interacts_with DB00159?
DB00159 modulates DB00091 -induced proinflammatory cytokine over-expression in osteoblastic cells in vitro . Several adverse outcomes are reported in subjects undergoing long term DB00091 ( DB00091 ) treatment . Severe osteopenia has been described in clinical and experimental reports , while beneficial effects of n-3 polyunsaturated fatty acids ( PUFAs ) on bone metabolism are recognized . In the present study we investigated the effects of n-3 versus n-6 PUFAs on osteoblastic cells treated with DB00091 , evaluating the expression of interleukin ( IL ) -1 & #223 ; , interleukin-6 ( P05231 ) , inducible nitric oxide synthase ( P35228 ) , and cyclooxygenase-2 ( P35354 ) in two different experimental protocols and the production of P05231 , IL-1 & #223 ; , and tumor necrosis factor alpha ( TNFalpha ) in cells challenged simultaneously with DB00091 and eicosapentaenoic acid ( EPA ) for 48h . IL-1 & #223 ; and P05231 up-regulation , induced by DB00091 , was counteracted by the addition of EPA in both protocols ; on the contrary , arachidonic acid ( AA ) magnified DB00091 the effects . P35354 and P35228 levels were not modified by DB00091 treatment . These in vitro results , that substantiate clinical reports of DB00091 -induced osteopenia , demonstrate a beneficial effect of EPA on DB00091 -altered cytokine profile , opening new perspectives in the non-pharmacological management of adverse outcomes in DB00091 -treated patients . Omega-3 polyunsaturated fatty acids and inflammatory processes : nutrition or pharmacology ? DB00159 ( EPA ) and docosahexaenoic acid ( DB01708 ) are n-3 fatty acids found in oily fish and fish oil supplements . These fatty acids are able to inhibit partly a number of aspects of inflammation including leucocyte chemotaxis , adhesion molecule expression and leucocyte-endothelial adhesive interactions , production of eicosanoids like prostaglandins and leukotrienes from the n-6 fatty acid arachidonic acid , production of inflammatory cytokines and T cell reactivity . In parallel , EPA gives rise to eicosanoids that often have lower biological potency than those produced from arachidonioc acid and EPA and DB01708 give rise to anti-inflammatory and inflammation resolving resolvins and protectins . Mechanisms underlying the anti-inflammatory actions of n-3 fatty acids include altered cell membrane phospholipid fatty acid composition , disruption of lipid rafts , inhibition of activation of the pro-inflammatory transcription factor nuclear factor kappa B so reducing expression of inflammatory genes , activation of the anti-inflammatory transcription factor P37231 ( i.e. peroxisome proliferator activated receptor γ ) and binding to the G protein coupled receptor Q5NUL3 . These mechanisms are interlinked . In adult humans , an EPA plus DB01708 intake greater than 2 g day⁻¹ seems to be required to elicit anti-inflammatory actions , but few dose finding studies have been performed . Animal models demonstrate benefit from n-3 fatty acids in rheumatoid arthritis ( RA ) , inflammatory bowel disease ( Q9UKU7 ) and asthma . Clinical trials of fish oil in patients with RA demonstrate benefit supported by meta-analyses of the data . Clinical trails of fish oil in patients with Q9UKU7 and asthma are inconsistent with no overall clear evidence of efficacy . The role of celecoxib in Rad51 expression and cell survival affected by gefitinib in human non-small cell lung cancer cells . Celecoxib ( DB00482 ) is a cyclooxygenase-2 ( P35354 ) selective inhibitor and gefitinib ( DB00317 (R) , ZD1839 ) is a selective epidermal growth factor receptor ( P00533 ) tyrosine kinase inhibitor for human non-small cell lung cancer ( NSCLC ) . The addition of celecoxib to gefitinib to prolong the survival of patients with NSCLC still remains controversial and needs to be investigated . The Rad51 protein is essential for homologous recombination repair , and is overexpressed in chemo- or radioresistant carcinomas . In this study , we characterize the role of celecoxib in the cytotoxicity , P27361 /2 activation and Rad51 expression affected by gefitinib in NSCLC cells . We show that celecoxib can enhance the cytotoxicity induced by gefitinib in NSCLC cells . Treatment with celecoxib alone has no effect on the P27361 /2 activation , Rad51 mRNA and protein levels , however , combined treatment with gefitinib results in a significant reduction of phospho- P27361 /2 and Rad51 protein levels , and triggers the degradation of Rad51 via a 26S proteasome-dependent pathway . Expression of constitutively active Q02750 /2 vectors ( Q02750 /2-CA ) significantly rescues the decreased P27361 /2 activity , and restores Rad51 protein levels and cell survival under co-treatment with gefitinib and celecoxib . Furthermore , blocking P27361 /2 activation by U0126 ( Q02750 /2 inhibitor ) and knocking down Rad51 expression by transfection with small interfering RNA of Rad51 can enhance the cytotoxicity of celecoxib . 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 . [ Measurement of rifampicin and clarithromycin in serum by high-performance liquid chromatography with electrochemical detection ] . DB01045 ( RFP ) induces hepatic drug-metabolizing enzymes , making drug interactions a very important clinical problem . DB01211 ( P62158 ) metabolism is reportedly enhanced by induction of hepatic drug-metabolizing enzymes ( P08684 ) by RFP , so that the blood lend of P62158 decreases when RFP is administered concurrently . We connected an electrochemical detector to a high-performance liquid chromatograph ( HPLC ) for simple , rapid , easy measurement of blood concentrations of RFP and P62158 . Using samples of patient serum , normal serum , and reference standards , we compared HPLC by an external laboratory and the results of LC/MS/MS analysis with those of this new assay . A strong correlation was seen between our HPLC results and those of the external laboratory in RFP levels ( r=0.975 , p < 0.01 ) . A strong correlation was also seen between results we obtained for P62158 with the electrochemical detector in this assay and values measured by LC/MS/MS analysis ( r=0.995 , p < 0.01 ) . Our method enabled simple , rapid measurement of RFP and P62158 by connecting the