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Nitridergic Modulation of the Antinociceptive Activity of Rosuvastatin in Mice  [PDF]
Viviana Noriega, Fernando Sierralta, Juan Carlos Prieto, Pilar Zanetta, Hugo F. Miranda
Pharmacology & Pharmacy (PP) , 2014, DOI: 10.4236/pp.2014.51010
Abstract:

Statins, 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase enzyme inhibitors, are lipid-lowering drugs, often used in the treatment of cardiovascular diseases (hyperlipidemia, atherosclerosis). It has been shown that statins have antiinflammatory effects independent of their lipid-lowering effects and these anti-inflammatory effects inhibit the inflammation and pain process. This study evaluated the antinociceptive and anti-inflammatory effects of rosuvastatin using the acetic acid writhing, the formalin hind paw, the orofacial formalin and the hot plate tests. The following experimental group were used: control, acute (1 day) and chronic (3 days) after oral gavage with rosuvastatin (3, 10, 30, 100 and 300 mg/kg). Rosuvastatin produced a dose-dependent antinociception, with different potency, in all the tests. Additionally, nitric oxide synthase inhibitors (Abbreviationsand aminoguanidine) were used to assess the nitric oxide participation on this induced rosuvastatin antinociception. The data demonstrated the antinociceptive and anti-inflammatory activity of rosuvastatin in algesiometer models of tonic or phasic pain. These activities seem to be induced by modulation of iNOS expression, a result that may be relevant in the pharmacological treatment of human pain where rosuvastatin and nitric oxide synthase inhibitors must be used.

Inhibition of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase (Ex Vivo) by Morus indica (Mulberry)  [PDF]
Vanitha Reddy Palvai,Asna Urooj
Chinese Journal of Biology , 2014, DOI: 10.1155/2014/318561
Abstract: Phytochemicals are the bioactive components that contribute to the prevention of cardiovascular and other degenerative diseases. Inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase would be an effective means of lowering plasma cholesterol in humans. The present study explores the HMG CoA reductase inhibitory effect of extracts from leaves of Morus indica varieties, M5, V1, and S36, compared with the statin, using an ex vivo method. The assay is based on the stoichiometric formation of coenzyme A during the reduction of microsomal HMG CoA to mevalonate. Dechlorophyllised extract of three varieties was studied at 300?μg. The coenzyme A released at the end of assay in control (100.31?nmoles) and statins (94.46?nm) was higher than the dechlorphyllised extracts of the samples. The coenzyme A released during the reduction of HMG CoA to mevalonate in dechlorophyllised extracts of the samples was as follows: S36 M5 V1. The results indicated that the samples were highly effective in inhibiting the enzyme compared to statins (standard drug). The results indicate the role of Morus varieties extracts in modulating the cholesterol metabolism by inhibiting the activity of HMG CoA reductase. These results provide scope for designing in vivo animal studies to confirm their effect. 1. Introduction Cholesterol as a constituent of all eukaryotic plasma membranes is essential for the growth and viability of higher organisms. For healthy statue cholesterol homeostasis is very important and is accomplished by a regulatory complex network [1]. The hypercholesterolemia and elevated LDL-C (LDL-cholesterol) concentration are the major risk factors for the development of atherosclerosis and coronary heart disease [2]. In this consequence, reducing plasma cholesterol levels is one of the major aims of public health organizations [3]. Hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA reductase) is the rate-limiting step in the biosynthesis of cholesterol in humans; inhibition of this enzyme would be an effective means of lowering plasma cholesterol. Drugs like statins, fibrates, niacin, and so forth are used to lower cholesterol. Due to the prevalence of these drugs adverse effects, search was made for an alternative natural drug [4]. Medicinal plants are good sources of therapeutic components and their use for medical purposes has a long history. Over past years, extracts of medicinal plants have gained increasing importance as a source of herbal drugs [5]. Exploration of the chemical constituents of the plants and pharmacological screening will thus
A Case of Dilated Cardiomyopathy Associated with 3-Hydroxy-3-Methylglutaryl-Coenzyme A (HMG CoA) Lyase Deficiency
Alexander A. C. Leung,Alicia K. Chan,Justin A. Ezekowitz,Alexander K. C. Leung
Case Reports in Medicine , 2009, DOI: 10.1155/2009/183125
Abstract: 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) lyase deficiency is an inborn error of metabolism characterized by impairment of ketogenesis and leucine catabolism resulting in an organic acidopathy. In 1994, a case of dilated cardiomyopathy and fatal arrhythmia was reported in a 7-month-old infant. We report a case of dilated cardiomyopathy in association with HMG CoA lyase deficiency in a 23-year-old man with the acute presentation of heart failure. To our knowledge, this is the first case reported in an adult.
