisetin may be a useful phytochemical agent for attenuating diet-induced obesity. Copyright © 2013 Elsevier Inc. All rights reserved. |
nfcorpus-queries-PLAIN-1983 | null | rapamycin |
nfcorpus-corpus-MED-2136 | null | The impact of cow's milk-mediated mTORC1-signaling in the initiation and progression of prostate cancer
Prostate cancer (PCa) is dependent on androgen receptor signaling and aberrations of the PI3K-Akt-mTORC1 pathway mediating excessive and sustained growth signaling. The nutrient-sensitive kinase mTORC1 is upregulated in nearly 100% of advanced human PCas. Oncogenic mTORC1 signaling activates key subsets of mRNAs that cooperate in distinct steps of PCa initiation and progression. Epidemiological evidence points to increased dairy protein consumption as a major dietary risk factor for the development of PCa. mTORC1 is a master regulator of protein synthesis, lipid synthesis and autophagy pathways that couple nutrient sensing to cell growth and cancer. This review provides evidence that PCa initiation and progression are promoted by cow´s milk, but not human milk, stimulation of mTORC1 signaling. Mammalian milk is presented as an endocrine signaling system, which activates mTORC1, promotes cell growth and proliferation and suppresses autophagy. Naturally, milk-mediated mTORC1 signaling is restricted only to the postnatal growth phase of mammals. However, persistent consumption of cow´s milk proteins in humans provide highly insulinotropic branched-chain amino acids (BCAAs) provided by milk´s fast hydrolysable whey proteins, which elevate postprandial plasma insulin levels, and increase hepatic IGF-1 plasma concentrations by casein-derived amino acids. BCAAs, insulin and IGF-1 are pivotal activating signals of mTORC1. Increased cow´s milk protein-mediated mTORC1 signaling along with constant exposure to commercial cow´s milk estrogens derived from pregnant cows may explain the observed association between high dairy consumption and increased risk of PCa in Westernized societies. As well-balanced mTORC1-signaling plays an important role in appropriate prostate morphogenesis and differentiation, exaggerated mTORC1-signaling by high cow´s milk consumption predominantly during critical growth phases of prostate development and differentiation may exert long-term adverse effects on prostate health. Attenuation of mTORC1 signaling by contemporary Paleolithic diets and restriction of dairy protein intake, especially during mTORC1-dependent phases of prostate development and differentiation, may offer protection from the most common dairy-promoted cancer in men of Western societies. |
nfcorpus-queries-PLAIN-1983 | null | rapamycin |
nfcorpus-corpus-MED-2137 | null | Rapalogs in cancer prevention
Common cancer is an age-related disease. Slow aging is associated with reduced and delayed carcinogenesis. Calorie restriction (CR), the most studied anti-aging intervention, prevents cancer by slowing down the aging process. Evidence is emerging that CR decelerates aging by deactivating MTOR (Target of Rapamycin). Rapamycin and other rapalogs suppress cellular senescence, slow down aging and postpone age-related diseases including cancer. At the same time, rapalogs are approved for certain cancer treatments. Can cancer prevention be explained by direct targeting of cancer cells? Or does rapamycin prevent cancer indirectly through slowing down the aging process? Increasing evidence points to the latter scenario. |
nfcorpus-queries-PLAIN-1983 | null | rapamycin |
nfcorpus-corpus-MED-2138 | null | Caloric restriction and incidence of breast cancer.
CONTEXT: Restricting caloric intake is one of the most effective ways to extend lifespan and to reduce spontaneous tumor occurrence in experimental animals, but whether similar associations hold in humans has not been appropriately studied. OBJECTIVE: To determine whether caloric restriction in early life reduces the risk of invasive breast cancer. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study using data from the Swedish Inpatient Registry, the Swedish Cancer Registry, the Swedish Death Registry, and the Swedish Fertility Registry. Participants were 7303 Swedish women hospitalized for anorexia nervosa prior to age 40 years between 1965 and 1998. Women were excluded (n = 31) if they were diagnosed with cancer prior to their first discharge from hospitalization for anorexia nervosa. MAIN OUTCOME MEASURE: Incidence of invasive breast cancer. RESULTS: Compared with the Swedish general population, women hospitalized for anorexia nervosa prior to age 40 years had a 53% (95% confidence interval [CI], 3%-81%) lower incidence of breast cancer; nulliparous women with anorexia nervosa had a 23% (95% CI, 79% higher to 75% lower) lower incidence, and parous women with anorexia nervosa had a 76% (95% CI, 13%-97%) lower incidence. CONCLUSIONS: Severe caloric restriction in humans may confer protection from invasive breast cancer. Low caloric intake prior to first birth followed by a subsequent pregnancy appears to be associated with an even more pronounced reduction in risk. |
nfcorpus-queries-PLAIN-1983 | null | rapamycin |
nfcorpus-corpus-MED-2139 | null | Prognostic and therapeutic implications of mTORC1 and Rictor expression in human breast cancer.
