interacts_with DB00188?
P01308 deficiency exacerbates cerebral amyloidosis and behavioral deficits in an Alzheimer transgenic mouse model . BACKGROUND : Although increasing evidence has indicated that brain insulin dysfunction is a risk factor for Alzheimer disease ( AD ) , the underlying mechanisms by which insulin deficiency may impact the development of AD are still obscure . Using a streptozotocin ( Q11206 ) -induced insulin deficient diabetic AD transgenic mouse model , we evaluated the effect of insulin deficiency on AD-like behavior and neuropathology . RESULTS : Our data showed that administration of Q11206 increased the level of blood glucose and reduced the level of serum insulin , and further decreased the phosphorylation levels of insulin receptors , and increased the activities of glycogen synthase kinase-3α/β and c-Jun N-terminal kinase in the P05067 / P49768 mouse brain . We further showed that Q11206 treatment promoted the processing of amyloid-β ( Aβ ) precursor protein resulting in increased Aβ generation , neuritic plaque formation , and spatial memory deficits in transgenic mice . CONCLUSIONS : Our present data indicate that there is a close link between insulin deficient diabetes and cerebral amyloidosis in the pathogenesis of AD . Apoptogenic interactions of plasmalemmal type-1 P21796 and Aβ peptides via GxxxG motifs induce Alzheimer 's disease - a basic model of apoptosis ? Human type-1 porin/ P21796 ( voltage-dependent anion channel ) carries a GxxxG motif in its N-terminal part , traversing the β-barrel , while the Alzheimer 's disease ( AD ) relevant amyloid peptides Aβ1-42 and Aβ1-40 show a series of corresponding motifs close to their C-terminus . GxxxG motifs are established as aggregation/membrane perturbation motifs . These peptide primary structure data support a proposal I recently made on the basis of a synopsis of recent literature . Accordingly , amyloid Aβ , cut from P05067 by beta-secretase P56817 and gamma-secretase , has been insinuated to induce Alzheimer 's disease via apoptosis by opening type-1 porin/ P21796 in cell membranes of hypometabolic neuronal cells . Considering the ubiquitous expression modus of P05067 , beta- and gamma-secretases and type-1 P21796 /eukaryotic porin a basic model of apoptosis might be given . DB00472 induces preventive and complex effects against colon cancer development in epithelial and stromal areas in rats . DB00472 ( FLX ) is a drug commonly used as antidepressant . However , its effects on tumorigenesis remain controversial . Aiming to evaluate the effects of FLX treatment on early malignant changes , we analyzed serotonin ( 5-HT ) metabolism and recognition , aberrant crypt foci ( Q9NQ94 ) , proliferative process , microvessels , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase-2 ( P35354 ) expression in colon tissue . Male Wistar rats received a daily FLX-gavage ( 30mgkg(-1) ) and , a single dose of 1,2 dimethylhydrazine ( Q03001 ; i.p. , 125mgkg(-1) ) . After 6 weeks of FLX-treatment , our results revealed that FLX and nor-fluoxetine ( N-FLX ) are present in colon tissue , which was related to significant increase in serotonin ( 5-HT ) levels ( P < 0.05 ) possibly through a blockade in P31645 mRNA ( serotonin reuptake transporter ; P < 0.05 ) resulting in lower 5-hydroxyindoleacetic acid ( 5-HIAA ) levels ( P < 0.01 ) and , P28335 receptor mRNA expressions . FLX-treatment decreased dysplastic Q9NQ94 development ( P < 0.01 ) and proliferative process ( P < 0.001 ) in epithelia . We observed a significant decrease in the development of malignant microvessels ( P < 0.05 ) , P15692 ( P < 0.001 ) , and P35354 expression ( P < 0.01 ) . These findings suggest that FLX may have oncostatic effects on carcinogenic colon tissue , probably due to its modulatory activity on 5-HT metabolism and/or its ability to reduce colonic malignant events . Analysis of a 26-kb region linked to the Mhc in zebrafish : genomic organization of the proteasome component beta/transporter associated with antigen processing-2 gene cluster and identification of five new proteasome beta subunit genes . Sequencing of zebrafish ( Danio rerio ) bacterial artificial chromosome and P1 artificial chromosome genomic clone fragments and of cDNA clones has led to the identification of five new loci coding for beta subunits of proteasomes ( PSMB ) . Together with the four genes identified previously , nine PSMB genes have now been defined in the zebrafish . Six of the nine genes reside in the zebrafish MHC ( Mhc ) class I region , four of them reside in a single cluster closely associated with TAP2 on a 26-kb long genomic fragment , and two reside at some distance from the fragment . In addition to homologues of the human genes P28074 through P28065 , two new genes , A5LHX3 and PSMB12 , have been found for which there are no known corresponding genes in humans . The new genes reside in the PSMB cluster in the Mhc . Homology and promoter region analysis suggest that the Mhc-associated genes might be inducible by P01579 . The zebrafish class I region contains representatives of three phylogenetically distinguishable groups of PSMB genes , X , Y , and Z . It is proposed that these genes were present in the ancestral PSMB region before Mhc class I genes became associated with it . A Q96RJ3 mutation associated with non-Hodgkin lymphoma alters TRAF recruitment and reveals new insights into Q96RJ3 signaling . The cytokine B cell activating factor ( Q9Y275 ) and its receptor , Q96RJ3 ( Q96RJ3 ) , modulate signaling cascades critical for B cell development and survival . We identified a novel mutation in Q96RJ3 , the gene encoding human Q96RJ3 , that is present in both tumor and germline tissue from a subset of patients with non-Hodgkin lymphoma . This mutation encodes a His159Tyr substitution in the cytoplasmic tail of Q96RJ3 adjacent to the Q13114 binding motif . Signaling through this mutant Q96RJ3 results in increased NF-κB1 and NF-κB2 activity and increased immunoglobulin production compared with the wild-type ( WT ) Q96RJ3 . This correlates with increased TRAF2 , Q13114 , and Q9Y4K3 recruitment to His159Tyr Q96RJ3 . In addition , we document a requirement for Q9Y4K3 in WT Q96RJ3 signaling . Together , these data identify a novel lymphoma-associated mutation in human Q96RJ3 that results in NF-κB activation and reveals Q9Y4K3 as a necessary component of normal Q96RJ3 signaling . Immunoaffinity purification of the functional 20S proteasome from human cells via transient overexpression of specific proteasome subunits . The proteasome is a multi-subunit proteolytic complex that plays a central role in protein degradation in all eukaryotic cells . It regulates many vital cellular processes therefore its dysfunction can lead to various pathologies including cancer and neurodegeneration . Isolation of enzymatically active proteasomes is a key step to the successful study of the proteasome regulation and functions . Here we describe a simple and efficient protocol for immunoaffinity purification of the functional 20S proteasomes from human P29320 293T cells after transient overexpression of specific proteasome subunits tagged with 3xFLAG . To construct 3xFLAG-fusion proteins , DNA sequences encoding the 20S proteasome subunits P28074 , P28066 , and P25788 were cloned into mammalian expression vector pIRES-hrGFP-1a . The corresponding recombinant proteins P28074 -3xFLAG , P28066 -3xFLAG , or P25788 -3xFLAG were transiently overexpressed in human P29320 293T cells and were shown to be partially incorporated into the intact proteasome complexes . 20S proteasomes were immunoprecipitated from P29320 293T cell extracts under mild conditions using antibodies against FLAG peptide . Isolation of highly purified 20S proteasomes were confirmed by SDS-PAGE and Western blotting using antibodies against different proteasome subunits . Affinity purified 20S proteasomes were shown to possess chymotrypsin- and trypsin-like peptidase activities confirming their functionality . This simple single-step affinity method of the 20S proteasome purification can be instrumental to subsequent functional studies of proteasomes in human cells . Effect of milk hydrolysates on inflammation markers and drug-induced transcriptional alterations in cell-based models . Nonsteroidal anti-inflammatory drugs ( NSAID ) are associated with gastrointestinal inflammation and subsequent damage to the intestinal tissue . Earlier studies in our laboratory have found that specific casein hydrolysates ( CH ) might be useful in the treatment of gastrointestinal wounds . The underlying mechanisms that support inflammation and wound healing are not completely understood , but transcriptional alterations may be used as markers for inflammation and wound healing . The bioactivity of 3 CH prepared by treatment of commercial casein with pepsin ( 60 min ) followed by corolase ( 0 , 10 , or 60 min ) were investigated in intestinal epithelial cells treated with the NSAID indomethacin . The bioactivity was evaluated as transcriptional alterations of transforming growth factor-β1 ( TGF-β1 ) , cyclooxygenase-2 ( P35354 ) , peroxisome proliferator-activated receptor-γ ( Q07869 -γ ) and nuclear factor κB ( NFκB ) by real-time PCR . Furthermore , the effect of CH on lipopolysaccharide-induced inflammation was evaluated in macrophages by measuring PG E(2) levels . Casein hydrolysates treated with corolase for 10 or 60 min after pepsin treatment downregulated transcription of TGF-β1 and NFκB ( P < 0.05 ) compared with the hydrolysate treated with pepsin only . Hydrolysate prepared by corolase treatment for 60 min after pepsin hydrolysis downregulated transcription of P35354 ( P < 0.05 ) compared with hydrolysate treated with corolase for only 10 min whereas transcription of Q07869 -γ was not affected ( P > 0.05 ) . Additionally , the hydrolysate prepared by pepsin treatment only ( 0 min corolase ) had a pro-inflammatory effect on macrophages