Inhibitory Activity of Some Plant Methanol Extracts on 3-Hydroxy-3-Methylglutaryl Coenzyme a Reductase
A. Gholamhoseinian,B. Shahouzehi,F. Sharifi-Far
International Journal of Pharmacology , 2010,
Abstract: Beta-hydroxy-beta-methylglutaryl coenzyme a reductase (HMG CoA reductase) is the key enzyme in cholesterol biosynthesis. Inhibition of this enzyme reduces the synthesis of cholesterol and could be used in the management of coronary artery disease. Drugs used for the management of cholesterol biosynthesis have showed some side effects that are cause of new trends in the nature. This study was designed to find new HMG CoA reductase inhibitors from natural resources. One hundred plants were botanically identified and their methanol extracts were prepared. Anti HMG-CoA reductase activity of the extracts were determined spectrophotometrically by NADPH oxidation, using HMG-CoA as the substrate. Quercus infectoria, Rosa damascena and Myrtus communis extracts showed more than 50% inhibitory effect on the enzyme activity and 21 extracts showed an inhibitory effect between 30-50 percent on activity of HMG-CoA reductase. Kinetic study of the enzyme was performed in the presence of two concentrations of the effective extracts (0.05 and 0.15 mg mL-1). These active extracts showed non-competitive inhibition by Lineweaver-Burk plot analysis. Under the standard condition, Km value for enzyme was 0.6 mM and Vmax value was 0.011 mM min-1. When 0.15 mg mL-1 of extracts of Quercus infectoria, Rosa damascena and Myrtus communis were used the Vmax values of 0.0041, 0.0031 and 0.0028 mM min-1 were obtained, respectively. Therefore, purification and characterization of their active constituents and in vivo examination of these active extracts, is necessary in order to be used as safer therapeutic agents in the future.
Rosuvastatin, a new HMG-CoA Reeductase Inhibitor with advantages over other available statins  [cached]
Dr Vishal R.Tandon,Dr. B. M. Gupta
Pharmaceutical Reviews , 2005,
Abstract: The Food and Drug administration (FDA) approved a new HMG-CoA reductase inhibitor (rosuvastatin) on august, 2003. Rosuvastatin, is a synthetic, single enantiomer formulated and administered as the calcium salt. Although, dihydroxy heptenoic acid side chain is characteristic of the statin class, but one particular feature of the rosuvastatin molecule is a polar methane sulphonamide group that confers a relatively low lipophilicity, which make rosuvastatin relatively hydrophilic1,2 and hepatoselective1,2,3. Mechanism of action: rosuvastatin is a reversible competitive inhibitor of HMG-CoA reductase, which is the most important rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor for cholesterol1,4. In overall, few studies strongly suggest that rosuvastatin has the relatively greater binding to HMG-CoA reductase in comparison to other statins5,6. Rosuvastatin is relatively selective for liver and as a result of this action it increases the number of hepatic LDL receptors, which has been shown to increase ten time more by this drug in comparison to pravastatin2. This increase in LDL receptors enhances the uptake and catabolism of Low Density Lipoprotein (LDL) and Very Low-Density Lipoprotein (VLDL). This ultimately results in reduced concentrations of VLDL and LDL in the circulation2,4,7. Additionally, significant increase in High Density Lipoprotein (HDL) is also observed with the use of rosuvastatin8. It is more potent than other statins such as atorvastatin, simvastatin and is 8-fold more potent than the hydrophilic comparator, pravastatin5,6.
