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Oliver Werz - One of the best experts on this subject based on the ideXlab platform.
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identification of multi target inhibitors of leukotriene and prostaglandin e2 biosynthesis by structural tuning of the flap inhibitor brp 7
European Journal of Medicinal Chemistry, 2018Co-Authors: Burcu Caliskan, Jana Gerstmeier, Oliver Werz, Uirike Garscha, Abdurrahman Olgac, Ulrich S Schubert, Erden BanogluAbstract:Abstract Leukotrienes (LTs) and prostaglandin (PG)E2 are enzymatically produced from arachidonic acid and represent highly bioactive lipid mediators with pro-inflammatory functions. Here, we report on novel multi-target inhibitors that potently and dually interfere with 5-Lipoxygenase-Activating Protein (FLAP) and microsomal prostaglandin E2 synthase (mPGES)-1 in LT and PGE2 biosynthesis, based on the previously identified selective FLAP inhibitor BRP-7 (8, IC50 = 0.31 μM). C (5)-substitution of the benzimidazole ring of BRP-7 by carboxylic acid and its bioisosteres provided compounds, exemplified by 57 that potently suppress LT formation (IC50 = 0.05 μM) by targeting FLAP along with inhibition of mPGES-1 (IC50 = 0.42 μM). Besides FLAP, also 5-lipoxygenase (5-LO) and LTC4 synthase activities were inhibited by 57, albeit with lower potency (IC50 = 0.6 and 6.2 μM) than FLAP. Docking studies and molecular dynamic simulations with FLAP, mPGES-1 and 5-LO provide valuable insights into potential binding interactions of the inhibitors with their targets. Together, these novel benzimidazole derivatives may possess potential as leads for development of effective anti-inflammatory drugs with multi-target properties for dually inhibiting LT and PGE2 production.
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an experimental cell based model for studying the cell biology and molecular pharmacology of 5 lipoxygenase activating Protein in leukotriene biosynthesis
Biochimica et Biophysica Acta, 2014Co-Authors: Jana Gerstmeier, Christina Weinigel, Dagmar Barz, Oliver Werz, Ulrike GarschaAbstract:Abstract Background Subcellular distribution of 5-lipoxygenase (5-LO) to the perinuclear region and interaction with the 5-LO-activating Protein (FLAP) are assumed as key steps in leukotriene biosynthesis and are prone to FLAP antagonists. Methods FLAP and/or 5-LO were stably expressed in HEK293 cells, 5-LO products were analyzed by HPLC, and 5-LO and FLAP subcellular localization was visualized by immunofluorescence microscopy. Results 5-LO and FLAP were stably expressed in HEK293 cells, and upon Ca 2 + -ionophore A23187 stimulation exogenous AA was efficiently transformed into the 5-LO products 5-hydro(pero)xyeicosatetraenoic acid (5-H(p)ETE) and the trans-isomers of LTB 4 . A23187 stimulation caused 5-LO accumulation at the nuclear membrane only when FLAP was co-expressed. Unexpectedly, A23187 stimulation of HEK cells expressing 5-LO and FLAP without exogenous AA failed in 5-LO product synthesis. HEK cells liberated AA in response to A23187, and transfected HEK cells expressing 12-LO generated 12-HETE after A23187 challenge from endogenous AA. FLAP co-expression increased 5-LO product formation in A23187-stimulated cells at low AA concentrations. Only in cells expressing FLAP and 5-LO, the FLAP antagonist MK886 blocked FLAP-mediated increase in 5-LO product formation, and prevented 5-LO nuclear membrane translocation and co-localization with FLAP. Conclusion The cellular biosynthesis of 5-LO products from endogenously derived substrate requires not only functional 5-LO/FLAP co-localization but also additional prerequisites which are dispensable when exogenous AA is supplied; identification of these determinants is challenging. General significance We present a cell model to study the role of FLAP as 5-LO interacting Protein in LT biosynthesis in intact cells and for characterization of putative FLAP antagonists.