HPLC and electrochemical detector in tandem . This system was used to modulate dosage during combined therapy with RFP and P62158 . The therapeutic effect for nontuberculous mycobacteriosis is expected to improve , and our HPLC is expected to be useful for simple , rapid , easy measurement of blood concentrations . Akt-dependent heme oxygenase-1 induction by NS-398 in P13671 glial cells : a potential role for CO in prevention of oxidative damage from hypoxia . We investigated whether increased heme oxygenase ( HO ) -1 activity by NS-398 is responsible for protection against hypoxia-induced damage in P13671 cells . The expression of P09601 was analyzed by Western blot and cell viability was analyzed by lactate dehydroxygease ( LDH ) activity . NS-398 increased P09601 expression in a concentration- and time-dependent manner during both normoxia and hypoxia ( 95 % N(2)/5 % CO(2) ) , but the latter was much more sensitive . Because induction of P09601 occurred due to hypoxia itself , NS-398 seemed to potentiate the expression of P09601 . The reduced cell viability due to hypoxia was significantly reversed by either NS-398 or [Ru(CO)(3)(Cl)(2)](2) , a CO-donor . Zinc protophorphrin ( ZnPPIX ) , a P09601 inhibitor , inhibited the protective effect of NS-398 against hypoxia . Treatment with glucose oxidase ( Q9UJM8 , 20 mU/ml ) increased ROS production and caused apoptotic death , as assayed by DCFH-DA and TUNEL , respectively . NS-398 significantly reduced Q9UJM8 -induced cell death and ROS production ; these effects were reversed by pre-treatment with oxyhemoglobin ( HbO(2) ) , a CO/NO scavenger , or ZnPPIX . Finally , NS-398 increased P37231 luciferase activity in transiently P37231 transfected P13671 cells , which was antagonized by ZnPPIX . NS-398 increased phosphorylation of Akt , and LY-294002 , a specific PI(3) kinase inhibitor , inhibited NS-398-induced P09601 expression . Taken together , we conclude that therapeutic use of NS-398 in the treatment of oxidative stress-oriented neuronal disorders would be beneficial through dual actions : P09601 induction and P35354 inhibition . Potential effects of peroxisome proliferator-activated receptor activator on LPS-induced lung injury in rats . Multiple factors contribute to the pathogenesis and prognosis of chronic obstructive pulmonary disease( P48444 ) , still requiring new therapeutic strategies and medications for the disease . The aim of the present study is to investigate the model of lipopolysaccharide ( LPS ) -induced chronic lung injury and hyperinflation and test therapeutic effects of peroxisome proliferator-activated receptor ( Q07869 ) -gamma agonist . Wister rats were challenged with intra-tracheal instillation of LPS at concentrations of 0.006 , 0.060 , 0.600 , and 6.000 mg/ml per kg , twice a week , for 1 , 2 , 4 and 6 weeks . Q07869 activator , 15-deoxy-Delta12,14-prostaglandin J2 ( 15D-PGJ2 ) , or vehicle ( PBS ) was administered orally and daily at the dose of 1 and 10 mg/ml per kg in animals challenged with LPS or PBS at the dose of 0.060 mg/ml per kg body weight twice a week for 4 weeks . We found that intra-tracheal exposure of LPS resulted in a dose-dependent pattern of chronic lung hyperinflation and hypertrophy , increased alveolar enlargement , reduced vascular endothelial growth factor ( P15692 ) and elevated tissue inhibitor of metalloproteinases ( P01033 ) -1 levels in bronchoalveolar lavage ( BAL ) fluid , and early changes of leukocyte influx and interferon ( IFN ) -gamma levels in bronchoalveolar lavage ( BAL ) fluid . P37231 agonist ameliorated these changes related with the dose used.LPS-induced lung disease model shows some similarities with human disease , and P37231 agonist maybe an alternative for P48444 therapy . Signaling pathways mediating induction of the early response genes prostaglandin G/H synthase-2 and egr-1 by serotonin via 5- Q13049 receptors . Signaling pathways responsible for serotonin ( 5-HT ) -mediated induction of early response genes prostaglandin G/H synthase-2 ( P35354 , cyclooxygenase-2 ) and egr-1 were investigated in rat mesangial cells . Gene induction by 5-HT was dependent on 5- Q13049 receptors that were pertussis toxin insensitive indicating coupling to a G-protein of the Gq family . Binding of 5-HT to this receptor activates phosphatidylinositol-specific phospholipase C ( P98160 ) and release of Ca2+ from internal stores , but this activation was not related to P35354 mRNA expression . Similarly , P19957 kinase was not involved in 5-HT signaling . Instead , inhibition of phosphatidylcholine-specific P98160 interfered with P35354 and egr-1 mRNA induction , suggesting this enzyme as a link between 5- Q13049 receptors and protein kinase C , an essential part of 5-HT-mediated signaling . The Q96HU1 kinase pathway was identified as common signaling pathway of 5-HT or phorbol ester-induced gene expression . Increase of intracellular DB02527 by forskolin or dibutyryl DB02527 did not induce P35354 or egr-1 mRNA expression by itself , but strongly inhibited 5-HT-mediated mRNA induction . P35354 mRNA and protein induction by 5-HT was also abolished by chelation of Ca2+ ions by EGTA , suggesting involvement of Ca2+-dependent enzymes . In contrast , egr-1 mRNA expression was superinduced in the presence of EGTA . Induction of Egr-1 protein was not changed by EGTA hinting to Ca2+-sensitive posttranscriptional steps . Activation of the Gq-coupled 5- Q13049 receptor thus leads to the expression of the early response genes P35354 and egr-1 , using common as well as differing signaling elements that allow differential regulation of the expression of these genes that are functionally related to renal hemodynamics and proliferation of mesangial cells , respectively . 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 . 