Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Focus upon therapeutic strategies that intersect between pathways that govern cellular metabolism and cellular survival may offer the greatest impact for the treatment of a number of neurodegenerative and metabolic disorders, such as diabetes mellitus. In this regard, we investigated the role of a Drosophila nicotinamidase (DN) in mammalian SH-SY5Y neuronal cells during oxidative stress. We demonstrate that during free radical exposure to nitric oxide generators DN neuronal expression significantly increased cell survival and blocked cellular membrane injury. Furthermore, DN neuronal expression prevented both apoptotic late DNA degradation and early phosphatidylserine exposure that may serve to modulate inflammatory cell activation in vivo. Nicotinamidase activity that limited nicotinamide cellular concentrations appeared to be necessary for DN neuroprotection, since application of progressive nicotinamide concentrations could abrogate the benefits of DN expression during oxidative stress. Pathways that involved sirtuin activation and SIRT1 were suggested to be vital, at least in part, for DN to confer protection through a series of studies. First, application of resveratrol increased cell survival during oxidative stress either alone or in conjunction with the expression of DN to a similar degree, suggesting that DN may rely upon SIRT1 activation to foster neuronal protection. Second, the overexpression of either SIRT1 or DN in neurons prevented apoptotic injury specifically in neurons expressing these proteins during oxidative stress, advancing the premise that DN and SIRT1 may employ similar pathways for neuronal protection. Third, inhibition of sirtuin activity with sirtinol was detrimental to neuronal survival during oxidative stress and prevented neuronal protection during overexpression of DN or SIRT1, further supporting that SIRT1 activity may be necessary for DN neuroprotection during oxidative stress. Implementation of further work to elucidate the cellular mechanisms that govern nicotinamidase activity in mammalian cells may offer novel avenues for the treatment of disorders tied to oxidative stress and cellular metabolic dysfunction.
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PMID:Enhanced tolerance against early and late apoptotic oxidative stress in mammalian neurons through nicotinamidase and sirtuin mediated pathways. 1869 Oct 73

Mammalian SIRT1 is an NAD-dependent deacetylase with critical roles in the maintenance of homeostasis and cell survival. Elevated levels of SIRT1 protein are evident in cancer in which SIRT1 can function as a cancer-specific survival factor. Here we demonstrate that elevated SIRT1 protein in human cells is not attributable to increased SIRT1 mRNA levels but, instead, reflects SIRT1 protein stability. RNAi-mediated depletion of JNK2 reduced the half-life of SIRT1 protein from >9 h to <2 h and this correlated with lack of SIRT1 protein phosphorylation at serine 27. In contrast, depletion of JNK1 had no effect upon SIRT1 protein stability and SIRT1 phosphorylation at serine 47 showed no correlation with SIRT1 protein stability. Thus we show that JNK2 is linked, directly or indirectly, with SIRT1 protein stability and that this function is coupled with SIRT1 phosphorylation at serine 27. Our observations identify a route for therapeutic modulation of SIRT1 protein levels in SIRT1-linked diseases including cancer, neurodegeneration and diabetes.
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PMID:JNK2-dependent regulation of SIRT1 protein stability. 1883 64

SIRT1 protects cells against oxidative stress and aging. Its activity may be modulated by dietary niacin (vitamin B3) intake. We studied the association of SIRT1 genetic variation with mortality in subjects with increased oxidative stress (type 2 diabetes and smokers) in relation to dietary niacin. In 4573 participants from the Rotterdam Study, including 413 subjects with prevalent and 378 with incident type 2 diabetes, three SIRT1 tagging SNPs were genotyped and all-cause mortality was studied (average follow-up 12 years). We found no association between SIRT1 variation and mortality in the total population or in smokers. In subjects with prevalent type 2 diabetes, homozygous carriers of the most common SIRT1 haplotype, 1, had 1.5 times (95%CI 1.1-2.1) increased mortality risk compared to noncarriers. This risk further increased among smokers and those with low niacin intake. In the lowest tertile of niacin intake, mortality risk was increased 2.3 (95%CI 1.1-4.9) and 5.7 (95%CI 2.5-13.1) times for heterozygous and homozygous carriers of haplotype 1. Subjects with incident diabetes showed similar findings but only when they smoked. We conclude that in subjects with type 2 diabetes, SIRT1 genetic variation influences survival in interaction with dietary niacin and smoking. Correction of niacin deficiency and SIRT1 modulators may prolong the life span of patients with diabetes.
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PMID:SIRT1 genetic variation and mortality in type 2 diabetes: interaction with smoking and dietary niacin. 1916 83