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structure based discovery of inhibitors of microsomal prostaglandin e2 synthase 1 5 lipoxygenase and 5 lipoxygenase activating Protein promising hits for the development of new anti inflammatory agents
Journal of Medicinal Chemistry, 2011Co-Authors: Rosa De Simone, Maria Giovanna Chini, Ines Bruno, Raffaele Riccio, Daniela Mueller, Oliver Werz, Giuseppe BifulcoAbstract:Microsomal prostaglandin E2 synthase (mPGES)-1 catalyzes the transformation of PGH2 to PGE2 that is involved in several pathologies like fever, pain, and inflammatory disorders. To identify novel mPGES-1 inhibitors, we used in silico screening to rapidly direct the synthesis, based on the copper-catalyzed 3 + 2 Huisgen's reaction (click chemistry), of potential inhibitors. We designed 26 new triazole-based compounds in accordance with the pocket binding requirements of human mPGES-1. Docking results, in agreement with ligand efficiency values, suggested the synthesis of 15 compounds that at least in theory were shown to be more efficient in inhibiting mPGES-1. Biological evaluation of these selected compounds has disclosed three new potential anti-inflammatory drugs: (I) compound 4 displaying selectivity for mPGES-1 with an IC50 value of 3.2 μM, (II) compound 20 that dually inhibits 5-lipoxygenase and mPGES-1, and (III) compound 7 apparently acting as 5-Lipoxygenase-Activating Protein inhibitor (IC50 = 0....
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structure based discovery of inhibitors of microsomal prostaglandin e2 synthase 1 5 lipoxygenase and 5 lipoxygenase activating Protein promising hits for the development of new anti inflammatory agents
Journal of Medicinal Chemistry, 2011Co-Authors: Rosa De Simone, Maria Giovanna Chini, Ines Bruno, Raffaele Riccio, Daniela Mueller, Oliver Werz, Giuseppe BifulcoAbstract:Microsomal prostaglandin E2 synthase (mPGES)-1 catalyzes the transformation of PGH2 to PGE2 that is involved in several pathologies like fever, pain, and inflammatory disorders. To identify novel m...
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mk 886 an inhibitor of the 5 lipoxygenase activating Protein inhibits cyclooxygenase 1 activity and suppresses platelet aggregation
European Journal of Pharmacology, 2009Co-Authors: Andreas Koeberle, Ulf Siemoneit, Hinnak Northoff, Bettina Hofmann, Gisbert Schneider, Oliver WerzAbstract:MK-886, an inhibitor of the 5-Lipoxygenase-Activating Protein (FLAP), potently suppresses leukotriene biosynthesis in intact cells and is frequently used to define a role of the 5-lipoxygenase (EC 1.13.11.34) pathway in cellular or animal models of inflammation, allergy, cancer, and cardiovascular disease. Here we show that MK-886 also interferes with the activities of cyclooxygenases (COX, EC 1.14.99.1). MK-886 inhibited isolated COX-1 (IC(50)=8 microM) and blocked the formation of the COX-1-derived products 12(S)-hydroxy-5-cis-8,10-trans-heptadecatrienoic acid (12-HHT) and thromboxane B(2) in washed human platelets in response to collagen as well as from exogenous arachidonic acid (IC(50)=13-15 microM). Isolated COX-2 was less affected (IC(50)=58 microM), and in A549 cells, MK-886 (33 microM) failed to suppress COX-2-dependent 6-keto-prostaglandin (PG)F(1alpha) formation. The distinct susceptibility of MK-886 towards COX-1 and -2 is apparent in automated molecular docking studies that indicate a preferred binding of MK-886 to COX-1 into the active site. MK-886 (10 microM) inhibited COX-1-mediated platelet aggregation induced by collagen or arachidonic acid whereas thrombin- or U-46619-induced (COX-independent) aggregation was not affected. Since leukotrienes and prostaglandins share (patho)physiological properties in the development and regulation of carcinogenesis, inflammation, and vascular functions, caution should be used when interpreting data where MK-886 is used as tool to determine the involvement of FLAP and/or the 5-lipoxygenase pathway in respective experimental models.