Molecular cloning, characterization and functional analysis of a 3-hydroxy-3- methylglutaryl coenzyme A reductase gene from Jatropha curcas
J Lin, Y Jin, M Zho, X Zhou, J Wang
African Journal of Biotechnology , 2009,
Abstract: 3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGR, EC: 1.1.1.34) catalyzes the first committed step in mevalonic acid (MVA) pathway for biosynthesis of isoprenoids. The full-length cDNA encoding HMGR was isolated from Jatropha curcas for the first time (designated as JcHMGR), which contained a 1950 bp ORF encoding 584 amino acids. The JcHMGR genomic DNA sequence was also obtained, revealing JcHMGR had 4 exons and 3 introns. The deduced JcHMGR protein showed high identity to other plant HMGRs and contained 2 transmembrane domains and a catalytic domain. The potential significance of JcHMGR gene was also discussed.
Long-term use of rosuvastatin: a critical risk benefit appraisal and comparison with other antihyperlipidemics  [cached]
Leonardo Calza
Drug, Healthcare and Patient Safety , 2009,
Abstract: Leonardo CalzaDepartment of Internal Medicine, Geriatrics and Nephrologic Diseases, Section of Infectious Diseases, “Alma Mater Studiorum” University of Bologna, S. Orsola-Malpighi Hospital, Bologna, ItalyAbstract: Rosuvastatin represents the latest inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase introduced in clinical practice for the treatment of hypercholesterolemia. In comparative trials, across dose ranges this statin reduced low-density lipoprotein (LDL) cholesterol and total cholesterol significantly more than atorvastatin, simvastatin, and pravastatin, and triglycerides significantly more than simvastatin and pravastatin. In healthy subjects with normal LDL cholesterol and elevated C-reactive protein, rosuvastatin treatment significantly decreased the incidence of cardiovascular events. Its chemical and pharmacokinetic properties (with a low lipophilicity and poor capacity to inhibit cytochrome P450 enzymes) suggest a very limited penetration in extrahepatic tissues with a lower risk of muscle toxicity and unlike metabolically mediated drug–drug interactions. This article reviews the most recent data on the pharmacologic and clinical properties of rosuvastatin, in order to enable the correct use of this statin for the treatment of hypercholesterolemia.Keywords: statin, HMG-CoA reductase, LDL cholesterol, pharmacokinetics, safety
Species-Specific Expansion and Molecular Evolution of the 3-hydroxy-3-methylglutaryl Coenzyme A Reductase (HMGR) Gene Family in Plants  [PDF]
Wei Li, Wei Liu, Hengling Wei, Qiuling He, Jinhong Chen, Baohong Zhang, Shuijin Zhu
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0094172
Abstract: The terpene compounds represent the largest and most diverse class of plant secondary metabolites which are important in plant growth and development. The 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR; EC 1.1.1.34) is one of the key enzymes contributed to terpene biosynthesis. To better understand the basic characteristics and evolutionary history of the HMGR gene family in plants, a genome-wide analysis of HMGR genes from 20 representative species was carried out. A total of 56 HMGR genes in the 14 land plant genomes were identified, but no genes were found in all 6 algal genomes. The gene structure and protein architecture of all plant HMGR genes were highly conserved. The phylogenetic analysis revealed that the plant HMGRs were derived from one ancestor gene and finally developed into four distinct groups, two in the monocot plants and two in dicot plants. Species-specific gene duplications, caused mainly by segmental duplication, led to the limited expansion of HMGR genes in Zea mays, Gossypium raimondii, Populus trichocarpa and Glycine max after the species diverged. The analysis of Ka/Ks ratios and expression profiles indicated that functional divergence after the gene duplications was restricted. The results suggested that the function and evolution of HMGR gene family were dramatically conserved throughout the plant kingdom.