via PG E(2) stimulation ( P < 0.05 ) . In conclusion , CH produced by a combination of pepsin and corolase treatments downregulated the transcription levels of TGF-β1 , P35354 , and NFκB . Spinal cord injury induces early and persistent lesional Q99571 receptor expression . Following spinal cord injury ( SCI ) , neuropathic , chronic pain is a major cause of disability . Recently , glial Q99571 receptor ( P2X4R ) has been identified as a major contributor to the development of neuropathic pain after peripheral nerve injury . Here we report analysis of P2X4R expression following rat SCI . Significant lesional accumulation of P2X4R+ cells was detected as early as 24 h after SCI , reaching maximum cell numbers on Day 7 . Thereafter cell numbers declined but persisted at significantly elevated , sub-maximal levels ( > 70 % ) until 1 month post injury . Double-immunolabeling identified the majority of lesional P2X4R+ cells as activated microglia/macrophages and surviving neurons/neurites . Increase of P2X4R+ , beta- P05067 + hypertrophic neurites correlated with proximity to the lesion . Further , P2X4R+ cells coexpressed the intracellular regulators of signalling cascades , P23219 ( > 20 % ) , P35354 ( > 5 % ) , RhoA ( > 60 % ) and RhoB ( > 10 % ) . Alzheimer 's disease and modern lifestyle : what is the role of stress ? This Editorial highlights a study by Baglietto-Vargas et al. 2015 published in this issue of J. Neurochem . Stress is one of the environmental factors that can contribute to Alzheimer 's disease pathogenesis . However , the role of modern-life stress has not been investigated yet . The authors reveal that modern-life stress reduces the number of dendritic spines in the hippocampus of Alzheimer 's disease transgenic mice . The mechanism underlying such effect involves an increase in corticotropin-releasing hormone ( P06850 ) release that stimulates the amyloid precursor protein ( P05067 ) processing and fosters the generation of Amyloid-β , which negatively affects dendritic spines . DB11320 reduces susceptibility to natural killer cells via down-regulation of P26718 ligands on human monocytic leukaemia THP-1 cells . Natural killer ( NK ) group 2D ( P26718 ) is a key activating receptor expressed on NK cells , whose interaction with ligands on target cells plays an important role in tumorigenesis . However , the effect of histamine on P26718 ligands on tumour cells is unclear . Here we showed that human monocytic leukaemia THP-1 cells constitutively express MHC class I-related chain A ( Q29983 ) and Q9BZM6 on their surface , and incubation with histamine reduced the expression in a dose-dependent and time-dependent manner as assessed by flow cytometry . Interferon-γ augmented the surface expression of the P26718 ligands , and this augmentation was significantly attenuated by histamine . The histamine H1 receptor ( P35367 ) agonist 2-pyridylethylamine and P25021 agonist dimaprit down-regulated the expression of P26718 ligands , and activation of P35367 and P25021 signalling by A23187 and forskolin , respectively , had the same effect , indicating that the histamine-induced down-regulation of P26718 ligands is mediated by P35367 and P25021 . Quantitative reverse transcription-PCR showed that mRNA levels of the P26718 ligands and relevant microRNAs were not significantly changed by histamine . DB11320 down-regulated the surface expression of endoplasmic reticulum protein 5 , and inhibition of matrix metalloproteinases did not impair this down-regulation , indicating that proteolytic shedding was not involved . Instead , pharmacological inhibition of protein transport and proteasome abrogated it , and histamine enhanced ubiquitination of Q29983 . Furthermore , histamine treatment significantly reduced susceptibility to NK cell-mediated cytotoxicity . These results suggest that histamine down-regulates P26718 ligands through the activation of an P35367 - and P25021 -mediated ubiquitin-proteasome pathway and consequently reduces susceptibility to NK cells . Pathways targeted by antidiabetes drugs are enriched for multiple genes associated with type 2 diabetes risk . Genome-wide association studies ( GWAS ) have uncovered > 65 common variants associated with type 2 diabetes ( T2D ) ; however , their relevance for drug development is not yet clear . Of note , the first two T2D-associated loci ( P37231 and Q14654 / Q09428 ) encode known targets of antidiabetes medications . We therefore tested whether other genes/pathways targeted by antidiabetes drugs are associated with T2D . We compiled a list of 102 genes in pathways targeted by marketed antidiabetic medications and applied Gene Set Enrichment Analysis ( MAGENTA [ Meta-Analysis Gene-set Enrichment of variaNT Associations ] ) to this gene set , using available GWAS meta-analyses for T2D and seven quantitative glycemic traits . We detected a strong enrichment of drug target genes associated with T2D ( P = 2 × 10(-5) ; 14 potential new associations ) , primarily driven by insulin and thiazolidinedione ( TZD ) targets , which was replicated in an independent meta-analysis ( Metabochip ) . The glycemic traits yielded no enrichment . The T2D enrichment signal was largely due to multiple genes of modest effects ( P = 4 × 10(-4) , after removing known loci ) , highlighting new associations for follow-up ( P33121 , P19838 , P11168 , incretin targets ) . Furthermore , we found that TZD targets were enriched for LDL cholesterol associations , illustrating the utility of this approach in identifying potential side effects . These results highlight the potential biomedical relevance of genes revealed by GWAS and may provide new avenues for tailored therapy and T2D treatment design . American ginseng improves neurocognitive function in senescence-accelerated mice : possible role of the upregulated insulin and choline acetyltransferase gene expression . AIM : To investigate the effects of American ginseng on neurocognitive function and glucose regulation in senescence-accelerated mice . METHODS : Male senescence-resistant inbred strains ( SAMR1 ) and senescence-prone inbred strains ( SAMP10 ) mice were divided into five groups and fed either a control diet or an American ginseng-supplemented diet ( 1 % or 2 % g/g ) from 6 weeks to 10 months of age . Bodyweight , levels of fasting plasma glucose ( FPG ) and grading scores were monitored every month and neurocognitive functions were evaluated at 9 months of age with a KUROBOX apparatus using a stress-free positive cue task . Gene expressions of peroxisome proliferator-activated receptor delta ( Q07869 -δ ) , insulin , choline acetyltransferase ( P28329 ) and amyloid precursor protein ( P05067 ) in the brain were measured by real-time quantitative reverse transcription polymerase chain reaction assays . RESULTS : American ginseng decreased FPG in SAMR1 mice , but increased FPG in SAMP10 mice . Correct visit ratios were higher in both SAMR1 and SAMP10 strains consuming an American ginseng-supplemented diet . Gene upregulation of insulin and P28329 in the brain , but not of Q07869 -δ or P05067 , was evident in American ginseng-fed groups . CONCLUSION : Daily consumption of American ginseng induced an enhancement in neurocognitive function in senescence-accelerated mice , which could be related to the upregulation of insulin and P28329 gene expression in the brain . Geriatr Gerontol Int 2012 ; 12 : 123-130 . A meta-analysis of antipseudomonal penicillins and cephalosporins in pediatric patients with fever and neutropenia . BACKGROUND : Antipseudomonal penicillins ( P05067 ) and antipseudomonal cephalosporins ( P25054 ) play important roles in the management of pediatric patients with fever and neutropenia ( FN ) . Our primary objective was to describe the risk of treatment failure in children treated with an P05067 or P25054 as initial empiric therapy for FN . Our secondary objectives were to compare P05067 with P25054 and third- with fourth-generation P25054 as initial empiric therapy in this population . METHODS : We performed electronic searches of Ovid Medline , EMBASE , and the Cochrane Central Register of Controlled Trials , limiting studies to prospective pediatric trials in FN in which at least 1 treatment arm consisted of an P05067 or P25054 antibiotic with or without an aminoglycoside . Data abstraction was conducted by 2 independent reviewers . RESULTS : From 7281 reviewed articles , 41 studies comprising 51 treatment regimens were included in the meta-analysis . Treatment failure , including antibiotic modification , occurred in 34 % and 41 % of patients treated with P05067 and P25054 monotherapy , respectively , and 41 % and 33 % of patients treated with P05067 - and P25054 -aminoglycoside combination therapy , respectively . There were no statistically significant differences in treatment failure including modification , mortality , or adverse events when comparing P05067 with P25054 monotherapy , P05067 with P25054 combination therapy , or third- with fourth-generation P25054 therapy . CONCLUSIONS : Our meta-analysis suggests that P05067 and P25054 monotherapy , as well as combination therapy with an aminoglycoside , are efficacious and safe therapeutic options for the empiric management of pediatric patients with FN . Specific antibiotic selection should be based on other important factors , such as cost , availability , and local epidemiologic and resistance patterns . Dose-dependent modulation of apoptotic processes by fluoxetine in maturing neuronal cells : an in vitro study . OBJECTIVES : Recent studies indicate that the selective serotonin reuptake inhibitor ( SSRI ) fluoxetine is not solely effective by the instant inhibition of the serotonin transporter ( P31645 ) but also by its influence on mitotic and/or apoptotic processes . METHODS : To investigate the effects of the compound in vitro , we treated neurons from different brain areas with increasing concentrations of fluoxetine . Additionally , human embryonic kidney ( P29320 -293 ) cells and P29320 -293 cells stably expressing the P31645 were used . Cell viability was quantified by MTT-assay and apoptosis via fluorescence-activated cell-sorting analyses . DB00472 's effect on the γ-aminobutyric acid ( GABA ) receptor was electrophysiologically investigated to test the hypothesis if a GABA-mimetic effect exists that might lead - additionally to the well-known N-methyl-D-aspartate ( DB01221 ) -antagonism - to increased apoptosis in immature neurons . RESULTS : In hippocampal , cortical , and both types of P29320 -293 cells , viability decreased and apoptosis increased in a dose-dependent manner ( 0.5-75 μM ) . In contrast , in mesencephalic and striatal cells the viability was unchanged or even slightly stimulated up to 20 μM fluoxetine . An anti-apoptotic effect of concentrations below 10 μM was observed in these cells . The GABA(A) receptor was directly activated by fluoxetine . CONCLUSIONS : We conclude that fluoxetine affects apoptotic processes independently from P31645 expression . Since especially the combined GABA-mimetic and DB01221 -antagonistic effects increase apoptosis in developing neuronal cells , whereas both effects are neuroprotective in adult neurons we hypothesise that these mechanisms explain the discrepancy of in vitro and in vivo studies . Cytotoxic effects of bortezomib in myelodysplastic syndrome/acute myeloid leukemia depend on autophagy-mediated lysosomal degradation of Q9Y4K3 and repression of P25786 . DB00188 ( Velcade ) is used widely for the treatment of various human cancers ; however , its mechanisms of action are not fully understood , particularly in myeloid malignancies . DB00188 is a selective and reversible inhibitor of the proteasome . Paradoxically , we find that bortezomib induces proteasome-independent degradation of the Q9Y4K3 protein , but not mRNA , in myelodysplastic syndrome ( P43034 ) and acute myeloid leukemia ( AML ) cell lines and primary cells . The reduction in Q9Y4K3 protein coincides with bortezomib-induced autophagy , and subsequently with apoptosis in P43034 /AML cells . RNAi-mediated knockdown of Q9Y4K3 sensitized bortezomib-sensitive and -resistant cell lines , underscoring the importance of Q9Y4K3 in bortezomib-induced cytotoxicity . DB00188 -resistant cells expressing an shRNA targeting Q9Y4K3 were resensitized to the cytotoxic effects of bortezomib due to down-regulation of the proteasomal subunit α-1 ( P25786 ) . To determine the molecular consequences of loss of Q9Y4K3 in P43034 /AML cells , in the present study , we applied gene-expression profiling and identified an apoptosis gene signature . Knockdown of Q9Y4K3 in P43034 /AML cell lines or patient samples resulted in rapid apoptosis and impaired malignant hematopoietic stem/progenitor function . In summary , we describe herein novel mechanisms by which Q9Y4K3 is regulated through bortezomib/autophagy-mediated degradation and by which it alters P43034 /AML sensitivity to bortezomib by controlling P25786 expression . Regulation of proteolytic processing of the amyloid beta-protein precursor by first messengers . A novel potential approach for the treatment of Alzheimer 's disease . Amyloid deposits in Alzheimer 's disease brains consist of aggregated amyloid beta-peptides ( A beta ) which are derived by proteolytic processing of the amyloid beta-protein precursor ( P05067 ) . Proteolytic P05067 processing can be regulated by the activity of neuronal cell surface receptors including the muscarinic m1 and m3 , the serotoninergic 5-HT2 and P28335 , vasopressin and bradykinin receptor subtypes . Receptor stimulation with appropriate agonists rapidly increases the rates of release of the alpha-secretase processing product APPs which is cleaved within the A beta domain and thus is a non-amyloidogenic derivative . Moreover , stimulation of m1 receptors also decreases the formation of A beta , a secreted potentially amyloidogenic and possibly neurotoxic P05067 fragment . Similar biochemical events occur in stimulation experiments of fresh rat brain slices suggesting that neuronal activity may be involved in regulating P05067 processing in mammalian brain . Activation of non-amyloidogenic P05067 processing and inhibition of amyloidogenic processing pathways by subtype-specific agonists of muscarinic , serotoninergic or peptidergic receptors provides a novel approach for the pharmacological modulation of P05067 processing in Alzheimer 's disease . Point mutation of the proteasome beta5 subunit gene is an important mechanism of bortezomib resistance in bortezomib-selected variants of Jurkat T cell lymphoblastic lymphoma/leukemia line . To study the mechanism of acquired resistance to bortezomib , a new antitumor drug that is the first therapeutic proteasome inhibitor , we established a series of bortezomib-resistant T lymphoblastic lymphoma/leukemia cell lines , designated the JurkatBs , from the parental Jurkat line via repeated drug selection . There were no significant differences in the growth curves or colony formation between the JurkatB cells and parental Jurkat cells . The effects of bortezomib on cytotoxicity , cell cycle arrest , and induction of apoptosis were decreased in JurkatB cells compared with parental Jurkat cells . A mutation in the proteasome beta5 subunit ( P28074 ) gene ( G322A ) , which encodes an amino acid change from Ala to DB00156 at polypeptide position 108 , was detected by sequencing full-length cDNA clones and direct polymerase chain reaction products of the P28074 gene . DB00188 caused less inhibition of chymotrypsin-like activity in resistant cells . When the G322A mutant P28074 was retrovirally introduced into parental Jurkat cells , it conferred bortezomib resistance to these cells , resulting in decreased cytotoxicity , apoptosis , and inhibition of chymotrypsin-like activity . The predicted structure of A108T-mutated P28074 shows a conformational change that suggests decreased affinity to bortezomib . In short , the G322A mutation of the P28074 gene is a novel mechanism for bortezomib resistance . The inhibitory effect and the molecular mechanism of glabridin on O14788 -induced osteoclastogenesis in RAW264.7 cells . Osteoblastic bone formation and osteoclastic bone resorption are in balance to maintain a constant , homeostatically controlled amount of bone . Excessive bone resorption by osteoclasts is involved in the pathogenesis of bone-related disorders . In the present study , we evaluated the inhibitory effects of glabridin , a flavonoid purified from licorice root , on the receptor activator of nuclear factor-κB ligand ( O14788 ) -induced osteoclast differentiation and its molecular mechanisms in murine osteoclast progenitor RAW264.7 cells . Glabridin significantly inhibited O14788 -induced tartrate-resistant acid phosphatase ( TRAP ) activity , the formation of multinucleated osteoclasts and resorption-pit formation . In mechanistic studies of the anti-osteoclastogenic potential of glabridin , we found that glabridin inhibited O14788 -induced expression of c-Fos and subsequent expression of O95644 , which is a master regulator of osteoclastogenesis . Interestingly , glabridin inhibited the O14788 -induced expression of signaling molecules ( Q9Y4K3 , Q9UQC2 , P28482 , P45983 and O14733 ) and osteoclast survival-related signaling pathways such as c-Src , PI3K and Akt2 . Glabridin also inhibited the bone resorptive activity of mature osteoclasts by inhibiting osteoclast-associated genes ( cathepsin K , P14780 , CAII , Q13488 , Q86WC4 and P51798 ) . Taken together , our data suggest that glabridin holds great promise for use in preventing osteoclastogenesis by inhibiting O14788 -induced activation of signaling molecules and subsequent transcription factors in osteoclast precursors and these findings may be useful for evaluating treatment options in bone-destructive diseases . [ Influence of insulin on human leukemia cell proliferation ] . As a hormone with a number of biological effects , insulin not only displays the function of classic metabolic regulation , but also can regulate cell proliferation and differentiation , and ensure growth and development of embryos and young individuals . In vitro insulin can stimulate cell proliferation and differentiation . P01308 is also an important growth regulator in vivo , which has been proved in more and more studies . The role of insulin at the cellular level is triggered by the binding of insulin to its receptor located in the cell surface . However , insulin at the higher concentration can also been triggered by insulin-like growth factor-1 ( DB01277 ) receptor . Its role varies in different cell lines . P06213 and insulin-like growth factor receptor-1 are widely expressed in human P43034 and AML cell membranes . Recently , many studies related to the relationship between hyperinsulinemia and cancer have been reported . In this review the role and its possible mechanism in promoting human leukemia cell proliferation and inhibiting human leukemia cell proliferation are summarized . Furthermore , the potential application prospect of insulin analogues also will be described . DB00188 -resistant myeloma cell lines : a role for mutated P28074 in preventing the accumulation of unfolded proteins and fatal ER stress . DB00188 is an effective agent for treating multiple myeloma ( MM ) . To investigate the underlying mechanisms associated with acquired resistance to this agent , we established two bortezomib-resistant MM cell lines , KMS-11/BTZ and OPM-2/BTZ , the 50 % inhibitory concentration values of which were respectively 24.7- and 16.6-fold higher than their parental cell lines . No activation of caspase and BH3-only proteins such as Noxa was noted in bortezomib-resistant cells after exposure to the drug . The accumulation of polyubiquitinated proteins was reduced in bortezomib-resistant cells compared with the parental cells , associated with avoidance of