interacts_with DB01095?
Discovery of ( 2E ) -3-{2-butyl-1-[2-(diethylamino)ethyl]-1H-benzimidazol-5-yl}-N-hydroxyacrylamide ( DB05223 ) , an orally active histone deacetylase inhibitor with a superior preclinical profile . A series of 3-(1,2-disubstituted-1H-benzimidazol-5-yl)-N-hydroxyacrylamides ( 1 ) were designed and synthesized as HDAC inhibitors . Extensive SARs have been established for in vitro potency ( Q13547 enzyme and COLO 205 cellular IC(50) ) , liver microsomal stability ( t(1/2) ) , cytochrome P450 inhibitory ( 3A4 IC(50) ) , and clogP , among others . These parameters were fine-tuned by carefully adjusting the substituents at positions 1 and 2 of the benzimidazole ring . After comprehensive in vitro and in vivo profiling of the selected compounds , DB05223 ( 3 ) was identified as a preclinical development candidate . 3 is a potent pan-HDAC inhibitor with excellent druglike properties , is highly efficacious in in vivo tumor models ( HCT-116 , PC-3 , A2780 , MV4-11 , Ramos ) , and has high and dose-proportional oral exposures and very good ADME , safety , and pharmaceutical properties . When orally dosed to tumor-bearing mice , 3 is enriched in tumor tissue which may contribute to its potent antitumor activity and prolonged duration of action . 3 is currently being tested in phase I and phase II clinical trials . DB01095 upregulates endothelial nitric oxide synthase activity via enhancement of its phosphorylation and expression and via an increase in tetrahydrobiopterin in vascular endothelial cells . BACKGROUND : An P04035 inhibitor , fluvastatin , appears to act directly on the blood vessel wall to stabilize plaques in situ , agents that share this property have been termed vascular statins . METHODS : We investigated the effects of fluvastatin on endothelial nitric oxide synthase ( P29474 ) phosphorylation and expression , as well as terahydrobiopterin ( BH4 ) metabolism , in human umbilical vein endothelial cells ( HUVEC ) . RESULTS : DB01095 was observed to enhance P29474 phosphorylation at DB00133 -1177 and DB00133 -633 through the P19957 -kinase/Akt and PKA pathways , respectively . Inhibition of P29474 phosphorylation using inhibitors of these pathways attenuated acute NO release in response to fluvastatin . The mRNA of P30793 ( GTPCH ) , the rate-limiting enzyme of the first step of de novo BH4 synthesis , as well as P29474 , was upregulated in HUVEC treated with fluvastatin . In parallel with this observation , fluvastatin increased intracellular BH4 . Pre-treatment of HUVEC with the selective GTPCH inhibitor , 2,4-diamino-6-hydroxypyrimidine , reduced intracellular BH4 and decreased citrulline formation following stimulation with ionomycin . Furthermore , the potentiating effect of fluvastatin was reduced by limiting the cellular availability of BH4 . CONCLUSIONS : Our data demonstrate that fluvastatin phosphorylates and activates P29474 , and increases P29474 expression in vascular endothelial cells . In addition to modulating P29474 , fluvastatin potentiates GTPCH gene expression and BH4 synthesis , thereby increasing NO production and preventing relative shortages of BH4 . P04035 inhibitor attenuates experimental autoimmune myocarditis through inhibition of T cell activation . OBJECTIVE : This study tested the hypothesis that 3-hydroxy-3-methyl-glutaryl coenzyme A ( HMG- DB01992 ) reductase inhibitor affects T cell-mediated autoimmunity through inhibition of nuclear factor-kappaB ( NFkappaB ) and reduces the severity of experimental autoimmune myocarditis ( EAM ) . METHODS : EAM was induced in Lewis rats by immunization with myosin . High-dose or low-dose fluvastatin or vehicle was administered orally for 3 weeks to rats with EAM . RESULTS : DB01095 reduced the pathophysiological severity of myocarditis . DB01095 inhibited expression of NFkappaB in the nuclei of myocardium in EAM . DB01095 reduced production of Th1-type cytokines , including interferon ( IFN ) -gamma and interleukin ( IL ) -2 , and inhibited expression of inflammatory cytokine mRNAs in the myocardium . Infiltration of P01730 -positive T cells into the myocardium and T cell proliferative responses were suppressed by fluvastatin . Plasma lipid levels did not differ between the groups . CONCLUSIONS : DB01095 ameliorates EAM by inhibiting T cell responses and suppressing Th1-type and inflammatory cytokines via inactivation of nuclear factor-kappaB , and this activity is independent of cholesterol reduction . 