interacts_with DB01184?
Q9Y6X2 negatively regulates O14788 -mediated osteoclastogenesis directly in osteoclast precursors and indirectly via osteoblasts . Cytokine signaling via various transcription factors regulates receptor activator of nuclear factor ( NF ) -kappaB ligand ( O14788 ) -mediated osteoclast differentiation from monocyte/macrophage lineage cells involved in propagation and resolution of inflammatory bone destruction . Protein inhibitor of activated P40763 ( Q9Y6X2 ) was initially identified as a molecule that inhibits DNA binding of P40763 and regulates many transcription factors through distinct mechanisms . To analyze Q9Y6X2 function in osteoclasts in vivo , we have generated transgenic mice in which Q9Y6X2 is specifically expressed in the osteoclast lineage using the tartrate-resistant acid phosphatase ( TRAP ) gene promoter . Q9Y6X2 transgenic mice showed an osteopetrotic phenotype due to impairment of osteoclast differentiation . Overexpression of Q9Y6X2 in RAW264.7 cells suppressed O14788 -induced osteoclastogenesis by inhibiting the expression of c-Fos and O95644 . Interestingly , Q9Y6X2 inhibits the transcriptional activity of microphthalmia-associated transcription factor ( O75030 ) independent of sumoylation . Down-regulation of Q9Y6X2 markedly enhances O14788 -mediated osteoclastogenesis in RAW264.7 cells . Furthermore , overexpression of Q9Y6X2 in mouse primary osteoblast ( DB00925 ) , down-regulates O14788 expression induced by interleukin-6 ( P05231 ) cytokine family , and inhibits osteoclast formation from bone marrow macrophages ( BMMs ) in vitro coculture system . Down-regulation of Q9Y6X2 leads to the accelerated expression of O14788 in DB00925 stimulated with P05231 and soluble P05231 receptor ( sIL-6R ) . Taken together , our results clearly indicate that Q9Y6X2 negatively regulates O14788 -mediated osteoclastogenesis directly in osteoclast precursors and indirectly via osteoblasts . DB00338 , a gastric proton pump inhibitor , inhibits melanogenesis by blocking Q04656 trafficking . DB00338 is a proton pump inhibitor used in the treatment of peptic ulcer disease and gastrosophageal reflux disease and acts by irreversibly blocking P20648 , a P-type H+/K+ ATPase in gastric parietal cells . We found that omeprazole and its closely related congeners inhibited melanogenesis at micromolar concentrations in B16 mouse melanoma cells , normal human epidermal melanocytes , and in a reconstructed human skin model . DB00338 topically applied to the skin of UV-irradiated human subjects significantly reduced pigment levels after 3 weeks compared with untreated controls . DB00338 had no significant inhibitory effect on the activities of purified human tyrosinase or on the mRNA levels of tyrosinase , dopachrome tautomerase , Pmel17 , or O75030 mRNA levels . Although melanocytes do not express P20648 , they do express Q04656 , a copper transporting P-type ATPase in the trans-Golgi network that is required for copper acquisition by tyrosinase . Q04656 relocalization from the trans-Golgi network to the plasma membrane in response to elevated copper concentrations in melanocytes was inhibited by omeprazole . DB00338 treatment increased the proportion of EndoH sensitive tyrosinase , indicating that tyrosinase maturation was impaired . In addition , omeprazole reduced tyrosinase protein abundance in the presence of cycloheximide , suggestive of increased degradation . Our findings are consistent with the hypothesis that omeprazole reduces melanogenesis by inhibiting Q04656 and by enhancing degradation of tyrosinase . DB01109 's anti-inflammatory effects require glucosamine 6-O-sulfation and are mediated by blockade of L- and P-selectins . DB01109 has been used clinically as an anticoagulant and antithrombotic agent for over 60 years . Here we show that the potent anti-inflammatory property of heparin results primarily from blockade of P16109 and P14151 . DB01109 and chemically modified analogs were tested as inhibitors of selectin binding to immobilized sialyl Lewis(X) and of cell adhesion to immobilized selectins or thrombin-activated endothelial cells . Compared with unfractionated heparin , the modified heparinoids had