interacts_with DB01240?
Purine receptor Q15077 mediates cellular response to γ-ray-induced DNA damage . We previously showed that nucleotide P2 receptor agonists such as DB00171 and UTP amplify γ-ray-induced focus formation of phosphorylated histone H2A variant P16104 ( γ P16104 ) , which is considered to be an indicator of DNA damage so far , by activating purine Q15077 and Q9H244 receptors . Therefore , we hypothesized that these P2 receptors play a role in inducing the repair response to γ-ray-induced DNA damage . In the present study , we tested this idea by using human lung cancer A549 cells . First , reverse-transcription polymerase chain reaction ( RT-PCR ) showed that Q15077 receptor is highly expressed in A549 cells , but Q9H244 receptor is only weakly expressed . Next , colony formation assay revealed that Q15077 receptor antagonist MRS2578 markedly reduced the survival rate of γ-ray-exposed A549 cells . The survival rate was also significantly reduced in Q15077 -knock-down cells , compared with scramble siRNA-transfected cells . Since it has reported that phosphorylation of P27361 /2 after activation of P00533 via Q15077 and Q9H244 receptors is involved in the repair response to γ-ray-induced DNA damage , we next examined whether γ-ray-induced phosphorylation of P27361 /2 was also inhibited by MRS2578 in A549 cells . We found that it was . Taken together , these findings indicate that purinergic signaling through Q15077 receptor , followed by P27361 /2 activation , promotes the cellular repair response to γ-ray-induced DNA damage . Estrogen upregulates endothelial nitric oxide synthase gene expression in fetal pulmonary artery endothelium . NO , produced by endothelial NO synthase ( P29474 ) , is a key mediator of pulmonary vasodilation during cardiopulmonary transition at birth . The capacity for NO production is maximal at term because pulmonary P29474 expression increases during late gestation . Since fetal estrogen levels rise markedly during late gestation and there is indirect evidence that the hormone enhances nonpulmonary NO production in adults , estrogen may upregulate P29474 in fetal pulmonary artery endothelium . Therefore , we studied the direct effects of estrogen on P29474 expression in ovine fetal pulmonary artery endothelial cells ( PAECs ) . DB00783 caused a 2.5-fold increase in NOS enzymatic activity in PAEC lysates . This effect was evident after 48 hours , and it occurred in response to physiological concentrations of the hormone ( 10(-10) to 10(-6) mol/L ) . The increase in NOS activity was related to an upregulation in P29474 protein expression , and P29474 mRNA abundance was also enhanced . P03372 antagonism with DB00947 completely inhibited estrogen-mediated P29474 upregulation , indicating that estrogen receptor activation is necessary for this response . In addition , immunocytochemistry revealed that fetal PAECs express estrogen receptor protein . Furthermore , transient transfection assays with a specific estrogen-responsive reporter system have demonstrated that the endothelial estrogen receptor is capable of estrogen-induced transcriptional transactivation . Thus , estrogen upregulates P29474 gene expression in fetal PAECs through the activation of PAEC estrogen receptors . This mechanism may be responsible for pulmonary P29474 upregulation during late gestation , thereby optimizing the capacity for NO-mediated pulmonary vasodilation at birth . DB01240 is a specific effector of adipose cell differentiation . Its dual role as a DB02527 - and Ca(2+)-elevating agent . The mitogenic-adipogenic activity of carbaprostacyclin ( cPGI2 ) , a stable analogue of prostacyclin ( DB01240 ) , has been proposed to be related to its ability to elicit DB02527 production and to activate the protein kinase A cascade ( Négrel , R. , Gaillard , D. , and Ailhaud , G. ( 1989 ) Biochem. J. 257 , 399-405 ) . In the present study , cPGI2 has been compared with other activators of the DB02527 pathway , namely isoproterenol , forskolin and 8-bromo- DB02527 , with respect to adipose cell differentiation . Carbaprostacyclin behaved as a much more potent and efficient effector of mouse Ob1771 preadipocyte differentiation than the latter agents . Moreover , cPGI2 also exerted a specific amplifying mitogenic-adipogenic role , as compared with isoproterenol in rat as well as human adipose precursor cells in primary culture , suggesting that the prostanoid was able to generate an additional second messenger . The fact that ionomycin was able to potentiate and amplify the differentiation induced by 8-bromo- DB02527 led us to give evidence , using preadipocytes preloaded with the fluorescent calcium chelator Indo-1 , that cPGI2 , besides its ability to activate adenyl cyclase , was also able to induce a transient increase in intracellular free calcium . This phenomenon was independent of DB02527 production or inositol phospholipid breakdown and appeared to be mediated after binding to a single class of P43119 . The potential to generate simultaneously two synergistic intracellular signals allows us to ascribe to DB01240 a key and specific role in the differentiation of adipose precursor cells in vitro that would likely lead in vivo to the recruitment of " dormant " preadipocytes to become adipocytes . P43119 -induced P40763 phosphorylation in human erythroleukemia cells is mediated via Galpha(s) and Galpha(16) hybrid signaling . Human prostacyclin receptor ( hIP ) stimulates P40763 via pertussis toxin-insensitive G proteins in human erythroleukemia ( HEL ) cells . Since hIP can utilize G(s) and G(q) proteins for signal transduction and that both G proteins can induce P40763 phosphorylation and activation via complex signaling networks , we sought to determine if one of them is predominant in mediating the hIP signal . Stimulation of P40763 DB00135 (705) and DB00133 (727) phosphorylations by the IP-specific agonist , cicaprost , was sensitive to inhibition of protein kinase A , phospholipase Cbeta , protein kinase C , calmodulin-dependent protein kinase II and O60674 /3 . Unlike Galpha(16)-mediated regulation of P40763 in the same cells , cicaprost-induced P40763 DB00135 (705) phosphorylation was resistant to inhibition of Src and MEK while P40763 DB00133 (727) phosphorylation distinctly required phosphatidylinositol-3 kinase . This unique inhibitor-sensitivity pattern of P40763 phosphorylation was reproduced in HEL cells by stimulating the G(16)-coupled C5a receptor in the presence of dibutyryl- DB02527 , suggesting that the change in inhibitor-sensitivity was due to activation of the G(s) pathway . This postulation was confirmed by expressing constitutively active Galpha(16)QL and Galpha(s)QL in human embryonic kidney 293 cells and the inhibitor-sensitivity of Galpha(16)QL-induced P40763 phosphorylations could be converted by the mere presence of Galpha(s)QL to resemble that obtained with cicaprost in HEL cells . In addition , the restoration of the Galpha(16)-mediated inhibitor-sensitivity upon cicaprost induction in Galpha(s)-knocked down HEL cells again verified the pivotal role of G(s) signal . Taken together , our observations illustrate that co-stimulation of G(s) and G(q) can result in the fine-tuning of P40763 activation status , and this may provide the basis for cell type-specific responses following activation of hIP . Cyclooxygenase inhibition abrogates aeroallergen-induced immune tolerance by suppressing prostaglandin I2 receptor signaling . BACKGROUND : The prevalence of allergic diseases has doubled in developed countries in the past several decades . Cyclooxygenase ( P36551 ) -inhibiting drugs augmented allergic diseases in mice by increasing allergic sensitization and memory immune responses . However , whether P36551 inhibition can promote allergic airway diseases by inhibiting immune tolerance is not known . OBJECTIVE : To determine the role of the P36551 pathway and prostaglandin I2 ( DB01240 ) signaling through the P43119 ( IP ) in aeroallergen-induced immune tolerance . METHODS : Wild-type ( WT ) BALB/c mice and IP knockout mice were aerosolized with ovalbumin ( OVA ) to induce immune tolerance prior to immune sensitization with an intraperitoneal injection of OVA/alum . The P36551 inhibitor indomethacin or vehicle was administered in drinking water to inhibit enzyme activity during the sensitization phase . Two weeks after sensitization , the mice were challenged with OVA aerosols . Mouse bronchoalveolar lavage fluid was harvested for cell counts and TH2 cytokine measurements . RESULTS : WT mice treated with indomethacin had greater numbers of total cells , eosinophils , and lymphocytes , and increased P05113 and P35225 protein expression in BAL fluid compared to vehicle-treated mice . Similarly , IP knockout mice had augmented inflammation and TH2 cytokine responses compared to WT mice . In contrast , the DB01240 analog cicaprost attenuated the anti-tolerance effect of P36551 inhibition . CONCLUSION : P36551 inhibition abrogated immune tolerance by suppressing DB01240 IP signaling , suggesting that DB01240 signaling promotes immune tolerance and that clinical use of P36551 -inhibiting drugs may increase the risk of developing allergic diseases . Differential radiosensitisation by ZD1839 ( DB00317 ) , a highly selective epidermal growth factor receptor tyrosine kinase inhibitor in two related bladder cancer cell lines . The epidermal growth factor receptor ( P00533 ) is expressed in a wide variety of epithelial tumours including carcinoma of the bladder . Stimulation of the P00533 pathway is blocked by ZD1839 ( DB00317 ) , a highly selective P00533 tyrosine kinase inhibitor . Radical radiotherapy is an established organ sparing treatment option for muscle invasive bladder cancer and this study has explored the possibility for the use of ZD1839 as a radiosensitiser in this scenario . The effect of combination treatment with ZD1839 ( 0.01 microM ) and ionising radiation in the established bladder cancer cell lines MGH-U1 and its radiosensitive mutant clone S40b was measured by clonogenic assays . A highly significant radiosensitising effect was seen in both cell lines ( P < 0.001 for MGH-U1 and S40b cell lines ) . This effect was independent of the concentration of the drug and the duration of exposure prior to treatment with ionising radiation . Cell cycle kinetics of both cell lines was not significantly altered with ZD1839 ( 0.01 microM ) as a single agent . A modest induction of apoptosis was observed with ZD1839 ( 0.01 microM ) as a single agent , but a marked induction was observed with the combination treatment of ZD1839 and ionising radiation . These results suggest a potentially important role for ZD1839 in combination with radiotherapy in the treatment of muscle invasive bladder cancer . Inhibition of histamine H1 receptor activity modulates