Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.15.1 (ACE)
18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The firm association of diabetes mellitus with congestive heart failure (CHF) has been undoubtedly established. Recent reports support the presence of the reciprocal interrelationships between CHF and glucose abnormalities. The present review provides an overview of some aspects of the multifactorial interrelationships between heart failure and diabetes mellitus. Patients with heart failure are generally at higher risk of developing type 2 diabetes mellitus. Several factors may be involved, such as a lack of physical activity, hypermetabolic state, intracellular metabolic defects, poor muscle perfusion, and poor nutrition. Serum levels of inflammatory cytokines and leptin are elevated in patients with heart failure. Activation of the sympathetic system in CHF not only increases insulin resistance but also decreases the release of insulin from the pancreatic beta cells, increases hepatic glucose production by stimulating both gluconeogenesis and glycogenolysis, and increases glucagon production and lipolysis. People who develop type 2 diabetes mellitus usually pass through the phases of nuclear peroxisome proliferator-activated receptor modulation, insulin resistance, hyperinsulinemia, pancreatic beta-cell stress and damage leading to progressively decreasing insulin secretion, and impaired fasting and postprandial blood glucose levels. Once hyperglycemia ensues, the risk of metabolic and cardiovascular complications also increases. It is possible that the cornerstone of diabetes mellitus prevention in patients with CHF could be controlled by increased physical activity in a cardiac rehabilitation framework. Pharmacologic interventions by some medications (metformin, orlistat, ramipril and acarbose) can also effectively delay progression to type 2 diabetes mellitus in general high risk populations, but the magnitude of the benefit in patients with CHF is unknown. In patients with CHF and overt diabetes mellitus, ACE inhibitors may provide a special advantage and should be the first-line agent. Recent reports have suggested that angiotensin receptor antagonists (angiotensin receptor blockers), similar to ACE inhibitors, provide beneficial effects in patients with diabetes mellitus and should be the second-line agent if ACE inhibitors are contraindicated. Treatment with HMG-CoA reductase inhibitors should probably now be considered routinely for all diabetic patients with CHF, irrespective of their initial serum cholesterol levels, unless there is a contraindication.
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PMID:Impaired glucose metabolism in patients with heart failure: pathophysiology and possible treatment strategies. 1544 70

Metabolic syndrome represents a common risk factor for premature cardiovascular disease and cancer whose core cluster includes diabetes, hypertension, dyslipidaemia and obesity. The liver is a target organ in metabolic syndrome patients in which it manifests itself with non-alcoholic fatty liver disease spanning steatosis through hepatocellular carcinoma via steatohepatitis and cirrhosis. Given that metabolic syndrome and non-alcoholic fatty liver disease affect the same insulin-resistant patients, not unexpectedly, there are amazing similarities between metabolic syndrome and non-alcoholic fatty liver disease in terms of prevalence, pathogenesis, clinical features and outcome. The available drug weaponry for metabolic syndrome includes aspirin, metformin, peroxisome proliferator-activated receptor agonists, statins, ACE (angiotensin I-converting enzyme) inhibitors and sartans, which are potentially or clinically useful also to the non-alcoholic fatty liver disease patient. Studies are needed to highlight the grey areas in this topic. Issues to be addressed include: diagnostic criteria for metabolic syndrome; nomenclature of non-alcoholic fatty liver disease; enlargement of the clinical spectrum and characterization of the prognosis of insulin resistance-related diseases; evaluation of the most specific clinical predictors of metabolic syndrome/non-alcoholic fatty liver disease and assessment of their variability over the time; characterization of the importance of new risk factors for metabolic syndrome with regard to the development and progression of non-alcoholic fatty liver disease.
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PMID:Review article: the metabolic syndrome and non-alcoholic fatty liver disease. 1622 69