He Guoping - One of the best experts on this subject based on the ideXlab platform.
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correlation of arachidonate 5 lipoxygenase activating Protein gene sg13s114t a polymorphism with acute coronary syndrome in male
Heart, 2012Co-Authors: He Guoping, Hui Jingjiao, Shen DandanAbstract:Objectives To investigate the possible association between arachidonate 5-lipoxygenase activating Protein (ALOX5AP) gene SG13S114T/A polymorphism and acute coronary syndrome (ACS) in male. Methods A case-control study was conducted in 374 ACS patients documented by coronary angiography and 288 control subjects without coronary artery disease. The ALOX5AP gene SG13S114T/A polymorphism was determined by PCR and restruction fragment length polymorphism analysis. Results Compared with those in control group, there was no statistical difference of frequencies of AA, AT and TT genotype (p>0.05) and the T allele frequency was obviously higher (68.06% vs 82.42%, p Conclusions The AT and TT genotype and the T allele of ALOX5AP gene SG13S114T/A may be associated with the susceptibility to ACS in male.
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interrelation among the serum leukotriene b4 level arachidonate 5 lipoxygenase activating Protein gene sg13s89g a polymorphism and risk of acute myocardial infarction
Heart, 2012Co-Authors: He Guoping, Hui Jingjiao, Ye Shan, Qi ChuanpingAbstract:Objectives To investigate the interrelation among the serum leukotriene (LT) B4 level, the arachidonate 5-lipoxygenase activating Protein (ALOX5AP) gene SG13S89G/A polymorphism and the risk of acute myocardial infarction (AMI) in the Chinese Han population of Changzhou region. Methods The polymorphism in the ALOX5AP gene SG13S89G/A was genotyped by PCR and restriction fragment length polymorphism analysis and the serum LTB4 level (M/IQR) was measured by ELISA in 262 patients with AMI (AMI group) and 132 subjects with chest pain who were free from coronary heart disease by coronarography (control group). Results As compared with those in control group, there were no significant differences in (AA+GA) and GG genetype (7.58% vs 4.96% and 92.42% vs 95.04%, respectively), and A allele frequencie (4.17% vs 2.67%) of ALOX5AP gene SG13S89G/A locus in AMI group (all the p value >0.05). Multivariable logistic regression analysis showed that there was no significant association between ALOX5AP gene SG13S89G/A polymorphism and the risk of AMI. The serum LTB4 level in AMI group was significantly higher than the one in control group (477.97/370.52 pg/ml vs 200.57/236.65 pg/ml, p 0.05). Conclusions The serum LTB4 level is significantly increased in patients with AMI; the ALOX5AP gene SG13S114G/A polymorphism may not be correlated to the risk of AMI and not influence the serum LTB4 level in Chinese Han population of Changzhou region.
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relationship of arachidonate 5 lipoxygenase activating Protein gene sg13s114t a polymorphism with acute myocardial infarction
Heart, 2012Co-Authors: He Guoping, Hui Jingjiao, Shen DandanAbstract:Objectives To investigate the association between 5-lipoxygenase activating Protein (ALOX5AP) gene SG13S114T/A polymorphism and acute myocardial infarction (AMI) in the Chinese Han population of Sunan region. Methods All of 300 patients with AMI and 415 control subjects free from coronary artery disease were recruited into the study. The ALOX5AP SG13S114T/A polymorph ism gene was determined by PCR and restriction fragment length polymorphism analysis. Results (1) Compared with the control group, there was statistical difference of the frequencies of TT and AT genotype in the AMI group (p value was 0.027 and 0.032 respectively); the frequencies of T allele was not significantly different (59.50% vs 64.82%, p=0.324). (2) subgroup revealed: The frequencies of AA, AT, TT genotype and the T allele of the SG13S114T/A had no association with AMI in male group, but the frequency of TT genotype had significant correlation with AMI in female. Multivariate logistic regression analysis indicated that there was significantly correlation between ALOX5AP gene SG13S114T/A AT and TT with AMI (p value was 0.000 and 0.001 respectively). Tallele had significantly association with AMI (p=0.038). There w as statistical difference of the frequencies of AT and TT genotype with AMI in both male and female (p value was 0.010 and 0.040 respectively in male group; p value was 0.010 and 0.004 respectively in female group), Tallele was a significant risk factor for AMI in the female carrier (p=0.026), but had no association with AMI in male (p=0.285). Conclusions Conclusion: The ALOX5AP gene SG13S114T/A polymorphism may be associated with the susceptibility to AMI in the Chinese Han population of Sunan region. The T allele was a significant genetical risk factor for AMI and was the susceptibility to AMI in the female.