proinflammatory cytokine production of dendritic cells through c-Rel activity . BACKGROUND : DB11320 exerts diverse effects on immune regulation through four types of histamine receptors ( HRs ) . Among them , type 1 receptor ( P35367 ) plays an important role in allergic inflammation . Dendritic cells ( DCs ) , which express at least three types of HRs , are professional antigen-presenting cells controlling the development of allergic inflammation . However , the molecular mechanisms involved in P35367 -mediated NF-ĸB signaling of DCs remain poorly defined . METHODS : Bone-marrow ( BM ) -derived DCs ( BM-DCs ) were treated with P35367 inverse agonists to interrupt basal P35367 -mediated signaling . The crosstalk of P35367 -mediated signaling and the NF-ĸB pathway was examined by NF-ĸB cellular activity using a luciferase reporter assay , NF-ĸB subunit analysis using Western blotting and P01375 -α promoter activity using chromatin immunoprecipitation . RESULTS : Blockage of P35367 signaling by inverse agonists significantly inhibited P01375 -α and P05231 production of BM-DCs . P35367 -specific agonists were able to enhance P01375 -α production , but this overexpression was significantly inhibited by NF-ĸB inhibitor . The P35367 inverse agonist ketotifen also suppressed cellular NF-ĸB activity , suggesting crosstalk between P35367 and NF-ĸB signaling in DCs . After comprehensive analysis of NF-ĸB subunits , c-Rel protein expression was significantly down-regulated in ketotifen-treated BM-DCs , which led to inhibition of the promoter activity of P01375 -α . Finally , adoptive transfer of the ketotifen-treated BM-DCs did not induce significant allergic airway inflammation compared to that of control cells in vivo . CONCLUSIONS : Our results suggest that c-Rel controls P35367 -mediated proinflammatory cytokine production in DCs . This study provides a potential mechanism of P35367 -mediated signaling and NF-ĸB pathway crosstalk in allergic inflammation . P43119 in tumor endothelial cells promotes angiogenesis in an autocrine manner . Molecules highly expressed in tumor endothelial cells ( TEC ) are important for specific targeting of these cells . Previously , using DNA microarray analysis , we found that the prostacyclin receptor ( IP receptor ) gene was upregulated in TEC compared with normal endothelial cells ( NEC ) . Although prostacyclin is implicated in re-endothelialization and angiogenesis , its role remains largely unknown in TEC . Moreover , the effect of the IP receptor on TEC has not been reported . In the present study we investigated the function of the IP receptor in TEC . The TEC were isolated from two types of human tumor xenografts in nude mice , while NEC were isolated from normal counterparts . DB01240 secretion levels in TEC were significantly higher than those in NEC , as shown using ELISA . Real-time RT-PCR showed that the IP receptor was upregulated in TEC compared with NEC . Furthermore , migration and tube formation of TEC were suppressed by the IP receptor antagonist RO1138452 . Immunohistostaining showed that the IP receptor was specifically expressed in blood vessels of renal cell carcinoma specimens , but not in glomerular vessels of normal renal tissue . These findings suggest that the IP receptor is a TEC-specific marker and might be a useful therapeutic target . [ Detection of a high-affinity prostaglandin I2 binding site in the human thyroid ] . This study is concerned with the identification and the pharmacological properties of P43119 binding sites on human thyroid membrane fractions . Scatchard analysis is not linear , revealing a high- and a low-affinity receptor binding site . ( 3 H ) DB01088 binding experiments were performed under various clinical conditions : in thyroid cancer the low-affinity binding sites disappear totally and the specific high-affinity binding sites are diminished according to the grade of differentiation of the cancer . An alteration in Bmax and Kd is also observed in cold nodules , in Hashimoto 's and Riedl 's thyroiditis and in hyperthyroidism , whereas hot nodules exhibit an increase in both the receptor subpopulations . The data provide evidence for specific DB01240 binding sites and support the suggestion of a direct regulatory key-role of DB01240 in thyroid intermediary metabolism . Contribution of 5- Q13049 receptor in nematode infection-induced murine intestinal smooth muscle hypercontractility . BACKGROUND & AIMS : Enteric nematode infection induces a smooth muscle hypercontractility that depends on interleukin ( IL ) -4 and P35225 activation of the signal transducer and activator of transcription ( P35610 ) 6 . Serotonin ( 5-HT ) is involved in the physiologic regulation of gut function . The present study investigated the contribution of 5-HT and its receptors in nematode-induced intestinal smooth muscle hypercontractility . METHODS : Mice were infected with Nippostrongylus brasiliensis ( N brasiliensis ) or Heligmosomoides polygyrus ( H polygyrus ) or injected intravenously with P35225 . Segments of jejunum were suspended in organ baths , and smooth muscle responses to 5-HT were determined in the presence or absence of specific 5-HT antagonists . P05112 , P35225 , and 5-HT receptor messenger RNA expressions were determined by real-time quantitative polymerase chain reaction . RESULTS : 5-HT evoked a modest contraction of smooth muscle in wild-type ( WT ) mice that was unaltered by the 5- Q13049 antagonist ketanserin . N brasiliensis infection induced a smooth muscle hypercontractility to 5-HT that was abolished by 5-HT(2A) antagonists but not by other 5-HT antagonists . Infection-induced up-regulation of 5- Q13049 expression was correlated with the smooth muscle hypercontractility to 5-HT . The infection-induced up-regulation of 5- Q13049 in WT mice was observed also in P05112 (-/-) mice but was not seen in P35225 (-/-) or P42226 (-/-) mice . In addition , smooth muscle responses to 5-HT and 5- Q13049 expression in WT mice were also enhanced by P35225 or H polygyrus infection . CONCLUSIONS : These data show that 5- Q13049 is one of the molecules downstream from P42226 activation that mediates changes in smooth muscle function . 5- Q13049 represents a novel therapeutic target for modulating immune-mediated effects on intestinal motility . P43119 /thromboxane receptor interactions and cellular responses in human atherothrombotic disease . Twenty-five years have passed since Vane and colleagues proposed a prostacyclin and thromboxane balance as critical to cardiovascular homeostasis . DB01240 prevents platelet aggregation and promotes vasodilatation , opposing the effects of thromboxane . Possible compensation by redundant functions , such as nitric oxide , long prevented appreciation of this balance . Effective use of low-dose aspirin in the secondary prevention of atherothrombosis suggested a clinical importance for the balance . However , it was not until the cyclooxygenase-2 inhibitor rofecoxib was withdrawn because of increased cardiovascular events that this critical balance was confirmed in humans . Moreover , clinical observations are supported by elegant animal receptor knockout experiments and subsequent human genetic variant studies . Combined , these findings provide valuable insight into the roles of these prostanoids in the development of atherothrombosis , emphasizing the need to reevaluate the use of selective prostacyclin- and thromboxane-based therapies in cardiovascular disease . P43119 up-regulates the expression of angiogenic genes in human endometrium via cross talk with epidermal growth factor Receptor and the extracellular signaling receptor kinase 1/2 pathway . DB01240 ( P06744 ) is a member of the prostanoid family of lipid mediators that mediates its effects through a seven-transmembrane G protein-coupled receptor ( IP receptor ) . Recent studies have ascertained a role for prostanoid-receptor signaling in angiogenesis . In this study we examined the temporal-spatial expression of the IP receptor within normal human endometrium and additionally explored the signaling pathways mediating the role of IP receptor in activation of target angiogenic genes . Quantitative RT-PCR analysis demonstrated the highest endometrial expression of the IP receptor during the menstrual phase compared with all other stages of the menstrual cycle . Immunohistochemical analysis localized the site of IP receptor expression to the glandular epithelial compartment with stromal and perivascular cell immunoreactivity . Expression of the immunoreactive IP receptor protein was greatest during the proliferative and early secretory phases of the menstrual cycle . To explore the role of the IP receptor in glandular epithelial cells , we used the Ishikawa endometrial epithelial cell line . Stimulation of Ishikawa cells and human endometrial biopsy explants with 100 nm iloprost ( a P06744 analog ) rapidly activated P27361 /2 signaling and induced the expression of proangiogenic genes , basic fibroblast growth factor , angiopoietin-1 , and angiopoietin-2 , in an epidermal growth factor receptor ( P00533 ) -dependent manner . Furthermore , P00533 colocalized with IP receptor in the glandular epithelial compartment . These data suggest that P06744 -IP interaction within glandular epithelial cells can promote the expression of proangiogenic genes in human endometrium via cross talk with the P00533 . Induction of prostacyclin/ DB01240 synthase expression after cerebral ischemia-reperfusion . DB01240 ( DB01240 ) , a potent vasodilator and inhibitor of platelet aggregation and leukocyte activation , is crucial in vascular diseases such as stroke . Q16647 ( PGIS ) is the key enzyme for DB01240 synthesis . Although expression of PGIS was noted in the brain , its role in ischemic insult remains unclear . Here we reported the temporal and spatial expression of PGIS mRNA and protein after 60-min transient ischemia . Northern blot and in situ hybridization revealed a delayed increase of PGIS mRNA in the ischemic cortex at 24- to 72-h after ischemia ; PGIS was detected mainly in the ipsilateral penumbra area , pyriform cortex , hippocampus , and leptomeninges . Western blot and immunohistochemical analysis revealed that PGIS proteins were expressed temporally and spatially similar to PGIS mRNA . PGIS was heavily colocalized with P16284 to endothelial cells at the leptomeninges , large and small vessels , and localized to neuronal cells , largely at the penumbra area . A substantial amount of PGIS was also detected in the macrophage and glial cells . To evaluate its role against ischemic infarct , we overexpressed PGIS by adenoviral gene transfer . When infused 72 h before ischemia ( - 72 h ) , Adv-PGIS reduced infarct volume by approximately 50 % . However , it had no effect on infarct volume when infused immediately after ischemia ( 0 h ) . Eicosanoid analysis revealed selective elevation of DB01240 at - 72 h while DB01240 and TXB2 were both elevated at 0 h , altering the DB01240 /thromboxane A2 ( TXA2 ) ratio from 10 to 4 . These findings indicate that PGIS protects the brain by enhancing DB01240 synthesis and creating a favorable DB01240 /TXA2 ratio . P15692 expression is augmented by hypoxia‑induced PGIS in human fibroblasts . Q16647 ( PGIS or Q16647 ) is an enzyme that catalyses the conversion of prostaglandin H2 ( PGH2 ) to prostaglandin I2 ( DB01240 ) . DB01240 promotes cancer growth by activating peroxisome proliferator-activated receptor δ ( PPARδ ) , and increases the expression levels of the pro-angiogenic factor vascular endothelial growth factor ( P15692 ) . We found that the expression of the PGIS gene was enhanced in WI-38 , TIG-3-20 and HEL human lung fibroblast cells and two cancer cell lines ( NB-1 and G361 ) under hypoxic conditions . The main localization of PGIS changed from the cytoplasm to the nucleus by hypoxia in WI-38 cells . The induced PGIS had an enzymatic activity since the intracellular level of 6-keto-prostaglandin , a useful marker of DB01240 biosynthesis in vivo , was increased with the increasing levels of PGIS . Expression of P15692 was increased in parallel with PGIS induction under hypoxic conditions . PGIS knockdown resulted in the decreased expression of P15692 mRNA . Since P15692 is a known PPARδ target gene , we examined the effects of siRNAs targeting PPARδ on the expression of P15692 under hypoxic conditions . Knockdown of PPARδ suppressed the expression of P15692 under hypoxic conditions in WI-38 cells . These findings suggest that PGIS is induced by hypoxia and regulates the expression of P15692 in fibroblasts . Fibroblasts in the hypoxic area of tumors may have an important role in tumor growth and angiogenesis . Catalog of 178 variations in the Japanese population among eight human genes encoding G protein-coupled receptors ( GPCRs ) . We screened DNAs from 48 Japanese individuals for single-nucleotide polymorphisms ( SNPs ) in eight genes encoding G protein-coupled receptors ( GPCRs ) by directly sequencing the entire relevant genomic regions except for repetitive-sequence elements . This approach identified 147 SNPs and 31 insertion/deletion polymorphisms among the eight GPCR genes . On average , we identified one SNP in every 584 nucleotides . Of the 147 SNPs , 69 were identified in P30556 , 12 in P50052 , nine in P35414 , 20 in P37288 , nine in P30518 , 16 in P21728 , six in P08514 , and six in P43119 . Twenty-one SNPs were located in 5' flanking regions , 76 in introns , 32 in exons , and 18 in 3' flanking regions . These variants should contribute to investigations of possible correlations between genotypes and phenotypes as regards susceptibility to disease or responsiveness to drug therapy . Human prostacyclin receptor . DB01240 , a member of the eicosanoid family of lipid mediators , is the major product of arachidonic acid metabolism formed in the marcovascular endothelium . It is a potent vasodilator , antithrombotic , and antiplatelet agent that mediates it effects through a membrane-associated receptor termed the IP . Cloning of the cDNA for IP , from human and other species , indicated its membership of the G protein-coupled receptor superfamily and has allowed detailed examination of the signaling and regulatory pathways utilized by this receptor . This article examines the current state of knowledge of the IP , its signaling and regulation , and its biological role in vivo and examines the possible existence of multiple P43119 sites . Glucocorticoid-induced surface expression of annexin 1 blocks beta2-integrin adhesion of human eosinophils to intercellular adhesion molecule 1 surrogate protein . BACKGROUND : Glucocorticoids attenuate the population of eosinophils and T lymphocytes in asthmatic airways . The decrease in airway eosinophilia is caused both by accelerated cell death and by induction of blockade of integrin adhesion . In this study , we examined the hypothesis that annexin 1 surface expression , which is upregulated by the glucocorticoid receptor , prevents integrin adhesion essential to cell migration by blocking intracellular translocation of cytosolic group IV phospholipase A2 ( P47712 ) . OBJECTIVE : To examine the relationship of the glucocorticoid on annexin 1 expression and the effect of blockade of annexin 1 activity on adhesion of human eosinophils in vitro . To determine the relationship between annexin 1surface expression and nuclear membrane translocation of P47712 . METHODS : Eosinophils isolated from human peripheral blood were pretreated with fluticasone propionate ( FP ) , and beta2-integrin adhesion was measured after stimulation with P05113 or eotaxin . Effects of FP on P47712 expression , phosphorylation , and translocation were determined . The role of annexin 1 was examined by using annexin 1 blocking antibody and/or mimetic peptides . RESULTS : DB00588 decreased stimulated eosinophil adhesion and caused 4-fold increase in annexin 1 expression on the plasma membrane . Inhibition of adhesion by FP was blocked with annexin 1 blocking antibody . Annexin 1 N-terminal mimetic peptide also blocked beta2-integrin adhesion . Translocation of P47712 to the nuclear membrane was significantly blocked by incubation with FP . Blockade was reversed with annexin 1 blocking antibody . CONCLUSION : Blockade of beta2-integrin adhesion by glucocorticoid is regulated by annexin 1 , which blocks P47712 translocation to nuclear membrane . Structure-activity relationships associated with 3,4,5-triphenyl-1H-pyrazole-1-nonanoic acid , a nonprostanoid prostacyclin mimetic . A series of phenylated pyrazoloalkanoic acid derivatives were synthesized and evaluated as inhibitors of ADP-induced human platelet aggregation . 3,4,5-Triphenyl-1H-pyrazole-1-nonanoic acid ( 8d ) , with an IC50 of 0.4 microM , was the most potent inhibitor identified in this study . Biochemical studies determined that 8d increased intraplatelet DB02527 accumulation and stimulated platelet membrane-bound adenylate cyclase in a concentration-dependent fashion . Displacement of [3H]iloprost by 8d from platelet membranes indicated that the platelet prostacyclin ( DB01240 ) receptor is the locus of biological action . Structure-activity studies demonstrated that the minimum structural requirements for binding to the platelet P43119 and inhibition of ADP-induced platelet aggregation within this series are a vicinally diphenylated pyrazole substituted with an omega-alkanoic acid side chain eight or nine atoms long . Potency depended upon both side-chain length and its topological relationship with the two phenyl rings . [ 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 . Pharmacological properties of thalidomide and its analogues . Thalidomide and its immunomodulatory imide drugs ( IMiDs ) analogues DB00480 ( DB00480 , DB00480 ) and CC-4047 ( Actimid , DB08910 ) have been used as anti-inflammatory and anticancerous drugs in the recent years . Thalidomide and IMiDs inhibit the cytokines tumour necrosis factor-alpha ( P01375 ) , interleukins ( IL ) 1-beta , 6 , 12 , and granulocyte macrophage-colony stimulating factor ( GM- P04141 ) . They also costimulate primary human T , NKT and NK lymphocytes inducing their proliferation , cytokine production , and cytotoxic activity . On the other hand , the compounds are anti-angiogenic , anti-proliferative , and pro-apoptotic . Thalidomide analogues have been used as inhibitors of alpha glucosidase and could be potential drugs for diabetes treatment . In this review , we explore the current trend of the different structures , the new patents , and the possible new applications in different pathologies . miRNA signature and Dicer requirement during human endometrial stromal decidualization in vitro . Decidualization is a morphological and biochemical transformation of endometrial stromal fibroblast into differentiated decidual cells , which is critical for embryo implantation and pregnancy establishment . The complex regulatory networks have been elucidated at both the transcriptome and the proteome levels , however very little is known about the post-transcriptional regulation of this process . miRNAs regulate multiple physiological pathways and their de-regulation is associated with human disorders including gynaecological conditions such as endometriosis and preeclampsia . In this study we profile the miRNAs expression throughout human endometrial stromal ( hESCs ) decidualization and analyze the requirement of the miRNA biogenesis enzyme Dicer during this process . A total of 26 miRNAs were upregulated and 17 miRNAs downregulated in decidualized hESCs compared to non-decidualized hESCs . Three miRNAs families , miR-181 , miR-183 and miR-200 , are down-regulated during the decidualization process . Using miRNAs target prediction algorithms we have identified the potential targets and pathways regulated by these miRNAs . The knockdown of Dicer has a minor effect on hESCs during in vitro decidualization . We have analyzed a battery of decidualization markers such as cell morphology , P01236 , P08833 , P55773 and P35625 secretion as well as P31260 , P35354 , SP1 , C/EBPß and Q12778 expression in decidualized hESCs with decreased Dicer function . We found decreased levels of P31260 and altered intracellular organization of actin filaments in Dicer knockdown decidualized hESCs compared to control . Our results provide the miRNA signature of hESC during the decidualization process in vitro . We also provide the first functional characterization of Dicer during human endometrial decidualization although surprisingly we found that Dicer plays a minor role regulating this process suggesting that alternative biogenesis miRNAs pathways must be involved in human endometrial decidualization . P35354 -derived prostacyclin confers atheroprotection on female mice . Female gender affords relative protection from cardiovascular disease until the menopause . We report that estrogen acts on estrogen receptor subtype alpha to up-regulate the production of atheroprotective prostacyclin , DB01240 , by activation of cyclooxygenase 2 ( P35354 ) . This mechanism restrained both oxidant stress and platelet activation that contribute to atherogenesis in female mice . Deletion of the P43119 removed the atheroprotective effect of estrogen in ovariectomized female mice . This suggests that chronic treatment of patients with selective inhibitors of P35354 could undermine protection from cardiovascular disease in premenopausal females . The anticoagulant effect of PGI2S and tPA in transgenic umbilical vein endothelial cells is linked to up-regulation of PKA and PKC . The selection of vascular grafts for coronary artery bypass surgery is crucial for a