The mammalian target of rapamycin (mTOR) plays a key role in the regulation of cellular metabolism, growth and proliferation. It forms two multi-protein complexes known as complex 1 (mTORC1) and 2 (mTORC2). Raptor and Rictor are the core proteins for mTORC1 and mTORC2, respectively. This study examines the relationship between mTORC1, Rictor and Raptor mRNA expression and human breast cancer. Furthermore, the correlation between mTORC1 and hTERT was investigated. Breast cancer tissues (n=150) and normal tissues (n=31) were analysed using reverse transcription and quantitative PCR. Transcript levels were correlated with clinicopathological data. Higher mTOR expression was noted in breast cancer tissue (P=0.0018), higher grade tumours (grade 2 vs. 3, P=0.047), in ductal tumours (P=0.0014), and was associated with worse overall survival (P=0.01). Rictor expression was significantly higher in background breast tissues compared with tumours and was inversely related to the Nottingham Prognostic Index (NPI1 vs. 2, P=0.03) and tumour grade (grade 1 vs. 3, P=0.01) and was associated with better overall (P=0.037) and disease-free survival (P=0.048). The mRNA expression of Raptor was higher in tumours compared with normal tissues. Furthermore, the expression of Raptor was associated with a higher tumour grade (grade 1 vs. 3, P=0.027). A highly significant positive correlation between mTOR and hTERT (P<0.00001) was observed. These observations are consistent with the role of mTORC1 in the anti-apoptosis pathway and suggest that selective inhibitors of mTORC1 may be more efficacious in human breast cancer. Our findings support the hypothesis that mTORC1 is an important upregulator of telomerase in breast cancer. |
nfcorpus-queries-PLAIN-1983 | null | rapamycin |
nfcorpus-corpus-MED-2501 | null | Amino acid sensing and regulation of mTORC1.
Amino acids play fundamental roles in the cell both as the building blocks of new proteins and as metabolic precursors. To adapt to their limitation during periods of protein starvation, multiple adaptive mechanisms have evolved, including a rapid cessation of new protein synthesis, an increase in amino acid biosynthesis and transport, and autophagy. Here, we discuss what we currently know about how amino acid limitation is sensed, and how this sensing might be transmitted to mTORC1 to regulate protein synthesis and autophagy. Copyright © 2012 Elsevier Ltd. All rights reserved. |
nfcorpus-queries-PLAIN-1983 | null | rapamycin |
nfcorpus-corpus-MED-2506 | null | Caloric restriction, the traditional Okinawan diet, and healthy aging: the diet of the world's longest-lived people and its potential impact on mor...
Long-term caloric restriction (CR) is a robust means of reducing age-related diseases and extending life span in multiple species, but the effects in humans are unknown. The low caloric intake, long life expectancy, and the high prevalence of centenarians in Okinawa have been used as an argument to support the CR hypothesis in humans. However, no long-term, epidemiologic analysis has been conducted on traditional dietary patterns, energy balance, and potential CR phenotypes for the specific cohort of Okinawans who are purported to have had a calorically restricted diet. Nor has this cohort's subsequent mortality experience been rigorously studied. Therefore, we investigated six decades of archived population data on the elderly cohort of Okinawans (aged 65-plus) for evidence of CR. Analyses included traditional diet composition, energy intake, energy expenditure, anthropometry, plasma DHEA, mortality from age-related diseases, and current survival patterns. Findings include low caloric intake and negative energy balance at younger ages, little weight gain with age, life-long low BMI, relatively high plasma DHEA levels at older ages, low risk for mortality from age-related diseases, and survival patterns consistent with extended mean and maximum life span. This study lends epidemiologic support for phenotypic benefits of CR in humans and is consistent with the well-known literature on animals with regard to CR phenotypes and healthy aging. |
nfcorpus-queries-PLAIN-1983 | null | rapamycin |
nfcorpus-corpus-MED-2512 | null | Extending healthy ageing: nutrient sensitive pathway and centenarian population
Ageing is a challenge for any living organism and human longevity is a complex phenotype. With increasing life expectancy, maintaining long-term health, functionality and well-being during ageing has become an essential goal. To increase our understanding of how ageing works, it may be advantageous to analyze the phenotype of centenarians, perhaps one of the best examples of successful ageing. Healthy ageing involves the interaction between genes, the environment, and lifestyle factors, particularly diet. Besides evaluating specific gene-environment interactions in relation to exceptional longevity, it is important to focus attention on modifiable lifestyle factors such as diet and nutrition to achieve extension of health span. Furthermore, a better understanding of human longevity may assist in the design of strategies to extend the duration of optimal human health. In this article we briefly discuss relevant topics on ageing and longevity with particular focus on dietary patterns of centenarians and nutrient-sensing pathways that have a pivotal role in the regulation of life span. Finally, we also discuss the potential role of Nrf2 system in the pro-ageing signaling emphasizing its phytohormetic activation. |