8-OH-DPAT ( P08908 agonist ) Attenuates 6-Hydroxy- dopamine-induced catalepsy and Modulates Inflammatory Cytokines in Rats . OBJECTIVE(S) : Neuroinflammation in Parkinson disease ( PD ) is associated with glial cells activation and production of different inflammatory cytokines . In this study , we investigated the effect of chronic administration of 8-OH-DPAT on 6-OHDA-induced catalepsy and levels of inflammatory cytokines in cerebrospinal fluid ( P04141 ) . MATERIALS AND METHODS : Catalepsy was induced by unilateral infusion of 6-OHDA ( 8 μg/2 μl/rat ) into the central region of the sabstantia nigra pars compacta ( SNc ) being assessed by the bar-test , 5 , 60 , 120 and 180 min after intraperitoneal ( IP ) administration of 8-OH-DPAT ( P08908 receptor agonist ; 0.25 , 0.5 and 1mg/kg , IP for 10 days ) . P04141 samples were collected on the tenth day of 8-OH-DPAT administration and analyzed by ELISA method to measure levels of P01375 -α , IL-1β and P05231 . RESULTS : Chronic injection of 8-OH-DPAT decreased catalepsy in a dose dependent manner when compared with the control group . The most anti-cataleptic effect was observed at the dose of 1 mg/kg of 8-OH-DPAT . Levels of P01375 -α in P04141 increased three weeks after 6-OHDA injection while there was a significant decrease in P01375 -α level of parkinsonian animals treated with 8-OH-DPAT ( 1 mg/kg , IP for 10 days ) . IL-1β and P05231 decreased and increased in parkinsonian rats and in 8-OH-DPAT-treated parkinsonian rats , respectively . CONCLUSION : Our study indicated that chronic administration of 8-OH-DPAT improves catalepsy in 6-OHDA-induced animal model of PD and restores central concentration of inflammatory cytokines to the basal levels . P08908 receptor agonists can be suggested as potential adjuvant therapy in PD by modulation of cerebral inflammatory cytokines . Mobilization of Ph chromosome-negative peripheral blood stem cells in chronic myeloid leukaemia patients with imatinib mesylate-induced complete cytogenetic remission . Imatinib mesylate ( IM , DB00619 , Glivec ) can induce a high rate of complete cytogenetic response ( CCR ) in chronic myeloid leukaemia ( CML ) patients , although to date the majority of patients continue to have detectable disease by sensitive reverse transcription polymerase chain reaction ( RT-PCR ) . It is therefore possible that these patients may ultimately relapse and require treatment such as autologous peripheral blood stem cell transplant ( APBSCT ) . We attempted mobilization of haemopoietic progenitor cells from 58 patients in CCR using recombinant human granulocyte colony-stimulating factor [ rHu- DB00099 ; 10 micro g/kg/d subcutaneously ( s.c. ) for at least 4 d ] alone , while continuing IM treatment . The median d 5 ( peak ) P28906 + count was 11.5/ microl ( range 0-108/ microl ) , and 43/58 ( 74 % ) patients underwent a median of two ( range 1-3 ) apheresis procedures . A median dose of 2.1 x 10(6)/kg P28906 + cells ( range 0.1-6.5 x 10(6)/kg ) was collected . Some 84 % of 31 collections analysed were negative for the Philadelphia ( Ph ) chromosome or breakpoint cluster region and Abelson murine leukaemia viral oncogene homologue ( P11274 - P00519 ) translocation by cytogenetics or fluorescent in situ hybridization respectively . No toxicity was reported with the regimen . Overall , the target P28906 + dose ( 2 x 10(6)/kg P28906 + ) was attained in 23/58 ( 40 % ) patients who entered the study . In summary , we have demonstrated that successful mobilization of Ph- P28906 + cells from IM-treated patients in CCR is possible using rHu-G- P04141 alone . Establishment of a double Philadelphia chromosome-positive acute lymphoblastic leukemia-derived cell line , TMD5 : effects of cytokines and differentiation inducers on growth of the cells . A double Philadelphia chromosome ( Ph ) -positive leukemia cell line with common-B cell phenotype , designated TMD5 , was established from the blast cells of a patient with double Ph-positive acute lymphoblastic leukemia . TMD5 cells expressed 190 kDa P11274 / P00519 chimeric protein and 145 kDa P00519 protein . The cells proliferated without added growth factors . Autocrine growth mechanism was not recognized . The addition of growth factors such as DB00099 , GM- P04141 , P08700 , P05231 , or Stem Cell Factor did not affect the growth . Herbimycin A suppressed the growth of TMD5 cells at the low concentration that did not affect Ph-negative cells . It suppressed tyrosine phosphorylation of intracellular proteins in TMD5 cells . Dexamethasone and dibutyryl cyclic AMP also suppressed the growth . They , however , did not affect the phosphorylation significantly . Neither all-trans retinoic acid nor interferon-alpha affected the growth . TMD5 cells , characterized minutely here and rare in that they have double Ph chromosomes , will be a useful tool for the study of Ph-positive leukemia . Increase in proinflammatory cytokines in peripheral blood without haemostatic changes after LPS inhalation . INTRODUCTION : Bronchoalveolar fibrin deposition is a characteristic of various lung disorders including acute lung injury , acute respiratory distress syndrome and sepsis . It is secondary to the activation of coagulation and inhibition of fibrinolysis in the alveolar space , and can be stimulated by lipopolysaccharide ( LPS ) inhalation . The aim of this study was to determine the relation between compartmental stress in the lung and systemic response after LPS inhalation by measuring haemostatic parameters . PATIENTS AND METHODS : 12 healthy subjects underwent a bronchial challenge test with LPS ; sequential dosages were performed for 5 biological markers ( P05231 ( P05231 ) , C-Reactive Protein ( CRP ) , P00734 Fragments 1 and 2 ( F 1+2 ) , cortisol and P00747 Activator Inhibitor 1 ( P05121 ) before endotoxin inhalation and 2 , 4 , 6 , 8 and 24 hours afterwards . RESULTS : P05231 and CRP levels in the peripheral blood were higher after LPS inhalation ; there was no activation of coagulation and no increase in P05121 level . CONCLUSION : This study confirms that despite systemic release of proinflammatory cytokines , LPS inhalation does not induce systemic haemostatic response to LPS challenge . [ Effects of plasminogen and streptokinase on the vital functions of nervous tissue cells in culture ] . In the protein-deficient media plasminogen stimulated the vital functions of cells and in concentrations 10(-7)-10(-10) M it protected cells of sympathetic ganglia , neocortex and continues cell lines under damaging actions of H2O2 ( 0.0001 M ) , NH4CI ( 0.01 M ) and cooling . DB00086 essentially influenced the mode of damaging effect of DB00171 ( 0.001 M ) . Even a