positive outcome . This study aimed to establish a novel line of vascular endothelial cells with a potent anticoagulant effect . A lentiviral vector was used to stably transfect human umbilical vein endothelial cells ( HUVECs ) with PGI2S alone ( HUVEC-PGI2S ) or both PGI2S and tPA ( HUVEC-PGI2S-tPA ) . Both HUVEC-PGI2S and HUVEC-PGI2S-tPA cells over-expressing PGI2S and tPA were compared to mock-transfected cells . The enzyme-linked immuno sorbent assay ( ELISAs ) demonstrated that the anticoagulation components , P01008 and P00747 , were up-regulated and coagulation factor FVIII was down-regulated in both cell lines . QRT-PCR and western blotting demonstrated the vasodilation and platelet disaggregation proteins PKA , PKC , and P43119 were up-regulated in both cell lines , but MAPK expression was not altered in either cell line . However , cell viability and colony formation assays and cell cycle analysis demonstrated that both cell lines had a lower rate of cell growth and induced P55008 phase arrest . HUVEC-PGI2S and HUVEC-PGI2S-tPA cells have a potent anticoagulant effect and their use in vascular heterografts may decrease the risk of thrombosis . [ Association and interaction of AGT , P30556 , P12821 , P07550 , P21728 , P35611 , P35612 , P20020 , P21731 and P35354 genes on the risk of hypertension in Antioquian population ] . INTRODUCTION : Hypertension is a multifactorial disease influenced by genetic and environmental components , with its prevalence varying across ethnic groups . Manifold studies on blood pressure regulatory system genes have been carried out -such as the renin-angiotensin-aldosterone system , the sympathetic nervous system , endothelial factor , and sodium balance- , but the results yielded were inconsistent among populations . OBJECTIVES : To evaluate the effect of both variants in genes AGT , P30556 , P12821 , P07550 , P21728 , P35611 , P35612 , P20020 , P21731 P35354 , and the result of the individual ancestry component on hypertension and blood pressure levels among population in Antioquia . METHODS AND MATERIALS : 107 cases and 253 controls were genotyped for 12 variants on genes AGT , P30556 , P12821 , P07550 , P21728 , P35611 , P35612 , P20020 , P21731 y P35354 , and for 20 ancestry informative markers . The association of polymorphisms and their interactions , and the association of ancestral genetic composition with hypertension and blood pressure levels were examined . RESULTS : Genes P35612 , rs4852706 ( OR=3.0 ; p=0.023 ) ; P21728 , rs686 ( OR=0.38 ; p=0.012 ) and P07550 , rs1042718 ( OR=10.0 ; p=0.008 ) ; as well as genotypic combinations of P21728 and P30556 ; AGT and P35611 ; and P35611 to P20020 and P35354 were associated to hypertension . The Amerindian ancestry component was associated to some decrease in diastolic blood pressure . CONCLUSION : Variants on genes P35612 , P21728 , P07550 , P30556 , AGT , P35611 , P20020 and P35354 individually or interacting , are associated to hypertension . The Amerindian ancestry component has an effect on blood pressure . Modulation of proinflammatory cytokine production in tumour necrosis factor-alpha ( P01375 ) -transgenic mice by treatment with cells engineered to secrete P05112 , P22301 or P35225 . P01375 is one of the major proinflammatory cytokines involved in the pathogenesis of chronic inflammatory joint disease , in human rheumatoid arthritis as well as in murine models of this disease . It was previously described that a highly destructive chronic spontaneous inflammatory arthritis develops in mice expressing a human P01375 transgene modified with the 3' untranslated region of beta-globin . The present study investigates in this mouse model the effects of the anti-inflammatory cytokines P05112 , P22301 and P35225 administered in vivo on proinflammatory cytokine expression . Groups of P01375 -transgenic mice were engrafted with xenogeneic transfected Chinese hamster ovary ( CHO ) fibroblasts secreting murine P05112 , P22301 or P35225 . In vivo treatments consisted of 3 or 4 weekly engraftments , starting when the mice were 4weeks old . Control groups of transgenic mice were engrafted with beta-galactosidase gene-transfected CHO cells or injected with medium . A significant decreased expression of P01375 transgene , endogenous mouse P01375 and IL-1 mRNA was observed in splenocytes of mice treated for 3 or 4 weeks with CHO/ P05112 and CHO/ P35225 , and , to a lesser extent , with CHO/ P22301 , compared with controls . Finally , attenuation of histological scores of arthritides was statistically significant only in the group of CHO/ P05112 -treated mice after 3weeks of treatment ( P < 0.05 ) , and was not significant in any other group . These results show that P05112 , P22301 or P35225 , administered by gene therapy , can decrease the mRNA steady state levels of both endogenous and transgenic cytokines in human P01375 transgenic mice . In addition , P05112 can slightly attenuate the development of arthritides in this model . Altered expression of inflammation-related genes in human carotid atherosclerotic plaques . OBJECTIVE : Inflammation is a pivotal process in atherosclerosis development and progression , but the underlying molecular mechanisms remain largely obscure . We have conducted an extensive expression study of atherosclerotic plaques to identify the inflammatory pathways involved in atherosclerosis . METHODS : We studied 11 human carotid plaques , their respective adjacent regions and 7 control arteries from different subjects . Expression of 92 genes was studied by TaqMan low-density array human inflammation panel . Human aortic endothelial and smooth muscle cells were used for in vitro experiments . RESULTS : The mRNA levels of 44/92 genes ( 48 % ) differed significantly between the tissues examined ( 13 up-regulated and 31 down-regulated ) . Dysregulated genes encode molecules belonging to different functional classes although most of them encode enzymes involved in the eicosanoid synthesis pathway . The expression of Q16647 and P43119 genes was decreased in human aortic endothelial and smooth muscle cells stimulated with oxLDL and P01375 -α . CONCLUSIONS : This study not only reveals several dysregulated genes in human lesions but also focuses the role played by the genes involved in the eicosanoid synthesis pathway during atherosclerotic development . The decrease of Q16647 and P43119 expression after oxLDL treatment mirrors the decreased mRNA levels in atherosclerotic lesions versus control arteries , which suggests that oxidation is important for Q16647 and P43119 regulation in human vessel cells during atherosclerosis development . Aripiprazole : a novel atypical antipsychotic drug with a uniquely robust pharmacology . Aripiprazole ( DB01238 ) is an atypical antipsychotic drug that has been recently introduced for clinical use in the treatment of schizophrenia . Aripiprazole has a unique pharmacologic profile that includes partial agonism at several G-protein coupled receptors ( GPCRs ) [ especially dopamine ( D2 ) and P08908 ] and antagonistic action at others ( especially 5- Q13049 ) . Clinical trials indicate that aripiprazole is effective in treating the positive and negative symptoms of schizophrenia . In short-term studies rapid onset of action ( within one week ) has been demonstrated . Preliminary data indicate that aripiprazole may also be effective in the treatment of manic symptoms of bipolar disorder . At recommended doses , aripiprazole appears to be safe and well tolerated in most adult patients with schizophrenia and schizoaffective disorder . There is only limited information available on the use of aripiprazole in children and adolescents , and pilot data suggest that a revised dosing strategy , based on weight , is indicated in this population . In the long-term studies , the use of aripiprazole was associated with continued efficacy , good compliance and increased time-to-relapse . Aripiprazole represents the first functionally selective atypical antipsychotic drug . Exploration of the antiplatelet activity profile of betulinic acid on human platelets . Betulinic acid , a natural pentacyclic triterpene acid , presents a diverse mode of biological actions including antiretroviral , antibacterial , antimalarial , and anti-inflammatory activities . The potency of betulinic acid as an inhibitor of human platelet activation was evaluated , and its antiplatelet profile against in vitro platelet aggregation , induced by several platelet agonists ( adenosine diphosphate , thrombin receptor activator peptide-14 , and arachidonic acid ) , was explored . Flow cytometric analysis was performed to examine the effect of betulinic acid on P16109 membrane expression and O95456 binding to activated platelets . Betulinic acid potently inhibits platelet aggregation and also reduced O95456 binding and the membrane expression of P16109 . Principal component analysis was used to screen , on the chemical property space , for potential common pharmacophores of betulinic acid with approved antithrombotic drugs . A common pharmacophore was defined between the NMR-derived structure of betulinic acid and prostacyclin agonists ( DB01240 ) , and the importance of its carboxylate group in its antiplatelet activity was determined . The present results indicate that betulinic acid has potential use as an antithrombotic compound and suggest that the mechanism underlying the antiplatelet effects of betulinic acid is similar to that of the P43119 agonists , a hypothesis that deserves further investigation . Reconstruction and functional analysis of altered molecular pathways in human atherosclerotic arteries . BACKGROUND : Atherosclerosis affects aorta , coronary , carotid , and iliac arteries most frequently than any other body vessel . There may be common molecular pathways sustaining this process . Plaque presence and diffusion is revealed by circulating factors that can mediate systemic reaction leading to plaque rupture and thrombosis . RESULTS : We used DNA microarrays and meta-analysis to study how the presence of calcified plaque modifies human coronary and carotid gene expression . We identified a series of potential human atherogenic genes that are integrated in functional networks involved in atherosclerosis . Caveolae and JAK/ P35610 pathways , and P06702 / P05109 interacting proteins are certainly involved in the development of vascular disease . We found that the system of caveolae is directly connected with genes that respond to hormone receptors , and indirectly with the apoptosis pathway . Cytokines , chemokines and growth factors released in the blood flux were investigated in parallel . High levels of RANTES , IL-1ra , MIP-1 alpha , MIP-1 beta , P60568 , P05112 , P05113 , P05231 , P13232 , Q16552 , DB00102 , P15692 and P01579 were found in plasma of atherosclerotic