nfcorpus-queries-PLAIN-1983 | null | rapamycin |
nfcorpus-corpus-MED-2514 | null | Why human lifespan is rapidly increasing: solving "longevity riddle" with "revealed-slow-aging" hypothesis
Healthy life span is rapidly increasing and human aging seems to be postponed. As recently exclaimed in Nature, these findings are so perplexing that they can be dubbed the 'longevity riddle'. To explain current increase in longevity, I discuss that certain genetic variants such as hyper-active mTOR (mTarget of Rapamycin) may increase survival early in life at the expense of accelerated aging. In other words, robustness and fast aging may be associated and slow-aging individuals died prematurely in the past. Therefore, until recently, mostly fast-aging individuals managed to survive into old age. The progress of civilization (especially 60 years ago) allowed slow-aging individuals to survive until old age, emerging as healthy centenarians now. I discuss why slow aging is manifested as postponed (healthy) aging, why the rate of deterioration is independent from aging and also entertain hypothetical use of rapamycin in different eras as well as the future of human longevity. |
nfcorpus-queries-PLAIN-1983 | null | rapamycin |
nfcorpus-corpus-MED-2943 | null | Long-term low-calorie low-protein vegan diet and endurance exercise are associated with low cardiometabolic risk.
BACKGROUND: Western diets, which typically contain large amounts of energy-dense processed foods, together with a sedentary lifestyle are associated with increased cardiometabolic risk. We evaluated the long-term effects of consuming a low-calorie low-protein vegan diet or performing regular endurance exercise on cardiometabolic risk factors. METHODS: In this cross-sectional study, cardiometabolic risk factors were evaluated in 21 sedentary subjects, who had been on a low-calorie low-protein raw vegan diet for 4.4 +/- 2.8 years, (mean age, 53.1 +/- 11 yrs), 21 body mass index (BMI)-matched endurance runners consuming Western diets, and 21 age- and gender-matched sedentary subjects, consuming Western diets. RESULTS: BMI was lower in the low-calorie low-protein vegan diet (21.3 +/- 3.1 kg/m(2)) and endurance runner (21.1 +/- 1.6 kg/m(2)) groups than in the sedentary Western diet group (26.5 +/- 2.7 kg/m(2)) (p < 0.005). Plasma concentrations of lipids, lipoproteins, glucose, insulin, C-reactive protein, blood pressure (BP), and carotid artery intima-media thickness were lower in the low-calorie low-protein vegan diet and runner groups than in the Western diet group (all p < 0.05). Both systolic and diastolic BP were lower in the low-calorie low-protein vegan diet group (104 +/- 15 and 62 +/- 11 mm Hg) than in BMI-matched endurance runners (122 +/- 13 and 72 +/- 9 mmHg) and Western diet group (132 +/- 14 and 79 +/- 8 mm Hg) (p < 0.001); BP values were directly associated with sodium intake and inversely associated with potassium and fiber intake. CONCLUSIONS: Long-term consumption of a low-calorie low-protein vegan diet or regular endurance exercise training is associated with low cardiometabolic risk. Moreover, our data suggest that specific components of a low-calorie low-protein vegan diet provide additional beneficial effects on blood pressure. |
nfcorpus-queries-PLAIN-1983 | null | rapamycin |
nfcorpus-corpus-MED-3918 | null | Herbal infusions as a source of calcium, magnesium, iron, zinc and copper in human nutrition.
The study material consisted of five herbs: chamomile (flowers), mint (leaves), St John's wort (flowers and leaves), sage (leaves) and nettle (leaves), sourced from three producers. The calcium, magnesium, iron, zinc and copper contents were determined for both dried herb samples and prepared infusions, and the extraction rates were calculated. Mineral components were determined using atomic absorption spectrometry. Analysis showed that the contents of individual elements in herbs and infusions depended on the type of raw material, as well as on its origin. Moreover, it was found that iron penetrated the herbal infusions to the lowest degree (4.4-12.4%), while copper did so to the highest (26.7-50.7%). It is felt that in average consumption the herbal infusions are not important as calcium, magnesium, iron, zinc and copper sources in human nutrition. |
nfcorpus-queries-PLAIN-1995 | null | red tea |
nfcorpus-corpus-MED-3919 | null | The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end pro...