inhibitory activity in this general order : over-O-sulfated heparin > heparin > 2-O,3-O-desulfated > or = N-desulfated/N-acetylated heparin > or = carboxyl-reduced heparin > or= N-,2-O,3-O-desulfated heparin >> 6-O-desulfated heparin . The heparinoids also showed similar differences in their ability to inhibit thioglycollate-induced peritonitis and oxazolone-induced delayed-type hypersensitivity . Mice deficient in P- or L-selectins showed impaired inflammation , which could be further reduced by heparin . However , heparin had no additional effect in mice deficient in both P- and L-selectins . We conclude that ( a ) heparin 's anti-inflammatory effects are mainly mediated by blocking P- and P14151 -initiated cell adhesion ; ( b ) the sulfate groups at P13671 on the glucosamine residues play a critical role in selectin inhibition ; and ( c ) some non-anticoagulant forms of heparin retain anti-inflammatory activity . Such analogs may prove useful as therapeutically effective inhibitors of inflammation . Therapy with interferon-beta modulates endogenous catecholamines in lymphocytes of patients with multiple sclerosis . OBJECTIVE : To investigate the endogenous dopaminergic/adrenergic system of lymphocytes in multiple sclerosis ( MS ) patients during treatment with interferon ( IFN ) -beta . METHODS : Patients with relapsing-remitting MS undergoing IFN-beta treatment were prospectively studied during the first year of treatment . Circulating lymphocytes were obtained at baseline and after 1 , 3 , 6 and 12 months of treatment and assayed for catecholamine ( CA ) production and mRNA expression of tyrosine hydroxylase ( TH , the rate-limiting enzyme in the synthesis of CA ) , beta(2)-adrenoceptors ( AR ) and D2 , D3 and D5 dopaminergic receptors ( DR ) . RESULTS : In cells from patients treated with IFN-beta for 12 months the production of CA hugely increased and was less sensitive to P01579 -induced inhibition . Expression of mRNA for TH , beta(2)-AR and P21918 was already enhanced after 1 month and further increased up to 6-12 months of treatment . On the contrary , P14416 mRNA progressively decreased and P35462 mRNA did not significantly change over the whole study period . CONCLUSIONS : In MS patients IFN-beta treatment enhances the ability of lymphocytes to produce CA , and induces extensive modifications of both beta(2)-AR and DR-operated pathways . The clinical relevance of these effects deserves consideration . P04035 inhibitors up-regulate anti-aging klotho mRNA via RhoA inactivation in IMCD3 cells . OBJECTIVE : Q9UEF7 is thought to play a critical role in the development of age-related disorders including arteriosclerosis . Statins may exert vascular protective effects , independent of the lowering of plasma cholesterol levels . We investigated the impact of statins on mRNA expression of the age-suppressor gene , klotho in mIMCD3 cells . METHODS AND RESULTS : Q9UEF7 mRNA levels were evaluated with real-time RT-PCR . DB01076 and pitavastatin increased the expression of klotho mRNA in a dose-dependent manner . This stimulatory effect was abolished by the addition of mevalonate , GGPP and FPP , essential molecules for isoprenylation of the small GTPase Rho . As was the case with the statin treatment , inhibition of Rho-kinase by Y27632 up-regulated klotho mRNA . In contrast to the statin treatment , stimulation with angiotensin II down-regulated klotho mRNA expression without obvious morphological changes . Furthermore , pretreatment with atorvastatin blunted the angiotensin II-induced response and ameliorated the decrease in klotho mRNA expression towards basal levels . RhoA activity was further evaluated by detection of its translocation . Angiotensin II activated RhoA , whereas statins potently inactivated RhoA and blocked RhoA activation by angiotensin II . CONCLUSION : Statins inactivate the RhoA pathway , resulting in over-expression of klotho mRNA , which may contribute to the novel pleiotropic effects of statins towards vascular protection . Dopamine agonists upregulate P05231 and P10145 production in human keratinocytes . AIM : Catecholamines regulate functions of the nervous , neuroendocrine and immune systems . Dopamine