Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Age-associated telomere shortening leads to replicative senescence of human endothelial cells (EC). Risk factors for cardiovascular disease (CVD) accelerate ageing, while there is a concomitant rise in oxidative stress known to promote stress-induced senescence (SIS) in vitro. Of all risk factors for CVD, smoking is most associated with the development of inflammation and accelerated atherosclerosis due to a prooxidant-antioxidant imbalance. We tested the hypothesis that SIS predominates in EC isolated from chronic smokers with premature atherosclerosis undergoing coronary artery bypass graft surgery (CABG). We isolated and cultured EC from segments of internal mammary arteries from smoker, former smoker, and nonsmoker coronary patients. Senescence of EC was induced by serial passage and quantified by the measurement of telomere length and senescence-associated beta-galactosidase activity. Compared with nonsmokers, smoker patients were 10 years younger at the time of CABG, evidence of premature atherosclerosis. Cellular senescence was independent of telomere length and directly related to oxidative damage. EC exhibited higher expression levels of markers of oxidative stress (lipid peroxydation level and caveolin-1 mRNA), inflammation (angiopoietin-like 2 mRNA), hypoxia (vascular endothelial growth factor (VEGF)-A mRNA), and cell damage (p53 mRNA). In conclusion, a high oxidative stress environment in EC isolated from atherosclerotic chronic smokers predisposes to SIS rather than replicative senescence.
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PMID:Stress-induced senescence predominates in endothelial cells isolated from atherosclerotic chronic smokers. 1901 71

Cardiovascular disease (CVD) is the most prevalent disease worldwide and there is intense interest in pharmaceutical approaches to reduce the burden of this chronic, aging-related condition. The sirtuin (SIRT) family of NAD(+)-dependent protein deacetylases and ADP-ribosyltransferases have emerged as exciting targets for CVD management that can impact the cardiovascular system both directly and indirectly, the latter by modulating whole body metabolism. SIRT1-4 regulate the activities of a variety of transcription factors, coregulators, and enzymes that improve metabolic control in adipose tissue, liver, skeletal muscle, and pancreas, particularly during obesity and aging. SIRT1 and 7 can control myocardial development and resist stress- and aging-associated myocardial dysfunction through the deacetylation of p53 and forkhead box O1 (FoxO1). By modulating the activity of endothelial nitric oxide synthase (eNOS), FoxO1, and p53, and the expression of angiotensin II type 1 receptor (AT1R), SIRT1 also promotes vasodilatory and regenerative functions in endothelial and smooth muscle cells of the vascular wall. Given the array of potentially beneficial effects of SIRT activation on cardiovascular health, interest in developing specific SIRT agonists is well-substantiated. Because SIRT activity depends on cellular NAD+ availability, enzymes involved in NAD+ biosynthesis, including nicotinamide phosphoribosyltransferase (Nampt), may also be valuable pharmaceutical targets for managing CVD. Herein we review the actions of the SIRT proteins on the cardiovascular system and consider the potential of modulating SIRT activity and NAD+ availability to control CVD.
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PMID:NAD(+), sirtuins, and cardiovascular disease. 1914 6

Sirtuin 1 (SIRT1), a member of the silent information regulator 2 in mammals, has recently been found to be involved in age-related diseases, such as cancer, metabolic diseases, cardiovascular disease, neurodegenerative diseases, osteoporosis and chronic obstructive pulmonary disease (COPD), mainly through deacetylation of substrates such as p53, forkhead box class O, peroxisome proliferator activated receptor gamma co-activator 1alpha, and nuclear factor-kappaB. It is widely reported that SIRT1 can promote not only carcinogenesis but also metastasis and insulin resistance, andhave beneficial effects in metabolic diseases, mediate high-density lipoprotein synthesis and regulate endothelial nitric oxide to protect against cardiovascular disease, have a cardioprotective role in heart failure, protect against neurodegenerative pathological changes, promote osteoblast differentiation, and also play a pivotal role as an anti-inflammatory mediator in COPD. However, there are controversial results suggesting that SIRT1 has an effect in protecting against DNA damage and accumulation of mutations, and preventing tumorigenesis. In addition, a high level of SIRT1 can induce cardiomyopathy and even heart failure. This article reviews recent developments relating to these issues.
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PMID:Silent information regulator, Sirtuin 1, and age-related diseases. 1926 Sep 74

Arterial components of the angiotensin II (Ang II) signaling cascade increase with aging and contribute to the pathogenesis of atherosclerosis, and inhibition of Ang II activity has been demonstrated to improve the morbidity and mortality of cardiovascular disease. Ang II signaling appears to play a critical role in regulating many of the stimuli and signals that govern vascular aging and atherogenesis. Recently, Ang II was reported to induce the premature senescence of vascular cells via the p53/p21-dependent pathway. The current review will discuss the mechanism by which Ang II contributes to vascular aging as well as the potential of anti-senescence therapy by inhibition of Ang II activity for age-associated diseases.
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PMID:[Role of the renin-angiotensin system in the regulation of vascular senescence]. 1934 33

Much attention has been paid to gene therapy since 1990's. No remarkable success has been achieved and several serious adverse effects such as leukemia in X-SCID gene therapy have been reported. Nevertheless, trials to treat hereditary disease, cancers and cardiovascular disease using therapeutic gene-loaded vectors are continuously being performed. Recently, some gene drugs such as p53-loaded adenovirus vector, oncolytic adenovirus and HGF plasmid DNA are produced and remain to be commercially available. Stem cell-based gene therapy will be main focus in hereditary disease gene therapy. In cancer gene therapy, regulation of anti-tumor immunity and improvement of gene-modified oncolytic virus will be more fully investigated.
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PMID:[Progress of human gene therapy]. 1950 11

