Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0948265 (metabolic syndrome)
 24,271 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study was undertaken on the basis of several reports in the literature that pancreatic beta cells are capable of replication/regeneration and also being afforded protection against damage induced by streptozotocin. Nicotinamide was reported to give protection against streptozotocin-induced damage in rats. In the present study, two thiazolidine-4-ones with nicotinamide substitution were administered to Swiss albino mice with streptozotocin diabetes for 15 days. Concurrently, one group received nicotinic acid. Both the test compounds reversed the hyperglycaemia diabetic mice. Damage to pancreatic islets was also reduced in these groups compared to diabetic control and nicotinic acid treated groups. Since these compounds have been earlier found have antioxidant activity, one of the possible mechanisms of action could be by reducing oxidative stress in pancreas. Further, possibly by releasing nicotinamide in vivo, the molecules could have contributed to the NAD pool in pancreas and afforded protection. It is concluded that the test compounds have potential to be developed for multiple beneficial action in conditions like metabolic syndrome.
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PMID:Antidiabetic effect through islet cell protection in streptozotocin diabetes: a preliminary assessment of two thiazolidin-4-ones in Swiss albino mice. 1903 38

Current treatment guidelines recommend lowering elevated low-density lipoprotein (LDL) cholesterol levels with a statin as the primary lipid-modifying intervention to reduce cardiovascular risk in patients with type 2 diabetes mellitus or metabolic syndrome. However, even with high-dose statin therapy or the combination of statin plus ezetimibe, many patients remain at substantial risk of a cardiovascular event. Increasingly, there is recognition of the importance of treating all components of the atherogenic dyslipidemic profile associated with both conditions, specifically low high-density lipoprotein cholesterol and elevated triglyceride levels, in addition to lowering LDL cholesterol. Both niacin (nicotinic acid) and fibrates are recommended as options for combination with a statin in this setting. Data from ongoing prospective outcomes studies are needed to evaluate the efficacy and safety of these combinations.
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PMID:A review of the current status of the management of mixed dyslipidemia associated with diabetes mellitus and metabolic syndrome. 1908 86

Retinoid X receptor (RXR) ligands are attractive candidates for clinical application because of their activity against tamoxifen-resistant breast cancer, taxol-resistant lung cancer, metabolic syndrome, and allergy. Though several RXR ligands, especially RXR antagonists, have been reported, the rational molecular design of such compounds is not well advanced. 4-[N-Methanesulfonyl-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)amino]nicotinic acid (5a) is a moderately RXRalpha-preferential agonist, and we examined the feasibility of replacing the methyl group on the sulfonamide with a longer alkyl chain or an aromatic ring as an approach to produce new RXR antagonists. Several of the resulting benzenesulfonanilide-type compounds showed RXR antagonist activity. This design strategy should be a useful approach for addressing the lack of structure diversity of RXR antagonists.
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PMID:Replacing alkyl sulfonamide with aromatic sulfonamide in sulfonamide-type RXR agonists favors switch towards antagonist activity. 1909 48

The last 20 years have witnessed dramatic reductions in cardiovascular risk using 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors ("statins") to lower levels of low-density lipoprotein cholesterol (LDL-C). Using this approach one can achieve a reduction in the risk of major cardiovascular events of 21% for every 1 mmol/l (39 mg/dl) decrease in LDL-C. However, despite intensive therapy with high dose "statins" to lower LDL-C levels below 2.6 mmol/l (100 mg/dl), the risk of a major cardiovascular event in patients with established coronary artery disease remains significant at a level approaching an annual risk of 9%, paving the way for new strategies for reducing the residual cardiovascular risk in this patient group. Early epidemiological studies have identified low levels of high-density lipoprotein cholesterol (HDL-C) (<1.0 mmol/l or 40 mg/dl), a common feature of type 2 diabetes mellitus and the metabolic syndrome, to be an independent determinant of increased cardiovascular risk. The beneficial effects of HDL-C on the cardiovascular system have been attributed to its ability to remove cellular cholesterol, as well as its anti-inflammatory, antioxidant and antithrombotic properties, which act in concert to improve endothelial function and inhibit atherosclerosis, thereby reducing cardiovascular risk. As such, raising HDL-C in patients with aggressively lowered LDL-C provides an additional strategy for addressing the residual cardiovascular risk present in these patients groups. Studies suggest that for every 0.03 mmol/l (1.0 mg/dl) increase in HDL-C, cardiovascular risk is reduced by 2-3%. Raising HDL-C can be achieved by both lifestyle changes and pharmacological means, the former of which include smoking cessation, aerobic exercise, weight loss and dietary manipulation. Therapeutic strategies have included niacin, fibrates, thiazolidinediones and bile acid sequestrants. Newly developed pharmacological agents include apolipoprotein A-I mimetics and the cholesteryl ester transfer protein (CETP) inhibitors, JTT-705 and torcetrapib, the latter of which has been recently withdrawn from clinical testing because of serious adverse effects. Emerging experimental studies investigating the complex pathways of HDL metabolism have identified several new targets for raising HDL-C with new pharmaceutical agents currently in development. For the time being, the long-acting formulations of nicotinic acid remain the most effective and best tolerated pharmacological strategy for raising HDL-C in patients already on statin therapy to control LDL-C. Therefore, raising HDL-C represents an important strategy for reducing residual cardiovascular risk in patients already optimally treated with statins, and should lead to further improvements in clinical outcomes in these patient groups.
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PMID:Targeting residual cardiovascular risk: raising high-density lipoprotein cholesterol levels. 1910 17

