interacts_with DB01095?
A P04035 inhibitor possesses a potent anti-atherosclerotic effect other than serum lipid lowering effects -- the relevance of endothelial nitric oxide synthase and superoxide anion scavenging action . We have determined whether the anti-atherosclerotic effect of a 3-hydroxy-3-methyl-glutaryl- DB01992 ( HMG- DB01992 ) reductase inhibitor ( fluvastatin ) is mediated through nitric oxide ( NO ) as well as affecting plasma lipids . NO related vascular responses , endothelial nitric oxide synthase ( P29474 ) mRNA and superoxide anion ( O(2)(-) ) release were examined in vascular walls of oophorectomized female rabbits fed 0.5 % cholesterol chow for 12 weeks with or without fluvastatin ( 2 mg/kg per day ) . Serum lipid profile was not different between two groups . NO dependent responses stimulated by acetylcholine and calcium ionophore A23187 and tone related basal NO response induced by N(G)-monomethyl-L-arginine acetate ( L- Q13145 ) ; nitric oxide synthase inhibitor were all improved by fluvastatin treatment . Endothelium independent vasorelaxation induced by nitroglycerin was not different between the two groups of rabbits ' arteries . DB01095 treatment increased cyclic GMP concentration in aorta of rabbits . P29474 mRNA expression and O(2)(-) release were measured in aorta using competitive reverse transcription-polymerase chain reaction ( RT-PCR ) and with lucigenin analogue , 2-methyl-3,7-dihydroimidazol [1,2-a]pyrazine-3-one ( MCLA ) chemiluminescence methods . P29474 mRNA in the endothelial cells of aorta was significantly up-regulated and O(2)(-) production was significantly reduced in fluvastatin treated rabbit aorta . Anti-macrophage staining area , but not anti-smooth muscle cell derived actin stained area in the aorta was also reduced by fluvastatin treatment . Conclusion , fluvastatin , a P04035 inhibitor , retards the initiation of atherosclerosis formation through the improvement of NO bioavailability by both up-regulation of P29474 mRNA and decrease of O(2)(-) production in vascular endothelial cells , and this means that part of the anti-atherosclerotic effect of fluvastatin may be due to nonlipid factors . DB01095 inhibits growth and alters the malignant phenotype of the P13671 glioma cell line . BACKGROUND : DB01095 is a member of the family of P04035 inhibitors ( statins ) extensively used in medical practice . Increasing evidence suggests that fluvastatin may be implicated in suppression of cancer growth and development . The aim of the present study was to investigate the anti-cancer potential of fluvastatin in P13671 rat malignant glioma cells . METHODS : First , the effects of fluvastatin on cell viability ( MTT assay ) , proliferation ( BrdU assay ) , cell morphology , and cytoskeleton were examined . Subsequently , its effect on extracellular signal regulated kinase 1 and 2 ( P27361 /2 ) and P45983 and 2 ( JNK 1/2 ) expression was estimated by Western blot . Finally , the influence of fluvastatin on cell migration and production of P14780 and P15692 was determined using a wound-healing assay and ELISA test , respectively . RESULTS : The results obtained showed that fluvastatin had a remarkable inhibitory and cytotoxic effect on tumor P13671 cells ( IC(50) = 8.6 μM , 48 h ) , but did not inhibit the growth of normal neuronal cells . The concentrations from 1 to 10 μM induced marked morphologic alterations typical for apoptosis including shrinkage of cytoplasm , chromatin condensation , and nucleus breakdown . CONCLUSION : The inhibitory effects of fluvastatin on cell proliferation seemed to be associated with decreased p- P27361 /2 expression , upregulation of p- P45983 /2 , and reduction in the P14780 and P15692 concentrations in culture media . The high anticancer ( antiproliferative , proapoptotic , antiinvasive ) activity of fluvastatin and lack of its toxicity against normal cells indicate a potential use of this statin in the treatment of malignant glioma . A randomized , placebo-controlled study of the effects of the p38 MAPK inhibitor SB- DB05250 on blood biomarkers of inflammation in P48444 patients . The p38 mitogen-activated protein kinase ( MAPK ) signaling upregulates inflammation and is known to be increased in chronic obstructive pulmonary disease ( P48444 ) . The authors assessed the pharmacology of the novel p38 MAPK inhibitor SB- DB05250 using blood biomarkers in P48444 . Seventeen P48444 patients ( forced expiratory volume in 1 second 50 % -80 % predicted ) using short-acting bronchodilators participated in a double-blind , double-dummy , randomized , crossover study . Patients received single oral doses of SB- DB05250 7.5 mg and 25 mg , prednisolone 10 mg and 30 mg , and placebo . Blood was obtained predose and at 1 , 2 , 6 , and 24 hours postdose . Whole-blood sorbitol-induced phosphorylated ( p ) heat shock protein ( HSP ) 27 levels as a marker of p38 pathway activation and lipopolysaccharide-induced tumor necrosis factor ( P01375 ) -alpha production were assessed . Both doses of SB- DB05250 , but not prednisolone , significantly ( P < .0001 ) reduced weighted mean ( WM ) pHSP27 ( 0-6 hours ) by 58 % compared with placebo . WM P01375 production ( 0-24 hours ) was significantly reduced compared with placebo by SB- DB05250 25 mg ( 40 % , P = .005 ) and 7.5 mg ( 33.4 % , P = .02 ) , while prednisolone 30 mg and 10 mg caused 81.5 % and 58.2 % suppression , respectively ( both P < .0001 ) . SB- DB05250 inhibited the p38 MAPK pathway to a greater degree than prednisolone did . SB- DB05250 inhibited P01375 production . SB- DB05250 is a potent p38 MAPK inhibitor that potentially suppresses inflammation in P48444 . DB00594 derivatives induce apoptosis by depleting ER Ca(2+) stores in vascular endothelial cells . BACKGROUND AND PURPOSE : DB00594 derivatives are blockers of the Na(+)/H(+) exchanger ( NHE ) and at micromolar concentrations have protective effects on cardiac and brain ischaemia/reperfusion injury but at higher concentrations also induce apoptosis . Here , we aimed to elucidate the mechanism related to this cytotoxic action . EXPERIMENTAL APPROACH : We quantified the expression of genes associated with endoplasmic reticulum ( ER ) stress and measured changes in luminal ER Ca(2+) concentration ( [Ca(2+)](ER) ) with a ' cameleon ' indicator , D1ER . KEY RESULTS : DB00594 derivatives induced apoptosis in vascular endothelial cells , an effect that increased at alkaline extracellular pH . The potency order for cytotoxicity was 5-(N,N-hexamethylene)-amiloride ( HMA ) > 5-(N-methyl-N-isobutyl) amiloride > 5-(N-ethyl-N-isopropyl) amiloride ( EIPA ) >> amiloride . HMA dose-dependently increased the transcription of the ER stress genes P35638 and O75807 and rapidly depleted [Ca(2+)](ER) , mimicking the effects of the sarco/endoplasmic reticulum ATPase ( SERCA ) inhibitor thapsigargin . The P19634 -specific inhibitor HOE 694 inhibited NHE activity by 87 % but did not alter [Ca(2+)](ER) . The decrease in [Ca(2+)](ER) evoked by amiloride derivatives was also observed in HeLa cells and was mirrored by an increase in cytosolic Ca(2+) concentration . CONCLUSIONS AND IMPLICATIONS : DB00594 derivatives disrupt ER and cytosolic Ca(2+) homeostasis by a mechanism unrelated to NHE inhibition , most likely by interfering with the activity of SERCA . We propose that ER Ca(2+) depletion and subsequent ER stress provide a rationale framework for the apoptotic effects of amiloride derivatives . DB06589 for the treatment of patients with advanced renal cell carcinoma . Dramatic advances in the care of patients with advanced renal cell carcinoma have occurred over the last ten years , including insights into the molecular pathogenesis of this disease , that have now been translated into paradigm-changing therapeutic strategies . Elucidating the importance of signaling cascades related to angiogenesis is notable among these achievements . DB06589 is a novel small molecule tyrosine kinase inhibitor that targets P17948 , -2 , and -3 ; P09619 -α , P09619 -β ; and c-kit tyrosine kinases . This agent exhibits a distinct pharmacokinetic profile as well as toxicity profile compared to other agents in the class of P15692 signaling pathway inhibitors . This review will discuss the scientific rationale for the development of pazopanib , as well as preclinical and clinical trials that led to approval of pazopanib for patients with advanced renal cell carcinoma . The most recent information , including data from 2010 national meeting of the American Society of Clinical Oncology , and the design of ongoing Phase III trials , will be discussed . Finally , an algorithm utilizing Level I evidence for the treatment of patients with this disease will be proposed . Potential opposite roles of the extracellular signal-regulated kinase ( P29323 ) pathway in autism spectrum and bipolar disorders . Signal transduction from the synapse to the nucleus subsequently involves transient increases in synaptic Ca2+ , activation of P62158 kinases , activation of the GTPase Ras , activation of the P29323 mitogen-activated protein kinase pathway , and finally GSK3 inhibition and