Phthalate esters are ubiquitous environmental contaminants that interact with peroxisome proliferator-activated receptors (PPARs), a family of nuclear receptors. Molecular docking and free energy calculations were performed in an effort to identify novel phthalate ligands of PPARgamma, a subtype expressed in a wide range of human tissues. The method was validated using several agonists and partial agonists of PPARgamma, whose binding orientations were correctly reproduced; however, reduced accuracy in docking was observed with ligands of increasing size and flexibility. Improved results were obtained by introduction of a more accurate scoring function based on the all-atom molecular mechanics potential CHARMM and a generalized Born/surface area solvation term ACE (analytical continuum electrostatics). Comparison of the lowest CHARMM/ACE energy of each phthalate vs the logarithm of the experimentally determined EC(50) value for PPARgamma trans-activation yielded a good correlation (R(2) = 0.82). Thus, we can reliably distinguish phthalates that bind and activate PPARgamma from those that do not, with the computational method predicting relative PPARgamma binding activities with some degree of accuracy. We have applied this method to screen a series of 73 mono-ortho-phthalate esters listed in the Available Chemicals Directory. Several putative PPARgamma binding phthalates were identified, including compounds that are known PPARgamma agonists. These findings support the use of computational methods to identify environmental chemicals that warrant further experimental evaluation for PPAR binding and trans-activation potential in cell-based models.
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PMID:Computational screening of phthalate monoesters for binding to PPARgamma. 1691 38

The antidiabetic compound pioglitazone, an activator of the intracellular peroxisome proliferator-activated receptor-gamma, and decreases metabolic and vascular insulin resistance. The drug is well tolerated, and its metabolic effects include improvements in blood glucose and lipid control. Vascular effects consist of improvements in endothelial function and hypertension, and a reduction in surrogate markers of artherosclerosis. In a large, placebo-controlled, outcome study in secondary prevention, PROactive study, the use of pioglitazone in addition to an existing optimized macrovascular risk management resulted in a significant reduction of macrovascular endpoints within a short observation period that was comparable to the effect of statins and angiotensin converting enzyme inhibitors in other trials. These results underline the value of pioglitazone for managing the increased cardiovascular risk of patients with a metabolic syndrome or Type 2 diabetes mellitus.
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PMID:Pioglitazone: an antidiabetic drug with cardiovascular therapeutic effects. 1691 64

The metabolic syndrome or cardiovascular dysmetabolic syndrome is characterized by obesity, central obesity, insulin resistance, atherogenic dyslipidemia, and hypertension. The major risk factors leading to this syndrome are physical inactivity and an atherogenic diet and cornerstone clinical feature is abdominal obesity or adiposity. In addition, patients usually have elevated triglycerides, low HDL cholesterol, elevated LDL cholesterol, other abnormal lipid parameters, hypertension, and elevated fasting blood glucose. Impaired fibrinolysis, increased susceptibility to thrombotic events, and raised inflammatory markers are also observed. Given that India has the largest number of subjects with type-2 diabetes in the world it can be extrapolated that this country also has the largest number of patients with the metabolic syndrome. Epidemiological studies confirm a high prevalence. Therapeutic approach involves intervention at a macro-level and control of multiple risk factors using therapeutic lifestyle approaches (diet control and increased physical activity, pharmacotherapy - anti-obesity agents) for control of obesity and visceral obesity, and targeted approach for control of individual risk factors. Pharmacological therapy is a critical step in the management of patients with metabolic syndrome when lifestyle modifications fail to achieve the therapeutic goals. Anti-obesity drugs such as sibutramine and orlistat can be tried to reduce weight and central obesity and jointly control the metabolic syndrome components. Other than weight loss, there is no single best therapy and treatment should consist of treatment of individual components of the metabolic syndrome. Newer drugs such as the endocannabinoid receptor blocker,rimonabant, appear promising in this regard. Atherogenic dyslipidemia should be controlled initially with statins if there is an increase in LDL cholesterol. If there are other lipid abnormalities then combination therapy of statin with fibrates, nicotinic acid, or ezetimibe should be considered. For insulin resistance, drugs such as thiazolidinediones and renin-angiotensin system blockers are available. Available evidence suggests that angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBS) may be more beneficial for treatment of hypertension in patients with metabolic syndrome compared to others as these drugs also prevent development of diabetes. Patients with metabolic syndrome also have elevations in fibrinogen and other coagulation factors leading to prothrombotic state and aspirin may be beneficial for primary prevention in these patients. The new developments in the treatment of metabolic syndrome with drugs, such as peroxisome proliferator-activated receptor (PPAR) agonists and cannabinoid receptor-1 antagonists, will broaden the horizons of the current treatment options. Fixed-dose combination polypharmacy using a single pill is an interesting concept that needs to be evaluated in long-term prospective trials in such patients.
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PMID:Management issues in the metabolic syndrome. 1721 77

