interacts_with DB00452?
The role of Q12809 K+ channels and a functional link between Q12809 K+ channels and P48061 in acute leukemic cell migration . Stromal cell-derived factor-1 ( P48061 ) and its unique receptor , P61073 , regulate stem/progenitor cell migration and retention in the bone marrow and are required for hematopoiesis . Recent studies found that Q12809 K(+) channels were important regulators of tumor cell migration . In this study , we investigated whether P48061 induced acute leukemic cell migration associated with Q12809 K(+) channels . Our results showed that E-4031 , a specific Q12809 K(+) channels inhibitor , significantly blocked P48061 -induced migration of leukemic cell lines , primary acute leukemic cells , leukemic stem cells and HEK293T cells transfected with herg-pEGFP . The migration of phenotypically recognizable subsets gave the indication that lymphoblastic leukemic cells were inhibited more than myeloid cells while in the presence of E-4031 which maybe associated with herg expression . P48061 increased Q12809 K(+) current expressed in oocytes and HEK293T cells transfected with herg-pEGFP . There were no significant changes of P61073 expression on both HL-60 cells and primary leukemic cells regardless if untreated or treated with E-4031 for 24 h ( P > 0.05 ) . The Q12809 K(+) current increased by P48061 might contribute to the mechanism of P48061 -induced leukemic cell migration . The data suggested that Q12809 K(+) channels functionally linked to cell migration induced by P48061 . No activation of human pregnane X receptor by hyperforin-related phloroglucinols . The acylated phloroglucinol , hyperforin , the main active ingredient of St . John 's Wort , exerts antidepressant properties via indirect inhibition of serotonin reuptake by selectively activating the canonical transient receptor potential channel 6 ( Q9Y210 ) . DB01892 treatment can lead to drug-drug interactions due to potent activation of the nuclear receptor O75469 ( O75469 ) , a key transcriptional regulator of genes involved in drug metabolism and transport . It was previously shown that synthetic acylated phloroglucinol derivatives activate Q9Y210 with similar potency as hyperforin . However , their interaction potential with O75469 remained unknown . Here we investigated five synthetic Q9Y210 -activating phloroglucinol derivatives and four Q9Y210 -nonactivating compounds compared with hyperforin and rifampicin for their potential to activate O75469 in silico and in vitro . Computational O75469 pharmacophore modeling did not indicate potent agonist or antagonist interactions for the Q9Y210 -activating derivatives , whereas one of them was suggested by docking studies to show both agonist and antagonist interactions . DB01892 and rifampicin treatment of HepG2 cells cotransfected with human O75469 expression vector and a P08684 promoter-reporter construct resulted in potent O75469 -dependent induction , whereas all Q9Y210 -activating compounds failed to show any O75469 activation or to antagonize rifampicin-mediated P08684 promoter induction . DB01892 and rifampicin treatment of primary human hepatocytes resulted in highly correlated induction of O75469 target genes , whereas treatment with the phloroglucinol derivatives elicited moderate gene expression changes that were only weakly correlated with those of rifampicin and hyperforin treatment . These results show that Q9Y210 -activating phloroglucinols do not activate O75469 and should therefore be promising new candidates for further drug development . Gain-of-function mutations in transient receptor potential P13671 ( Q9Y210 ) activate extracellular signal-regulated kinases 1/2 ( P27361 /2 ) . Gain-of-function mutations in the canonical transient receptor potential 6 ( Q9Y210 ) gene are a cause of autosomal dominant focal segmental glomerulosclerosis ( FSGS ) . The mechanisms whereby abnormal Q9Y210 activity results in proteinuria remain unknown . The P27361 /2 MAPKs are activated in glomeruli and podocytes in several proteinuric disease models . We therefore examined whether FSGS-associated mutations in Q9Y210 result in activation of these kinases . In 293T cells and cultured podocytes , overexpression of gain-of-function Q9Y210 mutants resulted in increased P27361 /2 phosphorylation , an effect dependent upon channel function . Pharmacologic inhibitor studies implicated several signaling mediators , including calmodulin and calcineurin , supporting the importance of Q9Y210 -mediated calcium influx in this process . Through medium transfer