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relationship of arachidonate 5 lipoxygenase activating Protein gene sg13s114t a polymorphism with the serum leukotriene b4 level in patients with acute myocardial infarction
Heart, 2012Co-Authors: He Guoping, Hui Jingjiao, Shen Dandan, Ye Shan, Qi ChuanpingAbstract:Objectives To investigate the association of the serum leukotrienes (LT) B4 level with the ALOX5AP gene SG13S114T/A polymorphism in patients with acute myocardial infarction (AMI) in Chinese Han population of Sunan region. Methods The ALOX5AP gene SG13S114T/A polymorphism was genotyped by PCR and restriction fragment length polymorphism analysis, and the serum LTB4 level (M/IQR) was measured by ELISA in 262 AMI patients (AMI group) and 132 subjects without coronary heart disease (CHD) (control group). Results Serum LTB4 level in AMI group was significantly higher than the one in control group (477.97/370.52 pg/ml vs 200.57/236.65 pg/ml, p 0.05), and there was also no significant difference in serum LTB4 level among any genotypes in this locus within the same gender (p>0.05). The serum LTB4 level was positively correlated with the smoking, and unrelated with the gender, age, hypertension, diabetes and hyperlipidaemia in AMI patients. Conclusions In Chinese Han population of Sunan region, there are polymorphisms of ALOX5AP gene SG13S114 in patients with AMI and subjects without CHD. The serum LTB4 level in AMI patients is higher than those in subjects without CHD, but unrelated with ALOX5AP gene SG13S114 polymorphism.
Shen Dandan - One of the best experts on this subject based on the ideXlab platform.
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correlation of arachidonate 5 lipoxygenase activating Protein gene sg13s114t a polymorphism with acute coronary syndrome in male
Heart, 2012Co-Authors: He Guoping, Hui Jingjiao, Shen DandanAbstract:Objectives To investigate the possible association between arachidonate 5-lipoxygenase activating Protein (ALOX5AP) gene SG13S114T/A polymorphism and acute coronary syndrome (ACS) in male. Methods A case-control study was conducted in 374 ACS patients documented by coronary angiography and 288 control subjects without coronary artery disease. The ALOX5AP gene SG13S114T/A polymorphism was determined by PCR and restruction fragment length polymorphism analysis. Results Compared with those in control group, there was no statistical difference of frequencies of AA, AT and TT genotype (p>0.05) and the T allele frequency was obviously higher (68.06% vs 82.42%, p Conclusions The AT and TT genotype and the T allele of ALOX5AP gene SG13S114T/A may be associated with the susceptibility to ACS in male.