patients and might also be integrated in the molecular networks underlying atherosclerotic modifications of these vessels . CONCLUSION : The pattern of cytokine and P06702 / P05109 up-regulation characterizes atherosclerosis as a proinflammatory disorder . Activation of the JAK/ P35610 pathway is confirmed by the up-regulation of P05231 , P42224 , Q00978 and Q13651 genes in coronary and carotid plaques . The functional network constructed in our research is an evidence of the central role of P35610 protein and the caveolae system to contribute to preserve the plaque . Moreover , Cav-1 is involved in SMC differentiation and dyslipidemia confirming the importance of lipid homeostasis in the atherosclerotic phenotype . P00533 ( P00533 ) transactivation by estrogen via the G-protein-coupled receptor , Q99527 : a novel signaling pathway with potential significance for breast cancer . The biological and biochemical effects of estrogen have been ascribed to its known receptors , which function as ligand-inducible transcription factors . However , estrogen also triggers rapid activation of classical second messengers ( DB02527 , calcium , and inositol triphosphate ) and stimulation of intracellular signaling cascades mitogen-activated protein kinase ( Q96HU1 K ) , PI3K and P29474 . These latter events are commonly activated by membrane receptors that either possess intrinsic tyrosine kinase activity or couple to heterotrimeric G-proteins . We have shown that estrogen transactivates the epidermal growth factor receptor ( P00533 ) to Q96HU1 K signaling axis via the G-protein-coupled receptor ( GPCR ) , Q99527 , through the release of surface-bound proHB- P01133 from estrogen receptor ( ER ) -negative human breast cancer cells [ Molecular Endocrinology 14 ( 2000 ) 1649 ] . This finding is consistent with a growing body of evidence suggesting that transactivation of EGFRs by GPCRs is a recurrent theme in cell signaling . GPCR-mediated transactivation of EGFRs by estrogen provides a previously unappreciated mechanism of cross-talk between estrogen and serum growth factors , and explains prior data reporting the P01133 -like effects of estrogen . This novel mechanism by which estrogen activates growth factor-dependent signaling and its implications for breast cancer biology are discussed further in this review . Chromosomal localization of the human prostanoid receptor gene family . Prostaglandins ( PGD2 , DB00917 , PGF2 alpha , and DB01240 ) and thromboxane A2 ( TXA2 ) are biologically active molecules derived from the metabolism of arachidonic acid by cyclooxygenases . They produce a wide variety of physiological and pathophysiological effects mediated through specific G protein-coupled cell surface receptors . In this study , we have mapped the chromosomal positions of the human genes that encode the DB00917 receptor subtypes ( P34995 , PTGER2 , and P43115 ) , the PGF2 alpha receptor ( P43088 ) , the P43119 ( P43119 ) , and the TXA2 receptor ( P21731 ) using in situ hybridization . The P34995 , P21731 , and P43119 genes mapped to chromosome 19 at positions 19p13.1 , 19p13.3 , and 19q13.3 , respectively . The P43088 and P43115 genes mapped to chromosome 1 at positions 1p31.1 and 1p31.2 , respectively , and PTGER2 gene mapped to chromosome band 5p13.1 . Coactivation of DB01221 receptors by glutamate and D-serine induces dilation of isolated middle cerebral arteries . N-methyl-D-aspartate ( DB01221 ) receptors are glutamate-gated cation channels that mediate excitatory neurotransmission in the central nervous system . In addition to glutamate , DB01221 receptors are also activated by coagonist binding of the gliotransmitter , D-serine . Neuronal DB01221 receptors mediate activity-dependent blood flow regulation in the brain . Our objective was to determine whether DB01221 receptors expressed by brain endothelial cells can induce vasodilation of isolated brain arteries . Adult mouse middle cerebral arteries ( MCAs ) were isolated , pressurized , and preconstricted with norepinephrine . N-methyl-D-aspartate receptor agonists , glutamate and DB01221 , significantly dilated MCAs in a concentration-dependent manner in the presence of D-serine but not alone . Dilation was significantly inhibited by DB01221 receptor antagonists , D-2-amino-5-phosphonopentanoate and 5,7-dichlorokynurenic acid , indicating a response dependent on DB01221 receptor glutamate and D-serine binding sites , respectively . Vasodilation was inhibited by denuding the endothelium and by selective inhibition or genetic knockout of endothelial nitric oxide synthase ( P29474 ) . We also found evidence for expression of the pan- DB01221 receptor subunit , Q9UHB4 , in mouse primary brain endothelial cells , and for the DB01221 receptor subunit Q14957 in cortical arteries in situ . Overall , we conclude that DB01221 receptor coactivation by glutamate and D-serine increases lumen diameter in pressurized MCA in an endothelial and P29474 -dependent mechanism . Dopamine receptors and psychiatric drug treatment . The established antipsychotic drugs act mainly by antagonizing dopamine mediated synaptic transmission in the brain . Increase in the rate of production of dopamine metabolites as well as the firing rate of dopamine-containing neurons can be interpreted as compensatory responses to an interruption of synaptic transmission at dopamine nerve terminals . The demonstration of involvement of limbic and cortical mechanisms in the antipsychotic activity of neuroleptic drugs is far more difficult than the involvement of nigro-striatal and tubero-infundibular mechanisms in the neurological and neuroendocrine effects of these drugs . Application of radioreceptor techniques to dopamine research has supported the findings obtained by other neuropsychopharmacological research techniques , providing more direct evidence of dopamine receptor blockade by neuroleptic drugs . Further research is needed especially in studying the nature of the time-dependent adaptive changes at the receptor sites as well as the differences between the different dopamine projections and neural systems in the brain . The different subtypes of dopamine receptors in the brain , currently called D1 and D2 dopamine receptors , seem to be parallel , although in many respects independently-acting regulatory systems . P14416 -selective antagonists such as sulpiride seem to cause selective D2 receptor up-regulation . P01236 secretion seems to be regulated by D2 dopamine receptors . The exact physiological role of D1 dopamine receptors as well as the clinical consequences of selective D1 antagonism is not known . DB00391 and clozapine are examples of atypical neuroleptic compounds that have quite different profile of action , the former having strong and selective antidopaminergic action , the latter combining a number of non- dopaminergic mechanisms with rather slight effects on dopamine receptors. ( ABSTRACT TRUNCATED AT 250 WORDS ) On the multiplicity of platelet prostaglandin receptors . I . Evaluation of competitive antagonism by aggregometry . Methods for the evaluation of competitive interactions at receptors associated with platelet activation and inhibition using aggregometry of human PRP have been developed . The evidence supports the suggestion that PGE1 and DB01240 share a common receptor for inhibition of platelet reactivity , but only a portion ( if any ) of the aggregation stimulation associated with DB00917 is the result of DB00917 binding ( without efficacy ) to this receptor . DB00917 ( at .3-20 microM ) is an effective antagonist of PGE1 , DB01240 , and PGD2 producing a shift of about one order of magnitude in the IC50-values obtained from complete aggregation inhibition dose response curves . The antagonism of PGD2 inhibition is particularly notable , 80 nM DB00917 levels are detectable . This and other actions of DB00917 indicate another platelet receptor for DB00917 . PGE1 acts at both the DB00917 and P43119 . Other substances showing DB01240 -like actions only at high doses ( 1-30 microM ) , display additive responses with DB01240 indicative of decreased affinity for the I2/E1 receptor and the absence of DB00917 -like aggregation stimulation activity . DB01240 methyl ester has intrinsic inhibitory action not associated with in situ ester hydrolysis . The methyl ester is dissaggregatory showing particular specificity for inhibition of release and second wave aggregation . DB05229 sodium , a stable prostacyclin analogue , elicits dilation of isolated porcine retinal arterioles : roles of P29474 and potassium channels . PURPOSE : DB01240 ( DB01240 ) is usually described as an endoEDRFsthelium-derived relaxing factor , but the vasoreactivity to DB01240 in the retinal arterioles and the underlying mechanisms are not fully understood . We examined the effects of DB01240 on the retinal microcirculation using beraprost sodium ( BPS ) , a stable DB01240 analogue , and the signaling mechanisms involved in this vasomotor activity . METHODS : Porcine retinal arterioles were isolated , cannulated , and pressurized without flow in vitro . Video microscopic techniques recorded the diametric responses to BPS . RESULTS : DB05229 sodium elicited dose-dependent ( 0.1 pM-0.1 μM ) vasodilation of the retinal arterioles that was abolished by the P43119 ( IP ) antagonist CAY10441 . DB05229 sodium-induced vasodilation decreased by 50 % after the endothelium was removed and was inhibited by the nitric oxide ( NO ) synthase inhibitor N(G)-nitro-L-arginine methyl ester ( L-NAME ) comparable with denudation . Inhibition of soluble guanylyl cyclase by 1H-1,2,4-oxadiazolo[4,3-a]quinoxalin-1-one ( ODQ ) and blockage of protein kinase A ( PKA ) by Rp-8-Br-cAMPS were comparable to L-NAME . DB05229 sodium-induced vasodilation was also inhibited by the nonselective potassium channel inhibitor , tetraethylammonium , and the adenosine triphosphate-sensitive potassium ( KATP ) channel blocker , glibenclamide . Residual vasodilation in the presence of glibenclamide decreased further with subsequent application of ODQ . CONCLUSIONS : DB05229 sodium , a stable DB01240 analogue , causes vasodilation of the retinal arterioles mediated via the IP receptor . The current findings suggest that BPS elicits endothelium-dependent and -independent dilation of the retinal arterioles mediated by NO induced by activation of PKA in the endothelium and the KATP channel activation in the vascular smooth muscle , respectively . DB01240 ( P06744 ) receptor binding and cyclic AMP synthesis activities of PGI1 analogues , SM-10906 and its methyl ester , SM-10902 , in mastocytoma P-815 cells . The prostacyclin I1 ( PGI1 ) analogue , SM-10906 and its methyl ester , SM-10902 , have been compared with the DB01240 analogue , iloprost , with respect to binding to the P43119 , stimulation of adenylate cyclase activity and