catastrophic ER stress as assessed by downregulation of P35638 expression . These resistant MM cells have a unique point mutation , G322A , in the gene encoding the proteasome beta5 subunit ( P28074 ) , likely resulting in conformational changes to the bortezomib-binding pocket of this subunit . KMS-11 parental cells transfected to express mutated P28074 also showed reduced bortezomib-induced apoptosis compared with those expressing wild-type P28074 or the parental cells . Expression of mutated P28074 was associated with the prevention of the accumulation of unfolded proteins . Thus , a fraction of MM cells may acquire bortezomib resistance by suppressing apoptotic signals through the inhibition of unfolded protein accumulation and subsequent excessive ER stress by a mutation of the P28074 gene . Genetic and epigenetic markers in the evaluation of pancreatic masses . BACKGROUND : Methylation markers have shown promise in the early diagnosis of pancreatic carcinoma . The aim of this study was to assess the diagnostic utility of hypermethylation status of candidate genes in combination with P01116 mutation detection in the evaluation of pancreatic masses . EXPERIMENTAL DESIGN : Sixty-one fine needle aspirates of pancreatic masses ( 43 pancreatic adenocarcinomas and 18 chronic pancreatitis ) were studied . Methylation status of P25021 , Q05925 , P09486 , P55290 and P25054 were analysed using melting curve analysis after DNA bisulfite treatment . P01116 mutations were also analysed . RESULTS : The methylation panel had a sensitivity of 73 % ( 27 of 37 , CI 95 % 56 to 86 % ) and a specificity of 100 % whenever two or more promoters were found hypermethylated . P01116 mutations showed a sensitivity of 77 % ( 33 of 43 , CI 95 % 62 to 88 % ) and a specificity of 100 % . Both molecular analyses added useful information to cytology by increasing the number of informative cases . When genetic and epigenetic analyses were combined sensitivity was 84 % ( 36 of 43 CI 95 % 69 to 93 % ) maintaining a 100 % specificity . CONCLUSIONS : Analysis of hypermethylation status of a panel of genes and P01116 mutation detection offer a similar diagnostic yield in the evaluation of pancreatic masses . The combined molecular analysis increases the number of informative cases without diminishing specificity . Synthesis and evaluation of ( S ) -2-(2-[18F]fluoroethoxy)-4- ( [ 3-methyl-1-(2-piperidin-1-yl-phenyl)-butyl-carbamoyl ] -methyl ) -benzoic acid ( [18F]repaglinide ) : a promising radioligand for quantification of pancreatic beta-cell mass with positron emission tomography ( PET ) . 18F-labeled non-sulfonylurea hypoglycemic agent ( S ) -2-(2-[(18)F]fluoroethoxy)-4- ( ( 3-methyl-1-(2-piperidin-1-yl-phenyl)-butylcarbamoyl ) -methyl ) -benzoic acid ( [(18)F]repaglinide ) , a derivative of the sulfonylurea-receptor ( Q09428 ) ligand repaglinide , was synthesized as a potential tracer for the non-invasive investigation of the sulfonylurea 1 receptor status of pancreatic beta-cells by positron emission tomography ( PET ) in the context of type 1 and type 2 diabetes . [(18)F] DB00912 could be obtained in an overall radiochemical yield ( RCY ) of 20 % after 135 min with a radiochemical purity higher than 98 % applying the secondary labeling precursor 2-[(18)F]fluoroethyltosylate . Specific activity was in the range of 50-60 GBq/micromol . Labeling was conducted by exchanging the ethoxy-moiety into a 2-[(18)F]fluoroethoxy group . To characterize the properties of fluorinated repaglinide , the affinity of the analogous non-radioactive (19)F-compound for binding to the human Q09428 isoform was assessed . [(19)F] DB00912 induced a complete monophasic inhibition curve with a Hill coefficient close to 1 ( 1.03 ) yielding a dissociation constant ( K(D) ) of 134 nM . Biological activity was proven via insulin secretion experiments on isolated rat islets and was comparable to that of repaglinide . Finally , biodistribution of [(18)F]repaglinide was investigated in rats by measuring the concentration of the compound in different organs after i.v. injection . Pancreatic tissue displayed a stable accumulation of approximately 0.12 % of the injected dose from 10 min to 30 min p.i . 50 % of the radioactive tracer could be displaced by additional injection of unlabeled repaglinide , indicating that [(18)F]repaglinide might be suitable for in vivo investigation with PET . Enhanced goblet cell hyperplasia in HDC knockout mice with allergic airway inflammation . BACKGROUND : DB11320 is known to have immunoregulatory roles in allergic reactions through histamine receptor 1 ( P35367 ) , P25021 , Q9Y5N1 and Q9H3N8 . However , its role in goblet cell hyperplasia in the airways of asthma patients is yet to be clarified . OBJECTIVE : This study was designed to examine the role of histamine in goblet cell hyperplasia using histamine-deficient mice ( Hdc-/- mice ) with allergic airway inflammation . METHODS : Wild-type and Hdc-/- C57BL/6 mice were sensitized with ovalbumin ( OVA ) . After a 2-week exposure to OVA , goblet cell hyperplasia was evaluated . Cell differentials and cytokines in BALF were analyzed . The mRNA levels of P98088 and Gob-5 gene were determined quantitatively . RESULTS : The number of eosinophils in BALF increased in both the sensitized wild-type mice and Hdc-/- mice with OVA inhalation . In addition , the numbers of alveolar macrophages and lymphocytes in BALF increased significantly in the sensitized Hdc-/- mice with OVA inhalation compared to the wild-type mice under the same conditions . The concentrations of P05112 ( P05112 ) , P05113 , P35225 , Interferon-gamma ( P01579 ) , tumor necrosis factor-alpha ( P01375 ) and P60568 in the BALF all increased significantly in both groups compared to those exposed to saline . In particular , the concentration of P01375 in the Hdc-/- mice exposed to OVA was significantly higher than that in the wild-type mice under the same conditions . The mRNA levels of Gob-5 and P98088 , and the ratio of the goblet cells in the airway epithelium significantly increased in Hdc-/- mice exposed to OVA compared to wild-type mice . CONCLUSIONS : These results suggested that histamine may play a regulatory role in goblet cell hyperplasia in allergic airway inflammation . Role of histamine receptors in the effects of histamine on the production of reactive oxygen species by whole blood phagocytes . AIMS : The diverse physiological functions of histamine are mediated through distinct histamine receptors . In this study we investigated the role of P25021 and Q9H3N8 in the effects of histamine on the production of reactive oxygen species by phagocytes in whole blood . MAIN METHODS : Changes in reactive oxygen species ( ROS ) production by whole blood phagocytes after treatment with histamine , Q9H3N8 agonists ( 4-methylhistamine , VUF8430 ) , P25021 agonist ( dimaprit ) and their combinations with Q9H3N8 antagonist ( JNJ10191584 ) and P25021 antagonist ( ranitidine ) were determined using the chemiluminescence ( CL ) assay . To exclude the direct scavenging effects of the studied compounds on the CL response , the antioxidant properties of all compounds were measured using several methods ( TRAP , ORAC , and luminol-HRP-H2O2 based CL ) . KEY FINDINGS : DB11320 , 4-methylhistamine , VUF8430 and dimaprit inhibited the spontaneous and OZP-activated whole blood CL in a dose-dependent manner . On the other hand , only VUF8430 was able to inhibit PMA-activated whole blood CL . DB00863 , but not JNJ10191584 , completely reduced the effects of histamine , 4-methylhistamine and dimaprit . The direct scavenging ability of tested compounds was negligible . SIGNIFICANCE : Our results demonstrate that the inhibitory effects of histamine on ROS production in whole blood phagocytes were caused by P25021 . Our results also suggest that Q9H3N8 agonists in concentrations higher than 10(-6)M may also influence ROS production via binding to P25021 . hsBAFF enhances activity of NK cells by regulation of P01730 (+) T lymphocyte function . B cell activating factor belonging to the P01375 family ( Q9Y275 , also called Q9Y275 , Q9Y275 , THANK , or zTNF4 ) is an important survival factor for B cells , and is able to regulate T cell activation . Recently , we have demonstrated that human soluble Q9Y275 ( hsBAFF ) potently elevates NK cell activity of murine splenic cells in vivo . In this study , we further show that hsBAFF markedly enhanced NK cell activity of in vitro mouse splenic cells . Purified NK cell activities treated with hsBAFF in the presence of P60568 or P01579 , but not with hsBAFF alone were obviously elevated . hsBAFF strongly increased the activity of NK cells co-incubated with mixed T and B lymphocytes or T lymphocytes alone , but not with B lymphocytes alone . We also found that culture supernatants , from mixed T and B lymphocytes or T lymphocytes alone , but not from B lymphocytes alone post-hsBAFF treatment , effectively increased NK cell activity , and noticed that P60568 and P01579 levels significantly increased in the culture supernatants of hsBAFF-treated T lymphocytes . Of importance , we pinpointed that hsBAFF elicited robust population of P01730 (+) T lymphocytes in vitro , and further demonstrated that hsBAFF induced significantly high P60568 and P01579 secretion of P01730 (+) T lymphocytes . These findings indicate that hsBAFF results in the elevation of NK cell activity by regulation of P01730 (+) T lymphocytes contributing to P60568 and P01579 generation . Growth factors expression in patients with erosive esophagitis . Although the pathogenesis and treatment of erosive esophagitis ( EE ) is well recognized , little is known about the cellular and molecular mechanisms of mucosal healing in EE patients . In this pilot study , we enrolled typical EE patients to evaluate what kinds of growth factors and their receptors were activated in their injured esophageal mucosa . Forty endoscopically proved EE patients were consecutively