Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. MicroRNAs (miRNAs), the small non-coding RNAs of approximately 22 nucleotides, are now recognized as a very large family present throughout the genomes of plants and metazoans. These small transcripts modulate protein expression by binding to complementary or partially complementary target protein-coding mRNAs and targeting them for degradation or translational inhibition. 2. The discovery of miRNAs has revolutionized our understanding of the mechanisms that regulate gene expression, with the addition of an entirely novel level of regulatory control. Considerable information on miRNAs has been accumulated in this rapidly evolving research field. We now know that miRNAs play pivotal roles in diverse processes, such as development and differentiation, control of cell proliferation and death, stress response and metabolism. Indeed, aberrant miRNA expression has been documented in human disease as well as in animal models, with evidence for a causative role in tumourigenesis. 3. One of the most active fields of miRNA research is miRNA regulation of apoptosis, a programmed cell death implicated in many human diseases, such as cancer, Alzheimer's disease, hypertrophy and heart failure. Thus far, nearly 30 of 500 human miRNAs have been validated experimentally to regulate apoptosis; this number is likely to increase with future studies. 4. The present review provides a comprehensive summary and analysis of the currently available data, focusing on the transcriptional controls, target genes and signalling pathways linking the apoptosis-regulating miRNAs and apoptotic cell death.
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PMID:MicroRNAs and apoptosis: implications in the molecular therapy of human disease. 1956 26

Our recent studies have shown that, as indicated by vagal stimulation, an acetylcholinesterase inhibitor donepezil, an anti-Alzheimer's disease drug, prevents progression of heart failure in rats with myocardial infarction, and activates a common cell survival signal shared by acetylcholine (ACh) in vitro. On the basis of this and evidence that vagal innervation is extremely poor in the left ventricle, we assessed the hypothesis that ACh is produced by cardiomyocytes, which promotes its synthesis via a positive feedback mechanism. Rat cardiomyocytes expressed choline acetyltransferase (ChAT) in the cytoplasm and vesicular acetylcholine transporter with the vesicular structure identified by immunogold electron microscopy, suggesting that cardiomyocytes possess components for ACh synthesis. Intracellular ACh in rat cardiomyocytes was identified with physostigmine or donepezil. However, with atropine, the basal ACh content was reduced. In response to exogenous ACh or pilocarpine, cardiomyocytes increased the transcriptional activity of the ChAT gene through a muscarinic receptor and ChAT protein expression, and, finally, the intracellular ACh level was upregulated by pilocarpine. Knockdown of ChAT by small interfering RNA accelerated cellular energy metabolism, which is suppressed by ACh. Although physostigmine had a minimal effect on the ChAT promoter activity by inhibiting acetylcholinesterase, donepezil resulted in elevation of the activity, protein expression and intracellular ACh level even in the presence of sufficient physostigmine. Orally administered donepezil in mice increased the ChAT promoter activity in a reporter gene-transferred quadriceps femoris muscle and the amount of cardiac ChAT protein. These findings suggest that cardiomyocytes possess an ACh synthesis system, which is positively modulated by cholinergic stimuli. Such an amplification system in cardiomyocytes may contribute to the beneficial effects of vagal stimulation on the ventricles.
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PMID:Cholinoceptive and cholinergic properties of cardiomyocytes involving an amplification mechanism for vagal efferent effects in sparsely innervated ventricular myocardium. 1967 11

Since the introduction of HMG-CoA reductase inhibitors (statins) for lowering lipids, a large amount of data has been published demonstrating their potential benefits in conditions as varied as cancer, osteoporosis, and Alzheimer's dementia. We reviewed the published literature on MEDLINE from articles between 1950 and 2008 on the non-atheroprotective effects of statins and noted consistent benefits of statin use in improving outcomes of ventricular arrhythmias, sudden cardiac death, cardiac transplant rejection, chronic obstructive pulmonary disease, and sepsis. However, for these conditions, the level of evidence was inadequate to recommend statin use. The evidence for improving outcomes in atrial fibrillation, mortality in heart failure, contrast-induced nephropathy, cataract, age-related macular degeneration, sub-arachnoid hemorrhage, osteoporosis, dementia, and cancer incidence was conflicting and inconclusive. Furthermore, we found that most of the literature consists of small observational studies and their conclusions are often not corroborated by results from larger or randomized studies. Pending large, well designed, randomized trials, we conclude that there is no definite evidence for the use of statins in any condition besides hyperlipidemia and atherosclerosis.
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PMID:Non-atheroprotective effects of statins: a systematic review. 1992 34