may modulate the activity of keratinocytes , which play a role in secreting cytokines and chemokines . The aim of this study was to evaluate the effect of dopaminergic agonists on the production of P05231 and P10145 by a non-tumoral human keratinocyte cell line ( HaCaT ) . METHODS : Cells were stimulated with dopamine and the P14416 agonist cabergoline . Levels of P05231 and P10145 in culture supernatants were then determined . Cell proliferation was also assessed . Assays were carried out in the presence or absence of the dopaminergic and β-adrenergic receptor antagonists ( sulpiride and propranolol , respectively ) and ascorbic acid . RESULTS : Dopamine stimulated the production of P05231 and P10145 in a concentration-dependent manner . The effects observed on the secretion of P05231 were more potent than those corresponding to P10145 and were reduced by ascorbic acid . The dopamine-induced P05231 secretion was partially reduced by sulpiride and abrogated by propranolol . The latter drug was able to block the effect of dopamine on the secretion of P10145 . The cabergoline-induced P05231 release was reduced by sulpiride . Cell viability was not affected by any of the drugs . CONCLUSIONS : Dopaminergic agonists can stimulate keratinocytes to produce P05231 and P10145 which are related to inflammatory cutaneous processes . These effects are mediated by dopaminergic and β-adrenergic receptors and by receptor-independent oxidative mechanisms . Solution structure of APETx1 from the sea anemone Anthopleura elegantissima : a new fold for an Q12809 toxin . APETx1 is a 42-amino acid toxin purified from the venom of the sea anemone Anthopleura elegantissima . This cysteine-rich peptide possesses three disulfide bridges ( C4-C37 , P13671 -C30 , and C20-C38 ) . Its pharmacological target is the Ether-a-gogo potassium channel . We herein determine the solution structure of APETx1 by use of conventional two-dimensional 1H-NMR techniques followed by torsion angle dynamics and refinement protocols . The calculated structure of APETx1 belongs to the disulfide-rich all-beta structural family , in which a three-stranded anti-parallel beta-sheet is the only secondary structure . APETx1 is the first Ether-a-gogo effector discovered to fold in this way . We therefore compare the structure of APETx1 to those of the two other known effectors of the Ether-a-gogo potassium channel , CnErg1 and BeKm-1 , and analyze the topological disposition of key functional residues proposed by analysis of the electrostatic anisotropy . The interacting surface is made of a patch of aromatic residues ( Y5 , Y32 , and F33 ) together with two basic residues ( K8 and P05783 ) at the periphery of the surface . We pinpoint the absence of the central lysine present in the functional surface of the two other Ether-a-gogo effectors . Effective dasatinib uptake may occur without human organic cation transporter 1 ( O15245 ) : implications for the treatment of imatinib-resistant chronic myeloid leukemia . We have previously shown that imatinib uptake into chronic myeloid leukemia ( CML ) cells is dependent on human organic cation transporter 1 ( O15245 ; O15245 ) , and that low O15245 expression is an important determinant of clinical outcome to imatinib treatment . We hypothesized that dasatinib might be transported differently than imatinib , possibly accounting for its favorable effects in imatinib-resistant patients . (14)C-dasatinib uptake was greater in KCL22-transfected cells with pcDNA3- O15245 plasmid ( high O15245 -expressing cells ) than in control cells ( P = .02 ) . However , hOCT inhibitors did not decrease dasatinib uptake into either control or primary cells , in contrast to their block on imatinib uptake . Dasa-tinib decreased the level of phosphorylated CrkL to 49.9 % in control and 40.3 % in high O15245 -expressing cells . Dasa-tinib efflux was investigated in confluent P08183 -transfected MDCKII cell monolayers . Both dasatinib and imatinib were transported from the basal to the apical layer , indicating that they were transported by P08183 , which was confirmed using the P08183 inhibitor PSC833 ( P = .001 and P < .001 , respectively ) . Compared with imatinib , dasatinib