experiments , we uncovered two distinct mechanisms for P29323 activation by mutant Q9Y210 , a cell-autonomous , P01133 receptor-independent mechanism and a non-cell-autonomous mechanism involving metalloprotease-mediated release of a presumed P01133 receptor ligand . The inhibitors KN-92 and H89 were able to block both pathways in mutant Q9Y210 expressing cells as well as the prolonged elevation of intracellular calcium levels upon carbachol stimulation seen in these cells . However , these effects appear to be independent of their effects on calcium/calmodulin-dependent protein kinase II and PKA , respectively . Phosphorylation of DB00156 -70 , DB00133 -282 , and DB00135 -31/285 were not necessary for P29323 activation by mutant Q9Y210 , although a phosphomimetic Q9Y210 S282E mutant was capable of P29323 activation . Taken together , these results identify two pathways downstream of mutant Q9Y210 leading to P29323 activation that may play a role in the development of FSGS . [ Changes in chemokine receptor 4 , interleukin-6 , and collagen X expression in the ATDC5 cell line stimulated by cyclic tensile strain and stromal cell-derived factor-1 ] . OBJECTIVE : This study further explores the stromal cell-derived factor-1 ( P48061 ) /chemokine receptor 4 ( P61073 ) signaling axis mechanism in temporomandibular joint osteoarthritis ( OA ) by detecting the changes in P61073 , interleukin ( IL ) -6 , and collagen X expression in the ATDC5 cell line stimulated by the cyclic tensile strain and P48061 . METHODS : P01308 -transferrin-selenium ( ITS ) was used to induce ATDC5 cells to differentiate into chondrocyte-like cells . After three weeks , the cells were divided into two groups : those with and without cyclic tensile strain . These groups were further divided into the negative control and P48061 groups . Strain force of 20 % was applied . After 12 h , the total proteins were extracted from cells of the four groups , and Western blot analysis was used to detect the changes in P61073 , P05231 , and collagen X expression . RESULTS : P48061 could enhance P61073 , P05231 , and collagen X expressions in the chondrocytes , and 20 % tensile strain force could further upregulate the three factors . CONCLUSION : Under abnormal tensile force , P48061 can upregulate its specific receptor P61073 , thus increasing its-binding efficiency and resulting in the activation of the P48061 / P61073 axis . This condition enhances the expressions of P05231 and other inflammatory factors and directly damages to cartilage tissue . Such damage directly promotes chondrocyte hypertrophy , which enhances collagen X expression . P01308 action on H292 bronchial carcinoma cells as compared to normal bronchial epithelial cells . DB00030 may contribute to bronchial carcinoma due to P08069 activation by high local concentrations . Therefore , effects of insulin and P05019 on human bronchial carcinoma cells ( H292 ) and normal bronchial epithelium cells ( P02100 ) were studied . TGF-β was included since it also influences carcinoma progression . H292 and P02100 cells expressed both the insulin receptor and the P08069 ; in H292 cells an additional , shorter , splicing variant ( IR-A ) of the insulin receptor was present . P06213 expression was around four to five times higher in H292 than in P02100 cells at mRNA and protein levels . P01308 and TGF-β exerted contrary actions on proliferation and gene expression in H292 cells . Genes regulated by insulin , P05019 , and TGF-β were linked to inflammation , cell adhesion , muscle contraction and differentiation . P01308 and P05019 also suppressed DNA repair genes . EC(50) for insulin-induced proliferation was around 5 nM in H292 and around 30 nM P02100 cells . The EC(50) values for gene expression ranged from 9 to 90 nM in both cell types , dependent on the gene studied . In H292 cells , the proliferative response was much stronger if TGF-β was present . In P02100 cells this interaction of insulin and TGF-β was not observed , and changes in gene expression were mostly lower by at least 10-fold as compared to H292 . All in all , the insulin effects in H292 were generally much stronger than in P02100 cells and - with regard to proliferation - occurred at lower concentrations . Thus , insulin will hardly induce cancer from normal bronchial cells but may favour progression of pre-existing tumours . Transcript profiling in peripheral T-cell lymphoma , not otherwise specified , and diffuse large B-cell lymphoma identifies distinct tumor profile signatures . To glean biological differences