Low levels of high-density lipoprotein cholesterol (HDL-C) represent a major cardiovascular risk factor, with a stronger relationship to coronary heart disease than that seen with elevated levels of low-density lipoprotein cholesterol (LDL-C). HDL-C has important antiatherogenic effects, including reverse cholesterol transport, inhibition of LDL-C oxidation, and antiplatelet and anti-inflammatory actions. Patients with low HDL-C are also at an amplified risk of coronary heart disease due to the common coexistence of other risk factors, including excess adiposity, metabolic syndrome, type 2 diabetes mellitus, hypertriglyceridemia, and the atherogenic dyslipidemia characterized by small dense LDL-C. First-line therapy of low HDL-C generally consists of nonpharmacologic measures such as improved fitness and weight loss. Current pharmaceutical options include statins, fibrates, and nicotinic acid. A host of novel approaches involving HDL-C and reverse cholesterol transport hold the promise of fundamentally changing the natural history of atherosclerosis, the most common and important chronic disease in humans.
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PMID:The importance of recognizing and treating low levels of high-density lipoprotein cholesterol: a new era in atherosclerosis management. 1912 82

Niacin (nicotinic acid) has recently been shown to increase serum adiponectin concentrations in men with the metabolic syndrome. However, little is known about the mechanism(s) by which niacin regulates the intracellular trafficking and secretion of adiponectin. Since niacin appears to exert its effects on lipolysis through receptor (GPR109A)-dependent and -independent pathways, the purpose of this investigation was to examine the role of the recently identified GPR109A receptor in adiponectin secretion. Initial in vivo studies in rats demonstrated that niacin (30 mg/kg po) acutely increases serum adiponectin concentrations, whereas it decreases NEFAs. Further in vitro studies demonstrated an increase in adiponectin secretion and a decrease in lipolysis in primary adipocytes following treatment with niacin or beta-hydroxybutyrate (an endogenous ligand of the GPR109A receptor), but these effects were blocked when adipocytes were pretreated with pertussis toxin. Niacin had no effect on adiponectin secretion or lipolysis in 3T3-L1 adipocytes, which have limited cell surface expression of the GPR109A receptor. To further substantiate these in vitro findings, wild-type and GPR109A receptor knockout mice were administered a single dose of niacin or placebo, and serum was obtained for the determination of adiponectin and NEFA concentrations. Serum adiponectin concentrations increased and serum NEFAs decreased in the wild-type mice within 10 min following niacin administration. However, niacin administration had no effect on adiponectin and NEFA concentrations in the GPR109A receptor knockout mice. These results demonstrate that the GPR109A receptor plays an important role in the dual regulation of adiponectin secretion and lipolysis.
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PMID:Niacin stimulates adiponectin secretion through the GPR109A receptor. 1914 78