The phospholipase neutral sphingomyelinase (N-SMase) has been recognized as a major mediator of processes such as inflammation, development and growth, differentiation and death of cells, as well as in diseases such as Alzheimer's, atherosclerosis, heart failure, ischemia/reperfusion damage, or combined pituitary hormone deficiency. Although activation of N-SMase by the proinflammatory cytokine TNF was described almost two decades ago, the underlying signaling pathway is unresolved. Here, we identify the Polycomb group protein EED (embryonic ectodermal development) as an interaction partner of nSMase2. In yeast, the N terminus of EED binds to the catalytic domain of nSMase2 as well as to RACK1, a protein that modulates the activation of nSMase2 by TNF in concert with the TNF receptor 1 (TNF-R1)-associated protein FAN. In mammalian cells, TNF causes endogenous EED to translocate from the nucleus and to colocalize and physically interact with both endogenous nSMase2 and RACK1. As a consequence, EED and nSMase2 are recruited to the TNF-R1.FAN.RACK1-complex in a timeframe concurrent with activation of nSMase2. After knockdown of EED by RNA interference, the TNF-dependent activation of nSMase2 is completely abrogated, identifying EED as a protein that both physically and functionally couples TNF-R1 to nSMase2, and which therefore represents the "missing link" that completes one of the last unresolved signaling pathways of TNF-R1.
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PMID:The Polycomb group protein EED couples TNF receptor 1 to neutral sphingomyelinase. 2008 May 39

Human induced pluripotent stem (iPS) cells hold great promise for therapy of a number of degenerative diseases such as ischemic heart failure, Parkinson's disease, Alzheimer's disease, diabetes mellitus, sickle cell anemia and Huntington disease. They also have the potential to accelerate drug discovery in 3 ways. The first involves the delineation of chemical components for efficient reprogramming of patient's blood cells or cells from biopsies, obviating the need for cellular delivery of reprogramming exogenous transgenes, thereby converting hope into reality for patients suffering from degenerative diseases. Patients worldwide stand to benefit from the clinical applicability of iPS cell-based cell replacement therapy for a number of degenerative diseases. The second is the potential for discovering novel drugs in a high throughput manner using patient-specific iPS cell-derived somatic cells possessing the etiology of the specific disease. The third is their suitability for toxicological testing of drugs and environmental factors. This review focuses on these potential applications of iPS cells with special emphasis on recent updates of iPS cell research contributing to the accelerated drug discovery.
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PMID:Induced pluripotent stem cells as a model for accelerated patient- and disease-specific drug discovery. 2008 56

Membrane proteins (MPs) are responsible for the interface between the exterior and the interior of the cell. These proteins are involved in numerous diseases, like cancer, cystic fibrosis, epilepsy, hyperinsulinism, heart failure, hypertension and Alzheimer disease. However, studies of these disorders are hampered by a lack of structural information about the proteins involved. Structural analysis requires large quantities of pure and active proteins. The majority of medically and pharmaceutically relevant MPs are present in tissues at low concentration, which makes heterologous expression in large-scale production-adapted cells a prerequisite for structural studies. Obtaining mammalian MP structural data depends on the development of methods that allow the production of large quantities of MPs. This review focuses on the heterologous expression systems now available to produce large amounts of MPs for structural proteomics, and describes the strategies that allowed the determination of the structure of the first heterologously expressed mammalian MPs.
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PMID:Heterologous expression of membrane proteins for structural analysis. 2009 36

Due to their implication in numerous diseases like cancer, cystic fibrosis, epilepsy, hyperinsulinism, heart failure, hypertension, and Alzheimer disease, membrane proteins (MPs) represent around 50% of drug targets. However, only 204 crystal structures of MPs have been solved. Structural analysis requires large quantities of pure and active proteins. The majority of medically and pharmaceutically relevant MPs are present in tissues at low concentration, which makes heterologous expression in large-scale production-adapted cells a prerequisite for structural studies. The yeast Saccharomyces cerevisiae is a convenient host for the production of mammalian MPs for functional and structural studies. Like bacteria, they are straightforward to manipulate genetically, are well characterized, can be easily cultured, and can be grown inexpensively in large quantities. The advantage of yeast compared to bacteria is that they have protein-processing and posttranslational modification mechanisms related to those found in mammalian cells. The recombinant rabbit muscle Ca(2+)-ATPase (adenosine triphosphatase), the first heterologously expressed mammalian MP for which the crystal structure was resolved, has been produced in S. cerevisiae. In this chapter, the focus is on expression of recombinant human integral MPs in a functional state at the plasma membrane of the yeast S. cerevisiae. Optimization of yeast culture and of MP preparations is detailed for two human receptors of the Hedgehog pathway: Patched and Smoothened.
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PMID:Heterologous expression of human membrane receptors in the yeast Saccharomyces cerevisiae. 2009 41