and similarities of peripheral T-cell lymphoma-not otherwise specified [ PTCL-NOS ] to diffuse large B-cell lymphoma ( DLBCL ) , a transcriptosome analysis was done on five PTCL-NOS and four DLBCL patients and validated by quantitative real-time reverse transcription-PCR on 10 selected genes . Normal peripheral blood T cells , peripheral blood B cells , and lymph node were used as controls . The resultant gene expression profile delineated distinct " tumor profile signatures " for PTCL-NOS and DLBCL . Several highly overexpressed genes in both PTCL-NOS and DLBCL involve the immune network , stroma , angiogenesis , and cell survival cascades that make important contributions to lymphomagenesis . Inflammatory chemokines and their receptors likely play a central role in these complex interrelated pathways : P13500 and P61073 in PTCL-NOS and P13501 and P32246 in DLBCL . Highly overexpressed oncogenes unique to PTCL-NOS are P17947 , O14965 , alpha- P09619 , and O60880 , whereas in DLBCL they are P11309 , Q9P1W9 , P07948 , Q16548 , and P51153 . Oncogenes common to both lymphomas are Q9Y5Q3 , MET , NF-kappaB2 , P06239 , and P07948 . Several tumor suppressors are also down-regulated ( P56180 , MGC154 , Q13635 , P78524 , and P41567 ) . This study illustrates the relevance of tumor-stroma immune trafficking and identified potential novel prognostic markers and targets for therapeutic intervention . Phosphodiesterase 4 inhibitors reduce human dendritic cell inflammatory cytokine production and Th1-polarizing capacity . Inhibitors of DB02527 -specific phosphodiesterase ( PDE ) 4 have been shown to inhibit inflammatory mediator release and T cell proliferation , and are considered candidate therapies for T(h)1-mediated diseases . However , little is known about how DB05876 inhibitors influence dendritic cells ( DC ) , the cells responsible for the priming of naive T(h) cells . Therefore , we investigated the PDE profile of monocyte-derived DC , and whether DB05876 inhibitors modulate DC cytokine production and T cell-polarizing capacity . We mainly found DB02527 -specific DB05876 enzymatic activity in both immature and mature DC . In contrast to monocytes that mainly express Q07343 , we found that P27815 is the predominant DB05876 subtype present in DC . Immature DC showed reduced ability to produce IL-12p70 and tumor necrosis factor ( P01375 ) -alpha upon lipopolysaccharide or P29965 ( P29965 ) stimulation in the presence of DB05876 inhibitors , whereas cytokine production upon P29965 stimulation of fully mature DC in the presence of DB05876 inhibitors was not affected . Exposure to DB05876 inhibitors for 2 days during DC maturation did not influence T cell-stimulatory capacity or acquisition of a mature phenotype , but increased the expression of the chemokine receptor P61073 . Furthermore , DC matured in the presence of DB05876 inhibitors showed reduced capacity to produce IL-12p70 and P01375 upon subsequent P29965 stimulation . Using these DB05876 inhibitor-matured DC to stimulate naive T cells resulted in a reduction of P01579 -producing ( T(h)1 ) cells . These findings indicate that DB05876 inhibitors can affect T cell responses by acting at the DC level and may increase our understanding of the therapeutic implication of DB05876 inhibitors for T(h)1-mediated disorders . Comparison of three GPCR structural templates for modeling of the Q9H244 nucleotide receptor . The P2Y(12) receptor ( P2Y(12)R ) is an ADP-activated G protein-coupled receptor ( GPCR ) that is an important target for antithrombotic drugs . Three homology models of P2Y(12)R were compared , based on different GPCR structural templates : bovine rhodopsin ( bRHO ) , human A(2A) adenosine receptor ( A(2A)AR ) , and human P61073 ( P61073 ) . By criteria of sequence analysis ( 25.6 % identity in transmembrane region ) , deviation from helicity in the second transmembrane helix ( TM2 ) , docked poses of ligands highlighting the role of key residues , accessibility of a conserved disulfide bridge that is reactive toward irreversibly-binding antagonists , and the presence of a shared disulfide bridge between the third extracellular loop ( EL3 ) and the N-terminus , the P61073 -based model appeared to be the most consistent with known characteristics of P2Y(12)R . The docked poses of agonist 2MeSADP and charged anthraquinone antagonist PSB-0739 in the binding pocket of P2Y(12)R-CXC agree with previously published site-directed mutagenesis studies of Arg256 and Lys280 . A sulfonate at position 2 of the anthraquinone core created a strong