short-term exposition ( 20 min ) of PC12 cells with both proteins ( each in the concentration 10(-9) M ) led to sharp alterations in intracellular DB00171 - or Ca(2+)-activated proteolysis . In some cases plasminogen and streptokinase provided acceleration of cultured tissue maturation , improvement of cell adhesion , high survival rate , the increase in quantity and length of processes and their arborisation . Electronic microscopy established the character of structural rearrangements of nervous tissue cells ( neurons , astrocytes , oligodendrocytes ) , reflecting the protective action of plasminogen and streptokinase . In the presence of plasminogen and especially streptokinase , the total number of cultured glioma P13671 and neuroblastoma IMR-32 cells , the intracellular contents of protein , RNA and DNA increased several-fold . Addition of plasminogen promoted formation of processes by neuroblastoma cells , this suggests initiation of differentiation of cellular elements . In cultures of sensitive and sympathetic ganglia streptokinase increased proliferation of Schwann cells . These proteins did not cause transformation of PC12 enterochromaffine cells to neurons , though plasminogen facilitated it . P00747 addition to cell cultures did not increase fibrinolytic activity of the culture medium in the culture medium , and streptokinase did not lose its plasminogen-activating capacity . ω-3 fatty acid eicosapentaenoic acid attenuates P25189 +-induced neurodegeneration in fully differentiated human SH-SY5Y and primary mesencephalic cells . DB00159 ( EPA ) , a neuroactive omega-3 fatty acid , has been demonstrated to exert neuroprotective effects in experimental models of Parkinson 's disease ( PD ) , but the cellular mechanisms of protection are unknown . Here , we studied the effects of EPA in fully differentiated human SH-SY5Y cells and primary mesencephalic neurons treated with P25189 (+) . In both in-vitro models of PD , EPA attenuated an P25189 (+) -induced reduction in cell viability . EPA also prevented the presence of electron-dense cytoplasmic inclusions in SH-SY5Y cells . Then , possible mechanisms of the neuroprotection were studied . In primary neurons , EPA attenuated an P25189 (+) -induced increase in Tyrosine-related kinase B ( TrkB ) receptors . In SH-SY5Y cells , EPA down-regulated reactive oxygen species and nitric oxide . This antioxidant effect of EPA may have been mediated by its inhibition of neuronal NADPH oxidase and cyclo-oxygenase-2 ( P35354 ) , as P25189 (+) increased the expression of these enzymes . Furthermore , EPA prevented an increase in cytosolic phospholipase A2 ( P47712 ) , an enzyme linked with P35354 in the potentially pro-inflammatory arachidonic acid cascade . Lastly , EPA attenuated an increase in the bax:bcl-2 ratio , and cytochrome c release . However , EPA did not prevent mitochondrial enlargement or a decrease in mitochondrial membrane potential . This study demonstrated cellular mechanisms by which EPA provided neuroprotective effects in experimental PD . Augmentation by citalopram of risperidone-induced monoamine release in rat prefrontal cortex . RATIONALE : A typical antipsychotics ( APDs ) , e.g. olanzapine and risperidone , have been reported to be effective adjunctive treatment for depression if selective serotonin ( 5-HT ) reuptake inhibitors ( SSRIs ) alone are ineffective . OBJECTIVES AND METHODS : We utilized microdialysis in awake , freely moving rats to study the effect of risperidone in combination with citalopram , an SSRI , on extracellular 5-HT , dopamine ( DA ) , and norepinephrine ( NE ) efflux in rat medial prefrontal cortex ( mPFC ) . RESULTS : DB00734 ( 1.0 mg/kg , s.c. ) , given alone , significantly increased 5-HT , DA , and NE concentrations in the mPFC . DB00215 ( 10 mg/kg , s.c. ) , by itself , produced a significant increase in 5-HT levels only . The combination of risperidone and citalopram produced significantly greater increases in efflux of both DA and NE than risperidone alone . However , the effect of this combination on extracellular 5-HT concentrations was not significantly different than that of citalopram alone . The augmentation of DA and NE efflux induced by risperidone plus citalopram could be partially blocked by the selective P08908 antagonist , WAY 100635 ( 0.2 mg/kg , s.c. ) . CONCLUSIONS : The results suggest that the ability of atypical APDs to augment the therapeutic efficacy of SSRIs in major depression and treatment-resistant depression may be due , at least in part , to potentiation of SSRI-induced increases in cortical DA and NE . The contributions of P08908 receptor stimulation and 5- Q13049 and alpha2 adrenergic receptor antagonism to this augmentation are discussed . 2(3H)-benzoxazolone and bioisosters as " privileged scaffold " in the design of pharmacological probes . The 2(3H)-benzoxazolone heterocycle and its bioisosteric surrogates ( such as 2(3H)-benzothiazolinone , benzoxazinone , etc. ) have received considerable attention from the medicinal chemists owing to their capacity to mimic a phenol or a catechol moiety in a metabolically stable template . These heterocycles and pyrocatechol have indeed similar pKa 's , electronic charge distribution , and chemical reactivity . Therapeutic applications of this template are very broad , and range from analgesic anti-inflammatory compounds ( including P37231 antagonists ) to antipsychotic and neuroprotective anticonvulsant compounds . High affinity ligands have been obtained also for dopaminergic ( D2 and D4 ) , serotoninergic ( P08908 and P28223 ) , sigma-1 and sigma-2 receptors . Owing to the high number of positive hits encountered with this heterocycle and its congeners , 2(3H)-benzoxazolone template certainly deserves the title of " privileged scaffold " in medicinal chemistry . Anti-inflammatory activity of Taraxacum officinale . Taraxacum officinale has been widely used as a folkloric medicine for the treatment of diverse diseases . The dried plant was extracted with 70 % ethanol to generate its ethanol extract ( TEE ) . For some experiments , ethyl acetate ( EA ) , n-butanol ( BuOH ) and aqueous ( Aq ) fractions were prepared in succession from TEE . TEE showed a scavenging activity in the 