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relationship of arachidonate 5 lipoxygenase activating Protein gene sg13s114t a polymorphism with acute myocardial infarction
Heart, 2012Co-Authors: He Guoping, Hui Jingjiao, Shen DandanAbstract:Objectives To investigate the association between 5-lipoxygenase activating Protein (ALOX5AP) gene SG13S114T/A polymorphism and acute myocardial infarction (AMI) in the Chinese Han population of Sunan region. Methods All of 300 patients with AMI and 415 control subjects free from coronary artery disease were recruited into the study. The ALOX5AP SG13S114T/A polymorph ism gene was determined by PCR and restriction fragment length polymorphism analysis. Results (1) Compared with the control group, there was statistical difference of the frequencies of TT and AT genotype in the AMI group (p value was 0.027 and 0.032 respectively); the frequencies of T allele was not significantly different (59.50% vs 64.82%, p=0.324). (2) subgroup revealed: The frequencies of AA, AT, TT genotype and the T allele of the SG13S114T/A had no association with AMI in male group, but the frequency of TT genotype had significant correlation with AMI in female. Multivariate logistic regression analysis indicated that there was significantly correlation between ALOX5AP gene SG13S114T/A AT and TT with AMI (p value was 0.000 and 0.001 respectively). Tallele had significantly association with AMI (p=0.038). There w as statistical difference of the frequencies of AT and TT genotype with AMI in both male and female (p value was 0.010 and 0.040 respectively in male group; p value was 0.010 and 0.004 respectively in female group), Tallele was a significant risk factor for AMI in the female carrier (p=0.026), but had no association with AMI in male (p=0.285). Conclusions Conclusion: The ALOX5AP gene SG13S114T/A polymorphism may be associated with the susceptibility to AMI in the Chinese Han population of Sunan region. The T allele was a significant genetical risk factor for AMI and was the susceptibility to AMI in the female.
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relationship of arachidonate 5 lipoxygenase activating Protein gene sg13s114t a polymorphism with the serum leukotriene b4 level in patients with acute myocardial infarction
Heart, 2012Co-Authors: He Guoping, Hui Jingjiao, Shen Dandan, Ye Shan, Qi ChuanpingAbstract:Objectives To investigate the association of the serum leukotrienes (LT) B4 level with the ALOX5AP gene SG13S114T/A polymorphism in patients with acute myocardial infarction (AMI) in Chinese Han population of Sunan region. Methods The ALOX5AP gene SG13S114T/A polymorphism was genotyped by PCR and restriction fragment length polymorphism analysis, and the serum LTB4 level (M/IQR) was measured by ELISA in 262 AMI patients (AMI group) and 132 subjects without coronary heart disease (CHD) (control group). Results Serum LTB4 level in AMI group was significantly higher than the one in control group (477.97/370.52 pg/ml vs 200.57/236.65 pg/ml, p 0.05), and there was also no significant difference in serum LTB4 level among any genotypes in this locus within the same gender (p>0.05). The serum LTB4 level was positively correlated with the smoking, and unrelated with the gender, age, hypertension, diabetes and hyperlipidaemia in AMI patients. Conclusions In Chinese Han population of Sunan region, there are polymorphisms of ALOX5AP gene SG13S114 in patients with AMI and subjects without CHD. The serum LTB4 level in AMI patients is higher than those in subjects without CHD, but unrelated with ALOX5AP gene SG13S114 polymorphism.
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arachidonate 5 lipoxygenase activating Protein gene sg13s114t a polymorphism and the susceptibility to acute coronary syndrome
Chinese Journal of Geriatric Heart Brain and Vessel Diseases, 2011Co-Authors: Shen DandanAbstract:Objective To investigate the possible association of arachidonate 5-lipoxygenase activating Protein(ALOX5AP)gene SG13S114T/A polymorphism with the susceptibility to acute coronary syndrome(ACS).Methods 714 in-patients with chest pain were chosen and were divided into ACS group(377 cases with ACS) and control group(337 subjects without ACS).The ALOX5AP gene SG13S114T/A polymorphism was determined by polymerase chain reaction and restriction fragment length polymorphism analysis,and multiple logistic regression analysis was performed.Results Genotype frequencies of ALOX5AP gene SG13S114T/A AA,AT and TT were 13.79%,50.93%and 35.28%respectively in patients of ACS group and 12.76%,38.58% and 48.66%respectively in control subjects.Compared with control group,there was statistical difference in frequencies of AT and TT genotypes in ACS group(P = 0.041,0.020).The AT genotype frequency in male ACS group was obeviously higher(40.7%vs 52.5%,P = 0.040) and the TT genotype frequency in female ACS group was significantly lower(61.8%vs 37.0%,P = 0.013) than control group.The frequencies of AT,TT genotypes and the T allele were related with attack of ACS(P = 0.004,0.001 and 0.013,respectively) and male ACS(P = 0.014,0.005 and 0.020,respectively).Conclusion The AT and TT genotypes and the T allele of ALOX5AP gene SG13S114T/A polymorphism may be associated with the susceptibility to ACS in the elderly, especially in the aged males.