CREB-activation . Genetic studies in autism have identified mutations and copy number variations in a number of genes involved in this synapse to nucleus signaling path . In particular , a gain of function mutation in the Q13936 gene , deletions and disruption of the Q96PV0 gene , a copy number variation encompassing the P27361 gene and a duplication of P62258 indicate that in a subset of autism patients the P29323 cascade is inappropriately activated . Predicted functional consequences of this hyperactivation would be an increase in complexity of the dendritic tree , and via inhibition of GSK3 , a delayed circadian phase . The latter effect indeed fits the frequent sleep disturbances observed in autistic patients . Interestingly , the sleep disturbances in bipolar disorder patients are frequently characterized as phase advanced . A selective evaluation of genetic mutations in bipolar patients indicates that the activity of the P29323 cascade , at least in a subset of patients , presumably is hypoactive . Thus , with respect to the P29323 pathway , autism and bipolar disorder seem each other 's counter pole . P01308 resistance determines phagocytic nicotinamide adenine dinucleotide phosphate oxidase overactivation in metabolic syndrome patients . OBJECTIVE : Metabolic syndrome ( MetS ) is associated with insulin resistance and increases the cardiovascular risk . Oxidative stress constitutes a potential mechanism that links insulin resistance and cardiovascular disease . The aim of this study was to analyze the relationship of NADPH oxidase activation with insulin resistance , and the effect of this interaction on the cardiovascular risk in MetS patients . METHODS : NADPH oxidase-dependent superoxide production and expression was evaluated by luminescence and western blot , respectively , in peripheral blood mononuclear cells obtained from 125 patients with MetS . P01308 resistance was defined by the homeostasis model assessment index . P14780 was quantified by enzyme-linked immunosorbent assay in plasma samples . To ascertain the mechanisms involved in vivo , we performed in-vitro experiments in cultured macrophages . RESULTS : Fifty-six percent of patients with MetS showed insulin resistance . Plasma matrix metalloproteinase-9 levels were higher ( P < 0.05 ) in insulin-resistant patients than in patients with insulin sensitivity . NADPH oxidase-dependent superoxide production was augmented ( P < 0.05 ) in insulin-resistant patients with respect to insulin-sensitive patients . The interaction between insulin resistance and abnormally high NADPH oxidase-mediated superoxide production was associated with the highest matrix metalloproteinase-9 values . Increased NADPH oxidase-dependent superoxide production was significantly associated with higher NADPH oxidase P13498 expression in insulin-resistant than in insulin-sensitive patients . Interestingly , insulin upregulated P13498 in peripheral blood mononuclear cells and in murine macrophages . CONCLUSION : P01308 resistance is associated with phagocytic NADPH oxidase activation . This association results in the highest cardiovascular risk in MetS patients . Initial characterization of the glutamate-cysteine ligase modifier subunit Gclm(-/-) knockout mouse . Novel model system for a severely compromised oxidative stress response . Glutamate-cysteine ligase ( GCL ) is the rate-limiting enzyme in the DB00143 biosynthesis pathway . In higher eukaryotes , this enzyme is a heterodimer comprising a catalytic subunit ( P48506 ) and a modifier subunit ( P48507 ) , which change the catalytic characteristics of the holoenzyme . To define the cellular function of P48507 , we disrupted the mouse Gclm gene to create a null allele . Gclm(-/-) mice are viable and fertile and have no overt phenotype . In liver , lung , pancreas , erythrocytes , and plasma , however , DB00143 levels in Gclm(-/-) mice were 9-16 % of that in Gclm(+/+) littermates . DB00151 levels in Gclm(-/-) mice were 9 , 35 , and 40 % of that in Gclm(+/+) mice in kidney , pancreas , and plasma , respectively , but remained unchanged in the liver and erythrocytes . Comparing the hepatic GCL holoenzyme with P48506 in the genetic absence of P48507 , we found the latter had an approximately 2-fold increase in K(m) for glutamate and a dramatically enhanced sensitivity to DB00143 inhibition . The major decrease in DB00143 , combined with diminished GCL activity , rendered Gclm(-/-) fetal fibroblasts strikingly more sensitive to chemical oxidants such as H(2)O(2) . We conclude that the Gclm(-/-) mouse