achieved superior intracellular levels and P11274 - P00519 suppression even in cells with low or blocked O15245 . Efflux of dasatinib and imatinib appear similar via P08183 . Dasatinib may therefore offer an advantage over imatinib in patients with low O15245 expression . [ DB00391 in the management of functional dyspepsia and delayed gastric emptying ] . DB00391 is a sulpiride isomer that exerts its prokinetic action through a dual mechanism : 1 ) as a P14416 antagonist and 2 ) as a serotonin 5HT(4) receptor agonist , conferring this drug with a cholinergic effect . At a dosage of 25mg three times daily , levosulpiride accelerates gastric and gallbladder emptying . Clinical trials have shown that this agent is more effective than placebo in reducing the symptoms of dyspepsia , while comparative studies have demonstrated that its effect is similar or superior to that of other dopamine antagonists . The safety profile of levosulpiride is good and the frequency of adverse events is similar to that of other D(2) dopamine antagonists . Therefore , this drug is a useful therapeutic option in the management of patients with functional dyspepsia , as well as in those with delayed gastric emptying . DB01296 sulfate inhibits P01375 and P01579 -induced production of P05362 in human retinal pigment epithelial cells in vitro . PURPOSE : DB01296 sulfate ( GS ) is a naturally occurring sugar that possesses some immunosuppressive effects in vitro and in vivo , but its mechanism is unknown . We investigated whether GS could modulate the proinflammatory cytokine-induced expression of the gene for intercellular adhesion molecule ( ICAM ) -1 , an inflammatory protein in human retinal pigment epithelial ( Q96AT9 ) cells . METHODS : ARPE-19 cells were used as a model to determine the effects of GS on the expression of the P05362 gene upregulated by P01375 or P01579 , by Western blot analysis and semiquantitative reverse transcription polymerase chain reaction ( RT-PCR ) . The activation and nuclear translocation of the nuclear factors NF-kappaB and P42224 were evaluated by immunocytochemistry , Western blot analysis , and electrophoretic mobility shift assay ( EMSA ) . RESULTS : Both P01375 and P01579 increased the expression of P05362 at the mRNA and protein levels in a time- and dose-dependent manner in ARPE-19 cells . GS effectively downregulated the P01375 - or P01579 -induced expression of P05362 in the protein and mRNA level in a dose-dependent manner . GS further inhibited the nuclear translocation of p65 proteins in P01375 and phosphorylated P42224 in P01579 -stimulated ARPE-19 cells . CONCLUSIONS : GS inhibits the expression of the P05362 gene in ARPE-19 cell stimulated with P01375 or P01579 through blockade of NF-kappaB subunit p65 and nuclear translocation of P42224 . This study has demonstrated a potentially important property of GS in reducing P05362 mediated inflammatory mechanisms in the eye . A genomic reservoir for Tnfrsf genes is developmentally regulated and imprinted in the mouse . P01375 receptor superfamily is composed of at least 26 members in the mouse , three of which exist as a cluster within the imprinted Kcnq1 domain on chromosome 7 . Tnfrsf22 , 23 and 26 contain typical cystein-rich domains and Tnfrsf22 and 23 can bind ligands but have no signaling capacity . Thus , they are assumed to be decoy receptors . The developmental expression profile of these genes is unknown and knowledge of their imprinting patterns is incomplete and controversial . We found that all three genes are expressed during mouse embryonic development , and that they have a strong maternal bias , indicating that they may be affected by the KvDMR , the Kcnq1 imprinting control region . We found expression of an antisense non-coding RNA , AK155734 , in embryos and some neonatal tissues . This RNA overlaps the Tnfrsf22 and possibly the Tnfrsf23 coding regions and is also expressed with a maternal bias . We were interested in exploring the evolutionary origins of the three Tnfrsf genes , because they are absent in the orthologous human Kcnq1 domain . To determine whether the genes were deleted from humans or acquired in the rodent lineage , we performed