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 . Effect of vitamin C on the availability of tetrahydrobiopterin in human endothelial cells . DB00126 has long been known for its beneficial vascular effects , but its mechanism of action remains unclear . Recent reports suggest that vitamin C may prevent endothelial dysfunction by scavenging free radicals and increasing the bioavailability of nitric oxide . To investigate this area further , we studied the effect of vitamin C ( 10(-4) M ) and Mn(III) tetrakis ( 4-benzoic acid ) porphyrin chloride ( MnTBAP ; 10(-5) M ) , a scavenger of superoxide , hydrogen peroxide , and peroxynitrite , on endothelial nitric oxide synthase ( P29474 ) enzymatic activity in cultured human umbilical vein endothelial cells . L- DB00155 formation ( a measure of P29474 enzymatic activity ) was significantly increased in cells treated for 24 h with vitamin C . No effect was observed after MnTBAP treatment . Chronic administration of vitamin C also had no effect on P29474 protein expression . Treatment with vitamin C for 24 h significantly increased levels of the P29474 co-factor tetrahydrobiopterin ( BH4 ) , whereas MnTBAP did not affect its levels . Sepiapterin ( 10(-4) M ) , a precursor of BH4 , significantly increased P29474 activity , whereas addition of vitamin C to cells treated with sepiapterin did not cause any further increase in P29474 activity . Our results suggest that the beneficial effect of vitamin C on endothelial function is best explained by increased intracellular BH4 content and subsequent enhancement of P29474 activity . This effect appears to be independent of the ability of vitamin C to scavenge superoxide anions . DB04958 , a P20273 -targeting recombinant humanized antibody with a different mode of action from rituximab . DB04958 is a humanized anti- P20273 monoclonal antibody currently in clinical trials for treatment of non-Hodgkin lymphoma ( Q9NZ71 ) and certain autoimmune diseases . Here we report the results of investigations of epratuzumab 's mode of action in comparison to and in combination with the anti- P11836 mAb , rituximab . In vitro cell growth inhibition , induction of apoptosis , and the ability of the mAbs to mediate complement-dependent cytotoxicity ( CDC ) and antibody-dependent cellular cytotoxicity ( ADCC ) were evaluated . We also investigated the potential activity of epratuzumab in the regulation of B-cell antigen receptor ( P11274 ) activation . DB04958 and rituximab displayed very distinct modes of action ; epratuzumab acts as an immunomodulatory agent , while rituximab is an acutely cytotoxic therapeutic antibody . DB04958 has distinct effects on cell growth from rituximab . For example , rituximab+anti-human IgG Fcgamma yielded marked inhibition of proliferation in human Q9NZ71 cell lines , while epratuzumab had little or no effect in this assay . However , when cells were immobilized and stimulated with anti-IgM , epratuzumab , but not rituximab , caused a significant antiproliferative effect . Unlike rituximab , no CDC could be detected , and ADCC was modest but significant with epratuzumab . Importantly , combining rituximab and epratuzumab did not decrease rituximab 's ability to induce apoptosis , CDC , and ADCC . In fact , the combination is more effective than rituximab alone in inhibiting proliferation of Daudi Burkitt lymphoma cells in the presence of second antibody , and at least equally effective to rituximab in the absence of crosslinking . These observations suggest that it may be possible to enhance clinical efficacy by combination therapy comprised of anti- P11836 and anti- P20273 mAbs . Msx2 promotes cardiovascular calcification by activating paracrine Wnt signals . In diabetic P01130 -/- mice , an ectopic P12643 -Msx2 gene regulatory program is upregulated in association with vascular calcification . We verified the procalcific actions of aortic Msx2 expression in vivo . CMV-Msx2 transgenic ( CMV-Msx2Tg(+) ) mice expressed 3-fold higher levels of aortic Msx2 than nontransgenic littermates . On high-fat diets , CMV-Msx2Tg(+) mice exhibited marked cardiovascular calcification involving aortic and coronary tunica media . This corresponded to regions of Msx2 immunoreactivity in adjacent adventitial myofibroblasts , suggesting a potential paracrine osteogenic signal . To better understand Msx2-regulated calcification , we studied actions in 10T1/2 cells . We found that conditioned media from Msx2-transduced 10T1/2 cells ( Msx2-CM ) is both pro-osteogenic and adipostatic ; these features are characteristic of Wnt signaling . Msx2-CM stimulated Wnt-dependent TCF/LEF transcription , and Msx2-transduced cells exhibited increased nuclear beta-catenin localization with concomitant alkaline phosphatase induction . Msx2 upregulated Wnt3a and Wnt7a but downregulated expression of the canonical inhibitor Dkk1 . Dkk1 treatment reversed osteogenic and adipostatic actions of Msx2 . DB06285 , a Q03431 agonist that inhibits murine vascular calcification , suppressed vascular P12643 -Msx2-Wnt signaling . Analyses of CMV-Msx2Tg(+) mice confirmed that Msx2 suppresses aortic Dkk1 and upregulates vascular Wnts ; moreover , TOPGAL(+) ( Wnt reporter ) ; CMV-Msx2Tg(+) mice exhibited augmented aortic LacZ expression . Thus , Msx2-expressing cells elaborated an osteogenic milieu that promotes vascular calcification in part via paracrine Wnt signals . c- P05412 promotes P11274 - P00519 -induced lymphoid leukemia by inhibiting methylation of the 5' region of Cdk6 . The transcription factor c- P05412 and its upstream kinase P45983 have been implicated in P11274 - P00519 -induced leukemogenesis . P45983 has been shown to regulate P10415 expression , thereby altering leukemogenesis , but the impact of c- P05412 remained unclear . In this study , we show that P45983 and c- P05412 promote leukemogenesis via separate pathways , because lack of c- P05412 impairs proliferation of p185( P11274 - P00519 )-transformed cells without affecting their viability . The decreased proliferation of c-Jun(Δ/Δ) cells is associated with the loss of cyclin-dependent kinase 6 ( Q00534 ) expression . In c-Jun(Δ/Δ) cells , Q00534 expression becomes down-regulated upon P11274 - P00519 -induced transformation , which correlates with CpG island methylation within the 5' region of Cdk6 . We verified the impact of Cdk6 deficiency using Cdk6(-/-) mice that developed P11274 - P00519 -induced B-lymphoid leukemia with significantly increased latency and an attenuated disease phenotype . In addition , we show that reexpression of Q00534 in P11274 - P00519 -transformed c-Jun(Δ/Δ) cells reconstitutes proliferation and tumor formation in Nu/Nu mice . In summary , our study reveals a novel function for the activating protein 1 ( AP-1 ) transcription factor c- P05412 in leukemogenesis by antagonizing promoter methylation . Moreover , we identify Q00534 as relevant and critical target of AP-1-regulated DNA methylation on P11274 - P00519 -induced transformation , thereby accelerating leukemogenesis . Expression of human all-trans-retinoic acid receptor beta and its ligand-binding domain in Escherichia coli . DB00755 , one of the hormonally active derivatives of vitamin A , occurs physiologically in plasma at a concentration below 10 nmol/l . The methods currently used for its quantification are based on HPLC , need about 1 ml of serum , are relatively laborious and thus not well suited for mass analysis . The affinity and specificity of retinoic acid receptors for all-trans-retinoic acid encouraged us to express both the entire human retinoic acid receptor beta ( P10826 ) and two versions of its retinoic acid-binding domain in Escherichia coli in the hope that these recombinant proteins might be used as binders in a ligand-binding assay for all-trans-retinoic acid . The recombinant receptors , the whole receptor [ P10826 -( Q93033 -Q448) ] , corresponding to domains A-F , and the ligand-binding domain [ P10826 -(E149-Q448) ] , corresponding to domains D-F , were expressed in the vector pET 3d/BL21 ( DE3 ) as inclusion bodies , solubilized with guanidinium chloride , renatured and purified by ion-exchange chromatography . P10826 -(P193-Q448) , corresponding to domains E-F , was expressed in the vector pET 3d/BL21(DE3)pLysS , and purified by reversed-phase chromatography . Under non-denaturing conditions , the expressed whole receptor [ P10826 -( Q93033 -Q448) ] and the D-F construct ( P10826 -(E149-Q448) ] behaved chromatographically as monomeric proteins whereas the E-F construct [ P10826 -(P193-Q448) ] had a strong tendency to aggregate . P10826 -( Q93033 -Q448) and P10826 -(E149-Q448) had similar Kd values for all-trans-retinoic acid ( 1.4 and 0.6 nmol/l respectively ) whereas P10826 -(P193-Q448) bound all-trans-retinoic acid less avidly ( Kd 9.6 nmol/l ) . DB00523 bound to P10826 -(E149-Q448) and P10826 -( Q93033 -Q448) as avidly as all-trans-retinoic acid . Competition experiments showed weak or no binding of 4-oxo-all-trans-retinoic acid , 4-oxo-13-cis-retinoic acid , 13-cis-retinoic acid , acitretin and retinol by P10826 -(E149-Q448) . 