Anna Helgadottir - One of the best experts on this subject based on the ideXlab platform.
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pde4d and alox5ap genetic variants and risk for ischemic cerebrovascular disease in sweden
Journal of the Neurological Sciences, 2007Co-Authors: Konstantinos Kostulas, Solveig Gretarsdottir, Vasilios Kostulas, Andrei Manolescu, Anna Helgadottir, Gudmar Thorleifsson, Larus J Gudmundsson, Unnur Thorsteinsdottir, Jeffrey R. Gulcher, Kari StefanssonAbstract:Abstract Background Genetic variants in Phosphodiesterase 4D ( PDE4D ) and 5-lipoxygenase activating Protein ( ALOX5AP ) have been shown to confer risk of Ischemic Cerebrovascular Disease (ICVD) in Iceland. We investigated whether these variants associate with ICVD in Sweden. Methods Previously published PDE4D and ALOX5AP gene variants were genotyped for cases (685) and controls (751). In PDE4D this consisted of SNP41, SNP45 and microsatellite AC008818-1 and in ALOX5AP four SNPs that define the HapA haplotype. Results The PDE4D SNPs, showed a non-significant risk in the ICVD group which increased for the Large Artery Atherosclerosis subtype (SNP45: RR=1.43, P =0.063, SNP41: RR=1.57, P =0.018). The SNP haplotype GA (SNP45, SNP41) showed an increased risk for LAA (RR=1.58, P =0.016) and the combined LAA and Cardioembolism (CE) (RR=1.34, P =0.031) subgroups. As the SNPs are in strong LD, this haplotype corresponds to the complement of the protective haplotype in the Icelandic study. No allele of the microsatellite marker, showed association to stroke or any subtype and nor did the Icelandic PDE4D at-risk haplotype (GA0). We did not confirm the association between ALOX5AP HapA haplotype and ICVD, but a non-significant risk was observed in the LAA subtype. Conclusion Our PDE4D findings although non-significant considering the number of markers and phenotypes tested, are consistent with the association observed in the original study, with a trend observed in the whole ICVD group, which was strengthened in the stroke subtype LAA and the combined group of LAA and CE stroke. This supports the notion that PDE4D contributes to the risk of developing stroke.
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A variant of the gene encoding leukotriene A4 hydrolase confers ethnicity-specific risk of myocardial infarction.
Nature Genetics, 2005Co-Authors: Anna Helgadottir, Agnar Helgason, Daniel F. Gudbjartsson, Kristinn P. Magnusson, Gudmundur Gudmundsson, Solveig Gretarsdottir, Andrei Manolescu, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Andrew A. HicksAbstract:Variants of the gene ALOX5AP (also known as FLAP) encoding arachidonate 5-lipoxygenase activating Protein are known to be associated with risk of myocardial infarction 1 . Here we show that a haplotype (HapK) spanning the LTA4H gene encoding leukotriene A4 hydrolase, a Protein in the same biochemical pathway as ALOX5AP, confers modest risk of myocardial infarction in an Icelandic cohort. Measurements of leukotriene B4 (LTB4) production suggest that this risk is mediated through upregulation of the leukotriene pathway. Three cohorts from the United States also show that HapK confers a modest relative risk (1.16) in European Americans, but it confers a threefold larger risk in African Americans. About 27% of the European American controls carried at least one copy of HapK, as compared with only 6% of African American controls. Our analyses indicate that HapK is very rare in Africa and that its occurrence in African Americans is due to European admixture. Interactions with other genetic or environmental risk factors that are more common in African Americans are likely to account for the greater relative risk conferred by HapK in this group.