interaction with the Lys174(EL2) side chain . The docking poses of the irreversibly-binding , active metabolite ( existing as two diastereoisomers in vivo ) of the clinically utilized antagonist DB00758 were compared . The free thiol group of the 4S diastereoisomer , but not the 4R isomer , was found in close proximity ( ~4.7 Å ) to the sulfur atom of a disulfide bridge involving Cys175 , suggesting greater activity in covalent binding . Therefore , ligand docking to the P61073 -based model of the P2Y(12)R predicted poses of both reversibly and irreversibly-binding small molecules , consistent with observed pharmacology and mutagenesis studies . DB01093 -treated HL60 cells : a model of neutrophil-like cells mainly expressing Q07343 subtype . The human promyelocytic HL60 cells acquired a neutrophilic phenotype after a 7- to 10-day DB01093 treatment . Fc gammaRII was up-regulated . Fc gammaRI was also up-regulated by an additional P01579 treatment . These cells are able to produce O2*- by NADPH oxidase activation in the presence of immune complexes or phorbol-12-myristate-13-acetate ( PMA ) . A change of their DB05876 subtype profile was also observed : Q07343 was the predominant isoenzyme , Q08499 was down-regulated and P27815 was no longer detectable . Additionally , the more NADPH oxidase was activated by PMA , the less P27815 was expressed , suggesting that NADPH oxidase activity could be used as a surrogate marker of P27815 down-regulation . DB01954 and DB03849 ( cilomilast ) , two selective DB05876 inhibitors , dose-dependently inhibited receptor-coupled activation of superoxide . These results suggest that Q07343 is the main subtype involved in regulating superoxide induced by Fc gammaRs activation . Furthermore , these cells , expressing almost exclusively Q07343 subtype , could be useful to identify selective Q07343 inhibitors . [ Medication of the month. DB08816 ( Brilique ) : potent oral antagonist of platelet activity ] . Dual antiplatelet therapy with clopidogrel combined with aspirin reduces ischemic events in acute coronary syndromes ( ACS ) . The individual response to clopidogrel is , however , very variable from one subject to another , and the risk of events seems higher when platelet inhibition is insufficient . DB08816 is a potent oral inhibitor of platelet activity . It binds reversibly to the Q9H244 adenosine diphosphate . The platelet inhibition that it induces is faster and more pronounced than that of clopidogrel . In patients who have an ACS ( PLATO study ) with or without ST-segment elevation , treatment with ticagrelor as compared with clopidogrel significantly reduced the rate of death from vascular causes , myocardial infarction , or stroke , without an increase in the rate of overall major bleeding but with an increase in the rate of non-procedure-related bleeding . In Belgium , Brilique is currently indicated in combination with aspirin for the prevention of atherothrombotic events in patients with ACS . Acute renal failure from hemoglobinuric and interstitial nephritis secondary to iodine and mefenamic acid . DB00784 ingestion , usually in excess and over prolonged period is known to produce interstitial nephritis , or less commonly papillary necrosis , with acute renal failure . However , it is not dose-dependent for the induction of tubulointerstitial damage . Excess iodine ingestion is known to produce toxicity and possible death , but acute renal failure is rare . There is evidence from clinical and experimental data that iodine has toxic effect on tubular epithelial cells . Iodine has not been documented to produce red cell hemolysis and hemoglobinuria . We present a unique case of acute renal failure from hemoglobinuric and acute interstitial nephritis secondary to suicidal ingestion of potassium iodide solution and also ingestion of a few mefenamic acid tablets . These agents led to potentiation of the renal injury from hemoglobinuric tubulopathy , probably from the iodine , and renal dysfunction from alteration of renal perfusion by selective P23219 inhibition of prostaglandin production , and induction of acute interstitial nephritis from mefenamic acid , leading to acute renal failure which was reversible by hemodialysis and supportive therapy . DB00452 -arginine conjugate , a novel HIV-1 Tat antagonist : synthesis and anti-HIV activities . HIV-1 transactivating protein Tat is essential for virus replication and progression of HIV disease . HIV-1 Tat stimulates transactivation by binding to HIV-1 transactivator responsive element ( TAR ) RNA , and