The increasing evidence that inflammation in the lungs leads to the structural changes observed in chronic obstructive pulmonary disease, whereas extrapulmonary symptoms and comorbidities may be systemic manifestations of these inflammatory processes, highlights an urgent need to discover novel, effective anti-inflammatory treatments for this disease. Some studies are suggesting that, by decreasing dynamic hyperinflation, bronchodilators might reduce systemic inflammation; inhaled corticosteroids and their combination with long-acting beta2-agonists might contribute to this goal. Even so, the opinion that suppression of the inflammatory response might improve systemic complications is stimulating a search for novel anti-inflammatory therapies. Many drugs include those that inhibit the recruitment and activation of inflammatory cells and/or antagonise their products. However, many of these therapeutic strategies are not specific for neutrophilic inflammation because they affect other cell types, thus, it is difficult to interpret whether any clinical benefit observed is a result of a reduction in airway neutrophils. In any case, there is some evidence that drugs used to treat a co-morbid condition, such as statins, angiotensin converting enzyme (ACE) inhibitors and angiontensin II type 1 (AT1) receptor blockers as well as glycosaminoglycans and peroxisome proliferator-activated receptor (PPAR) agonists, might benefit chronic obstructive pulmonary disease patients because they deal with the extrapulmonary, systemic component of chronic obstructive pulmonary disease.
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PMID:Targeting systemic inflammation: novel therapies for the treatment of chronic obstructive pulmonary disease. 1790 58

Antihypertensive drugs that inhibit the renin-angiotensin system (RAS) have been proposed to have additional benefits beyond their classic effects on the cardiovascular system, including reducing the risk of new-onset diabetes. Whether RAS inhibitors vary in ability to protect against new-onset diabetes is, however, unknown. The angiotensin II type 1 receptor (AT(1)) blocker telmisartan has been discovered to also activate the peroxisome proliferator-activated receptor-gamma (PPARgamma), an established antidiabetic drug target. In patients with hypertension and biochemical features of the metabolic syndrome, telmisartan has had beneficial effects on lipid and glucose metabolism. As a selective modulator of PPARgamma, telmisartan does not cause the side effects of fluid retention and weight gain associated with conventional thiazolidinedione ligands of PPARgamma. These observations raise the possibility that combined AT(1) receptor blockade and selective PPARgamma modulation with molecules such as telmisartan could provide greater protection from new-onset diabetes and cardiovascular disease than drugs that target either the RAS or PPARgamma alone. The cardioprotective and antidiabetic effects of telmisartan are being assessed in two large clinical trials, the ONgoing Telmisartan Alone in combination with Ramipril Global Endpoint Trial (ONTARGET) and the Telmisartan Randomised AssessmeNt Study in ACE-I iNtolerant subjects with cardiovascular Disease (TRANSCEND).
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PMID:Beyond the classic angiotensin-receptor-blocker profile. 1858 Aug 62

The beneficial effect achieved by the treatment of endothelial dysfunction in chronic cardiovascular diseases is already an evidence belonging to the basic treatment of the disease. Given the fact that the vascular system is uniform and consubstantial both physiologically, pathophysiologically and in terms of therapy, and that it plays a key role in age-related macular degeneration (AMD)--a disease leading to tragic loss of vision with its etiology and therapy being unknown--endothelial dysfunction should be treated. The pleiotropic effects of ACE-inhibitors, AR-blockers and statins and third generation beta blockers help to restitute the balance between vasodilators and vasoconstrictors in endothelial dysfunction caused by oxidative stress, the balance of growth factors and their inhibitors, pro- and anti-inflammatory substances and prothrombotic and fibrinolytic factors, inhibit the formation of oxidative stress and its harmful effects; while aspirin with its pleiotropic effects acting as an antiaggregation substance on platelets helps to set the endothelial layer back to its normal balance regarding its vasodilating, antithrombotic, antiadhesive and anti-inflammatory functions; trimetazidine as an adjuvant agent helps to normalize, to restore the disturbed metabolism of the retinal tissue functioning insufficiently, in the end. The angiotensin II receptor blocker telmisartan with its peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist effect inhibits the development of choroidal neovascularisation (CNV) and improves it clinically favourably. The third generation beta adrenergic receptor blocker carvedilol and nebivolol as well as the peroxisome proliferator-activated receptor-gamma agonist pioglitazone elicit their antioxidant vascular protective effects mitochondrially. For the above reasons it is suggested that, as a part of long term primary and/or secondary prevention, the following groups of patients with AMD receive--taking into consideration all possible side effects--ACE-inhibitor and/or AR blocker and statin and aspirin treatment, and trimetazidine as adjuvant medicine, and third generation beta adrenergic receptor blockers: 1. those without macular degeneration but being above the age of 50 and having risk factors inducing endothelial dysfunction; 2. those, who already developed AMD in one eye as a prevention in the second, unaffected eye; and 3. those patients who developed AMD in both eyes in order to ameliorate or merely slow the progression of the disease. Besides, it is advisory and important to eliminate AMD risk factors (cardiovascular risk factors also) inducing oxidative stress with consecutive endothelial dysfunction.
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PMID:[A new possible strategy for prevention and preventive treatment of age-related macular degeneration resting on recent clinical and pathophysiological observations]. 1925 46