Endothelial dysfunction is a characteristic of aging-related vascular disease and is worsened during diabetes. High glucose can impair endothelial cell (EC) function through cellular accumulation of reactive oxygen species, an insult that can also limit replicative lifespan. Nicotinamide phosphoribosyltransferase (Nampt), also known as PBEF and visfatin, is rate-limiting for NAD+ salvage from nicotinamide and confers resistance to oxidative stress via SIRT1. We therefore sought to determine if Nampt expression could resist the detrimental effects of high glucose and confer a survival advantage to human vascular EC in this pathologic environment. Human aortic EC were infected with retrovirus encoding eGFP or eGFP-Nampt, and FACS-selected to yield populations with similar, modest transgene expression. Using a chronic glucose exposure model we tracked EC populations to senescence, assessed cellular metabolism, and determined in vitro angiogenic function. Overexpression of Nampt increased proliferation and extended replicative lifespan, and did so preferentially during glucose overload. Nampt expression delayed markers of senescence and limited reactive oxygen species accumulation in high glucose through a modest increase in aerobic glycolysis. Furthermore, tube networks formed by Nampt-overexpressing EC were more extensive and glucose-resistant, in accordance with SIRT1-mediated repression of the anti-angiogenic transcription factor, FoxO1. We conclude that Nampt enables proliferating human EC to resist the oxidative stress of aging and of high glucose, and to productively use excess glucose to support replicative longevity and angiogenic activity. Enhancing endothelial Nampt activity may thus be beneficial in scenarios requiring EC-based vascular repair and regeneration during aging and hyperglycemia, such as atherosclerosis and diabetes-related vascular disease.
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PMID:Nicotinamide phosphoribosyltransferase imparts human endothelial cells with extended replicative lifespan and enhanced angiogenic capacity in a high glucose environment. 1930 75

Individuals who live to 85 and beyond without developing major age-related diseases may achieve this, in part, by lacking disease susceptibility factors, or by possessing resistance factors that enhance their ability to avoid disease and prolong lifespan. Healthy aging is a complex phenotype likely to be affected by both genetic and environmental factors. We sequenced 24 candidate healthy aging genes in DNA samples from 47 healthy individuals aged eighty-five years or older (the 'oldest-old'), to characterize genetic variation that is present in this exceptional group. These healthy seniors were never diagnosed with cancer, cardiovascular disease, pulmonary disease, diabetes, or Alzheimer disease. We re-sequenced all exons, intron-exon boundaries and selected conserved non-coding sequences of candidate genes involved in aging-related processes, including dietary restriction (PPARG, PPARGC1A, SIRT1, SIRT3, UCP2, UCP3), metabolism (IGF1R, APOB, SCD), autophagy (BECN1, FRAP1), stem cell activation (NOTCH1, DLL1), tumor suppression (TP53, CDKN2A, ING1), DNA methylation (TRDMT1, DNMT3A, DNMT3B) Progeria syndromes (LMNA, ZMPSTE24, KL) and stress response (CRYAB, HSPB2). We detected 935 variants, including 848 single nucleotide polymorphisms (SNPs) and 87 insertion or deletions; 41% (385) were not recorded in dbSNP. This study is the first to present a comprehensive analysis of genetic variation in aging-related candidate genes in healthy oldest-old. These variants and especially our novel polymorphisms are valuable resources to test for genetic association in models of disease susceptibility or resistance. In addition, we propose an innovative tagSNP selection strategy that combines variants identified through gene re-sequencing- and HapMap-derived SNPs.
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PMID:Genetic variation in healthy oldest-old. 1968 May 56

The prevalence of cardiovascular diseases rises with aging and is one of the main causes of mortality in western countries. In view of the progressively aging population, there is an urge for a better understanding of age-associated cardiovascular diseases and its underlying molecular mechanisms. The risk factors for cardiovascular diseases include unhealthy diet, diabetes, obesity, smoking, alcohol consumption, physical inactivity, and aging. Increased production of oxygen-derived free radicals plays an important role in mediating cardiovascular diseases. Oxidative stress affects the availability and/or balance of key-regulators of vascular homeostasis and favors the development of cardiovascular diseases. Reactive oxygen species are generated by different intracellular molecular pathways principally located in the cytoplasm and in the mitochondria. The mitochondrial protein p66Shc and the deacetylase enzyme SIRT1 were shown to be involved in different aspects of cardiovascular diseases. This review focuses on the latest scientific advances in understanding cardiovascular diseases associated to aging, as well as delineating the possible therapeutic implications of p66Shc and SIRT 1 in this process.
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PMID:Cardiovascular determinants of life span. 1975 18