while secreted extracellularly , it acts as an immunosuppressor , an activator of quiescent T-cells for productive HIV-1 infection , and by binding to CXC chemokine receptor type 4 ( P61073 ) as a chemokine analogue . Here we present a novel HIV-1 Tat antagonist , a neomycin B-hexaarginine conjugate ( NeoR ) , which inhibits Tat transactivation and antagonizes Tat extracellular activities , such as increased viral production , induction of P61073 expression , suppression of CD3-activated proliferation of lymphocytes , and upregulation of the CD8 receptor . Moreover , Tat inhibits binding of fluoresceine isothiocyanate ( FITC ) -labeled NeoR to human peripheral blood mononuclear cells ( PBMC ) , indicating that Tat and NeoR bind to the same cellular target . This is further substantiated by the finding that NeoR competes with the binding of monoclonal Abs to P61073 . Furthermore , NeoR suppresses HIV-1 binding to cells . Importantly , NeoR accumulates in the cell nuclei and inhibits the replication of M- and T-tropic HIV-1 laboratory isolates ( EC(50) = 0.8-5.3 microM ) . A putative model structure for the TAR-NeoR complex , which complies with available experimental data , is presented . We conclude that NeoR is a multitarget HIV-1 inhibitor ; the structure , and molecular modeling and dynamics , suggest its binding to TAR RNA . NeoR inhibits HIV-1 binding to cells , partially by blocking the P61073 HIV-1 coreceptor , and it antagonizes Tat functions . NeoR is therefore an attractive lead compound , capable of interfering with different stages of HIV infection and AIDS pathogenesis . Association study of 25 type 2 diabetes related Loci with measures of obesity in Indian sib pairs . Obesity is an established risk factor for type 2 diabetes ( T2D ) and they are metabolically related through the mechanism of insulin resistance . In order to explore how common genetic variants associated with T2D correlate with body mass index ( BMI ) , we examined the influence of 25 T2D associated loci on obesity risk . We used 5056 individuals ( 2528 sib-pairs ) recruited in Indian Migration Study and conducted within sib-pair analysis for six obesity phenotypes . We found associations of variants in P61073 ( rs932206 ) and Q03014 ( rs5015480 ) with higher body mass index ( BMI ) ( β=0.13 , p=0.001 ) and ( β=0.09 , p=0.002 ) , respectively and weight ( β=0.13 , p=0.001 ) and ( β=0.09 , p=0.001 ) , respectively . P61073 variant was also strongly associated with body fat ( β=0.10 , p=0.0004 ) . In addition , we demonstrated associations of P61073 and Q03014 with overweight/obesity ( OR=1.6 , p=0.003 ) and ( OR=1.4 , p=0.002 ) , respectively , in 1333 sib-pairs ( 2666 individuals ) . We observed marginal evidence of associations between variants at six loci ( Q9NQB0 , Q9Y4Z2 , Q9Y261 , LOC646279 , FLJ39370 and Q6YHU6 ) and waist hip ratio ( WHR ) , BMI and/or overweight which needs to be validated in larger set of samples . All the above findings were independent of daily energy consumption and physical activity level . The risk score estimates based on eight significant loci ( including nominal associations ) showed associations with WHR and body fat which were independent of BMI . In summary , we establish the role of T2D associated loci in influencing the measures of obesity in Indian population , suggesting common underlying pathophysiology across populations . 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 . Effect of genetic polymorphisms on the pharmacokinetics and efficacy of glimepiride in a Korean population . BACKGROUNDS : DB00222 is a commonly used sulfonylurea hypoglycemic agent . There is considerable interindividual variation in the response to sulfonylurea for patients with type 2 diabetes . The purpose of this study was to investigate whether genetic variations influence the efficacy of glimepiride in healthy Korean subjects . METHODS : A single 2-mg oral dose of glimepiride was administered to 46 healthy volunteers . Serial blood sampling for 12h after oral dosing was performed for determination of plasma glimepiride , glucose and insulin levels . We tested the association of seven single nucleotide polymorphisms ( SNPs ) in four candidate genes with the efficacy of glimepiride . RESULTS : Pharmacodynamic profiles for plasma glucose and insulin showed no statistically significant differences among genotype groups , and parameters were not different from one another . There were no association of the Q14654 , O75052 , Q9NQB0 and Q09428 gene polymorphisms and the efficacy of glimepiride . CONCLUSIONS : Knowledge of these polymorphisms provides no clinical useful information for the pharmacogenetic therapeutic approach for Korean patients with type 2 diabetes . Phosphodiesterase inhibitors control A172 human glioblastoma cell death through DB02527 -mediated activation of protein kinase A and Epac1/Rap1 pathways . AIMS : We investigated whether DB02527 -mediated protein kinase A(PKA) and Epac1/Rap1 pathways differentially affect brain tumor cell death using 4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone(rolipram) , specific phosphodiesterase type IV ( PDE IV ) inhibitor . MAIN METHODS : A172 and U87MG human glioblastoma cells were used . Percentage of cell survival was determined by MTT assay . PKA and Epac1/Rap1 activation was determined by western blotting and pull-down assay , respectively . Cell cycle and hypodiploid cell formation were assessed by flow cytometry analysis . KEY FINDINGS : Non-specific PDE inhibitors , isobutylmethylxanthine( DB07954 ) and theophylline reduce survival percentage of A172 and U87MG cells . The expression of P27815 and Q07343 was detected in A172 and U87MG cells . DB01954 -treated A172 or U87MG cell survival was lower in the presence of forskolin , adenylate cyclase activator , than that in its absence . Co-treatment with rolipram and forskolin also enhanced CREB phosphorylation on serine 133 that was inhibited by H-89 , PKA inhibitor and DB02527 -responsive guanine nucleotide exchange factor 1(Epac1) , a Rap GDP exchange factor-mediated Rap1 activity in A172 cells . When A172 cells were treated with cell-permeable dibutyryl- DB02527 (dbcAMP) , PKA activator or 8-(4-chloro-phenylthio)-2'-O-methyladenosine-3',5'-cyclic monophosphate(CPT) , Epac1 activator , basal level of cell death was increased and cell cycle was arrested at the phase of G2/M . DB01954 -induced A172 cell death was also increased by the co-treatment with dbcAMP or CPT , but it was inhibited by the pre-treatment with H-89 . SIGNIFICANCE : These findings demonstrate that PKA and Epac1/Rap1 pathways could cooperatively play a role in rolipram-induced brain tumor cell death . It suggests that rolipram might regulate glioblastoma cell density through dual pathways of PKA- and Epac1/Rap1-mediated cell death and cell cycle arrest . Bcr-Abl activates O14965 and Q96GD4 in chronic myeloid leukemia cells via AKT signaling . This study explored molecular mechanisms by which Bcr-Abl induced expression of O14965 and B ( O14965 and Q96GD4 ) in chronic myeloid leukemia cells . Lentiviral transduction of Bcr-Abl into either Ba/ P13726 or P28906 (+) hematopoietic stem/progenitor cells potently increased levels of O14965 and Q96GD4 in association with phosphorylation of AKT and stimulated their proliferation . Bcr-Abl-mediated expression of O14965 and Q96GD4 were decreased in P28906 (+) HSPCs when AKT was inactivated by an shRNA against AKT , suggesting that Bcr-Abl induced expression of O14965 and Q96GD4 via AKT signaling . DB05220 , an inhibitor of O14965 , significantly inhibited the proliferation of freshly isolated P28906 (+) CML cells in a dose-dependent manner as measured by colony forming assay . Importantly , inhibition of O14965 in P28906 (+) leukemia cells freshly isolated from individuals with blast crisis of CML with Bcr-Abl T315I mutant ( n = 2 ) by DB05220 significantly impaired the engraftment of these cells in severely immunocompromised mice and decreased the weight of spleens . Taken together , Bcr-Abl induces expression of O14965 and Q96GD4 at least in part via AKT . Inhibition of O14965 could be useful to overcome imatinib-resistance mediated by Bcr-Abl mutants . P48061 and [N33A] P48061 in 5637 and HeLa cells : regulating P00533 phosphorylation via calmodulin/calcineurin . In the human neoplastic cell lines 5637 and HeLa , recombinant P48061 elicited , as expected , downstream signals via both G-protein-dependent and β-arrestin-dependent pathways responsible for inducing a rapid and a late wave , respectively , of P27361 /2 phosphorylation . In contrast , the structural variant [N33A] P48061 triggered no β-arrestin-dependent phosphorylation of P27361 /2 , and signaled via G protein-dependent pathways alone . Both P48061 and [N33A] P48061 , however , generated signals that transinhibited P00533 phosphorylation via intracellular pathways . 1 ) Prestimulation of P61073 / P00533 -positive 5637 or HeLa cells with P48061 modified the HB- P01133 -dependent activation of P00533 by delaying the peak phosphorylation of tyrosine 1068 or 1173 . 