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effects of a 5 lipoxygenase activating Protein inhibitor on biomarkers associated with risk of myocardial infarction a randomized trial
JAMA, 2005Co-Authors: Hakon Hakonarson, Daniel F. Gudbjartsson, Andrei Manolescu, Anna Helgadottir, Sverrir Thorvaldsson, Florian Zink, Margret B Andresdottir, David O Arnar, Karl Andersen, Axel SigurdssonAbstract:ContextMyocardial infarction (MI) is the leading cause of death in the world. Variants in the 5-lipoxygenase–activating Protein (FLAP) gene are associated with risk of MI.ObjectiveTo determine the effect of an inhibitor of FLAP on levels of biomarkers associated with MI risk.Design, Setting, and PatientsA randomized, prospective, placebo-controlled, crossover trial of an inhibitor of FLAP (DG-031) in MI patients who carry at-risk variants in the FLAP gene or in the leukotriene A4 hydrolase gene. Of 268 patients screened, 191 were carriers of at-risk variants in FLAP (87%) or leukotriene A4 hydrolase (13%). Individuals were enrolled in April 2004 and were followed up by designated cardiologists from a university hospital in Iceland until September 2004.InterventionsPatients were first randomized to receive 250 mg/d of DG-031, 500 mg/d of DG-031, 750 mg/d of DG-031, or placebo. After a 2-week washout period, patients received DG-031 if they had received placebo first or placebo if they had received DG-031 first. Treatment periods lasted for 4 weeks.Main Outcome MeasuresChanges in levels of biomarkers associated with risk of MI.ResultsIn response to 750 mg/d of DG-031, production of leukotriene B4 was significantly reduced by 26% (95% confidence interval [CI], 10%-39%; P = .003) and myeloperoxidase was significantly reduced by 12% (95% CI, 2%-21%; P = .02). The higher 2 doses of DG-031 produced a nonsignificant reduction in C-reactive Protein (16%; 95% CI, −2% to 31%; P = .07) at 2 weeks. However, there was a more pronounced reduction (25%; 95% CI, 5%-40%; P = .02) in C-reactive Protein at the end of the washout period that persisted for another 4 weeks thereafter. The FLAP inhibitor DG-031 was well tolerated and was not associated with any serious adverse events.ConclusionIn patients with specific at-risk variants of 2 genes in the leukotriene pathway, DG-031 led to significant and dose-dependent suppression of biomarkers that are associated with increased risk of MI events.
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association between the gene encoding 5 lipoxygenase activating Protein and stroke replicated in a scottish population
American Journal of Human Genetics, 2005Co-Authors: Anna Helgadottir, Solveig Gretarsdottir, Andrei Manolescu, Gudmar Thorleifsson, Struan F A Grant, D St Clair, J Cheung, Alireza Pasdar, Lawrence J Whalley, Hakon HakonarsonAbstract:Cardiovascular diseases, including myocardial infarction (MI) and stroke, most often occur on the background of atherosclerosis, a condition attributed to the interactions between multiple genetic and environmental risk factors. We recently reported a linkage and association study of MI and stroke that yielded a genetic variant, HapA, in the gene encoding 5-lipoxygenase–activating Protein (ALOX5AP), that associates with both diseases in Iceland. We also described another ALOX5AP variant, HapB, that associates with MI in England. To further assess the contribution of the ALOX5AP variants to cardiovascular diseases in a population outside Iceland, we genotyped seven single-nucleotide polymorphisms that define both HapA and HapB from 450 patients with ischemic stroke and 710 controls from Aberdeenshire, Scotland. The Icelandic at-risk haplotype, HapA, had significantly greater frequency in Scottish patients than in controls. The carrier frequency in patients and controls was 33.4% and 26.4%, respectively, which resulted in a relative risk of 1.36, under the assumption of a multiplicative model (P=.007). We did not detect association between HapB and ischemic stroke in the Scottish cohort. However, we observed that HapB was overrepresented in male patients. This replication of haplotype association with stroke in a population outside Iceland further supports a role for ALOX5AP in cardiovascular diseases.