represents a model of chronic DB00143 depletion that will be very useful in evaluating the role of the P48507 subunit and DB00143 in numerous pathophysiological conditions as well as in environmental toxicity associated with oxidant insult . Combined effect of oxidative stress-related gene polymorphisms on atherosclerosis . It is well known that oxidative stress plays critical roles in the pathogenesis of atherosclerosis . In this study , we enrolled 1746 type 2 diabetic subjects , determined 4 common genetic variants related to oxidative stress ( glutamate-cysteine ligase modifier subunit ( P48507 ) C-588T , myeloperoxidase G-463A , human paraoxonase 1 Gln192Arg and NAD(P)H oxidase P13498 C242T polymorphisms ) , and measured carotid intima-media thickness ( IMT ) as a surrogate marker for atherosclerosis . P48507 C-588T polymorphism was associated with average IMT ( AveIMT ) ( r=0.090 , p=0.0008 ) , but the association between the other 3 polymorphisms and AveIMT did not reach the statistical significance . However , AveIMT was significantly greater as the total number of 4 concomitant " pro-oxidant alleles " in each subject was increased ( r=0.108 , p < 0.0001 ) . Furthermore , the number of " pro-oxidant alleles " was a risk factor for a high AveIMT independently of conventional risk factors ( p=0.0003 ) . In conclusion , accumulation of oxidative stress-associated alleles was associated with carotid atherosclerosis in type 2 diabetic patients . Effect of pioglitazone treatment on endoplasmic reticulum stress response in human adipose and in palmitate-induced stress in human liver and adipose cell lines . Obesity and elevated cytokine secretion result in a chronic inflammatory state and may cause the insulin resistance observed in type 2 diabetes . Recent studies suggest a key role for endoplasmic reticulum stress in hepatocytes and adipocytes from obese mice , resulting in reduced insulin sensitivity . To address the hypothesis that thiazolidinediones , which improve peripheral insulin sensitivity , act in part by reducing the endoplasmic reticulum stress response , we tested subcutaneous adipose tissue from 20 obese volunteers treated with pioglitazone for 10 wk . We also experimentally induced endoplasmic reticulum stress using palmitate , tunicamycin , and thapsigargin in the human HepG2 liver cell line with or without pioglitazone pretreatment . We quantified endoplasmic reticulum stress response by measuring both gene expression and phosphorylation . Pioglitazone significantly improved insulin sensitivity in human volunteers ( P = 0.002 ) but did not alter markers of endoplasmic reticulum stress . Differences in pre- and posttreatment endoplasmic reticulum stress levels were not correlated with changes in insulin sensitivity or body mass index . In vitro , palmitate , thapsigargin , and tunicamycin but not oleate induced endoplasmic reticulum stress in HepG2 cells , including increased transcripts P35638 , O75460 , O75807 , and Q9NZJ5 , and increased P17861 splicing along with phosphorylation of eukaryotic initiation factor eIF2alpha , P45983 , and c-jun . Although patterns of endoplasmic reticulum stress response differed among palmitate , tunicamycin , and thapsigargin , pioglitazone pretreatment had no significant effect on any measure of endoplasmic reticulum stress , regardless of the inducer . Together , our data suggest that improved insulin sensitivity with pioglitazone is not mediated by a reduction in endoplasmic reticulum stress . Q07973 as a potential target for cancer therapy . Increasing evidence has accumulated to suggest that vitamin D may reduce the risk of cancer through its biologically active metabolite , DB00136 , which inhibits proliferation and angiogenesis , induces differentiation and apoptosis , and regulates many other cellular functions . Thus , it is plausible to assume that rapid clearance of DB00136 by highly expressed Q07973 could interrupt the normal physiology of cells and might be one cause of cancer initiation and progression . In fact , enhancement of Q07973 expression has been reported in literature for many cancers . Based on these findings , Q07973 -specific inhibitors and vitamin D analogs which are resistant to Q07973 -dependent catabolism might be useful for cancer treatment . Q07973 -specific inhibitor VID400 , which is an azole compound , markedly enhanced and prolonged the antiproliferative activity of DB00136 in the human keratinocytes . Likewise , Q07973 -resistant analogs such as 2α-(3-hydroxypropoxy)- DB00136 ( O2C3 ) and its P06681 -epimer