enrolled . Messenger RNA expressions , which includes keratinocyte growth factor ( KGF ) and its receptor ( P21802 ) , epidermal growth factor ( P01133 ) and its receptor ( P00533 ) , hepatocyte growth factor ( P14210 ) and its receptor ( HGFR ) , basic fibroblast growth factor ( P09038 ) , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase ( P36551 ) -1 and P35354 , were measured using real-time polymerase chain reaction ( PCR ) . Data were compared between the injured EE mucosa and their normal esophageal mucosa above EE . The mRNA expressions of P14210 , HGFR , P01133 , P15692 , and P35354 , but not P00533 , KGF , P21802 , P09038 , and P23219 , were significantly increased in the injured mucosa of EE patients compared with those of normal mucosa ( P < 0.05 ) . The study found that P14210 , HGFR , P01133 , P15692 , and , P35354 are activated in the injured mucosa of EE patients ; their activation might be involved in mucosal repair and ulcer healing of EE . aChE and BuChE inhibition by rivastigmin have no effect on peripheral insulin resistance in elderly patients with Alzheimer disease . BACKGROUND : P01308 resistance ( IR ) may play a role in most pathogenic processes that promote the development of Late Onset Alzheimer Disease ( LOAD ) . This study was designed to determine the interaction between inhibition of both butyrylcholinesterase ( BuChE ) and acetylcholinesterase ( P22303 ) with rivastigmine and peripheral insulin resistance ( IR ) in LOAD . METHODS : Seventy-Nine consecutive elderly patients , 31 late onset AD and 48 non-demented patients were evaluated . IR was calculated with HOMA . All of the patients were evaluated through comprehensive geriatric assessments at baseline and in the 6th and 12th months . RESULTS : End of the study , compared to the baseline values , there was a significant increase in the 6th month in both MMSE and IADL scores ( t =2.200 , p = 0.036 for MMSE and t =2.724 , p= 0.011 for IADL , respectively ) . DB00989 was improved both the scores of MMSE and IADL in elderly patients with LOAD , but there was no significance or correlation between HOMA scores and cognitive status . CONCLUSION : In conclusion , inhibition of both BuChE and P22303 with rivastigmine was improved the cognition without affecting on the peripheral IR in the elderly patients with LOAD by HOMA . Due to the complexity of disease pathogenesis , it is too early to make general comments , and further longitudinal and long-term studies on this issue are needed . Interplay between inhibitory ferric and stimulatory curcumin regulates phosphorylation-dependent human cystic fibrosis transmembrane conductance regulator and ΔF508 activity . Curcumin potentiates cystic fibrosis transmembrane conductance regulator ( P13569 ) activation in an DB00171 -independent but phosphorylation-dependent manner . The underlying molecular mechanisms are unclear . Here , P29320 -293T cells cultured in an Fe(3+)-containing medium were transiently transfected with P13569 constructs , and the role of the inhibitory Fe(3+) bridge between intracellular loop 3 and the regulatory domain of P13569 in this pathway was investigated . The results showed that ethylenediaminetetraacetic acid ( DB00974 ) stimulated phosphorylation-dependent P13569 activation and the stimulation was suppressed by the deletion of the regulatory domain or the insertion of a C832A mutation that removes the Fe(3+)-binding interface . Furthermore , curcumin potentiation of P13569 was significantly weakened not only by Fe(3+)-insensitive mutations at the interface between the regulatory domain and intracellular loop 3 but also by N-ethylmaleimide or DB00974 pretreatment that removes Fe(3+) . More importantly , potentiation of P13569 was completely suppressed by sufficient Fe(3+) . Finally , the insertion of Fe(3+)-insensitive H950R/S768R increased the curcumin-independent activity of ΔF508 but weakened its curcumin potentiation . Thus , Fe(3+) homeostasis in epithelia may play a critical role in regulating P13569 activity , and targeting Fe(3+)-chelating potentiators may direct new therapies for cystic fibrosis . Biological and immunological studies of bovine hypothalamic DB05394 . P06850 B ( CRF-B ) is a peptide(s) isolated from bovine hypothalamic extracts by Sephadex G-100 chromatography on the basis of its ability to stimulate secretion of adrenocorticotropin ( DB01285 ) in vitro and in vivo . It is similar in molecular size to the 41-residue ovine CRF ( oCRF ) or rat CRF ( rCRF ) recently elucidated and appears to be their bovine counterpart . Immunoreactivity of CRF-B was examined in homologous radioimmunoassays ( RIAs ) for oCRF or rCRF , using several anti-oCRF and anti-rCRF antibodies . CRF-B cross-reacted well with anti-oCRF antibodies but poorly with anti-rCRF antibodies . Purification of CRF-B with preparative isoelectric focusing yielded four CRF peaks , B-1 ( pH 4.7 ) , B-2 ( pH 5.5 ) , B-3 ( pH 6.3 ) , and B-4 ( pH 7.0 ) , which accounted for 16 , 30 , 46 , and 8 % of the total immunoreactivity , respectively . CRF B-2 , B-3 , and B-4 showed both immunological activity and biological activity in vitro ( cell culture assay ) and in vivo ( Arimura assay ) , whereas CRF B-1 showed only immunoreactivity . Their relative bioactivity/immunoreactivity ratios were 0 ( B-1 ) , 1 ( B-2 ) , 1 ( B-3 ) , and 3 ( B-4 ) . All of these CRF-B subtypes exhibited RIA displacement curves parallel to that for the oCRF standard and coeluted with oCRF on Sephadex G-100 chromatography , which suggests that their molecular modifications are relatively minor . Euscaphic acid isolated from roots of Rosa rugosa inhibits LPS-induced inflammatory responses via O00206 -mediated NF-κB inactivation in RAW 264.7 macrophages . As an attempt to search for bioactive natural products exerting anti-inflammatory activity , we have evaluated the anti-inflammatory effects of euscaphic acid ( 19α-hydroxyursane-type triterpenoids , EA ) isolated from roots of Rosa rugosa and its underlying molecular mechanisms in lipopolysaccharide ( LPS ) -induced RAW 264.7 macrophages . EA concentration-dependently reduced the production of nitric oxide ( NO ) , prostaglandin E2 ( DB00917 ) , tumor necrosis factor-α ( P01375 -α ) , and interleukin-1β ( IL-1β ) induced by LPS in RAW 264.7 macgophages . Consistent with these data , expression levels of inducible nitric oxide synthase ( P35228 ) and cyclooxygenase-2 ( P35354 ) protein and P35228 , P35354 , P01375 -α , and IL-1β mRNA were inhibited by EA in a concentration-dependent manner . In addition , EA attenuated LPS-induced DNA binding and transcriptional activity of nuclear factor-kappa B ( NF-κB ) , which was accompanied by a parallel reduction of degradation and phosphorylation of inhibitory kappa Bα ( IκBα ) and consequently by decreased nuclear translocation of p65 subunit of NF-κB . Pretreatment with EA significantly inhibited the LPS-induced phosphorylation of IκB kinase β ( IKKβ ) , p38 , and JNK , whereas the phosphorylation of P27361 /2 was unaffected . Furthermore , EA interfered with the LPS-induced clustering of Q9Y4K3 ( Q9Y4K3 ) with interleukin receptor associated kinase 1 ( P51617 ) and transforming growth factor-β-activated kinase 1 ( TAK1 ) . Taken together , these results suggest that EA inhibits LPS-induced inflammatory responses by interference with the clustering of Q9Y4K3 with P51617 and TAK1 , resulting in blocking the activation of IKK and MAPKs signal transduction to downregulate NF-κB activations . G(alpha)12/13 inhibition enhances the anticancer effect of bortezomib through P28074 downregulation . DB00188 is a proteasome inhibitor approved for anticancer therapy . However , variable sensitivity of tumor cells exists in this therapy probably due to differences in the expression of proteasome subunits . G(alpha)(12/13) serves modulators or signal transducers in diverse pathways . This study investigated whether cancer cells display differential sensitivity to bortezomib with reference to G(alpha)(12/13) expression , and if so , whether G(alpha)(12/13) affects the expression of proteasome subunits and their activities . DB00188 treatment exhibited greater sensitivities in Huh7 and SNU886 cells ( epithelial type ) than SK-Hep1 and SNU449 cells ( mesenchymal type ) that exhibited higher levels of G(alpha)(12/13) . Overexpression of an active mutant of G(alpha)(12) ( Galpha(12)QL ) or G(alpha)(13) ( G(alpha)(13)QL ) diminished the ability of bortezomib to induce cytotoxicity in Huh7 cells . Moreover , transfection with the minigene that disturbs G protein-coupled receptor-G protein coupling ( CT12 or Q9NXZ2 ) increased it in SK-Hep1 cells . Consistently , MiaPaCa2 cells transfected with CT12 or Q9NXZ2 exhibited a greater sensitivity to bortezomib . Evidence of G(alpha)(12/13) 's antagonism on the anticancer effect of bortezomib was verified in the reversal by G(alpha)(12)QL or G(alpha)(13)QL of the minigenes ' enhancement of cytotoxity . Real-time polymerase chain reaction assay enabled us to identify P28074 , multicatalytic endopeptidase complex-like-1 , and proteasome activator subunit-1 repression by CT12 or Q9NXZ2 . Furthermore , G(alpha)(12/13) inhibition enhanced the ability of bortezomib to repress P28074 , as shown by immunoblotting and proteasome activity assay . Moreover , this inhibitory effect on P28074 was attenuated by G(alpha)G(alpha)(12)QL or G(alpha)(13)QL . In conclusion , the inhibition of G(alpha)(12/13) activities may enhance the anticancer effect of bortezomib through P28074 repression , providing insight into the G(alpha)(12/13) pathway for the regulation of proteasomal activity . Proteasomal serine hydrolases are up-regulated by and required for influenza virus infection . Interactions between viruses and their host cells are important determinants of virus replication and of immune responses to the virus . However , these interactions and resulting consequences of these interactions remain poorly