inhibition of thrombin-induced Ca2+ mobilization in mastocytoma P-815 cells . SM-10906 displaced [3H]iloprost binding to the membrane fraction , the IC50 value being 100 nM , but showed very low affinity for the prostaglandin E ( PGE ) receptor . SM-10906 dose-dependently stimulated GTP-dependent adenylate cyclase activity in the membrane fraction , the EC50 value being 35 nM . Furthermore , SM-10906 prevented a thrombin-induced increase in the intracellular Ca2+ concentration , the IC50 value being 300 nM . These IC50 and EC50 values are much lower than those of SM-10902 . These results demonstrate that SM-10906 , a stable PGI1 derivative , is an agonist for the [3H]iloprost-binding ( DB01240 ) receptor , and that it prevents thrombin-induced Ca2+ mobilization through stimulation of the adenylate cyclase system in mastocytoma cells . On the other hand , a methyl ester derivative of PGI1 , SM-10902 , was inactive in the binding assay , but it seems to be a partial agonist for adenylate cyclase activity [ corrected ] . Induction of prostacyclin receptor expression in human erythroleukemia cells . We have identified both high-affinity ( KD = 36 +/- 3 nM ) and low-affinity ( KD = 2.1 +/- 0.8 microM ) prostacyclin ( DB01240 ) -receptor sites on human erythroleukemia ( HEL ) cells using the radiolabelled prostacyclin analogue . [3H]iloprost . The addition of the phorbol ester , TPA , to the culture medium caused a 5-10-fold increase in the number of both the low- and the high-affinity sites , without any change in their affinity constants . DB01088 stimulated HEL cell membrane adenylate cyclase activity 5-fold . This stimulation was potentiated in the presence of GTP , indicating a conventional P43119 -G2-adenylate cyclase system . HEL cells represent a source of prostacyclin receptor mRNA which may be of value in expression cloning of this receptor . 17 DB00783 -mediated growth inhibition of MDA-MB-468 cells stably transfected with the estrogen receptor : cell cycle effects . P03372 ( ER ) -negative MDA-MB-468 human breast cancer cells were stably transfected with wild-type human ER and utilized as a model for investigating estrogen- and aryl hydrocarbon ( Ah ) -responsiveness . Treatment of the stably transfected cells with 10 nM 17 beta-estradiol ( E2 ) resulted in a significant inhibition ( > 60 % ) of cell proliferation and DNA synthesis , which was blocked by 10(-7) M ICI 182 780 . Analysis by flow cytometry indicated that treatment with E2 increased the percentage of cells in G0/ P55008 ( from 68.8 to 89.4 ) and decreased cells in S ( from 18.4 to 3.4 ) and G2/M ( from 12.8 to 7.2 ) phases of the cell cycle . The effects of E2 on the major cyclins , cyclin-dependent kinases and cyclin-dependent kinase inhibitors , retinoblastoma protein ( RB ) , Q01094 , and cyclin-dependent kinase activities were also investigated in the stably transfected MDA-MB-468 cells . The results demonstrated that the growth inhibitory effects of 10(-8) M E2 in ER stably transfected MDA-MB-468 cells were associated with modulation of several factors required for cell cycle progression and DNA synthesis , including significant induction of the cyclin-dependent kinase inhibitor p21cip-1 ( > 4-fold increase after 12 h ) and decreased Q01094 and P12004 protein levels . These results show that the growth-inhibitory effects of E2 in the stably transfected cells were due to multiple factors which result in growth arrest in G0/ P55008 and inhibition of DNA synthesis . DB11320 contributes to tissue remodeling via periostin expression . DB11320 is thought to have a critical role in the synthesis of extracellular matrix in skin and may be involved in tissue remodeling of allergic diseases . Recent studies revealed that periostin , a matricelluar protein , contributed to tissue remodeling ; however , a link between periostin and histamine remains unproven . We investigated whether periostin was involved in histamine-induced collagen production . Cultured dermal fibroblasts derived from wild-type ( WT ) or periostin knockout ( PN(-/-) ) mice were stimulated with histamine , and then collagen and periostin production was evaluated . DB11320 induced collagen gene expression in WT fibroblasts in the late phase but not in the early phase , whereas no effect on collagen expression was observed in histamine-stimulated PN(-/-) fibroblasts . In WT fibroblasts , histamine directly induced periostin expression in a dose-dependent manner , and an H1 receptor antagonist blocked both periostin and collagen expression . DB11320 activated extracellular signal-regulated kinase 1/2 ( P27361 /2 ) through the H1 receptor . Q15063 induction was inhibited by either H1 antagonist or P27361 /2 inhibitor treatment in vitro and was attenuated in P35367 (-/-) mice . Elevated expression of periostin was found in lesional skin from atopic dermatitis patients . These results suggest that histamine mediates periostin induction and collagen production through activation of the H1 receptor-mediated P27361 /2 pathway ; furthermore , histamine may accelerate the chronicity of atopic dermatitis . Bayesian analysis and the GUSTO trial . Global Utilization of DB00086 and Tissue P00747 Activator in Occluded Arteries . Beneficial vasoactive endothelial effects of fluvastatin : focus on prostacyclin and nitric oxide . Statins are believed to exert beneficial effects against cardiovascular disease beyond correction of dyslipidemia . There are however still very sparse data on how individual statins interact with the production of vasoactive eicosanoids and nitric oxide ( NO ) in human vascular endothelial cells . Here we have determined how fluvastatin affects the mRNA expression of genes associated with vascular reactivity as well as the formation of two major vasodilators , prostacyclin ( DB01240 ) and NO , in human endothelial cells . Also , the influence of fluvastatin on arterial resistance was assessed in isolated small arteries . We show that the promoter activity of prostacyclin synthase ( Q16647 ) , the mRNA expression of Q16647 and endothelial nitric oxide synthase ( P29474 ) , and the production of DB01240 and NO are significantly induced by fluvastatin . Also , strong rapid dilatation ex vivo was observed , with the equal contribution of DB01240 and NO . Our findings in cell culture experiments and in isolated human arteries indicate that fluvastatin-evoked endothelium-derived vasodilator production may confer protection of the endothelial cells via both acute and long-term effects of fluvastatin treatment . If these effects take place in vivo , we suggest a protective pleiotropic role of fluvastatin on the cardiovascular system , particularly at the level of the vascular endothelium , to ameliorate the process of atherogenesis and in the acute manner to reduce vascular tone . Exploring schizophrenia drug-gene interactions through molecular network and pathway modeling . In this study , we retrieved 39 schizophrenia-related antipsychotic drugs from the DrugBank database . These drugs had interactions with 142 targets , whose corresponding genes were defined as drug targeted genes . To explore the complexity between these drugs and their related genes in schizophrenia , we constructed a drug-target gene network . These genes were overrepresented in several pathways including : neuroactive ligand-receptor pathways , glutamate metabolism , and glycine metabolism . Through integrating the pathway information into a drug-gene network , we revealed a few bridge genes connected the sub-networks of the drug-gene network : Q12879 , O60391 , Q14957 , Q13224 , P21728 , and P14416 . These genes encode ionotropic glutamate receptors belonging to the DB01221 receptor family and dopamine receptors . DB00502 was the only drug to directly interact with these pathways and receptors and consequently may have a unique action at the drug-gene interaction level during the treatment of schizophrenia . This study represents the first systematic investigation of drug-gene interactions in psychosis . A curated database of miRNA mediated feed-forward loops involving MYC as master regulator . BACKGROUND : The MYC transcription factors are known to be involved in the biology of many human cancer types . But little is known about the Myc/microRNAs cooperation in the regulation of genes at the transcriptional and post-transcriptional level . METHODOLOGY/PRINCIPAL FINDINGS : Employing independent databases with experimentally validated data , we identified several mixed microRNA/Transcription Factor Feed-Forward Loops regulated by Myc and characterized completely by experimentally supported regulatory interactions , in human . We then studied the statistical and functional properties of these circuits and discussed in more detail a few interesting examples involving Q01094 , P60484 , P06400 and P15692 . CONCLUSIONS/SIGNIFICANCE : We have assembled and characterized a catalogue of human mixed Transcription Factor/microRNA Feed-Forward Loops , having Myc as master regulator and completely defined by experimentally verified regulatory interactions . Dopamine receptors D1 and D2 are related to observed maternal behavior . The dopamine pathway and especially the dopamine receptors 1 and 2 ( P21728 and P14416 ) are implicated in the regulation of mothering in rats . Evidence for this in humans is lacking . Here , we show that genetic variation in both P21728 and P14416 genes in a sample of 187 Caucasian mothers predicts variation in distinct maternal behaviors during a 30-min mother-infant interaction at 6 months postpartum . Two P21728 single-nucleotide polymorphisms ( SNPs rs265981 and rs686 ) significantly associated with maternal orienting away from the infant ( P = 0.002 and P = 0.003 , respectively ) , as did P21728 haplotypes ( P = 0.03 ) . Two P14416 SNPs ( rs1799732 and rs6277 ) significantly associated with maternal infant-directed vocalizing ( P = 0.001 and P = 0.04 , respectively ) , as did P14416 haplotypes ( P = 0.01 ) . We present evidence for heterosis in P21728 where heterozygote mothers orient away from their infants significantly less than either homozygote group . Our findings provide important evidence that genetic variation in receptors critical for mothering in non-human species also affect human maternal behaviors . The findings also highlight the importance of exploring multiple dimensions of the complex human mothering phenotype . Expression of prostacyclin receptors in luteinizing hormone-releasing hormone immortalized neurons : role in the control of hormone secretion . PGs of the E series are involved in the control of P01148 secretion . The present experiments were conducted to clarify whether DB01240 ( prostacyclin ) might be also involved in such a control , using multiple methodological approaches on immortalized P01148 -secreting neurons . A