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the gene encoding 5 lipoxygenase activating Protein confers risk of myocardial infarction and stroke
Nature Genetics, 2004Co-Authors: Anna Helgadottir, Gudmundur Gudmundsson, Solveig Gretarsdottir, Andrei Manolescu, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Helga Jonsdottir, Nilesh J Samani, Struan F A Grant, Gudmundur ThorgeirssonAbstract:We mapped a gene predisposing to myocardial infarction to a locus on chromosome 13q12–13. A four-marker single-nucleotide polymorphism (SNP) haplotype in this locus spanning the gene ALOX5AP encoding 5-lipoxygenase activating Protein (FLAP) is associated with a two times greater risk of myocardial infarction in Iceland. This haplotype also confers almost two times greater risk of stroke. Another ALOX5AP haplotype is associated with myocardial infarction in individuals from the UK. Stimulated neutrophils from individuals with myocardial infarction produce more leukotriene B4, a key product in the 5-lipoxygenase pathway, than do neutrophils from controls, and this difference is largely attributed to cells from males who carry the at-risk haplotype. We conclude that variants of ALOX5AP are involved in the pathogenesis of both myocardial infarction and stroke by increasing leukotriene production and inflammation in the arterial wall.
Giuseppe Bifulco - One of the best experts on this subject based on the ideXlab platform.
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structure based discovery of inhibitors of microsomal prostaglandin e2 synthase 1 5 lipoxygenase and 5 lipoxygenase activating Protein promising hits for the development of new anti inflammatory agents
Journal of Medicinal Chemistry, 2011Co-Authors: Rosa De Simone, Maria Giovanna Chini, Ines Bruno, Raffaele Riccio, Daniela Mueller, Oliver Werz, Giuseppe BifulcoAbstract:Microsomal prostaglandin E2 synthase (mPGES)-1 catalyzes the transformation of PGH2 to PGE2 that is involved in several pathologies like fever, pain, and inflammatory disorders. To identify novel mPGES-1 inhibitors, we used in silico screening to rapidly direct the synthesis, based on the copper-catalyzed 3 + 2 Huisgen's reaction (click chemistry), of potential inhibitors. We designed 26 new triazole-based compounds in accordance with the pocket binding requirements of human mPGES-1. Docking results, in agreement with ligand efficiency values, suggested the synthesis of 15 compounds that at least in theory were shown to be more efficient in inhibiting mPGES-1. Biological evaluation of these selected compounds has disclosed three new potential anti-inflammatory drugs: (I) compound 4 displaying selectivity for mPGES-1 with an IC50 value of 3.2 μM, (II) compound 20 that dually inhibits 5-lipoxygenase and mPGES-1, and (III) compound 7 apparently acting as 5-Lipoxygenase-Activating Protein inhibitor (IC50 = 0....
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structure based discovery of inhibitors of microsomal prostaglandin e2 synthase 1 5 lipoxygenase and 5 lipoxygenase activating Protein promising hits for the development of new anti inflammatory agents
Journal of Medicinal Chemistry, 2011Co-Authors: Rosa De Simone, Maria Giovanna Chini, Ines Bruno, Raffaele Riccio, Daniela Mueller, Oliver Werz, Giuseppe BifulcoAbstract:Microsomal prostaglandin E2 synthase (mPGES)-1 catalyzes the transformation of PGH2 to PGE2 that is involved in several pathologies like fever, pain, and inflammatory disorders. To identify novel m...