The 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductases
Jon A Friesen, Victor W Rodwell
Genome Biology , 2004, DOI: 10.1186/gb-2004-5-11-248
Abstract: The human hmgr gene that encodes the single human HMG-CoA reductase is located on chromosome 5, map location 5q13.3-5q14, and is over 24.8 kilobases (kb) long. The 20 exons of the 4,475-nucleotide transcript, which range in size from 27 to 1,813 base-pairs, encode the membrane-anchor domain (exons 2-10), a flexible linker region (exons 10 and 11), and the catalytic domain (exons 11-20) of the resulting 888-residue polypeptide (Figure 1).Genome sequencing has identified hmgr genes in organisms from all three domains of life, and over 150 HMGR sequences are recorded in public databases. Higher animals, archaea, and eubacteria have only a single hmgr gene, although the lobster has both a soluble and a membrane-associated isozyme, both of which are encoded by a single gene). By contrast, plants, which use both HMGR-dependent and HMGR-independent pathways to synthesize isoprenoids, have multiple HMGR isozymes that appear to have arisen by gene duplication and subsequent sequence divergence [1]. Yeast has two HMGR isozymes derived from two different genes (hmgr-1 and hmgr-2). Comparison of amino-acid sequences and phylogenetic analysis reveals two classes of HMGR, the Class I enzymes of eukaryotes and some archaea and the Class II enzymes of certain eubacteria and archaea, suggesting evolutionary divergence between the two classes (Figure 2, Table 1) [2,3]. The catalytic domain is highly conserved in eukaryotes, but the membrane-anchor domain (consisting of between two and eight membrane-spanning helices) is poorly conserved, and the HMGRs of archaea and of certain eubacteria lack a membrane-anchor domain.The HMGRs of different organisms are multimers of a species-specific number of identical monomers. High-resolution crystal structures have been solved for the Class I human enzyme (HMGRH) [4,5] and for the Class II enzyme of Pseudomonas mevalonii (HMGRP) [6,7], including protein forms bound to either the HMG-CoA substrate or the coenzyme (NADH or NADPH) or both, or bound
The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, simvastatin, lovastatin and mevastatin inhibit proliferation and invasion of melanoma cells
Sharon A Glynn, Dermot O'Sullivan, Alex J Eustace, Martin Clynes, Norma O'Donovan
BMC Cancer , 2008, DOI: 10.1186/1471-2407-8-9
Abstract: The ability of lovastatin, mevastatin and simvastatin to inhibit the melanoma cell proliferation was examined using cytotoxicity and apoptosis assays. Effects on cell migration and invasion were assessed using transwell invasion and migration chambers. Hypothesis testing was performed using 1-way ANOVA, and Student's t-test.Lovastatin, mevastatin and simvastatin inhibited the growth, cell migration and invasion of HT144, M14 and SK-MEL-28 melanoma cells. The concentrations required to inhibit proliferation of melanoma cells (0.8–2.1 μM) have previously been achieved in a phase I clinical trial of lovastatin in patients with solid tumours, (45 mg/kg/day resulted in peak plasma concentrations of approximately 3.9 μM).Our results suggest that statin treatment is unlikely to prevent melanoma development at standard doses. However, higher doses of statins may have a role to play in adjuvant therapy by inhibiting growth and invasion of melanoma cells.The statins are group of drugs routinely used in the treatment of lipid disorders, including hypercholesterolemia. Statins exert their effects through the inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase). HMG-CoA reductase catalyses the conversion of HMG-CoA into mevalonate in the mevalonate biosynthetic pathway [1,2].In addition to the cholesterol lowering effects of statins, a number of recent studies suggest that the cancer incidence rates may be lower in patients receiving statins. The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) trial to evaluate the efficacy of lovastatin for preventing coronary events, found a significantly decreased incidence of new melanomas in the lovastatin arm compared with the placebo arm. In addition, among the 41 participants who developed melanoma, there was a trend, although not statistically significant, toward earlier stage at diagnosis in the lovastatin group [3]. A recent meta-analysis described the incidence of melanoma in 12
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