phylogenetic analyses . Our data suggest that TNFRSF sequences were duplicated and/or degenerated or eliminated from the P51787 region several times during the evolution of mammals . In humans , multiple mutations ( point mutations and/or deletions ) have accumulated on the ancestral TNFRSF , leaving a single short non-functional sequence . Imatinib has the potential to exert its antileukemia effects by down-regulating Q12809 K+ channels in chronic myelogenous leukemia . Imatinib is a powerful protein tyrosine kinase ( PTK ) inhibitor that specifically targets P11274 - P00519 , P10721 , and P09619 kinases , has become the current first-line therapy for all newly diagnosed chronic myeloid leukemia ( CML ) . Beside PTKs , PTK inhibitors alter the activity of a large number of voltage-dependent ion channels . Q12809 K(+) channels are highly expressed in leukemia cells and appear of exceptional importance in favoring leukemogenesis . The present study explored a possible regulatory effect of imatinib upon Q12809 K(+) channels as a means to uncover new molecular events involved in the antileukemic activity of this PTK inhibitor in CML . The results demonstrated that Q12809 was highly detected in K562 cells and primary CML cells , and down-regulated by imatinib at mRNA and protein levels . Furthermore , imatinib markedly reduced hERG currents in HEK293T-hERG cells , this effect was accompanied by inhibition of CML cell proliferation and apoptosis , as well as suppression of vascular endothelial growth factor ( P15692 ) secretion . Moreover , these antileukemia effects of imatinib were potentiated by E-4031 , a specific Q12809 inhibitor . Together , these results provide evidence of a novel potential molecular mechanism of antileukemic activities by imatinib which , independent of targeting tyrosine kinase , highlight Q12809 K(+) channels as a therapeutic target for CML treatment . Activation of PPARgamma by rosiglitazone attenuates intestinal Cl- secretion . The thiazolidinedione ( TZD ) drugs rosiglitazone ( Ro ) and pioglitazone ( Po ) are PPARgamma agonists in widespread clinical use as insulin-sensitizing agents in Type 2 diabetes . On the basis of recent evidence implicating PPARgamma as a positive modulator of intestinal epithelial differentiation , we hypothesized that TZD drugs might attenuate intestinal secretory function . To evaluate this possibility , we examined the effects of Ro and Po on electrogenic Cl- secretion [ short-circuit current ( I(sc) ) ] in mouse intestinal segments and in cultured human intestinal epithelial cells ( HT29-Cl.19A ) . As hypothesized , oral administration of Ro ( 20 mg.kg(-1).day(-1) ) to mice for 8 days markedly reduced intestinal I(sc) responses to DB02527 (forskolin)- and Ca2+ (carbachol)-dependent stimuli . In these Ro-treated mice , cholera toxin-induced intestinal fluid accumulation was reduced 65 % . With continued Ro treatment , the I(sc) response to carbachol recovered significantly , whereas that to forskolin remained attenuated . Treatment of HT29 cells for 5 days with 10 muM Ro or Po in vitro brought about a similar hyposecretory state . In HT29 cells , the loss of DB02527 -dependent Cl- secretion was attributable to a reduced expression of P13569 Cl- channel , P51787 K+ channel , and Na-K-2Cl cotransporter-1 proteins . The transient loss of Ca2+-dependent Cl- secretion involved an impairment of basolateral Ca2+-stimulated K+ channel activity without a detectable loss of K(Ca)3.1 channel protein . Our results establish TZD drugs as important modulators of intestinal Cl- secretory function . DB09280 - DB08820 in Patients with Cystic Fibrosis Homozygous for Phe508del P13569 . Upregulation of P51787 / P15382 K+ channels by Q9UEF7 . Q9UEF7 is a transmembrane protein expressed primarily in kidney , parathyroid gland , and choroid plexus . The extracellular domain could be cleaved off and released into the systemic circulation . Q9UEF7 is in part effective as β-glucuronidase regulating protein stability in the cell membrane . Q9UEF7 is a major determinant of aging and life span.Overexpression of Q9UEF7 increases and Q9UEF7 deficiency decreases life span . Q9UEF7 deficiency may further result in