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 . 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 . Determination of fenofibric acid concentrations by HPLC after anion exchange solid-phase extraction from human serum . Triglycerides are increasingly being recognized as a risk factor for cardiovascular disease . Research efforts to identify sources of variability in triglyceride-lowering response to the lipid-lowering drug fenofibrate require quantification of the active acidic form of this Q07869 agonist . Anion-exchange solid-phase extraction , in combination with reverse-phase high-performance liquid chromatography ( HPLC ) , rapidly and accurately determines steady-state fenofibric acid serum concentrations . Chromatographic separation under isocratic conditions , with use of ultraviolet detection at 285 nm , provides clean baseline and sharp peaks for clofibric acid , 1-napthyl acetic acid ( internal standards ) , and fenofibric acid . Commonly prescribed and over-the-counter nonsteroidal anti-inflammatory drugs ( NSAIDs ) were screened for assay interference , and the assay was employed to quantify fenofibric acid in more than 800 human subject specimens . DB01039 analysis was found to be linear over the range of 0.5 to 40 mg/L and was validated with either internal standard . Accuracies ranged from 98.65 % to 102.4 % , whereas the within- and between-day precisions ranged from 1.0 % to 2.2 % and 2.0 % to 6.2 % , respectively . NSAIDs had minimal interference with the assay , which succeeded in quantifying fenofibric acid in more than 843 of 846 serum samples from human subjects , many taking a variety of coadministered medications . Anion-exchange solid-phase extraction in combination with reverse-phase HPLC accurately determines steady-state fenofibric acid serum concentrations in humans without interference from NSAIDs or commonly administered medications . This method is suitable for quantification of fenofibric acid for clinical pharmacokinetic studies in patients with dyslipidemia . Identification of N-(4-piperidinyl)-4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxamide ( DB05037 ) , a novel cyclin dependent kinase inhibitor using fragment-based X-ray crystallography and structure based drug design . The application of fragment-based screening techniques to cyclin dependent kinase 2 ( P24941 ) identified multiple ( > 30 ) efficient , synthetically tractable small molecule hits for further optimization . Structure-based design approaches led to the identification of multiple lead series , which retained the key interactions of the initial binding fragments and additionally explored other areas of the DB00171 binding site . The majority of this paper details the structure-guided optimization of indazole ( 6 ) using information gained from multiple ligand- P24941 cocrystal structures . Identification of key binding features for this class of compounds resulted in a series of molecules with low nM affinity for P24941 . Optimisation of cellular activity and characterization of pharmacokinetic properties led to the identification of 33 ( DB05037 ) , which is currently being evaluated in clinical trials for the treatment of human cancers . Novel phenolic antioxidants as multifunctional inhibitors of inducible P19320 expression for use in atherosclerosis . A series of novel phenolic compounds has been discovered as potent inhibitors of P01375 -inducible expression of vascular cell adhesion molecule-1 ( P19320 ) with concurrent antioxidant and lipid-modulating properties . Optimization of these multifunctional agents led to the identification of 3a ( DB05399 ) as a clinical candidate with demonstrated efficacies in animal models of atherosclerosis and hyperlipidemia . P12004 -dependent kinase 5 phosphorylates endothelial nitric oxide synthase at serine 116 . DB00435 ( NO ) production in endothelial cells ( EC ) is regulated by multisite phosphorylation of specific serine and threonine residues in endothelial NO synthase ( P29474 ) . Among these , P29474 -Ser116 is phosphorylated in the basal state , and its phosphorylation contributes to basal NO production . Here , we investigated the mechanism by which P29474 -Ser116 is phosphorylated during the basal state using bovine aortic EC . Although a previous study suggested that protein kinase C was involved in P29474 -Ser116 phosphorylation , overexpression of various protein kinase C isoforms did not affect P29474 -Ser116 phosphorylation . An in silico analysis using a motif scan revealed that the