1,1-diphenyl-2-picrylhydrazyl ( DPPH ) assay , a diminishing effect on intracellular reactive oxygen species ( ROS ) level , and an anti-angiogenic activity in the chicken chorioallantoic ( P62158 ) assay . In the carrageenan-induced air pouch model , TEE inhibited production of exudate , and significantly diminished nitric oxide ( NO ) and leukocyte levels in the exudate . It also possessed an inhibitory effect on acetic acid-induced vascular permeability and caused a dose-dependent inhibition on acetic acid-induced abdominal writhing in mice . Suppressive effects of TEE on the production of NO and expression of inducible nitric oxide synthase ( P35228 ) and cyclooxygenase-2 ( P35354 ) in lipopolysaccharide ( LPS ) -stimulated macrophages were also assessed . Among the fractions , the n-butanol fraction ( BuOH ) was identified to be most effective in the P62158 assay . Collectively , Taraxacum officinale contains anti-angiogenic , anti-inflammatory and anti-nociceptive activities through its inhibition of NO production and P35354 expression and/or its antioxidative activity . The antifibrotic effects of plasminogen activation occur via prostaglandin E2 synthesis in humans and mice . P00747 activation to plasmin protects from lung fibrosis , but the mechanism underlying this antifibrotic effect remains unclear . We found that mice lacking plasminogen activation inhibitor-1 ( P05121 ) , which are protected from bleomycin-induced pulmonary fibrosis , exhibit lung overproduction of the antifibrotic lipid mediator prostaglandin E2 ( DB00917 ) . P00747 activation upregulated DB00917 synthesis in alveolar epithelial cells , lung fibroblasts , and lung fibrocytes from saline- and bleomycin-treated mice , as well as in normal fetal and adult primary human lung fibroblasts . This response was exaggerated in cells from Pai1-/- mice . Although enhanced DB00917 formation required the generation of plasmin , it was independent of proteinase-activated receptor 1 ( P25116 ) and instead reflected proteolytic activation and release of P14210 with subsequent induction of P35354 . That the P14210 / P35354 / DB00917 axis mediates in vivo protection from fibrosis in Pai1-/- mice was demonstrated by experiments showing that a selective inhibitor of the P08581 c- DB00134 increased lung collagen to WT levels while reducing P35354 protein and DB00917 levels . Of clinical interest , fibroblasts from patients with idiopathic pulmonary fibrosis were found to be defective in their ability to induce P35354 and , therefore , unable to upregulate DB00917 synthesis in response to plasmin or P14210 . These studies demonstrate crosstalk between plasminogen activation and DB00917 generation in the lung and provide a mechanism for the well-known antifibrotic actions of the fibrinolytic pathway . Cyclooxygenase-independent inhibition of H2O2-induced cell death by S-ketoprofen in renal cells . The stress response of the distal tubule to oxidative attack may be relevant to recovery from acute renal failure . In distal tubular Madin-Darby cells ( MDCK ) , H(2)O(2) induced up-regulation of cyclooxygenases ( P23219 and P35354 ) , prostaglandin-E(2) production and caspase-independent cell death . Cell death was inhibited by S-ketoprofen , but not by the much weaker P36551 inhibitor R-ketoprofen . Interestingly , we identified 15-deoxy-Delta(12,14)-prostaglandin-J(2) ( 15d-PGJ(2) ) , a peroxisome-proliferator activated receptor-gamma agonist , as a lethal prostaglandin whose effect was reproduced by the P37231 agonist ciglitazone . Nevertheless , H(2)O(2)-induced cell death was unaffected by other non-steroidal anti-inflammatory drugs ( NSAIDs ) or all-trans-retinoic acid . Moreover , c-Jun-N-terminal kinase inhibitor SP600125 prevented 15-deoxy-Delta(12,14)-PGJ(2)-induced cell death , but not H(2)O(2)-induced cell death . P37231 antagonist GW9662 showed no affect on the cell death . These results indicated that protection by S-ketoprofen was P36551 -independent and PPARgamma independent . Moreover , the IC(50) value of the action of S-ketoprofen for the inhibition of H(2)O(2)-induced MDCK cell death ( approximately equal 140microM ) was much higher than the IC(50) value for the inhibition of P23219 and P35354 activities ( approximately equal 1microM ) . Further design of S-ketoprofen derivatives devoid of P36551 inhibitory activity will give opportunity to protect the kidney against oxidative attack while avoiding unwanted effects of NSAID . [ Signal transduction inhibitor -- STI571 -- a new treatment for chronic myeloid leukemia ( CML ) , which opens a new targeted approach to cancer therapy ] . Chronic myeloid leukemia ( CML ) , in most of the cases , is the molecular consequence of the t(9,22) translocation , resulting in the Philadelphia ( Ph ) chromosome and the creation of the fusion gene P11274 - P00519 . The fusion gene is translated to the protooncogen P11274 - P00519 , a constitutively activated tyrosine kinase that is linked to the malignant transformation . Thus , this tyrosine kinase became an attractive target for drug design . The development of the novel investigational drug DB00619 is based on its potent and selective ability to inhibit this fusion tyrosine kinase . In preclinical studies , DB00619 selectively inhibited the growth of CML cells that carry the Ph chromosome . In this review we discuss the drug development and design , its mechanism of action , the preclinical studies and the results of phase I and II clinical trials . Mutation of the calmodulin binding motif IQ of the L-type Ca(v)1.2 Ca2+ channel to EQ induces dilated cardiomyopathy and death . Cardiac excitation-contraction coupling ( EC coupling ) links the electrical excitation of the cell membrane to the mechanical contractile machinery of the heart . DB01373 channels are major players of EC coupling and are regulated by voltage and Ca(2+)/calmodulin ( P62158 ) . P62158 binds to the IQ motif located in the C terminus of the Ca(v)1.2 channel and induces Ca(2+)-dependent inactivation ( CDI ) and facilitation ( P05231 ) . Mutation of DB00167 to DB00142 ( Ile1624Glu ) in the IQ motif abolished regulation of the channel by CDI and P05231 . Here , we addressed the physiological consequences of such a mutation in the heart . Murine hearts expressing the Ca(v)1.2(I1624E) mutation were generated in adult heterozygous mice through inactivation of the floxed WT Ca(v)1.2( Q401N2 ) allele by tamoxifen-induced cardiac-specific activation of the MerCreMer Cre recombinase . Within 10 days after the first tamoxifen injection these mice developed dilated cardiomyopathy ( DCM ) accompanied by apoptosis of cardiac myocytes ( CM ) and fibrosis . In Ca(v)1.2(I1624E) hearts , the activity of phospho- P62158 kinase II and phospho-MAPK was increased . CMs expressed reduced levels of Ca(v)1.2(I1624E) channel protein and I(Ca) . The Ca(v)1.2(I1624E) channel showed " CDI " kinetics . Despite a lower sarcoplasmic reticulum Ca(2+) content , cellular contractility and global Ca(2+) transients remained unchanged because the EC coupling gain was up-regulated by an increased neuroendocrine activity . Treatment of mice with metoprolol and captopril reduced DCM in Ca(v)1.2(I1624E) hearts at day 10 . We conclude that mutation of the IQ motif to IE leads to dilated cardiomyopathy and death . Functional changes in rheumatoid fibroblast-like synovial cells through activation of peroxisome proliferator-activated receptor gamma-mediated signalling pathway . P37231 ( PPARgamma ) is a ligand dependent transcriptional factor known to be a regulator of adipogenesis . Recent studies have also shown that stimulation of PPARgamma inhibits the transcriptional activities of other nuclear factors and down-regulates proinflammatory cytokine synthesis in T cells and monocytes . We examined , in the present study , the functional significance of PPARgamma expressed in fibroblast-like synovial cells ( FLS ) isolated from patients with rheumatoid arthritis ( RA ) . Incubation of FLS with a synthetic PPARgamma ligand , troglitazone , inhibited endogenous production of P01375 , P05231 and P10145 , as well as matrix metalloprotease-3 ( P08254 ) , without inducing apoptosis of the cells . The gelatinase activity of FLS culture media was also inhibited by troglitazone . Electrophoretic mobility shift assay ( EMSA ) showed a significant reduction in the DNA binding activity of NF-kappaB in troglitazone-treated FLS in response to P01375 or IL-1beta . Moreover , long-term cultivation of FLS with troglitazone resulted in morphological changes with marked lipid accumulation in these cells . Our results show a negative regulatory function for PPARgamma on cytokine and MMP production together with inhibition of cytokine-mediated inflammatory responses in rheumatoid synovial cells . Our results also suggest that FLS could differentiate into adipocyte-like cells in the presence of proper stimulatory signals including PPARgamma . Bayesian analysis and the GUSTO trial . Global Utilization of DB00086 and Tissue P00747 Activator in Occluded Arteries . P18509 , interleukin-6 and glucocorticoids regulate the release of vascular endothelial growth factor in pituitary folliculostellate cells . There is increasing evidence that hormones play an important role in the control of endothelial cell function and growth by regulating the production of vascular endothelial growth factor ( P15692 ) . P15692 regulates vascular permeability and represents the most powerful growth factor for endothelial cells . In the normal anterior pituitary , P15692 has been detected only in folliculostellate ( FS ) cells . In the present study , the regulation of the release of P15692 from FS-like mouse TtT/GF cells , and from FS cells of rat pituitary monolayer cell cultures was investigated using a specific P15692 ELISA . Basal release of P15692 was demonstrated in cultures of both TtT/GF cells and rat pituitary cells . Interestingly , the P15692 secretion was stimulated by both forms of pituitary adenylate cyclase-activating polypeptide ( PACAP-38 and PACAP-27 ) , indicating that this hypothalamic peptide regulates endothelial cell function and growth within the pituitary . P15692 secretion was also stimulated by interleukin-6 ( P05231 ) whereas basal , P05231 - and PACAP-stimulated secretion was inhibited by the synthetic glucocorticoid dexamethasone . The inhibitory action of dexamethasone was reversed by the glucocorticoid receptor antagonist DB00834 , suggesting that in FS cells functional glucocorticoid receptors mediate the inhibitory action of glucocorticoids on the P15692 secretion . The endocrine and auto-/paracrine control of P15692 production in pituitary FS cells by PACAP , P05231 and glucocorticoids may play an important role both in angiogenesis and vascular permeability regulation within the pituitary under physiological and pathophysiological conditions . 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 . Genetic mechanism of aspirin-induced urticaria/angioedema . PURPOSE OF REVIEW : DB00945 -induced urticaria/angioedema is a major aspirin-related hypersensitivity often associated with aspirin-intolerant asthma . Genetic studies on aspirin-intolerant asthma have shown chronic overproduction of cysteinyl leukotrienes . The genetic analysis of aspirin-induced urticaria/angioedema is limited , however . RECENT FINDINGS : A recent study on HLA genotypes has suggested that the HLA alleles DRB11302 and DQB10609 may be genetic markers for aspirin-induced urticaria/angioedema . A polymorphism study that examined nine single-nucleotide polymorphisms of five leukotriene-related genes [ P09917 ( encoding P09917 ) , P20292 ( P09917 -activating protein ) , P35354 ( cyclooxygenase 2 ) , Q16873 ( leukotriene C4 synthase ) , and Q9Y271 ( cysteinyl leukotriene receptor 1 ) ] found that promoter polymorphisms of P09917 ( -1708A > G ) and Q9Y271 ( -634C > T ) were significantly different between aspirin-intolerant asthma and aspirin-induced urticaria/angioedema , suggesting different contributions to the lipoxygenase pathway . A second polymorphism study , conducted on histamine-related genes , did not find any significant associations with aspirin-induced urticaria/angioedema for the genes P50135 ( encoding histamine N-methyltransferase ) , P35367 or P25021 ( encoding histamine receptor types 1 and 2 respectively ) , or the gene encoding high-affinity IgE receptor Ibeta ( FcepsilonRIbeta ) ; however , the FcepsilonRIalpha gene promoter polymorphism was significantly