The metabolic syndrome is a multiplex risk factor for atherosclerotic cardiovascular disease. The core components of the dyslipidemia of the metabolic syndrome, which most likely initiate atherosclerosis, are the "lipid triad" of high plasma triglycerides, low levels of high-density lipoprotein cholesterol (HDL-C), and a preponderance of small, dense low-density lipoprotein (LDL) particles. Postprandial lipemia is also recognized as an important component. Dysregulation of fat metabolism in the liver with overproduction of very-low-density lipoprotein 1 (VLDL1) particles is considered the hallmark of the dyslipidemia of the metabolic syndrome. The cornerstone of therapy is therapeutic lifestyle change. If this does not correct the dyslipidemia, drug therapy may be required. LDL-C lowering with statins is the first-line treatment; however, there is ongoing debate as to whether further aggressive LDL-lowering therapy with higher-dose statins as opposed to comprehensive lipid management is the optimal therapy to reduce cardiovascular risk in subjects with the metabolic syndrome. Combination of a statin with a fibrate and/or nicotinic acid can improve all components of the dyslipidemia. However, there are, as yet, no large cardiovascular outcome studies that show a reduction in cardiovascular morbidity or mortality using combination therapy. The current LDL-C goal in high-risk patients with the metabolic syndrome is below 100 mg/dL, with a non-HDL goal of below 130 mg/dL. However, in very high-risk patients, such as those with established cardiovascular disease, an LDL-C goal of below 70 mg/dL is recommended.
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PMID:Pathogenesis and management of the dyslipidemia of the metabolic syndrome. 1940 Jul 42

In the treatment of dyslipidemia and coronary heart disease, niacin extended-release (ER) (Niaspan) uniquely targets the atherogenic lipid abnormalities of the metabolic syndrome. Niacin ER raises high-density lipoprotein cholesterol more effectively than other agents, while reducing triglyceride and lipoprotein(a) levels and increasing low-density lipoprotein particle size. It is formulated to minimize the toxicities and adverse effects associated with other niacin formulations, making niacin ER more tolerable for patients. Previous concerns of hyperglycemia have been addressed by numerous studies demonstrating that morbidity and mortality benefits outweigh potential increases in glucose levels. Niacin ER is an important lipid-lowering agent in preventing fatal and nonfatal coronary events and slowing the progression of atherosclerosis.
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PMID:Clinical utility of extended-release niacin: update and summary. 1980 95

Although statin therapy represents a cornerstone of cardiovascular disease (CVD) prevention, a major residual CVD risk (60-70% of total relative risk) remains, attributable to both modifiable and non-modifiable risk factors. Among the former, low levels of HDL-C together with elevated triglyceride (TG)-rich lipoproteins and their remnants represent major therapeutic targets. The current pandemic of obesity, metabolic syndrome, and type 2 diabetes is intimately associated with an atherogenic dyslipidemic phenotype featuring low HDL-C combined with elevated TG-rich lipoproteins and small dense LDL. In this context, there is renewed interest in pharmacotherapeutic strategies involving niacin and fibrates in monotherapy and in association with statins. This comprehensive, critical review of available data in dyslipidemic subjects indicates that niacin is more efficacious in raising HDL-C than fibrates, whereas niacin and fibrates reduce TG-rich lipoproteins and LDL comparably. Niacin is distinguished by its unique capacity to effectively lower Lp(a) levels. Several studies have demonstrated anti-atherosclerotic action for both niacin and fibrates. In contrast with statin therapy, the clinical benefit of fibrates appears limited to reduction of nonfatal myocardial infarction, whereas niacin (frequently associated with statins and/or other agents) exerts benefit across a wider range of cardiovascular endpoints in studies involving limited patient numbers. Clearly the future treatment of atherogenic dyslipidemias involving the lipid triad, as exemplified by the occurrence of the mixed dyslipidemic phenotype in metabolic syndrome, type 2 diabetes, renal, and auto-immune diseases, requires integrated pharmacotherapy targeted not only to proatherogenic particles, notably VLDL, IDL, LDL, and Lp(a), but also to atheroprotective HDL.
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PMID:Niacin and fibrates in atherogenic dyslipidemia: pharmacotherapy to reduce cardiovascular risk. 2015 65

Retinoid X receptor (RXR) agonists are candidate agents for the treatment of metabolic syndrome and type 2 diabetes via activation of peroxisome proliferator-activated receptor (PPAR)/RXR or liver X receptor (LXR)/RXR-heterodimers, which control lipid and glucose metabolism. Reporter gene assays or binding assays with radiolabeled compounds are available for RXR ligand screening, but are unsuitable for high-throughput screening. Therefore, as a first step towards stabilizing a fluorescence polarization (FP) assay system for high-throughput RXR ligand screening, we synthesized fluorescent RXR ligands by modification of the lipophilic domain of RXR ligands with a carbostyril fluorophore, and selected the fluorescent RXR agonist 6-[ethyl(1-isobutyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinolin-7-yl)amino]nicotinic acid 8d for further characterization. Compound 8d showed FP in the presence of RXR and the FP was decreased in the presence of the RXR agonist LGD1069 (2). This compound should be a lead compound for use in high-throughput assay systems for screening RXR ligands.
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PMID:Fluorescent retinoid X receptor ligands for fluorescence polarization assay. 2066 26


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