Genetic and environmental factors influence insulin sensitivity (IS) during one's lifetime. Actually, uterine environment may affect IS at birth and later in life. In particular, various exogenous toxic substances, coupled to a genetic predisposition, may remarkably influence the regulation of the hypothalamus-hypophysis-adrenal gland axis, and the production or the activity of insulin, cerebral incretins, pro-inflammatory cytokines, and placental hormones. Owing to this reaction against environmental injuries, fetal growth and endocrine system development may be impaired, leading to low or large birth weight, or prematurity. Reduced growth in early life has been related to insulin resistance, which can be silent for years and evident in predisposed adults. The incidence of type 2 diabetes mellitus and obesity associated with sedentary lifestyle patterns and inadequate dieting behaviors in children and adolescents has rapidly increased during the last decade. Recent evidences suggest that the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor- (PPAR-) gene and the angiotensin converting enzyme (ACE) I/D gene polymorphism combined with environmental factors, such as phthalates interfering with the post receptorial action of insulin, alter insulin-sensible tissues. Therefore, IS, deriving from a complex interaction between genotype and environment, may change during life and depends on previous metabolic control, which is a sort of metabolicmemory. The goal for the future is preventing the complications associated with impaired IS through the control of exogenous factors and the use of drugs selectively effective on its pathogenesis.
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PMID:Influence of environment on insulin sensitivity. 1939 33

Aldosterone production causes vascular injury and may occur despite the long-term administration of angiotensin converting enzyme-inhibitors (ACE-I) (ie, aldosterone breakthrough). The angiotensin II receptor blocker (ARB) telmisartan can function as a ligand for peroxisome proliferator-activated receptor (PPAR) gamma. Stimulation of PPAR gamma has been demonstrated to raise adiponectin production and suppress angiotensin II type 1 receptor expression. Thus, we investigated the effect of the ACE-I perindopril erbumin (perindopril) and the ARB telmisartan on plasma levels of aldosterone and adiponectin.Patients with essential hypertension were randomly assigned to receive 48 weeks of perindopril (2-8 mg/d) or telmisartan (20-80 mg/d). We measured adiponectin, aldosterone, angiotensin II, and renin at weeks 0, 8, 24, and 48.A total of 53 subjects were randomized. Data on 51 subjects (25 in the perindopril group and 26 in the telmisartan group; mean age, 65.1 years) were available for analyses. Plasma aldosterone decreased significantly in both the telmisartan (69.9+/-5.6 to 58.1+/-5.4 pg/mL) and perindopril (74.1+/-4.7 to 64.7+/-5.3 pg/mL) groups at 8 weeks, but returned toward the baseline in the perindopril group (67.9+/-4.1 pg/mL) at 24 weeks. Plasma glycated hemoglobin levels or urine albumin did not change significantly after the treatment in either group.Telmisartan seemed to be more effective at suppressing aldosterone and raising adiponectin levels than perindopril; however, improvements in insulin sensitivity and albuminuria were not detected. These results are consistent with the idea that the use of an ARB with PPAR gamma stimulating activity is equivalent to ACE-I for the treatment of hypertension.
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PMID:Effects of ARB or ACE-inhibitor administration on plasma levels of aldosterone and adiponectin in hypertension. 1960 54


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