hearing loss and cardiac arrhythmia . The present study explored whether Q9UEF7 modifies activity and protein abundance of P51787 / P15382 , a K(+) channel required for proper hearing and cardiac repolarization . To this end , cRNA encoding P51787 / P15382 was injected in Xenopus oocytes with or without additional injection of cRNA encoding Q9UEF7 . P51787 / P15382 expressing oocytes were treated with human recombinant Q9UEF7 protein ( 30 ng/mL ) for 24 h . Moreover , oocytes which express both P51787 / P15382 and Q9UEF7 were treated with 10 μM DSA L ( D-saccharic acid-1,4-lactone ) , a β-glucuronidase inhibitor . The P51787 / P15382 depolarization-induced current ( I(Ks) ) was determined utilizing dual electrode voltage clamp , while P51787 / P15382 protein abundance in the cell membrane was visualized utilizing specific antibody binding and quantified by chemiluminescence . P51787 / P15382 channel activity and P51787 / P15382 protein abundance were upregulated by coexpression of Q9UEF7 . The effect was mimicked by treatment with human recombinant Q9UEF7 protein ( 30 ng/mL ) and inhibited by DSA L ( 10 μM ) . In conclusion , Q9UEF7 upregulates P51787 / P15382 channel activity by “mainly” enhancing channel protein abundance in the plasma cell membrane , an effect at least partially mediated through the β-glucuronidase activity of Q9UEF7 protein . Augmented potassium current is a shared phenotype for two genetic defects associated with familial atrial fibrillation . Mutations in multiple genes have been implicated in familial atrial fibrillation ( AF ) , but the underlying mechanisms , and thus implications for therapy , remain ill-defined . Among 231 participants in the Vanderbilt AF Registry , we found a mutation in P51787 ( encoding the alpha-subunit of slow delayed rectifier potassium current [ I(Ks) ] ) and separately a mutation in natriuretic peptide precursor A ( P01160 ) gene ( encoding atrial natriuretic peptide , P01160 ) , both segregating with early onset lone AF in different kindreds . The functional effects of these mutations yielded strikingly similar I(Ks) " gain-of-function . " In Chinese Hamster Ovary ( CHO ) cells , coexpression of mutant P51787 with its ancillary subunit P15382 generated approximately 3-fold larger currents that activated much faster than wild-type ( WT ) -I(Ks) . Application of the WT P01160 peptide fragment produced similar changes in WT-I(Ks) , and these were exaggerated with the mutant P01160 S64R peptide fragment . Anantin , a competitive P01160 receptor antagonist , completely inhibited the changes in I(Ks) gating observed with P01160 S64R . Computational simulations identified accelerated transitions into open states as the mechanism for variant I(Ks) gating . Incorporating these I(Ks) changes into computed human atrial action potentials ( AP ) resulted in 37 % shortening ( 120 vs. 192 ms at 300 ms cycle length ) , reflecting loss of the phase II dome which is dependent on L-type calcium channel current . We found striking functional similarities due to mutations in P51787 and P01160 genes which led to I(Ks) " gain-of-function " , atrial AP shortening , and consequently altered calcium current as a common mechanism between diverse familial AF syndromes . DB00588 -induced regulation of the balance within macrophage subpopulations . In asthma , treatment with inhaled corticosteroids reduces chronic peribronchial inflammation and restores the balance within macrophage subpopulations . This study investigates whether corticosteroids can regulate monocyte differentiation in vitro and thereby influence the balance of functionally distinct macrophages . Graded doses of fluticasone propionate ( FP ) were added to cultures of normal peripheral blood monocytes in the presence or absence of P05112 . Cells were harvested after 7 days ' culture . Double immunofluorescence studies were performed on cytospins of differentiated macrophages using the MoAbs RFD1 and RFD7 to distinguish inductive and suppressive macrophages by their respective phenotypes . Macrophage function was determined by quantifying allostimulation in a mixed leucocyte reaction and by measuring tumour necrosis factor-alpha ( P01375 ) production . FP reduced the number of mature cells with a D1+ antigen-presenting phenotype and up-regulated the development of cells with the D1/D7+ and D7+ phenotypes . Functionally , this was associated with reduced stimulation of T cell proliferation in a mixed leucocyte reaction ( P08235 ) . DB00588 also reversed the increase in both D1+ expression and P01375 production induced by P05112 . The effect of FP persisted for 24 h after removal of FP from the culture medium . These results suggest that FP treatment of asthmatics may have a direct beneficial effect by normalizing the macrophage subset imbalance that contributes to the chronic peribronchial inflammation present in this condition . Exposure to an organophosphate ( DB00677 ) during a defined period in neonatal life induces permanent changes in brain muscarinic receptors and behaviour in adult mice . The organophosphate DB00677 ( DB00677 ) is a well-known inhibitor of cholinesterases . We have recently observed that neonatal exposure to a single subsymptomal dose of DB00677 induces permanent alterations in muscarinic cholinergic receptors ( MAChRs ) and in spontaneous behaviour , in the mice as adults . In order to determine if there is a critical period for these effects , neonatal mice were given a single oral dose of 1.5 mg/kg DB00677 b.wt. on postnatal day 3 , 10 or 19 , causing equal inhibition of P22303 . At the adult age of 4 months the mice were tested for spontaneous motor behaviour , and were subsequently sacrificed for measurement of density of MAChRs and subpopulations of MAChRs in the cerebral cortex by using the antagonist quinuclidinyl benzilate ( [3H]QNB ) , and agonist carbachol , respectively . At adult age , mice exposed to DB00677 on postnatal day ( P01160 ) 3 or 10 showed significant ( P < or = 0.01 ) alterations in spontaneous motor behaviour and a significant ( P < or = 0.01 ) decrease in muscarinic receptor density . There were no alterations mice exposed on P01160 19 . The proportions and affinity-constants of high- and low-affinity MAChR binding sites were not affected in mice showing altered MAChR density . The lack of effect on mice exposed on P01160 19 was not due to differences in P22303 activity . 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 . Enhancement of cytotoxicity of natural product drugs against multidrug resistant variant cell lines of human head and neck squamous cell carcinoma and breast carcinoma by tesmilifene . N,N-diethyl-2-[4-(phenylmethyl)phenoxyl]ethanamine ( tesmilifene ) , a tamoxifen derivative with antihistamine activity , greatly enhanced the survival of doxorubicin-treated , advanced stage breast cancer patients in a phase III trial . However , the molecular basis of tesmilifene action is not firmly established . The effects of tesmilifene on activity of several anticancer drugs was investigated using human head and neck squamous cell carcinoma ( HNSCC ) and breast carcinoma cell lines as a model system . Multidrug resistant ( MDR ) variants of an HNSCC cell line , HN-5a/V15e , and a breast carcinoma cell line , MCF-7/V25a , both highly overexpressed mdr1 ( P08183 ) mRNA and the proteins P-glycoprotein and glutathione transferase-pi . Drug sensitivities were measured by a vital stain after 4 days of continuous exposure to anticancer drug in the absence and presence of tesmilifene at a concentration that alone had no antiproliferative effect . DB04905 had minimal effect on drug cytotoxicity against the parental cell lines . However , the same tesmilifene treatment enhanced cytotoxicity of docetaxel , paclitaxel , epirubicin , doxorubicin , and vinorelbine against both MDR cell lines by up to 50 % . Flow cytometric measurement of annexin V/propidium iodide staining demonstrated that tesmilifene increased the killing of HN-5a/V15e cells caused by docetaxel after 24 and 48h exposure . DB04905 increased accumulation of radiolabelled vincristine in HN-5a/V15e cells , over 4h , by up to 100 % . The results suggest that tesmilifene might be effective in the treatment of tumors that are resistant to natural product drugs . The mechanism of enhancement appears to be related to expression of an ABC pump-dependent , MDR phenotype .