RT-PCR procedure to detect mouse P43119 ( IP ) messenger RNA was first applied , and the results obtained showed the presence of a specific transcript in two cell lines of immortalized P01148 neurons ( GT1-1 and GN11 cell lines ) . Receptor binding assays on membrane preparations from GT1-1 cells showed the presence of a single specific and saturable class of binding sites ( Kd = 4.6 nM ; 10,000 sites/cell ) for [3H]iloprost , a stable analog of DB01240 . Competition experiments showed that the binding sites labeled by [3H]iloprost possess the pharmacological characteristics of IP receptors . In functional studies , DB01240 and its analogs , iloprost and cicaprost , were able to stimulate P01148 release from the GT1-1 cells with elevated potencies ( EC50 = 0.6-4.3 nM ) ; PGE1 was only slightly less active ( EC50 = 28.5 nM ) , whereas DB00917 , considered the major PG involved in P01148 secretion , was poorly effective ( EC50 = 921 nM ) . The relative potencies ( EC50 ) of these compounds in stimulating the intracellular accumulation of DB02527 were in line with their P01148 -releasing activities . In conclusion , these results indicate that immortalized P01148 -secreting neurons express IP receptors through which DB01240 may exert relevant effects on P01148 release . DB01240 -IP signaling and prostaglandin E2-EP2/EP4 signaling both mediate joint inflammation in mouse collagen-induced arthritis . Prostaglandin (PG)I2 ( prostacyclin [ P06744 ] ) and DB00917 are abundantly present in the synovial fluid of rheumatoid arthritis ( RA ) patients . Although the role of DB00917 in RA has been well studied , how much DB01240 contributes to RA is little known . To examine this issue , we backcrossed mice lacking the P43119 ( IP ) to the DBA/1J strain and subjected them to collagen-induced arthritis ( CIA ) . IP-deficient ( IP-/- ) mice exhibited significant reduction in arthritic scores compared with wild-type ( WT ) mice , despite anti-collagen antibody production and complement activation similar to WT mice . IP-/- mice also showed significant reduction in contents of proinflammatory cytokines , such as interleukin ( IL ) -6 in arthritic paws . Consistently , the addition of an IP agonist to cultured synovial fibroblasts significantly enhanced P05231 production and induced expression of other arthritis-related genes . On the other hand , loss or inhibition of each PGE receptor subtype alone did not affect elicitation of inflammation in CIA . However , a partial but significant suppression of CIA was achieved by the combined inhibition of EP2 and EP4 . Our results show significant roles of both DB01240 -IP and DB00917 -EP2/EP4 signaling in the development of CIA , and suggest that inhibition of DB00917 synthesis alone may not be sufficient for suppression of RA symptoms . [ GH-secreting pituitary adenomas -- correlation between clinical features , growth potential and histopathological studies ] . We compared clinical features , including endocrinological and radiological findings , histological features and the proliferative parameters ( P12004 , MIB-1 and AgNORs ) with immunohistochemical features in growth hormone ( GH ) secreting pituitary adenomas . 18 cases were divided into two groups based on immunohistochemical intracytoplasmic stainings for cytokeratin : a prominent dot-like pattern ( group I , 6 cases ) and a diffuse perinuclear pattern ( group II , 12 cases ) . Patients in group I ( 6 females , m = 37.6 years old ) were younger , showed female predominance and had a shorter history of acromegaly compared with patients in group II ( 7 males , 5 females , m = 44.9 years old ) . Although the size of the adenomas tend to be larger in group I , no difference was recognized in plasma GH levels between the two groups . Increased serum prolactin ( PRL ) levels were accompanied more common in group I . Abnormal GH responses to TRH and P01148 injection and GH suppressions to bromocriptine administration were more frequently noted in group II than group I . Surgical approaches were transcranial in most cases of group I and transphenoidal in group II . There was no difference in surgical results as to the correction rate of GH levels between the two groups . Histopathologically , group I adenomas were mostly chromophobic , weakly positive for GH , and were generally negative for PRL and alpha-subunit . On the other hand , group II adenomas were mostly acidophilic , diffusely stained for GH , and were often positive for PRL and alpha-subunit . However , there was no significant difference in proliferating parameters between the two groups. ( ABSTRACT TRUNCATED AT 250 WORDS ) High-dose aspirin in dogs increases vascular resistance with limited additional anti-platelet effect when combined with potent Q9H244 inhibition . INTRODUCTION : With the arrival of the potent Q9H244 antagonists , ticagrelor and prasugrel , the need for co-treatment with aspirin in acute coronary syndromes must be re-examined . This study assessed whether high-dose aspirin : a ) provides additional anti-platelet efficacy , assessed in vivo and ex vivo , when combined with Q9H244 inhibition ; and/or b ) has a negative effect on vascular function . MATERIALS AND METHODS : Using an anaesthetized dog model of thrombosis , the effects of aspirin ( 50mg/kg ) in addition to clopidogrel and ticagrelor were evaluated at two levels of Q9H244 inhibition , maximal ( ≥96 % ) and sub-maximal ( ~80 % ) , as assessed by ex vivo ADP-induced whole blood impedence aggregometry . RESULTS : In the absence of aspirin , maximal and sub-maximal Q9H244 inhibition inhibited arachidonic acid-induced platelet aggregation by approximately 80 % and 24 % , respectively , without affecting platelet TXA2 formation . During maximal Q9H244 inhibition , aspirin provided less additional inhibition of ex vivo arachidonic acid- and collagen-induced platelet aggregation , as compared with sub-maximal Q9H244 inhibition , without additional anti-thrombotic effect in vivo . DB00945 significantly decreased in vivo DB01240 production ( 27 % ) and increased vascular resistance ( 16 % ) , independently of Q9H244 antagonism . CONCLUSION : In the dog , Q9H244 antagonists inhibit TXA2-mediated platelet-aggregation independently of aspirin . DB00945 provides less additional anti-platelet effects during maximal compared with sub-maximal Q9H244 inhibition but increases vascular resistance . Identification of the prostacyclin receptor by use of [15-3H1]19-(3-azidophenyl)-20-norisocarbacyclin , an irreversible specific photoaffinity probe . The prostaglandin I ( DB01240 ) receptor of mouse mastocytoma P-815 cells was characterized by photo-affinity labeling with the stable DB01240 analogue [ 15-3H1 ] -19-(3-azidophenyl)-20-norisocarbacyclin ( [ 3H ] APNIC ) used as a potential photoaffinity probe for the receptor . [3H]APNIC bound to the mastocytoma membrane with high affinity and in a saturable manner . Scatchard plot analysis indicated a single binding site with a Kd of 4.7 nM and a Bmax of 0.58 pmol/mg protein . The binding of [3H]APNIC was dose dependently inhibited by APNIC and iloprost , another stable DB01240 agonist , and to a much lesser extent by DB00917 . The binding of the radioligand showed sensitivity to the guanine nucleotide guanosine 5'-O-(3-thio-triphosphate) ( GTP gamma S ) . Photolysis of [3H]APNIC-prelabeled membranes resulted in incorporation of radiolabel into a protein of approximately 43 kDa . Photolabeling was inhibited by DB01240 agonists and other prostaglandins with specificity for the P43119 and was modulated by GTP gamma S . A protein of approximately 45 kDa was also labeled by [3H]APNIC in the membrane of porcine platelets , membranes that are known to be abundant in DB01240 receptors . These results demonstrate that [3H]APNIC specifically labels a protein that may represent the P43119 and that this radioprobe will be a useful reagent for further characterization and purification of the P43119 . Adenoviral expression of vascular endothelial growth factor-C induces lymphangiogenesis in the skin . The growth of blood and lymphatic vasculature is mediated in part by secreted polypeptides of the vascular endothelial growth factor ( P15692 ) family . The prototype P15692 binds P15692 receptor ( VEGFR ) -1 and P35968 and is angiogenic , whereas P49767 , which binds to P35968 and P35916 , is either angiogenic or lymphangiogenic in different assays . We used an adenoviral gene transfer approach to compare the effects of these growth factors in adult mice . Recombinant adenoviruses encoding human P49767 or P15692 were injected subcutaneously into C57Bl6 mice or into the ears of nude mice . Immunohistochemical analysis showed that P49767 upregulated P35968 and P35916 expression and P15692 upregulated P35968 expression at 4 days after injection . After 2 weeks , histochemical and immunohistochemical analysis , including staining for the lymphatic vessel endothelial hyaluronan receptor-1 ( Q9Y5Y7 ) , the vascular endothelial marker platelet-endothelial cell adhesion molecule-1 ( P16284 ) , and the proliferating cell nuclear antigen ( P12004 ) revealed that P49767 induced mainly lymphangiogenesis in contrast to P15692 , which induced only angiogenesis . These results have significant implications in the planning of gene therapy using these growth factors . Specific components of prostanoid-signaling pathways are present in non-small cell lung cancer cells . In the present study , we measured prostanoid synthesis and the expression of genes associated with prostanoid signaling in human non-small cell lung carcinoma ( NSCLC ) cell lines and in primary human tumors . Consistent with the proposed growth promoting role of DB00917 , we found that NSCLC cell lines frequently co-expressed the genes encoding cyclooxygenase-2 and the prostaglandin E2 ( DB00917 ) receptors EP1 , 2 and 4 concomitant with the synthesis of DB00917 . In contrast , NSCLC cells did not synthesize appreciable amounts of prostaglandin I2 ( DB01240 , prostacyclin ) , lacked DB01240 synthase ( PGIS ) and did not express the gene coding for the P43119 IP at detectable levels . In agreement with this finding , PGIS mRNA levels were dramatically diminished in primary human tumor samples as compared to matched normal lung tissue . Finally , thromboxane A2 ( TxA2 ) was synthesized in NSCLC cell lines , but transcription of the gene coding for the TxA2 receptor TP was not observed in these cells . In marked contrast , lung fibroblasts synthesized all three prostanoids and their receptors at high levels . While the observed expression patterns were consistent with the existence of autocrine/paracrine DB00917 signaling loops in NSCLC cells , DB01240 - and TxA2-mediated signals may play a role in tumor stroma cells . Ca2+-calmodulin and janus kinase 2 are required for activation of sodium-proton