ED-71 ( DB05295 ) , and 19nor- 2α-(3-hydroxypropyl)- DB00136 ( MART-10 ) showed potent biological effects . Our in vivo studies using rats revealed that MART-10 had a low calcemic effect , which is a suitable property as an anticancer drug . Much lower affinity of MART-10 for vitamin D binding protein ( DBP ) as compared with DB00136 may be related to its more potent cellular activities . Based on these results , we conclude that ( 1 ) high affinity for P11473 , ( 2 ) resistance to Q07973 -dependent catabolism , ( 3 ) low affinity for DBP , and ( 4 ) low calcemic effect may be required for designing potent vitamin D analogs for cancer treatment . Statin decreases endothelial microparticle release from human coronary artery endothelial cells : implication for the Rho-kinase pathway . OBJECTIVE : Elevated plasma levels of endothelial microparticles ( EMPs ) are associated with the presence of clinical atherosclerosis . Considering the anti-inflammatory properties of P04035 inhibitors on the endothelium , we studied the effect of fluvastatin on the release of EMPs in cultured human coronary artery endothelial cells ( HCAEC ) . METHODS AND RESULTS : EMPs were generated in P01375 -activated HCAECs . The absolute number of EMPs was enumerated using a novel two-color flow cytometric immunostaining technique with TruCount beads as an internal reference . EMPs are defined as EC membrane vesicles ( 1-2 microm in size ) with a characteristic immunophenotype . The addition of fluvastatin to P01375 -activated HCAECs significantly suppressed Q7L5Y9 release . DB01095 suppressed P01375 -induced Rho activation . The Rho-kinase inhibitor , Y-27632 , reproduced the effect of statin . CONCLUSION : Q7L5Y9 release from P01375 -activated HCAECs is suppressed by fluvastatin . In addition , the Rho/Rho-kinase may play an important role in modulating Q7L5Y9 release . DB00435 modulates the frog heart ventricle morphodynamics . The aim of this work was to investigate in the avascular heart of the frog Rana esculenta the influence of nitric oxide ( NO ) on ventricular systolic and diastolic functions by using a novel image analysis technique . The external volume variations of the whole ventricle were monitored during the heart cycle by video acquisition ( visible light ) and analysed by an appropriately developed software with a specific formula for irregular convex solids . The system , which measures the rate of volume changes and the ejection fraction , directly determined the volumetric behaviour of the working frog heart after stimulation or inhibition of NOS-NOcGMP pathway . End-diastolic volume ( EDVext ) , end-systolic volume ( ESVext ) , contraction and relaxation velocities ( dV/dtsys and dV/dtdia , respectively ) , stroke volume ( SV ) and ejection fraction ( EF ) , were measured before and after perfusion with NOS substrate ( L-arginine ) , NO donor ( SIN-1 ) , cGMP analogue (8-Br-cGMP),NOS inhibitors ( NG-monomethyl-L-arginine , L-NMMA ; L-N(5)-(1-iminoethyl)-ornithine , L-NIO ; DB02207 ,7-NI ) and guanylyl cyclase inhibitor ( ODQ ) . The results showed that NO reduces ventricular systolicfunction improving diastolic filling , while NOS inhibition increases contractility impairing ventricular filling capacity . The presence of activated P29474 ( p- P29474 ) was morphologically documented , further supporting that the mechanical activity of the ventricular pump in frog is influenced by a tonic release of NOS-generated NO . Discrimination between agonists and antagonists by the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid-selective glutamate receptor . A mutation analysis of the ligand-binding domain of P48058 subunit . The crystal structures of the ligand-binding core of the agonist complexes of the glutamate receptor-B ( P42262 ) subunit of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid ( AMPA ) -selective glutamate receptor indicate that the distal anionic group of agonist molecules are stabilized by interactions with an N-terminal region of an alpha-helix ( helix F ) in the lobe 2 ( " domain 2 , " Armstrong , N. , and Gouaux , E. ( 2000 ) Neuron 28 , 165-181 ) of the two-lobed ligand-binding domain . We used site-directed mutagenesis to further analyze the role of this region in the recognition of both agonists and antagonists by the AMPA receptor . Wild-type and mutated versions of the ligand-binding domain of P48058 were expressed in insect cells as secreted soluble polypeptides and subjected to binding assays using [(3)H]AMPA , an agonist , and [(3)H]Ro 48-8587 ( 