associated with aspirin-induced urticaria/angioedema . This finding has been supported by in vitro functional studies . SUMMARY : The HLA alleles DRB11302 and DQB10609 , and the P09917 and FcepsilonRIalpha promoter polymorphisms , may contribute to the pathogenesis of aspirin-induced urticaria/angioedema . Further investigation to identify candidate genetic markers would help to elucidate the pathogenic mechanism of this condition . Growth factors expression in patients with erosive esophagitis . Although the pathogenesis and treatment of erosive esophagitis ( EE ) is well recognized , little is known about the cellular and molecular mechanisms of mucosal healing in EE patients . In this pilot study , we enrolled typical EE patients to evaluate what kinds of growth factors and their receptors were activated in their injured esophageal mucosa . Forty endoscopically proved EE patients were consecutively enrolled . Messenger RNA expressions , which includes keratinocyte growth factor ( KGF ) and its receptor ( P21802 ) , epidermal growth factor ( P01133 ) and its receptor ( P00533 ) , hepatocyte growth factor ( P14210 ) and its receptor ( HGFR ) , basic fibroblast growth factor ( P09038 ) , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase ( P36551 ) -1 and P35354 , were measured using real-time polymerase chain reaction ( PCR ) . Data were compared between the injured EE mucosa and their normal esophageal mucosa above EE . The mRNA expressions of P14210 , HGFR , P01133 , P15692 , and P35354 , but not P00533 , KGF , P21802 , P09038 , and P23219 , were significantly increased in the injured mucosa of EE patients compared with those of normal mucosa ( P < 0.05 ) . The study found that P14210 , HGFR , P01133 , P15692 , and , P35354 are activated in the injured mucosa of EE patients ; their activation might be involved in mucosal repair and ulcer healing of EE . Targeting other abnormal signaling pathways in sarcoma : P00533 in synovial sarcomas , P37231 in liposarcomas . 15-Deoxy-delta 12,14-prostaglandin J2 inhibits the expression of granulocyte-macrophage colony-stimulating factor in endothelial cells stimulated with lipopolysaccharide . P04141 ( GM- P04141 ) , one of major hematopoietic growth factors , activates mature leukocytes . GM- P04141 is produced by endothelial cells stimulated with lipopolysaccharide ( LPS ) , and the LPS-induced GM- P04141 production may play an important role in the activation of neutrophils on the endothelial surface . 15-Deoxy-delta 12,14-prostaglandin J2 ( 15d-PGJ2 ) is a ligand for peroxisome proliferator-activated receptor-gamma ( P37231 ) and modulates inflammatory reactions by regulating the expression of various genes . We studied the effect of 15d-PGJ2 on the LPS-induced GM- P04141 expression in endothelial cells . Human umbilical vein endothelial cells ( HUVEC ) were cultured and the expressions of GM- P04141 mRNA and protein were analyzed by reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay , respectively . 15d-PGJ2 inhibited the LPS-induced GM- P04141 expression in a concentration-dependent manner ; but ciglitazone , another agonist for P37231 , had no effect . This suggests that 15d-PGJ2 inhibits GM- P04141 expression through a mechanism unrelated to P37231 . 15d-PGJ2 induced , by itself , the expression of interleukin-8 , a potent proinflammatory chemokine , in HUVEC . 15d-PGJ2 may regulate inflammatory reactions by controlling the balance of various cytokines . Acetylbritannilactone suppresses lipopolysaccharide-induced vascular smooth muscle cell inflammatory response . To investigate the mechanism of action by which a new anti-inflammatory active compound , 1-O-acetylbritannilactone ( P00519 ) isolated from Inula britannica-F. , inhibits inflammatory responses in vascular smooth muscle cells ( VSMCs ) . Enzyme immunoassay was used to measure the levels of prostandin E(2) ( PGE(2) ) production . Immunocytochemistry staining and Western blot analysis were performed to detect the nuclear translocation of nuclear factor-kappaB ( NF-kappaB ) p65 and the expression of IkappaB-alpha , pIkappaB-alpha and cyclooxygenase-2 ( P35354 ) . Electrophoretic mobility shift assays ( EMSA ) were used to detect DNA-binding activity of NF-kappaB in VSMCs . P00519 ( 5 , 10 , 20 micrommol/l ) had several concentration-dependent effects , including inhibition of lipopolysaccharide ( LPS ) -induced PGE(2) production and P35354 expression , and blockade of NF-kappaB activation and translocation . These effects were owing to reductions in IkappaB-alpha phosphorylation and degradation induced by LPS . In addition , P00519 directly inhibited the binding of active NF-kappaB to specific DNA cis-element . These results indicate that P00519 is a potent inhibitor of LPS-stimulated VSMC inflammatory responses through blockade of NF-kappaB activity and inhibition of inflammatory gene P35354 expression . Ex vivo binding of flibanserin to serotonin P08908 and 5- Q13049 receptors . DB04908 has been reported to be an agonist at P08908 -receptors and an antagonist at 5- Q13049 receptors , with higher affinity for P08908 receptors . Despite the fact that less receptor occupation is required by full agonists than by antagonists to exert their effects , flibanserin was shown to exert 5- Q13049 antagonism at doses ( 4-5 mg kg-1 ) that are lower or equal to those required to stimulate P08908 receptors . In order to understand this phenomenon , the interaction of flibanserin with P08908 and 5- Q13049 receptors was evaluated in ex vivo binding studies . This interaction was evaluated in the prefrontal cortex , hippocampus and midbrain by using [3H]8-OH-DPAT and [3H]ketanserin to label P08908 and 5- Q13049 receptors , respectively . DB04908 was given at 1 , 10 and 30 mg kg-1 intraperitoneally . The dose of 1 mg kg-1 displaced both radioligands preferentially in the frontal cortex . The doses of 10 and 30 mg kg-1 reduced the binding of both radioligands in all the three brain regions non-selectively by about 50 % and 70 % , respectively . The displacement was maximal after 0.5 h and was reduced or not evident after 3 h . We conclude that 5-HT2 antagonism brought about by low doses of flibanserin may reflect functional mechanisms more than