defined . Numerous recent quantitative proteomic approaches have measured host proteins affected by virus infection . Here , we used activity-based protein profiling ( P05067 ) to measure functional alterations in host serine hydrolases after influenza A virus infection of Madin-Darby canine kidney and human A549 lung cells . We identified 62 serine proteases . We then combined the P05067 approach with stable isotope labeling to directly measure how serine hydrolase activities were affected by virus infection . Differentially regulated SHs mapped into a few key cellular pathway systems , most notably the proteasomal system . The specific serine protease inhibitors DB06692 and Pefablock and specific proteasomal inhibitors DB00188 and MG132 significantly inhibited influenza virus growth . Some inhibitors also down-regulated activities of several proteasomal proteins , including P25786 , P25787 , and PMSB3 . Genetic knockdown of PMSA2 also attenuated influenza virus replication . These findings further our understanding of enzymatic cellular processes affected by influenza virus and may be beneficial in the search for additional antiviral therapeutic targets . Potentiator ivacaftor abrogates pharmacological correction of ΔF508 P13569 in cystic fibrosis . Cystic fibrosis ( CF ) is caused by mutations in the CF transmembrane conductance regulator ( P13569 ) . Newly developed " correctors " such as DB09280 ( VX-809 ) that improve P13569 maturation and trafficking and " potentiators " such as ivacaftor ( VX-770 ) that enhance channel activity may provide important advances in CF therapy . Although VX-770 has demonstrated substantial clinical efficacy in the small subset of patients with a mutation ( G551D ) that affects only channel activity , a single compound is not sufficient to treat patients with the more common P13569 mutation , ΔF508 . Thus , patients with ΔF508 will likely require treatment with both correctors and potentiators to achieve clinical benefit . However , whereas the effectiveness of acute treatment with this drug combination has been demonstrated in vitro , the impact of chronic therapy has not been established . In studies of human primary airway epithelial cells , we found that both acute and chronic treatment with VX-770 improved P13569 function in cells with the G551D mutation , consistent with clinical studies . In contrast , chronic VX-770 administration caused a dose-dependent reversal of VX-809-mediated P13569 correction in ΔF508 homozygous cultures . This result reflected the destabilization of corrected ΔF508 P13569 by VX-770 , markedly increasing its turnover rate . Chronic VX-770 treatment also reduced mature wild-type P13569 levels and function . These findings demonstrate that chronic treatment with P13569 potentiators and correctors may have unexpected effects that can not be predicted from short-term studies . Combining these drugs to maximize rescue of ΔF508 P13569 may require changes in dosing and/or development of new potentiator compounds that do not interfere with P13569 stability . Evaluation of hypoxia inducible factor expression in inflammatory and neurodegenerative brain models . The neuroinflammatory process is thought to contribute to the progression of neurological disorders and brain pathologies . The release of pro-inflammatory cytokines and chemokines by activated glial cells , astrocytes and microglia plays an important role in this process . However , the role of hypoxia-inducible factor-1α ( HIF-1α ) , the key transcription factor regulating the expression of hypoxia-inducible genes , during glial activation is less known . Thus , we examined the significance of HIF-1α in three experimental models : first in an acute model of inflammation induced by pro-inflammatory cytokines P01375 -α , IL-1β and IFN-γ ; secondly , in a chronic model of inflammation using an APPswe/PS1dE9 ( P05067 / P49768 ) transgenic mouse model of Alzheimer 's disease and thirdly via the inhibition of the PI3K/AKT pathway in a model of neuronal apoptosis . During acute glial inflammation induced by in vitro administration of P01375 -α , IL-1β and IFN-γ , mRNA expression levels of HIF-1α were significantly upregulated ; however , this effect was blocked by SP600126 , a pharmacological inhibitor of mitogen-activated protein kinases ( MAPKs ) . These data suggest that MAPKs could be involved in HIF-1α regulation . In addition , we observed that HIF-1α is not involved in the neuronal apoptotic process mediated by P19957 -kinase inhibition , which is regulated by c-Jun . Finally , we did not detect significant differences in the expression of HIF-1α mRNA in P05067 / P49768 mice during the course of the study ( 3-12 months of age ) . Thus , we demonstrated that HIF-1α has a prominent role in acute but not in chronic inflammatory processes , such as the one which occurs in the P05067 / P49768 experimental model of AD . Moreover , HIF-1α is not involved in neuronal apoptosis after PI3K/AKT inhibition . P26718 -mediated immunity underlying paroxysmal nocturnal haemoglobinuria and related bone marrow failure syndromes . It is considered that a similar immune mechanism acts in the pathogenesis of bone marrow ( BM ) failure in paroxysmal nocturnal haemoglobinuria ( PNH ) and its related disorders , such as aplastic anaemia ( AA ) and myelodysplastic syndromes ( P43034 ) . However , the molecular events in immune-mediated marrow injury have not been elucidated . We recently reported an abnormal expression of stress-inducible P26718 ( natural-killer group 2 , member D ) ligands , such as ULBP ( UL16-binding protein ) and Q29983 /B ( major histocompatibility complex class I chain-related molecules A/B ) , on granulocytes in some PNH patients and the granulocyte killing by autologous lymphocytes in vitro . The present study found that the expression of P26718 ligands was common to both granulocytes and BM cells of patients with PNH , AA , and P43034 , indicating their exposure to some incitement to induce the ligands . The haematopoietic colony formation in vitro by the patients ' marrow cells significantly improved when their BM cells were pretreated with antibodies against P26718 receptor , suggesting that the antibodies rescued haematopoietic cells expressing P26718 ligands from damage by autologous lymphocytes with P26718 . Clinical courses of patients with PNH and AA showed a close association of the expression of P26718 ligands with BM failure and a favourable response to immunosuppressive therapy . We therefore propose that P26718 -mediated immunity may underlie the BM failure in PNH and its-related marrow diseases . Genetic interaction between genes involved in NF-κB signaling pathway in systemic lupus erythematosus . Recently , multiple genetic associations have been found between genes involved in nuclear factor-kappaB ( NF-κB ) signaling pathway and systemic lupus erythematosus ( SLE ) or other autoimmune diseases . This study was undertaken to replicate some of these associations and further test for genetic interactions among these genes in SLE in a Chinese population . Ten single-nucleotide polymorphisms ( SNPs ) in P19838 , Q04864 , inhibitor of κB-like ( IκBL ) , IκB kinase β ( O14920 ) , tumor necrosis factor receptor associated factor 6 ( Q9Y4K3 ) , tumor necrosis factor a-induced protein 3 ( P21580 ) , P21580 interacting protein 1 ( Q15025 ) were genotyped in 898 Chinese patients with SLE and 988 healthy controls by Sequenom MassArray technology . Single-marker genetic association analysis was performed , and additive and multiplicative interactions were analyzed . Associations of P21580 rs2230926 ( p=1.43 × 10(-3) ) and Q15025 rs10036748 ( p=4.33 × 10(-3) ) with SLE were replicated in our study . Two other SNPs , P19838 rs28362491 and IκBL rs2071592 , showed nominal evidence for association ( p=4.70 × 10(-2) and p=5.90 × 10(-3) , respectively ) but these were not significant after applying Bonferroni correction . Additive interaction analysis revealed significant interaction between P19838 rs28362491 and P21580 rs2230926 ( RERI=0.98 , 95 % CI=0.02-1.93 ; AP=43.2 % , 95 % CI=0.12-0.74 ) . Significant multiplicative interaction was observed between P19838 rs28362491 and Q15025 rs3792783 ( p=0.03 ) . Our results provide evidence for gene-gene interactions , which further support the important role of NF-κB signaling pathway in the genetic basis of SLE and the notion of genetic interactions accounting for missing heritability . DB08879 -- an anti- Q9Y275 human monoclonal antibody for rheumatoid arthritis . INTRODUCTION : Q9Y275 ( Q9Y275 ) is a major regulatory factor that controls the development and survival of B cells . Elevated serum levels of Q9Y275 have been associated with rheumatoid arthritis ( RA ) . DB08879 is a fully human monoclonal antibody that inhibits Q9Y275 and it is being developed for the treatment of RA . This review aims to summarize up-to-date pharmacological and clinical data of belimumab in the treatment of RA . AREAS COVERED : A literature search was performed on PubMed using keywords , including belimumab , LymphoStat-B , benlysta , Q9Y275 inhibitor , rheumatoid arthritis and autoimmune disease . References of relevant studies were searched by hand . Abstracts of international conferences up to October 2012 were also included . DB08879 was well tolerated in the treatment of RA over 24 weeks . It significantly increased American College of Rheumatology ( P10323 )20 responses at week 24 , especially in patients with high disease activity , positive rheumatoid factor , no anti- P01375 treatment experience and those who had failed methotrexate therapy . However , belimumab failed to demonstrate significantly improved ACR50 and ACR70 responses in the single Phase II clinical trial of RA . EXPERT OPINION : These results suggest that the clinical efficacy of belimumab for RA needs to be further investigated in future clinical trials . Careful patient selection may be