2 ) Prestimulation with the synthetic variant [N33A] P48061 , while preserving P61073 -related chemotaxis and P61073 internalization , abolished P00533 phosphorylation . 3 ) In cells knockdown of β-arrestin 2 , P48061 induced a full inhibition of P00533 like [N33A] P48061 in non-silenced cells . 4 ) P00533 phosphorylation was restored as usual by inhibiting PCK , calmodulin or calcineurin , whereas the inhibition of CaMKII had no discernable effect . We conclude that both recombinant P48061 and its structural variant [N33A] P48061 may transinhibit P00533 via G-proteins/calmodulin/calcineurin , but [N33A] P48061 does not activate β-arrestin-dependent P27361 /2 phosphorylation and retains a stronger inhibitory effect . Therefore , we demonstrated that P48061 may influence the magnitude and the persistence of signaling downstream of P00533 in turn involved in the proliferative potential of numerous epithelial cancer . In addition , we recognized that [N33A] P48061 activates preferentially G-protein-dependent pathways and is an inhibitor of P00533 . DB01184 treatment for gastroparesis : demographic and pharmacogenetic characterization of clinical efficacy and side-effects . BACKGROUND : DB01184 is a useful alternative to metoclopramide for treatment of gastroparesis due to better tolerability . Effectiveness and side-effects from domperidone may be influenced by patient-related factors including polymorphisms in genes encoding drug-metabolizing enzymes , drug transporters , and domperidone targets . AIMS : The aim of this study was to determine if demographic and pharmacogenetic parameters of patients receiving domperidone are associated with response to treatment or side-effects . METHODS : Patients treated with domperidone for gastroparesis provided saliva samples from which DNA was extracted . Fourteen single-nucleotide polymorphisms ( SNPs ) in seven candidate genes ( P08183 , P10635 , P14416 , P15382 , Q9Y6J6 , Q12809 , P51787 ) were used for genotyping . SNP microarrays were used to assess single-nucleotide polymorphisms in the ADRA1A , P35368 , and P25100 loci . RESULTS : Forty-eight patients treated with domperidone participated in the study . DNA was successfully obtained from each patient . Age was associated with effectiveness of domperidone ( p=0.0088 ) . Genetic polymorphism in Q12809 was associated with effectiveness of domperidone ( p=0.041 ) . The efficacious dose was associated with polymorphism in P08183 gene ( p=0.0277 ) . The side-effects of domperidone were significantly associated with the SNPs in the promoter region of P25100 gene . CONCLUSIONS : Genetic characteristics associated with response to domperidone therapy included polymorphisms in the drug transporter gene P08183 , the potassium channel Q12809 gene , and α1D -- adrenoceptor P25100 gene . Age was associated with a beneficial response to domperidone . If verified in a larger population , this information might be used to help determine which patients with gastroparesis might respond to domperidone and avoid treatment in those who might develop side-effects . Post-translational and cell type-specific regulation of P61073 expression by cytokines . We have investigated the regulation and function of the chemokine receptor P61073 on neutrophils . P61073 is hardly detectable on neutrophils in the peripheral blood . However , overnight culture strongly up-regulates P61073 expression on the cell surface . The functional activity of P61073 on cultured neutrophils was confirmed by stromal cell-derived factor ( SDF ) -induced migration and up-regulation of the integrins CD11b and CD11c . P61073 surface expression on neutrophils but not on lymphocytes and monocytes is rapidly down-regulated after stimulation with P01375 and P01579 , resulting in significantly decreased SDF-induced functional responses of neutrophils . In contrast to surface expression , P61073 mRNA expression was several-fold increased in cytokine-stimulated neutrophils , suggesting a post-translational regulation . By confocal microscopy we demonstrate that P61073 is internalized after stimulation with P01375 and P01579 . Tauhe down-modulation of P61073 surface expression in response to P01375 and P01579 was fully reversible after cytokine removal . Further , P61073 down-modulation could be completely blocked by hypertonic sucrose and significantly reduced by chlorpromazine indicating the involvement of clathrin-coated pits . Internalization of P61073 by cytokines in a cell type-specific manner is a novel and functionally important mechanism of chemokine receptor regulation .