SIRT1, human ortholog of yeast SIR2 protein, deacetylates histones and several other transcription factors. Recently, SIRT1 has emerged as a drug target for treating age related diseases, type II diabetes, neurodegeneration, inflammation and cancer. Here, we have optimized production of functionally active wild type full-length SIRT1 protein and its N-terminal deleted mutants. In a comparative study, we found that the region containing 192-208 amino acids towards the N-terminus is critical for right conformational folding of the protein to retain its deacetylase activity. The EC(50) and IC(50) values obtained with standard modulators showed that the SRT(748) & SRT(556) can deacetylate substrate and are activated by resveratrol, whereas, deacetylase activity of all the other deletion mutants (SRT(540), SRT(532), SRT(507) and SRT(503)) was lost. We further report that the peptide substrate K(m) for SRT(748) (70+/-5.2 microM) was comparable to SRT(556) (93+/-5.4 microM). The K(m) for NAD(+) substrate was 176 & 274 microM for SRT(748) and SRT(556), respectively. Similar substrate affinity studies demonstrate that either of the protein (SRT(748) or SRT(556)) can be utilized for screening SIRT1 modulators. We have also examined critical regions in SIRT1 required for deacetylase activity as well as kinetic analyses of SIRT1 proteins.
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PMID:Comparative deacetylase activity of wild type and mutants of SIRT1. 1994 70

Reduced sarcoplasmic calcium ATPase (SERCA2a) expression has been shown to play a significant role in the cardiac dysfunction in diabetic cardiomyopathy. The mechanism of SERCA2a repression is, however, not known. This study was designed to examine the effect of resveratrol (RSV), a potent activator of SIRT1, on cardiac function and SERCA2a expression in chronic type 1 diabetes. Adult male mice were injected with streptozotocin (STZ) and fed with either a regular diet or a diet enriched with RSV. STZ administration produced progressive decline in cardiac function, associated with markedly reduced SERCA2a and SIRT1 protein levels and increased collagen deposition; RSV treatment to these mice had a tremendous beneficial effect both in terms of improving SERCA2a expression and on cardiac function. In cultured cardiomyocytes, RSV restored SERCA2 promoter activity, which was otherwise highly repressed in high-glucose media. Protective effects of RSV were found to be dependent on its ability to activate Silent information regulator (SIRT) 1. In cardiomyocytes, overexpression of SIRT1 was found sufficient to activate SERCA2 promoter in a dose-dependent manner. In contrast, pretreatment of cardiomyocytes with SIRT1 antagonist, splitomycin, blocked these beneficial effects of RSV. In addition, SIRT1 knockout (+/-) mice were also found to be more sensitive to STZ-induced decline in SERCA2a mRNA. The data demonstrate that, in chronic diabetes, 1) the enzymatic activity of cardiac SIRT1 is reduced, which contributes to reduced expression of SERCA2a and 2) through activation of SIRT1, RSV enhances expression of SERCA2a and improves cardiac function.
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PMID:Resveratrol, an activator of SIRT1, upregulates sarcoplasmic calcium ATPase and improves cardiac function in diabetic cardiomyopathy. 2000 78

The rising incidence of diabetes, metabolic syndrome, and subsequent vascular diseases is now a major public health problem in industrialized countries. New therapeutic strategies to prevent these diseases are urgently needed worldwide. It is well known that calorie restriction (CR) can retard the aging process in organisms ranging from yeast to rodents, and delay the onset of numerous age-related diseases including diabetes. Molecules that mimic CR metabolically are therefore potentially new therapeutic targets for age-related diseases. Silent information regulator 2 (Sir2) is an important player in CR-mediated life span extension. There is also increasing evidence that one of the seven mammalian sirtuins, SIRT1, is involved in regulating cellular processes such as apoptosis. SIRT1 has also been implicated in glucose homeostasis and lipid metabolism in various tissues including adipose tissues, liver, pancreas, and skeletal muscle. This review summarizes current understanding of the biological functions of SIRT1, and discusses its potential as a pharmacological target for fighting metabolic and vascular diseases.
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PMID:SIRT1, a calorie restriction mimetic, in a new therapeutic approach for type 2 diabetes mellitus and diabetic vascular complications. 2004 6

Sirtuins are a family of conserved proteins with deacetylase and ADP-ribosyltransferase activity. In humans they are coded by seven genes (SIRT1-7). The most widely investigated and best known sirtuin is SIRT1, which can be activated by the natural phytocompound resveratrol and plays a role in several physiologic (embryogenesis, glucose metabolism, apoptosis, autophagy, chromatin integrity, and transcriptional state) and pathologic (diabetes, cancer, cardiovascular disorders, and neurodegeneration) conditions. In the field of neurodegeneration, resveratrol and SIRT1 have proved beneficial in in vitro and in vivo models of Alzheimer's disease (AD), reducing amyloid-beta protein accumulation, considered one of the pathogenic mechanisms. In contrast to these promising biological data, however, genetic studies linking SIRT1 variability to AD are negative (this is the case for other sirtuins too, e.g., SIRT3). In this review, we summarize the in vitro, in vivo, and genetic experimental results linking SIRT1 and the other sirtuins to AD, while a description of sirtuins' biochemical features and modulating compounds, as well as sirtuins' involvement in other neurodegenerative disorders are discussed as collateral aims.
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PMID:Sirtuins as novel targets for Alzheimer's disease and other neurodegenerative disorders: experimental and genetic evidence. 2006 22


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