necessary for belimumab to achieve optimal clinical outcomes in RA . Characterization of bortezomib-adapted I-45 mesothelioma cells . BACKGROUND : DB00188 , a proteasome-specific inhibitor , has emerged as a promising cancer therapeutic agent . However , development of resistance to bortezomib may pose a challenge to effective anticancer therapy . Therefore , characterization of cellular mechanisms involved in bortezomib resistance and development of effective strategies to overcome this resistance represent important steps in the advancement of bortezomib-mediated cancer therapy . RESULTS : The present study reports the development of I-45-BTZ-R , a bortezomib-resistant cell line , from the bortezomib-sensitive mesothelioma cell line I-45 . I-45-BTZ-R cells showed no cross-resistance to the chemotherapeutic drugs cisplatin , 5-fluorouracil , and doxorubicin . Moreover , the bortezomib-adapted I-45-BTZ-R cells had decreased growth kinemics and did not over express proteasome subunit beta5 ( P28074 ) as compared to parental I-45 cells . I-45-BTZ-R cells and parental I-45 cells showed similar inhibition of proteasome activity , but I-45-BTZ-R cells exhibited much less accumulation of ubiquitinated proteins following exposure to 40 nm bortezomib . Further studies revealed that relatively low doses of bortezomib did not induce an unfolded protein response ( UPR ) in the bortezomib-adapted cells , while higher doses induced UPR with concomitant cell death , as evidenced by higher expression of the mitochondrial chaperone protein Bip and the endoplasmic reticulum ( ER ) stress-related pro-apoptotic protein P35638 . In addition , bortezomib exposure did not induce the accumulation of the pro-apoptotic proteins p53 , Mcl-1S , and noxa in the bortezomib-adapted cells . CONCLUSION : These results suggest that UPR evasion , together with reduced pro-apoptotic gene induction , accounts for bortezomib resistance in the bortezomib-adapted mesothelioma cell line I-45-BTZ-R . Association of heparanase gene ( Q9Y251 ) single nucleotide polymorphisms with hematological malignancies . Q9Y251 , endo-beta-D-glucuronidase , degrades heparan sulfate glycosaminoglycans - the principal polysaccharide of the basement membrane and extracellular matrix . Q9Y251 activity plays a decisive role in biological processes associated with remodeling of the extracellular matrix , such as cancer metastasis , angiogenesis and inflammation . In the hematopoietic system , heparanase is thought to be associated with normal differentiation and function of myeloid cells and platelets . We investigated heparanase polymorphisms in patients with acute myeloid leukemia ( AML ) , myelodysplastic syndrome ( P43034 ) , acute lymphoblastic leukemia ( ALL ) , chronic myeloid leukemia ( CML ) , Hodgkin 's disease ( HD ) and multiple myeloma ( MM ) . Significant correlation was found between rs11099592 and rs6535455 heparanase gene ( Q9Y251 ) single nucleotide polymorphisms ( SNPs ) and ALL ( chi2(1d.f.)=4.96 , P=0.026 ) . Genotype frequency comparisons revealed a significant association with rs4693602 ( chi2(2d.f.)=7.276 , P=0.026 ) in MM patients and rs4364254 ( chi2(2d.f.)=6.226 , P=0.044 ) in AML patients . Examination of Q9Y251 gene mRNA expression by real-time RT-PCR indicated a significant low Q9Y251 gene expression level in ALL patients and a high expression level in MM and AML patients , compared to healthy controls . Moreover , statistically significant correlation was found between heparanase mRNA expression level and three Q9Y251 gene SNPs ( rs4693608 , rs11099592 and rs4364254 ) among healthy individuals . These data suggest that certain Q9Y251 gene SNPs may contribute to basal heparanase gene expression and that alterations in this gene are an important determinant in the pathogenesis of ALL , AML and MM . Preserved cognition in patients with early Alzheimer disease and amnestic mild cognitive impairment during treatment with rosiglitazone : a preliminary study . OBJECTIVE : P01308 resistance ( impaired insulin action ) has been associated with Alzheimer disease ( AD ) and memory impairment , independent of AD . Peroxisome proliferator-activated receptor-gamma ( P37231 ) agonists improve insulin sensitivity and regulate in-vitro processing of the amyloid precursor protein ( P05067 ) . Authors evaluated the effects of the P37231 agonist rosiglitazone on cognition and plasma levels of the P05067 derivative beta-amyloid ( Abeta ) in humans . METHODS : In a placebo-controlled , double-blind , parallel-group pilot study , 30 subjects with mild AD or amnestic mild cognitive impairment were randomized to a 6-month course of rosiglitazone ( 4 mg daily ; N = 20 ) or placebo ( N = 10 ) . Primary endpoints were cognitive performance and plasma Abeta levels . RESULTS : Relative to the placebo group , subjects receiving rosiglitazone exhibited better delayed recall ( at Months 4 and 6 ) and selective attention ( Month 6 ) . At Month 6 , plasma Abeta levels were unchanged from baseline for subjects receiving rosiglitazone but declined for subjects receiving placebo , consistent with recent reports that plasma Abeta42 decreases with progression of AD . CONCLUSIONS : Findings provide preliminary support that rosiglitazone may offer a novel strategy for the treatment of cognitive decline associated with AD . Future confirmation in a larger study is needed to fully demonstrate rosiglitazone 's therapeutic potential . Regulation of P28074 protein and β subunits of mammalian proteasome by constitutively activated signal transducer and activator of transcription 3 ( P40763 ) : potential role in bortezomib-mediated anticancer therapy . The ubiquitin-proteasome system facilitates the degradation of ubiquitin-tagged proteins and performs a regulatory role in cells . Elevated proteasome activity and subunit expression are found in several cancers . However , the inherent molecular mechanisms responsible for increased proteasome function in cancers remain unclear despite the well investigated and defined role of the mammalian proteasome . This study was initiated to elucidate the mechanisms involved in the regulation of β subunits of the mammalian proteasome . Suppression of P40763 tyrosine phosphorylation coordinately decreased the mRNA and protein levels of the β subunits of the 20 S core complex in DU145 cells . Notably , P28074 , a molecular target of bortezomib , was shown to be a target of P40763 . Knockdown of P40763 decreased P28074 protein . Inhibition of phospho- P40763 substantially reduced P28074 protein levels in cells expressing constitutively active- P40763 . Accumulation of activated P40763 resulted in the induction of P28074 promoter and protein levels . In addition , a direct correlation was observed between the endogenous levels of P28074 and constitutively active P40763 . P28074 and P40763 protein levels remained unaltered following the inhibition of proteasome activity . The P01133 -induced concerted increase of β subunits was blocked by inhibition of the P01133 receptor or P40763 but not by the PI3K/AKT or MEK/ P29323 pathways . Decreased proteasome activities were due to reduced protein levels of catalytic subunits of the proteasome in P40763 -inhibited cells . Combined treatments with bortezomib and inhibitor of P40763 abrogated proteasome activity and enhanced cellular apoptosis . Overall , we demonstrate that aberrant activation of P40763 regulates the expression of β subunits , in particular P28074 , and the catalytic activity of the proteasome . No evidence of mutations of the P28074 ( beta-5 subunit of proteasome ) in a case of myeloma with clinical resistance to DB00188 . DB00991 : kinetic and dynamic profile in the treatment of pain . DB00991 ( 4,5-diphenyl-2-oxazolepropionic acid ) is a non-steroidal anti-inflammatory drug ( NSAID ) which is effective in models of inflammation , pain and pyrexia . It is effective and well tolerated in the clinical management of adult rheumatoid arthritis ( RA ) , osteoarthritis ( OA ) , ankylosing spondylitis , soft tissue disorders and post operative dental pain . DB00991 has a high oral bioavailability ( 95 % ) , with peak plasma concentrations at 3 to 5 hours after dosing . It is metabolised in the liver by oxidative and conjugative pathways and readily eliminated by the renal and faecal routes . DB00991 's strong analgesic qualities are particularly useful in painful musculoskeletal conditions such as periarthritis of the shoulder , since it exhibits actions such as inhibition of P23219 and P35354 isoenzymes , inhibition of nuclear translocation of NF-kappaB and of metalloproteases , and modulates the endogenous cannabinoid system . This editorial addresses the accompanying paper by Barbara Heller and Rosanna Tarricone on the management of shoulder periarthritis pain , in which they studied the efficacy and safety of oxaprozin compared to the comparator drug diclofenac over a 15 day period . Both oxaprozin and diclofenac compared well in the primary study endpoint of reduction in shoulder pain . DB00991 and diclofenac were well tolerated and oxaprozin showed better improvement in shoulder function and in the mental health item of the SF-36 quality of life component . The study by Heller and Tarricone is an addition to the large number of clinical trials which demonstrate that oxaprozin has equal efficacy in comparison with standard doses of commonly used anti-rheumatic agents such as aspirin , diclofenac , ibuprofen , indomethacin etc. in several different painful musculoskeletal conditions . Biophysical and pharmacological characterization of hypotonically activated chloride currents in cortical astrocytes . Rat cortical astrocytes regulate their cell volume in response to hypotonic challenge . This regulation is believed to depend largely on the release of chloride or organic osmolytes through anion channels . Using whole-cell recordings , we identified weakly outwardly rectifying chloride currents that