The steroid hormone output of the adrenal gland is crucial in the maintenance of hormonal homeostasis, with hormonal imbalances being associated with numerous clinical conditions which include, amongst others, hypertension, metabolic syndrome, cardiovascular disease, insulin resistance and type 2 diabetes. Aspalathus linearis (Rooibos), which has been reported to aid stress-related symptoms linked to metabolic diseases, contains a wide spectrum of bioactive phenolic compounds of which aspalathin is unique. In this study the inhibitory effects of Rooibos and the dihydrochalcones, aspalathin and nothofagin, were investigated on adrenal steroidogenesis. The activities of both cytochrome P450 17α-hydroxylase/17,20 lyase and cytochrome P450 21-hydroxylase were significantly inhibited in COS-1 cells. In order to study the effect of these compounds in H295R cells, a human adrenal carcinoma cell line, a novel UPLC-MS/MS method was developed for the detection and quantification of twenty-one steroid metabolites using a single chromatographic separation. Under both basal and forskolin-stimulated conditions, the total amount of steroids produced in H295R cells significantly decreased in the presence of Rooibos, aspalathin and nothofagin. Under stimulated conditions, Rooibos decreased the total steroid output 4-fold and resulted in a significant reduction of aldosterone and cortisol precursors. Dehydroepiandrosterone-sulfate levels were unchanged, while the levels of androstenedione (A4) and 11β-hydroxyandrostenedione (11βOH-A4) were inhibited 5.5 and 2.3-fold, respectively. Quantification of 11βOH-A4 showed this metabolite to be a major product of steroidogenesis in H295R cells and we confirm, for the first time, that this steroid metabolite is the product of the hydroxylation of A4 by human cytochrome P450 11β-hydroxylase. Taken together our results demonstrate that Rooibos, aspalathin and nothofagin influence steroid hormone biosynthesis and the flux through the mineralocorticoid, glucocorticoid and androgen pathways, thus possibly contributing to the alleviation of negative effects arising from elevated glucocorticoid levels. Copyright © 2011 Elsevier Ltd. All rights reserved. |
nfcorpus-queries-PLAIN-1995 | null | red tea |
nfcorpus-corpus-MED-3920 | null | Acute neurocognitive effects of epigallocatechin gallate (EGCG).
Green tea is reported to have wide ranging beneficial health outcomes across epidemiological studies, which have been attributed to its flavonoid content. We investigated whether the flavonoid epigallocatechin gallate (EGCG) modulates brain activity and self-reported mood in a double-blind, placebo controlled crossover study. Participants completed baseline assessments of cognitive and cardiovascular functioning, mood and a resting state electroencephalogram (EEG) before and then 120 min following administration of 300 mg EGCG or matched placebo. EGCG administration was associated with a significant overall increase in alpha, beta and theta activity, also reflected in overall EEG activity, more dominant in midline frontal and central regions, specifically in the frontal gyrus and medial frontal gyrus. In comparison to placebo the EGCG treatment also increased self-rated calmness and reduced self rated stress. This pattern of results suggests that participants in the EGCG condition may have been in a more relaxed and attentive state after consuming EGCG. This is in keeping with the widespread consumption of green tea for its purported relaxing/refreshing properties. The modulation of brain function due to EGCG is deserving of further controlled human studies. Copyright © 2011 Elsevier Ltd. All rights reserved. |
nfcorpus-queries-PLAIN-1995 | null | red tea |
nfcorpus-corpus-MED-3921 | null | Consumption of Hibiscus sabdariffa L. aqueous extract and its impact on systemic antioxidant potential in healthy subjects.
BACKGROUND: To evaluate health benefits attributed to Hibiscus sabdariffa L. a randomized, open-label, two-way crossover study was undertaken to compare the impact of an aqueous H. sabdariffa L. extract (HSE) on the systemic antioxidant potential (AOP; assayed by ferric reducing antioxidant power (FRAP)) with a reference treatment (water) in eight healthy volunteers. The biokinetic variables were the areas under the curve (AUC) of plasma FRAP, ascorbic acid and urate that are above the pre-dose concentration, and the amounts excreted into urine within 24 h (Ae(0-24) ) of antioxidants as assayed by FRAP, ascorbic acid, uric acid, malondialdehyde (biomarker for oxidative stress), and hippuric acid (metabolite and potential biomarker for total polyphenol intake). RESULTS: HSE caused significantly higher plasma AUC of FRAP, an increase in Ae(0-24) of FRAP, ascorbic acid and hippuric acid, whereas malondialdehyde excretion was reduced. Furthermore, the main hibiscus anthocyanins as well as one glucuronide conjugate could be quantified in the volunteers' urine (0.02% of the administered dose). CONCLUSION: The aqueous HSE investigated in this study enhanced the systemic AOP and reduced the oxidative stress in humans. Furthermore, the increased urinary hippuric acid excretion after HSE consumption indicates a high biotransformation of the ingested HSE polyphenols, most likely caused by the colonic microbiota. Copyright © 2012 Society of Chemical Industry. |
nfcorpus-queries-PLAIN-1995 | null | red tea |
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