9-imidazol-1-yl-8-nitro-2,3,5,6-tetrahydro[1,2,4]triazolo[1,5-c] quinazoline-2,5-dione ) , a high affinity AMPA receptor antagonist , as radioligands . Single alanine substitutions at residues DB00149 -672 and DB00156 -677 severely affected the affinities for all agonists , as seen in ligand competition assays , whereas similar mutations at residues DB00128 -673 , DB00133 -674 , DB00145 -675 , DB00133 -676 , and Lys-678 selectively affected the binding affinities of one or two of the agonists . In striking contrast , the binding affinities of [(3)H]Ro 48-8587 and of another competitive antagonist , DB03759 , were not affected by any of these alanine mutations , suggesting the absence of critical side-chain interactions . Together with ligand docking experiments , our results indicate a selective engagement of the side chains of the helix F region in agonist binding , and suggest that conformational changes involving this region may play a critical role in receptor activation . Activity of the rat P48058 promoter in transfected cortical neurons and glia . AMPA ( alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate ) receptors are assembled from four subunits , GluR1-4 . Although P48058 is widely expressed in brain its abundance is less than GluR1-3 . We have isolated approximately 5 kb of the rat P48058 promoter region and analyzed its capacity to drive expression of a luciferase reporter gene in transfected rat cortical neurons and glia , and P13671 glioma cells . Multiple transcriptional start sites were identified in a GC-rich region lacking TATA-boxes between -1090 and -1011 bp from ATG . In transfected mixed cortical cultures , luciferase expression driven by P48058 promoter segments were found predominantly in TuJ1-positive neurons , indicating neuronal preference of P48058 . The P48058 promoter fragments were 6-12-fold more active in neurons than glia , compared with a 30-fold neuronal selectivity of GluR2 . Deletion of the P48058 transcriptional initiation region decreased luciferase activity in neurons , but increased activity in P13671 cells , suggesting that regulatory elements governing neuronal expression reside in this region . An intron within the 5'-untranslated region and Sp1 , IK2 and E-box sites are conserved in the rat , mouse and human P48058 promoters . The relative activity of P48058 and GluR2 promoters in transfected cells correlates with their expression in brain , and in both promoters regulatory elements for neuronal expression reside near the initiation sites . DB00731 and mitiglinide , but not sulfonylureas , induce insulin secretion through a mechanism mediated by calcium release from endoplasmic reticulum . DB00731 and mitiglinide ( glinides ) are characterized as rapid-onset and short-acting insulinotropic agents . Although both compounds do not have a sulfonylurea structure , it has been postulated that insulin secretion is preceded by their binding to Kir6.2/ Q09428 complex , and a mechanism of insulin secretion of glinides has been accounted for by this pathway . However , we hypothesized the involvement of additional mechanisms of insulin secretion enhanced by glinides , and we analyzed the pattern of time course of insulin secretion from MIN6 cells with the existence of agents that have specific pharmacologic actions . Dose-dependent effects of tolbutamide , glibenclamide , nateglinide , and mitiglinide were observed . P01308 secretion induced by 3 microM tolbutamide and 1 nM glibenclamide was completely inhibited by 10 microM diazoxide and 3 microM verapamil , although the latter half-component of insulin secretion profile induced by 3 microM nateglinide or 30 nM mitiglinide remained with the existence of those agents . Glinides enhanced insulin secretion even in Ca2+-depleted medium , and its pattern of secretion was same as the pattern with existence of verapamil . The latter half was suppressed by 1 microM dantrolene , and concomitant addition of verapamil and dantrolene completely suppressed the entire pattern of insulin secretion enhanced by nateglinide . Thus , we conclude that glinide action is demonstrated through two pathways , dependently and independently , from the pathway through K( DB00171 ) channels . We also demonstrated that the latter pathway involves the intracellular calcium release from endoplasmic reticulum via ryanodine receptor activation . DB01095 enhances the inhibitory effects of a selective AT1 receptor blocker , valsartan , on atherosclerosis . We investigated the effects of a P04035 inhibitor ( statin ) on the inhibitory effects of an angiotensin