could be activated in response to hypotonic challenge . These currents exhibited the following permeability sequence upon replacement of chloride in the bathing solution with various anions : I- > NO3- > Cl- > Gluc- > or = MeS- > Ise- . Interestingly , extracellular I- , albeit showing the greatest permeability , blocked the currents with an IC50 of approximately 50 mM . Currents were almost completely inhibited by 123 microM P16860 and partially inhibited by 200 microM niflumic acid or 200 microM DIDS . Additionally , the total number of Cl- ions effluxed through the hypotonically activated channels was markedly similar to the total solute efflux during volume regulation . We therefore propose the hypotonically activated chloride channel as a major contributor to volume regulation of astrocytes . To examine potential candidate chloride channel genes expressed by astrocytes , we employed RT-PCR to demonstrate the presence of transcripts for P51788 , 3 , 4 , 5 , and 7 , as well as for P21796 and P13569 in cultured astrocytes . Moreover , we performed immunostaining with antibodies against each of these channels and showed the strongest expression of P51788 and P51790 , strong expression of P51795 and P21796 , weak expression of P51798 and very weak expression of P51793 and P13569 . Intriguingly , although we found at least seven Cl- channel proteins from three different gene families in astrocytes , none appeared to be active in resting cells . DB00989 improves hippocampal neurogenesis and depression-like behaviors via P08908 receptor stimulation in olfactory bulbectomized mice . DB00989 is a non-competitive inhibitor of both acetylcholinesterase ( P22303 ) and butylcholinesterase ( BuChE ) used to treat mild to moderate dementia in Alzheimer 's disease ( AD ) patients . Although rivastigmine reportedly ameliorates cognitive dysfunction in these patients , its ability to improve Behavioral and Psychological Symptoms of Dementia ( BPSD ) remains unclear . To determine whether rivastigmine treatment antagonizes depression-like behaviors , we chronically administered rivastigmine ( 0.1-1.0mg/kg ) to olfactory bulbectomized ( OBX ) mice once a day for 2weeks , starting 2weeks after bulbectomy . Chronic treatment at 0.3 or 1.0mg/kg dose dependently and significantly improved depression-like behaviors , as assessed by tail suspension ( Q16762 ) , forced swim ( P19883 ) , locomotion and novelty-suppressed feeding ( NSFT ) tests . Importantly , co-administration with WAY-100635 ( 1.0mg/kg ) , a P08908 receptor antagonist , but not ketanserin ( 1.0mg/kg , ) , a 5- Q13049 receptor antagonist , completely blocked rivastigmine-induced anti-depressive effects , suggesting that P08908 receptor stimulation mediates this activity . Consistent with this observation , rivastigmine treatment significantly rescued impaired neurogenesis observed in OBX mice in a P08908 receptor-dependent manner . Furthermore , enhanced protein kinase B ( Akt ) and extracellular signal-regulated kinase ( P29323 ) phosphorylation seen following rivastigmine treatment was closely associated with improved neurogenesis . These effects were blocked by WAY-100635 but not ketanserin treatment . Finally , we confirmed that P08908 but not 5- Q13049 receptor stimulation by specific agonists mimicked rivastigmine-induced anti-depression activity and promoted hippocampal neurogenesis . We conclude that , in addition to enhancing the cholinergic system , rivastigmine treatment restores normal function of the hippocampal serotonergic system , an activity that likely ameliorates depressive behaviors in AD patients . The Q9Y275 /APRIL system : emerging functions beyond B cell biology and autoimmunity . The Q9Y275 system plays a key role in the development of autoimmunity , especially in systemic lupus erythematosus ( SLE ) . This often leads to the assumption that Q9Y275 is mostly a B cell factor with a specific role in autoimmunity . Focus on Q9Y275 and autoimmunity , driven by pharmaceutical successes with the recent approval of a novel targeted therapy DB08879 , has relegated other potential roles of Q9Y275 to the background . Far from being SLE-specific , the Q9Y275 system has a much broader relevance in infection , cancer and allergy . In this review , we provide the latest views on additional roles of the Q9Y275 system in health and diseases , as well as an update on Q9Y275 and autoimmunity , with particular focus on current clinical trials . Endocytosis of the vasopressin receptor by anterior pituitary cells is increased by DB05394 ( CRF ) . Endocytosis of certain receptors such as the transferrin receptor and the P01133 -receptor appears to be influenced by second messengers . If second messengers are involved in modulation of endocytosis , not only endocytosis of the stimulated receptor itself but also of receptors for other ligands on the cell surface may be influenced by receptor occupancy . P06850 ( CRF ) and vasopressin act synergistically on secretion of DB01285 from the anterior pituitary . The results presented here demonstrate that CRF increases retrieval of the vasopressin receptor in anterior pituitary cells in primary culture without influencing the surface binding of vasopressin . This is not a function of an increased membrane turnover since endocytosis of the transferrin receptor is not influenced by CRF . 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 . Comparison of the effects of cytoprotective drugs on human plasma adrenocorticotropic hormone and cortisol levels with continual stress exposure . Cetraxate hydrochloride ( cetraxate ) , ecabet sodium ( ecabet ) , and sulpiride , which are cytoprotective drugs , have been used to treat peptic ulcers and acute or chronic gastritis . They are reported to improve mucosal blood flow in the stomach . One of the most important factors believed to cause gastric ulcers is mental and/or physiological stress . When people feel stress , the hypothalamo-pituitary-adrenal ( Q9Y251 ) axis is activated . Therefore , corticotropin-releasing hormone ( P06850 ) , adrenocorticotropic hormone ( DB01285 ) , and cortisol can be indicators of stress . We examined the effects of cetraxate , ecabet and sulpiride on the plasma levels of DB01285 and cortisol under stress conditions by repetitive blood sampling . Venous blood samples were taken before and 20-240 min after a single administration of the drugs or a placebo . A single dose of ecabet caused significant suppression of increases in plasma DB01285 -like immunoreactive substance ( IS ) levels at 90 to 120 min and cortisol levels at 240 min , compared with the response to placebo . DB00391 only suppressed increases in plasma cortisol levels at 180 to 240 min , compared with the response to placebo . A single dose of cetraxate had no effect on plasma DB01285 -IS and cortisol levels . Ecabet may have a modulatory effect on the Q9Y251 axis while sulpiride may have a partial modulatory effect on the Q9Y251 axis . These effects might be beneficial in stress-related disease . Rosiglitazone regulates P05231 -stimulated lipolysis in porcine adipocytes . Interleukin ( IL ) -6 , a proinflammatory cytokine , stimulates adipocyte lipolysis and induces insulin resistance in obese and diabetic subjects . However , the effects of the anti-diabetic drug rosiglitazone on P05231 -stimulated lipolysis and the underlying molecular mechanism are largely unknown . In this study , we demonstrated that rosiglitazone suppressed P05231 -stimulated lipolysis in differentiated porcine adipocytes by inactivation of extracellular signal-related kinase ( P29323 ) . Meanwhile , rosiglitazone enhanced the lipolysis response of adipocytes to isoprenaline . In addition , rosiglitazone significantly reversed P05231 -induced down-regulation of several genes such as perilipin A , peroxisome proliferators activated receptor gamma ( Q07869 & gamma ; ) , and fatty acid synthetase , as well as the up-regulation of P05231 mRNA . However , mRNA expression of Q07869 & gamma ; coactivator-1 alpha ( DB01053 -1 & alpha ; ) was enhanced by rosiglitazone in P05231 -stimulated adipocytes . These results indicate that rosiglitazone suppresses P05231 -stimulated lipolysis in porcine adipocytes through multiple molecular mechanisms . Potent and selective activation of the pancreatic beta-cell type K( DB00171 ) channel by two novel diazoxide analogues . AIMS/HYPOTHESIS : We investigated the pharmacological properties of two novel DB00171 sensitive potassium ( K( DB00171 ) ) channel openers , 6-Chloro-3-isopropylamino-4 H-thieno [ 3,2- e ] -1,2,4-thiadiazine 1,1-dioxide ( NNC 55-0118 ) and 6-chloro-3-(1-methylcyclopropyl)amino-4 H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide ( NN414 ) , on the cloned cardiac ( Kir6.2/SUR2A ) , smooth muscle ( Kir6.2/SUR2B ) and pancreatic beta cell ( Kir6.2/ Q09428 ) types of K( DB00171 ) channel . METHODS : We studied the effects of these compounds on whole-cell currents through cloned K( DB00171 ) channels expressed in Xenopus oocytes or mammalian cells ( HEK293 ) . We also used inside-out macropatches excised from Xenopus oocytes . RESULTS : In P29320 293 cells , NNC 55-0118 and NN414 activated Kir6.2/ Q09428 currents with EC(50) values of 0.33 micromol/l and 0.45 micromol/l , respectively , compared with that of 31 micro mol/l for diazoxide . Neither compound activated Kir6.2/SUR2A or Kir6.2/SUR2B channels expressed in oocytes , nor did they activate Kir6.2 expressed in the absence of Q09428 . Current activation was dependent on the presence of intracellular MgATP , but was not supported by MgADP . CONCLUSION/INTERPRETATION : Both NNC 55-0118 and NN414 selectively stimulate the pancreatic beta-cell type of K( DB00171 ) channel with a higher potency than diazoxide , by interaction with the Q09428 subunit . The high selectivity and efficacy of the compounds could prove useful for treatment of disease states where inhibition of insulin secretion is beneficial .