Numerous studies have linked individual vascular factors to dementia including Alzheimer's disease (AD). We investigated different vascular risk profiles in relation to dementia and AD among very old people. A standardized follow-up procedure was applied three times to a dementia-free cohort (n=1270, age >or= 75) over a nine-year period to detect dementia and AD cases using the DSM-III-R criteria. We examined two vascular risk profiles, which were scored by counting the number of corresponding vascular factors: 1) atherosclerotic profile included systolic pressure >or= 160 mmHg, diabetes/prediabetes, and stroke; and 2) cerebral hypoperfusion profile constituted diastolic pressure < 70 mmHg, pulse pressure < 70 mmHg, and heart failure. Data were analyzed with Cox proportional-hazards models controlling for major potential confounders. During the 6406 person-years of follow-up, 428 subjects developed dementia, including 328 AD cases. All components of vascular profiles were significantly or marginally associated with increased dementia risk. The risk of dementias was increased with increasing score of both risk profiles (p for trend <or= 0.001); subjects with a score >or= 2 in either profile had an approximately twofold-increased risk for dementia and AD. These data suggest that aggregation of atherosclerotic- and hypoperfusion-related vascular factors increases the risk of dementia in very old people. Severe cerebral atherosclerosis and insufficient perfusion are involved in the development of dementia including AD.
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PMID:Vascular risk profiles for dementia and Alzheimer's disease in very old people: a population-based longitudinal study. 2016 87

Statins have been shown to reduce cardiovascular events across a broad spectrum of patients at risk, irrespective of baseline LDL-cholesterol levels. In a meta-analysis of 14 statin trials involving more than 90,000 participants, statin therapy reduced the 5-year incidence of cardiovascular events by about 20% for each mmol/L of LDL-cholesterol reduction. The results of the Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) study suggest that the degree of reduction in Japanese subjects may be greater than this for the same degree of LDL-cholesterol reduction. Given the success of statins in preventing cardiovascular events, it is not surprising that they have been tested in a variety of related conditions, three of which are discussed in this article. Heart failure is characterized by inflammation, endothelial dysfunction and neurohumeral activation, conditions that are ameliorated by statin therapy. The Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) showed no significant benefit of rosuvastatin upon the primary endpoint, cardiovascular death, myocardial infarction and stroke. However, subgroups identified by the biomarkers plasma amino-terminal pro-brain natriuretic and C-reactive protein showed a reduction in events. Aortic stenosis and atherosclerosis share common risk factors, including hypertension and hypercholesterolemia. Although non-randomized cohort studies have suggested that statins slow the progression of aortic stenosis, this was not shown in either of the two randomized placebo-controlled trials testing this hypothesis. Similarly, Alzheimer's disease shares many risk factors with atherosclerosis, and several observational studies have reported a lower risk of developing this condition in patients taking statins. However, two recently completed clinical trials indicate that neither atorvastatin nor simvastatin slow the progression of early Alzheimer's disease. In conclusion, although statins are effective, established therapy for the prevention of vascular events in patients at risk, they have as yet not proven to be successful for these newer indications.
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PMID:Exploring new indications for statins beyond atherosclerosis: Successes and setbacks. 2020 67

IL-33 plays an important role in inflammatory diseases including hypersensitive diseases like asthma, autoimmune diseases like rheumatoid arthritis, cardiovascular diseases like heart failure and neurodegenerative diseases like Alzheimer's disease. Here we reported the generation of an IL-33 transgenic mouse, in which mouse IL-33 full-length cDNA was controlled under the CMV promoter. The transgenic IL-33 was released as a cleaved form with molecular weight of 18kDa in pulmonary, nephritic, cardiac and pancreatic tissues in transgenic mice and the pI of 18kDa peptide was about pH 3-5 on the 2D PAGE which was similar with the activated peptide of IL-33. Histological analysis showed massive airway inflammation with infiltration of eosinophils around bronchi and small blood vessels, hyperplasia of goblet cells and accumulation of mucus-like material in pulmonary tissue of transgenic mice. An increase of IL-5, IL-8, IL-13 and IgE was detected in bronchoalveolar lavage fluid (BALF) of transgenic mice, which are inflammatory factors. These findings suggest transgenic IL-33 could be cleaved and secreted in an activated form and play an important role in the pathogenesis of pulmonary inflammation.
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PMID:Over-expression of IL-33 leads to spontaneous pulmonary inflammation in mIL-33 transgenic mice. 2041 15


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