II type-1 receptor ( AT1 ) blocker on atherosclerosis and explored cellular mechanisms . We gave apolipoprotein E null mice a high-cholesterol diet for 10 weeks and measured atherosclerotic plaque area and lipid deposition . Neither 1 mg/kg per day of valsartan nor 3 mg/kg per day of fluvastatin had any effect on blood pressure or cholesterol concentration ; however , both drugs decreased plaque area and lipid deposition after 10 weeks . We then reduced the doses of both drugs to 0.1 mg/kg per day and 1 mg/kg per day , respectively . At these doses , neither drug had an effect on atherosclerotic lesions . When both drugs were combined at these doses , a significant reduction in atherosclerotic lesions was observed . Similar inhibitory effects of valsartan or fluvastatin on the expressions of nicotinamide-adenine dinucleotide/nicotinamide-adenine dinucleotide phosphate oxidase subunits P13498 and p47phox , production of superoxide anion , the expression of monocyte chemoattractant protein-1 , and intercellular adhesion molecule-1 expression were observed . These results suggest that concomitant AT1 receptor and cholesterol biosynthesis blockade , particularly when given concomitantly , blunts oxidative stress and inflammation independent of blood pressure or cholesterol-related effects . Physical activity modifies the association between P13498 gene polymorphisms and small artery elasticity in a Chinese population . Emerging evidence suggests that increased superoxide production is responsible for a significant proportion of endothelial dysfunction . The relationship between variants of the P13498 gene and cardiovascular diseases is currently debated . In the present study , we investigated the influence of P13498 polymorphisms ( rs1049255 and rs7195830 ) on arterial elasticity in a Chinese population . In the 2178 participants enrolled in the GaoYou study , we measured large artery elasticity ( C1 ) and small artery elasticity ( P06681 ) non-invasively , genotyped the P13498 polymorphisms and calculated energy expenditure . The AA genotype of the rs1049255 polymorphism was associated with a lower P06681 than were the GG/AG genotypes ( 5.31±0.11 vs. 5.52±0.06 ml mm Hg(-1) × 100 ; P=0.01 ) . Further analyses revealed an interaction between P13498 polymorphisms and physical activity with respect to P06681 ( P=0.007 for rs1049255 and P=0.038 for rs7195830 ) . In less physically active participants , the AA genotype of the rs1049255 polymorphism was associated with a significantly lower P06681 than the GG/AG genotypes ( 4.69±0.16 vs. 5.26±0.19 ml mm Hg(-1) × 100 ; P=0.008 ) . In physically active participants , the GG/AG genotypes of rs7195830 polymorphism were correlated with higher P06681 values than the AA genotype ( 5.84±0.08 vs. 5.08±0.32 ml mm Hg(-1) × 100 ; P=0.049 ) . Haplotype analyses revealed higher P06681 values in rs1049255G-rs7195830G carriers ( P=0.0015 ) . In conclusion , the rs1049255 and rs7195830 polymorphisms of the P13498 gene were associated with P06681 in a Chinese population ; physical activity could modify this genetic effect . DB01780 signaling reveals 14-3-3 protein function as a novel step in left-right patterning during amphibian embryogenesis . To gain insight into the molecular mechanisms underlying the control of morphogenetic signals by H+ flux during embryogenesis , we tested DB01780 -A ( FC ) , a compound produced by the fungus Fusicoccum amygdali Del . In plant cells , FC complexes with 14-3-3 proteins to activate H+ pumping across the plasma membrane . It has long been thought that FC acts on higher plants only ; here , we show that exposing frog embryos to FC during early development specifically results in randomization of the asymmetry of the left-right ( LR ) axis ( heterotaxia ) . Biochemical and molecular-genetic evidence is presented that 14-3-3-family proteins are an obligate component of Xenopus FC receptors and that perturbation of 14-3-3 protein function results in heterotaxia . The subcellular localization of 14-3-3 mRNAs and proteins reveals novel cytoplasmic destinations , and a left-right asymmetry at the first cell division . Using gain-of-function and loss-of-function experiments , we show that P62258 protein is likely to be an endogenous and extremely early aspect of LR patterning . These data highlight a striking conservation of signaling pathways across kingdoms , suggest common mechanisms of polarity establishment between C. elegans and vertebrate embryos , and uncover a novel entry point into the pathway of left-right asymmetry determination .