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

Epidemiological studies show a strong association between low birth weight and hypertension, renal, and cardiovascular disease, especially after catch-up growth. Senescence is an important contributor to the progression of chronic disease. Developmentally programmed premature senescence may be a link among low birth weight, catch-up growth, and adult disease. Low birth weight was induced by feeding pregnant rats a low-protein diet from day 12 of gestation to 10 days postdelivery. Low- and normal-birth-weight male offspring were weaned onto regular or high-calorie diets to enhance catch-up growth. Kidneys and hearts of offspring were analyzed for RNA and protein markers of stress-induced senescence (p16, p21, p53, Rb). Markers of mitochondrial stress (p66Shc) and activation of endoplasmic reticulum protein secretion (Ero1alpha) were analyzed as regulators of reactive oxygen species generation. Reactive oxygen species are known to be associated with premature aging. Senescence markers were not different in low- or normal-birth-weight kidneys at birth. During rapid catch-up growth, p16 and p21 increased significantly in low-birth-weight kidneys and hearts (P < 0.01). Renal p16 levels increased progressively and were significantly higher in low-birth-weight kidneys at 3 and 6 mo (P < or = 0.02). Renal p66Shc and Ero1alpha were significantly higher in low- compared with normal- birth-weight kidneys at 6 mo, suggesting reactive oxygen species generation (P < or = 0.03). Low-birth-weight rats exhibit accelerated senescence in kidneys and hearts after rapid catch-up growth, a likely important link between early growth and subsequent hypertension, renal, and cardiovascular disease.
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PMID:Accelerated senescence in kidneys of low-birth-weight rats after catch-up growth. 1982 76

Damaged DNA can lead to aneuploidy and/or chromosomal instability, which is believed to be major contributor to tumor progression. Genotoxic and oncogenic stresses-induced DNA damage activate the tumor suppressor pathways initiate DNA damage response (DDR). One of the cellular fates in response to DDR is permanent growth arrest in mitotically active cells, including stem cells, leading to senescence and adaptive changes in postmitotic cells. These cellular alterations happen through complex interactions and function to disorder the existing cellular homeostasis. This is a disease state similar to metabolic syndrome occurred by the systemic DDR to inhibit ongoing malignant transformation. Significant metabolic changes occurred by the influence of the major tumor suppressor proteins p53 and FOXO discussed in the article. After a strong correlation established between the systemic DNA damage response to inhibit ongoing malignant transformation and metabolic syndrome characteristics, logical extrapolations for type 2 diabetes, cardiovascular disease, and aging are carried out. Finally, therapeutic evaluations are performed in the light of the novel pathophysiological data implying that "metabolic syndrome" is a real disease.
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PMID:Metabolic syndrome is a real disease and premalignant state induced by oncogenic stresses to block malignant transformation. 2009 80

Damaged DNA can lead to aneuploidy and/or chromosomal instability, which is believed to be major contributor to tumor progression. DNA damage in response to genotoxic and oncogenic stresses activate the tumor suppressor pathways initiating DNA damage response (DDR). One of the cellular fates in response to DDR is permanent growth arrest in mitotically active cells, including stem cells, leading to senescence. On the other hand, DDR reasons in adaptive changes in postmitotic cells. These cellular alterations happen through complex interactions and function to disrupt the existing cellular homeostasis. Significant metabolic changes occurred by the influence of the major tumor suppressor protein p53 and other related factors such as FOXO, AMPK, PARP, NF-kappaB and PGC-1 are discussed in the article. After a strong correlation established between the systemic DNA damage response to inhibit ongoing malignant transformation and metabolic syndrome characteristics, logical extrapolations for type 2 diabetes, cardiovascular disease, and aging are carried out. Finally, therapeutic evaluations are performed in the light of the novel pathophysiological data implying that "metabolic syndrome" is a real disease.
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PMID:Systemic DNA damage response and metabolic syndrome as a premalignant state. 2033 25

Due to improvements in lifestyle and healthcare, the proportion of aged people is rising steadily, especially in developed countries. With aging, some physiological functions are altered and resemble those occurring in disease conditions such as hypertension, chronic coronary disease and diabetes. Thus, there is the urge to better understand molecular and cellular mechanisms underlying aging and aging-related diseases. In rodents and possibly primates, calorie restriction is an effective approach to extend lifespan by reducing free radical-induced damage. Increased production of oxygen-derived free radicals plays an important role in the process of aging. Reactive oxygen species are generated by different intracellular molecular pathways principally located in the cytoplasm and in the mitochondria. The mitochondrial protein p66(Shc) is considered a longevity assurance gene since its genetic deletion extends the lifespan of rodents and displays protective effects in several models of cardiovascular disease. Silent mating type information regulation 2 homolog 1 Saccharomyces cerevisiae (SIRT1) is a nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase that may also be involved in aging and diseases. SIRT1 also deacetylates a number of nonhistone target proteins, including p53, endothelial nitric oxide synthase and forkhead box protein. This review focuses on the latest scientific advances in understanding aging as well as delineates the possible therapeutic implications of p66(Shc) and SIRT1 in this process.
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PMID:Anti-aging medicine: molecular basis for endothelial cell-targeted strategies - a mini-review. 2043 Dec 81


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