P29474 -Ser116 residue might be a substrate for proline-directed protein kinases . Roscovitine , a specific inhibitor of cyclin-dependent kinase ( CDK ) , 1 , 2 , and 5 , but not an inhibitor of mitogen-activated protein kinase kinase or glycogen synthase kinase 3beta , inhibited P29474 -Ser116 phosphorylation dose dependently . Furthermore , purified P06493 , 2 , or 5 directly phosphorylated P29474 -Ser116 in vitro . Ectopic expression of the dominant-negative Q00535 but not dominant-negative P06493 or dominant-negative P24941 repressed P29474 -Ser116 phosphorylation and increased NO production . In addition , Q00535 activity was detected in bovine aortic EC , and coimmunoprecipitation and confocal microscopy studies revealed a colocalization of P29474 and Q00535 . Cotransfection of Q00535 and p25 , the specific Q00535 activator , increased P29474 -Ser116 phosphorylation and decreased NO production , but its parent molecule , p35 , and p39 , another activator , were not detected in bovine aortic EC , which suggests the existence of a novel Q00535 activator . Overall , this is the first study to find that Q00535 is a physiological kinase responsible for P29474 -Ser116 phosphorylation and regulation of NO production . Lipid-lowering response of the P04035 inhibitor fluvastatin is influenced by polymorphisms in the low-density lipoprotein receptor gene in Brazilian patients with primary hypercholesterolemia . Although the efficacy of fluvastatin ( P04035 inhibitor ) in the treatment of primary hypercholesterolemia is well documented , a wide interindividual variation treatment response has been observed . We have studied the possible role of the AvaII ( exon 13 ) , HincII ( exon 12 ) , and PvuII ( intron 15 ) polymorphisms at the low-density lipoprotein receptor ( P01130 ) gene on lipid-lowering response in 55 patients ( 36 to 70 years old ) with primary hypercholesterolemia treated with fluvastatin for 16 weeks . P01130 genotypes were determined by PCR-RFLP . The results indicate that the AvaII and PvuII polymorphisms influence the cholesterol-lowering response of the P04035 inhibitor DB01095 . Patients carrying A+A+ ( AvaII ) or P1P1 ( PvuII ) homozygous genotypes presented lower reduction in total cholesterol , LDL-C and apolipoprotein B levels after 16 weeks of treatment with fluvastatin , when compared to other genotypes ( P < 0.05 ) . Our data also support the previous assumption that the AvaII , HincII , and PvuII polymorphisms of the P01130 gene are associated with variation of serum cholesterol levels . Therefore , the identification of the P01130 genetic profile may provide better prediction of a patient 's clinical response to fluvastatin . Study of retinoic acid effect upon retinoic acid receptors beta ( P10826 ) in P13671 cultured glioma cells . Using monoclonal antibodies against the P10276 and P10826 retinoic receptors , we demonstrated that these receptors were present together in P13671 glioma cells as two isoforms of 50 and 55 kDa . For P10826 , the 50 kDa isoform predominated ( 60 to 80 % of the total of the two isoforms ) . After a treatment for 48 h with retinoic acid 10 microM , the 55 kDa form was enhanced , while no effect was observed either on P10276 isoforms from P13671 cells and on both P10276 and P10826 forms from neuroblastoma SKN SH SY5Y used as a control . Using purified neuronal and glial rat brain nuclei , we showed that the 55 kDa isoform from P10826 predominated in glial cells . These results suggest that retinoic acid treatment of P13671 cells led to a partial differentiation , the enhancement of the heavy form of P10826 being a marker of this phenomenon . Novel antimicrobial peptides from the venom of the eusocial bee Halictus sexcinctus ( Hymenoptera : Halictidae ) and their analogs . Two novel antimicrobial peptides , named halictines , were isolated from the venom of the eusocial bee Halictus sexcinctus . Their primary sequences were established by P19957 -QTOF mass spectrometry , Edman degradation and enzymatic digestion as DB00145 - DB00134 - DB00150 - DB00133 -Lys- DB00167 - DB00149 - DB00145 - DB00117 - DB00149 - DB00167 - DB00125 -NH2 ( P42357 -1 ) , and DB00145 -Lys- DB00150 - DB00134 - DB00133 - DB00149 - DB00149 -Lys- DB00117 - DB00167 - DB00149 -Lys-NH2 ( P42357 -2 ) . Both peptides exhibited potent antimicrobial activity against Gram-positive and Gram-negative bacteria but also noticeable hemolytic activity . The CD spectra of P42357 -1 and P42357 -2 measured in the presence of trifluoroethanol or SDS showed