receptor-mediated effects . Peroxisome-proliferator activator receptor-gamma activation decreases attachment of endometrial cells to peritoneal mesothelial cells in an in vitro model of the early endometriotic lesion . The aim of this study was to investigate whether peroxisome proliferator-activated receptor ( Q07869 ) -gamma activation has an effect on the attachment of endometrial cells to peritoneal mesothelial cells in a well-established in vitro model of the early endometriotic lesion . The endometrial epithelial cell line EM42 and mesothelial cell line LP9 were used for this study . EM42 cells , LP9 cells or both were treated with the P37231 agonist ciglitazone ( CTZ ) at varying concentrations ( 10 , 20 and 40 microM ) x 48 h with subsequent co-culture of EM42 and LP9 cells . The rate of EM42 attachment and invasion through LP9 cells was then assessed and compared with control ( EM42 and LP9 cells co-cultured without prior treatment with CTZ ) . Next , attachment of CTZ-treated and untreated EM42 cells to hyaluronic acid ( HA ) , a cell adhesion molecule ( P62158 ) on peritoneal mesothelial cells , were assessed . Although there was no difference in EM42 attachment when LP9 cells alone were treated with CTZ , treatment of EM42 cells with 40 microM CTZ decreased EM42 attachment to LP9 cells by 27 % ( P < 0.01 ) . Treatment of both EM42 and LP9 cells with 40 microM CTZ decreased EM42 attachment to LP9 by 37 % ( P < 0.01 ) . Treatment of EM42 cells with 40 microM CTZ decreased attachment to HA by 66 % ( P = 0.056 ) . CTZ did not decrease invasion of EM42 cells through the LP9 monolayer . CTZ may inhibit EM42 cell proliferation . In conclusion , CTZ significantly decreased EM42 attachment to LP9 cells and HA in an in vitro model of the early endometriotic lesion . DB00316 -inhibitable P35354 . Although paracetamol potently reduces pain and fever , its mechanism of action has so far not been satisfactorily explained . It inhibits both P23219 and P35354 weakly in vitro , but reduces prostaglandin synthesis markedly in vivo . In mouse macrophage J774.2 cells , P35354 induced for 48 hr with high concentrations of NSAIDs is more sensitive to inhibition with paracetamol than endotoxin-induced P35354 . In the rat pleurisy model of inflammation , a second peak of P35354 protein appears 48 hr after administration of the inflammatory stimulus , during the resolution phase of the inflammatory process . Inhibition of the activity of this late-appearing P35354 with indomethacin or a selective P35354 inhibitor , delays resolution and the inflammation is prolonged . Cultured lung fibroblasts also express P35354 activity after stimulation with IL-1beta which is highly sensitive to inhibition with paracetamol . Thus , evidence is accumulating for the existence of a P35354 variant or a new P36551 enzyme which can be inhibited with paracetamol . DB06779 , a low-molecular-weight heparin , promotes angiogenesis mediated by heparin-binding P15692 in vivo . Tumors are angiogenesis dependent and vascular endothelial growth factor-A ( P15692 ) , a heparin-binding protein , is a key angiogenic factor . As chemotherapy and co-treatment with anticoagulant low-molecular-weight heparin ( LMWH ) are common in cancer patients , we investigated whether angiogenesis in vivo mediated by P15692 is modulated by metronomic-type treatment with : ( i ) the LMWH dalteparin ; ( ii ) low-dosage cytostatic epirubicin ; or ( iii ) a combination of these two drugs . Using the quantitative rat mesentery angiogenesis assay , in which angiogenesis was induced by intraperitoneal injection of very low doses of P15692 , dalteparin sodium ( Fragmin(®) ) and epirubicin ( Farmorubicin(®) ) were administered separately or in combination by continuous subcutaneous infusion at a constant rate for 14 consecutive days . DB06779 was administered at 27 , 80 , or 240 IU/kg/day , i.e. , doses that reflect the clinical usage of this drug , while epirubicin was given at the well-tolerated dosage of 0.4 mg/kg/day . While dalteparin significantly stimulated angiogenesis in an inversely dose-dependent manner , epirubicin did not significantly affect angiogenesis . However , concurrent treatment with dalteparin and epirubicin significantly inhibited angiogenesis . The effect of dalteparin is the first demonstration of a proangiogenic effect of any LMWH in vivo . The fact that co-treatment with dalteparin and epirubicin significantly inhibited angiogenesis suggests a complex drug effect . DB00159 inhibits prostaglandin D2 generation by inhibiting cyclo-oxygenase-2 in cultured human mast cells . BACKGROUND : DB00159 ( EPA ) is catalysed by cyclo-oxygenase ( P36551 ) , as is arachidonic acid , and is a competitive inhibitor of arachidonate metabolism . OBJECTIVES : We examined the effect of EPA on prostaglandin ( PG ) D2 generation in the cultured human mast cells with IgE-anti-IgE challenge incubation . METHODS : Cultured human mast cells were incubated with EPA ( 1 micromol/L ) for 20 h , then challenged with anti-IgE incubation after treatment with IgE . At the same time , P36551 inhibitors were tested to identify P23219 and P35354 activity . PGD2 synthetic activity was also assayed in a cell-free homogenate of cultured mast cells with P36551 inhibitors and EPA . DB11320 in the culture medium and in cells was assayed with the HPLC-fluorescent method . PGD2 and PGD3 were assayed with gas chromatography-mass spectrometry and the stable isotope dilution method . RESULTS : Although EPA incubation did not affect histamine release by cultured human mast cells in response to IgE-anti-IgE challenge incubation , it did decrease PGD2 generation by inhibiting the P35354 pathway . In contrast , in the cell-free homogenate of cultured human mast cells , EPA inhibited both P23219 and P35354 activities . CONCLUSION : Pre-incubation with EPA primarily affects the P35354 pathway in cultured human mast cells and reduces PGD2 generation in response to IgE-anti-IgE challenge incubation . These findings suggest that P23219 and P35354 have different substrate flow systems in mast cells . They also suggest that endogenous EPA diet supplementation would reduce PGD2 production and could serve as an anti-inflammatory substrate in human mast cells .