exchange by the Gi-coupled 5-hydroxytryptamine 1a receptor . The type 1 sodium-proton exchanger ( P19634 ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 remain incompletely defined . In this work , we present evidence that stimulation of the 5-hydroxytryptamine 1A ( P08908 ) receptor results in the formation of a signaling complex that includes activated O60674 ( Jak2 ) , Ca2+/calmodulin ( P62158 ) , and P19634 , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist-induced association of P62158 and P19634 as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 is activated through this pathway : P08908 receptor --> G(i2)alpha and/or G(i3)alpha --> Jak2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 --> induction of a conformational change in P19634 that unmasks an obscured proton-sensing and/or proton-transporting region of P19634 --> activation of P19634 . The G(i/o)-coupled P08908 receptor now joins a handful of Gq-coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2+ . We have also shown for the first time that the association of P62158 with P19634 in living cells is a dynamic process . Involvement of 5-HT₇ receptors in vortioxetine 's modulation of circadian rhythms and episodic memory in rodents . Since poor circadian synchrony and cognitive dysfunction have been linked to affective disorders , antidepressants that target key 5-HT ( serotonin ) receptor subtypes involved in circadian rhythm and cognitive regulation may have therapeutic utility . DB09068 is a multimodal antidepressant that inhibits P28221 , 5- Q9H205 , P34969 receptor activity , 5-HT reuptake , and enhances the activity of P08908 and P28222 receptors . In this study , we investigated the effects of vortioxetine on the period length of O15055 ::LUC expression , circadian behavior , and episodic memory , using tissue explants from genetically modified O15055 ::LUC mice , locomotor activity rhythm monitoring , and the object recognition test , respectively . Incubation of tissue explants from the suprachiasmatic nucleus of O15055 ::LUC mice with 0.1 μM vortioxetine increased the period length of O15055 bioluminescence . Monitoring of daily wheel-running activity of Sprague-Dawley rats treated with vortioxetine ( 10 mg/kg , s.c. ) , alone or in combination with the P08908 receptor agonist flesinoxan ( 2.5 mg/kg , s.c. ) or the P34969 receptor antagonist SB269970 ( 30 mg/kg , s.c. ) , just prior to activity onset revealed significant delays in wheel-running behavior . The increase in circadian period length and the phase delay produced by vortioxetine were abolished in the presence of the P34969 receptor partial agonist AS19 . Finally , in the object recognition test , vortioxetine ( 10 mg/kg , i.p. ) increased the time spent exploring the novel object during the retention test and this effect was prevented by AS19 ( 5 mg/kg , i.p. ) . In conclusion , the present study shows that vortioxetine , partly via its P34969 receptor antagonism , induced a significant effect on circadian rhythm and presented promnesic properties in rodents . P35367 antagonist cetirizine impairs working memory processing speed , but not episodic memory . BACKGROUND AND PURPOSE : The histaminergic neurotransmitter system is currently under investigation as a target for drug treatment of cognitive deficits in clinical disorders . The therapeutic potential of new drugs may initially be screened using a model of histaminergic dysfunction , for example , as associated with the use of centrally active antihistamines . Of the selective second generation antihistamines , cetirizine has been found to have central nervous system effects . The aim of the present study was to determine whether cetirizine can be used as a tool to model cognitive deficits associated with histaminergic hypofunction . EXPERIMENTAL APPROACH : The study was conducted according to a three-way , double-blind , cross-over design . Treatments were single oral doses of cetirizine 10 and 20 mg and placebo . Effects on cognition were assessed using tests of word learning , memory scanning , vigilance , divided attention , tracking and visual information processing speed . KEY RESULTS : DB00341 10 mg impaired tracking performance and both doses impaired memory scanning speed . None of the other measures indicated impaired performance . CONCLUSION AND IMPLICATIONS : DB00341 affects information processing speed , but these effects were not sufficient to serve as a model for cognitive deficits in clinical disorders . Effects of two Asian sand dusts transported from the dust source regions of Inner Mongolia and northeast China on murine lung eosinophilia . The quality and quantity of toxic materials adsorbed onto Asian sand dust ( P51689 ) are different based on dust source regions and passage routes . The aggravating effects of two ASDs ( ASD1 and ASD2 ) transported from the source regions of Inner Mongolia and northeast China on lung eosinophilia were compared to clarify the role of toxic materials in P51689 . The ASDs contained different amounts of lipopolysaccharides ( LPS ) and β-glucan ( ASD1 < ASD2 ) and SiO2 ( ASD1 > ASD2 ) . CD-1 mice were instilled intratracheally with ASD1 , ASD2 and/or ovalbumin ( OVA ) four times at 2-week intervals . ASD1 and ASD2 enhanced eosinophil recruitment induced by OVA in the submucosa of the airway , with goblet cell proliferation in the bronchial epithelium . ASD1 and ASD2 synergistically increased OVA-induced eosinophil-relevant cytokines interleukin-5 ( P05113 ) , P35225 ( ASD1 < ASD2 ) and chemokine eotaxin ( ASD1 > ASD2 ) in bronchoalveolar lavage fluid . ASD2 aggravating effects on lung eosinophilia were greater than ASD1 . The role of LPS and β-glucan in ASD2 on the production of pro-inflammatory mediators was assessed using in vitro bone marrow-derived macrophages ( BMDMs ) from wild type , O60603 -deficient ( O60603 -/- ) , O00206 -/- , and MyD88-/- mice ( on Balb/c background ) . ASD2-stimulated O60603 -/- BMDMs enhanced P05231 , IL-12 , P01375 -α , P13500 and MIP-1α secretion compared with ASD2-stimulated O00206 -/- BMDMs . Protein expression from ASD2-stimulated MyD88-/- BMDM were very low or undetectable . The in vitro results indicate that lung eosinophilia caused by P51689 is O00206 dependent . Therefore , the aggravation of OVA-related lung eosinophilia by P51689 may be dependent on toxic substances derived from microbes , such as LPS , rather than SiO2 . P43119 signaling and early embryo development in the mouse . BACKGROUND : DB01240 ( P06744 (2) ) plays an important role in mouse embryo development and implantation . However , it is unclear whether its action is mediated via the I prostaglandin receptor ( IP ) . METHODS : We compared the preimplantation development of IP deleted ( IP-/- ) embryos and wild-type ( WT ) embryos . We also evaluated the effect of iloprost , a stable P06744 (2) analog , and L-165041 , a peroxisome proliferator activated receptor delta ( PPARdelta ) ligand , on IP-/- versus WT embryos . Finally , we compared the development of heterozygous IP deficient embryos carrying a normal maternal IP allele versus paternal IP allele . RESULTS : Development of IP-/- embryos lagged behind WT embryos and was not enhanced by either the P06744 (2) analog or the PPARdelta ligand . WT embryos had slightly higher , although statistically not significant , implantation rates than IP-/- embryos . Heterozygous IP deficient embryos carrying a normal maternal IP allele showed better development and responded to the P06744 (2) analog , unlike those carrying the normal paternal IP allele . CONCLUSIONS : IP receptors play an important role in preimplantation embryo development and mediate the embryo 's response to exogenous P06744 (2) . Early embryo development depends on the oocyte IP receptor . Enhancement of the P11362 signaling in the P11362 - P08908 heteroreceptor complex in midbrain raphe 5-HT neuron systems . Relevance for neuroplasticity and depression . New findings show existence of P11362 - P08908 heteroreceptor complexes in 5-HT nerve cells of the dorsal and median raphe nuclei of the rat midbrain and hippocampus . Synergistic receptor-receptor interactions in these receptor complexes indicated their enhancing role in hippocampal plasticity . The existence of P11362 - P08908 heteroreceptor complexes also in midbrain raphe 5-HT nerve cells open up the possibility that antidepressant drugs by increasing extracellular 5-HT levels can cause an activation of the P09038 / P11362 mechanism in these nerve cells as well . Therefore , the agonist modulation of the P11362 - P08908 heteroreceptor complexes and their specific role is now determined in rat medullary raphe RN33B cells and in the caudal midline raphe area of the midbrain rich in 5-HT nerve cells . The combined i.c.v. treatment with P09038 and the P08908 agonist 8-OHDPAT synergistically increased P11362 and P27361 /2 phosphorylation in the raphe midline area of the midbrain and in the RN33B cells . Cotreatment with P09038 and the P08908 agonist induced RN33B cell differentiation as seen from development of an increased number and length of extensions per cell and their increased 5-HT immunoreactivity . These signaling and differentiation events were dependent on the receptor interface since they were blocked by incubation with TMV but not by TMII of the P08908 receptor . Taken together , the P08908 autoreceptors by being part of a P11362 - P08908 heteroreceptor complex in the midbrain raphe 5-HT nerve cells appears to have also a trophic role in the central 5-HT neuron systems besides playing a key role in reducing the firing of these neurons . Non-prostanoid prostacyclin mimetics . 6 . Derivatives of 2-[3-[2-(4,5-Diphenyl-2-oxazolyl)ethyl]phenoxy]acetic acid modified beta-to the oxazole ring . 2-[3-[2-(4,5-Diphenyl-2-oxazolyl)ethyl]phenoxy]acetic acid , 1 , has been described as a non-prostanoid DB01240 mimetic that demonstrates anti-thrombotic properties of long duration in animal models of thrombosis . The effects of substitution and modification of the carbon beta-to the oxazole heterocycle of 1 were examined and equated with the potency of the compounds as inhibitors of ADP-induced human platelet aggregation in vitro . Potency was sensitive to both the size of the substituent and the identity of the beta-atom . The carbamates 13c-e demonstrated IC50 's of 0.28-0.36 microM and were significantly more potent than the progenitor 1 , IC50 = 1.2 microM . The ethyl carbamate 13c displaced [ 3H ] -iloprost from platelet membranes in a concentration-dependent fashion that was half maximal at 20 nM , which compares with IC50 's of 171 nM for 1 and 39 nM or unlabelled iloprost . Carbamate 13c stimulated platelet adenylate cyclase but the maximal effect was less than that observed for DB01240 , identifying 13c as a partial agonist at the platelet P43119 .