ability to form an amphipathic alpha-helical secondary structure in an anisotropic environment such as bacterial cell membrane . NMR spectra of P42357 -1 and P42357 -2 measured in trifluoroethanol/water confirmed formation of helical conformation in both peptides with a slightly higher helical propensity in P42357 -1 . Altogether , we prepared 51 of P42357 -1 and P42357 -2 analogs to study the effect of such structural parameters as cationicity , hydrophobicity , alpha-helicity , amphipathicity , and truncation on antimicrobial and hemolytic activities . The potentially most promising analogs in both series are those with increased net positive charge , in which the suitable amino acid residues were replaced by Lys . This improvement basically relates to the increase of antimicrobial activity against pathogenic Pseudomonas aeruginosa and to the mitigation of hemolytic activity . Role of histone deacetylation in cell-specific expression of endothelial nitric-oxide synthase . Histone acetylation plays an important role in chromatin remodeling and gene expression . The molecular mechanisms involved in cell-specific expression of endothelial nitric-oxide synthase ( P29474 ) are not fully understood . In this study we investigated whether histone deacetylation was involved in repression of P29474 expression in non-endothelial cells . Induction of P29474 expression by histone deacetylase ( HDAC ) inhibitors trichostatin A ( P32119 ) and sodium butyrate was observed in all four different types of non-endothelial cells examined . Chromatin immunoprecipitation assays showed that the induction of P29474 expression by P32119 was accompanied by a remarkable increase of acetylation of histone H3 associated with the P29474 5'-flanking region in the non-endothelial cells . Moreover , DNA methylation-mediated repression of P29474 promoter activity was partially reversed by P32119 treatment , and combined treatment of P32119 and DB01262 ( AzadC ) synergistically induced P29474 expression in non-endothelial cells . The proximal Sp1 site is critical for basal activity of P29474 promoter . The induction of P29474 by inhibition of HDACs in non-endothelial cells , however , appeared not mediated by the changes in Sp1 DNA binding activity . We further showed that Sp1 bound to the endogenous P29474 promoter and associated with Q13547 in non-endothelial HeLa cells . Combined P32119 and AzadC treatment increased Sp1 binding to the endogenous P29474 promoter but decreased the association between Q13547 and Sp1 in HeLa cells . Our data suggest that Q13547 plays a critical role in P29474 repression , and the proximal Sp1 site may serve a key target for HDCA1-mediated P29474 repression in non-endothelial cells . Anti-allergic function and regulatory mechanisms of KR62980 in allergen-induced airway inflammation . The ligand-activated transcription factor , peroxisome proliferator-activated receptor ( Q07869 )gamma , and its ligands inhibit pro-inflammatory cytokine production by immune cells , thus exerting anti-inflammatory activity . As a non-thiazolidinedione PPARgamma ligand , KR62980 has anti-diabetic and anti-adipogenic activities , but its anti-inflammatory function has yet to be characterized . In this study , we investigated the functions and mechanisms of KR62980 in the activation and differentiation of P01730 + T helper ( Th ) cells by comparing its effects with those of a thiazolidinedione PPARgamma ligand , rosiglitazone . KR62980 dose-dependently and significantly suppressed TCR-triggered Th cell proliferation by suppressing P60568 /IL-2Ralpha-mediated signaling . Both KR62980 and rosiglitazone suppressed IFNgamma production in a dose-dependent manner , whereas P05112 gene expression was specifically suppressed by only KR62980 . In addition , sustained KR62980 treatment diminished Th2 cytokine production by inhibiting c-Maf expression . In vivo administration of KR62980 in a model of allergic asthma significantly attenuated eotaxin-induced eosinophil infiltration , allergic cytokine production and collagen deposition in the lung . KR62980 also decreased goblet cell hyperplasia in the airway and mucous cell metaplasia in nasal epithelium , concurrent with decreases of allergic Th2 cytokines and Q16552 in the draining lymph node . In conclusion , a novel PPARgamma ligand , KR62980 , suppresses in vitro Th2 cell differentiation and attenuates in vivo OVA-induced airway inflammation , suggesting a beneficial role for KR62980 in the treatment of allergic asthma and allergic rhinitis .