interacts_with DB00549?
DB06643 for joints and bones . DB06643 is an investigational , fully human monoclonal antibody with a high affinity and specificity for receptor activator of nuclear factor kappaB ligand ( O14788 ) , a cytokine member of the tumor necrosis factor family . O14788 , an essential mediator of osteoclast formation , function , and survival , plays a major role in the pathogenesis of postmenopausal osteoporosis , structural damage in rheumatoid arthritis , and bone loss associated with other skeletal disorders . DB06643 suppresses bone turnover by inhibiting the action of O14788 on osteoclasts . DB06643 reduces bone turnover and increases bone mineral density in postmenopausal women with low bone mineral density , reduces fracture risk in women with postmenopausal osteoporosis , and inhibits structural damage in patients with rheumatoid arthritis when added to ongoing methotrexate treatment . It is generally well tolerated , with a good safety profile . Adverse and serious adverse events , including infections and malignancy , are similar in patients treated with denosumab or placebo . Stimulation of cloned human serotonin P28221 beta receptor sites in stably transfected P13671 glial cells promotes cell growth . The involvement of serotonin P28221 beta receptor sites was investigated in the growth of rat P13671 glial cells permanently transfected with a gene encoding a human P28221 beta receptor . The 5-HT receptor identity of control and transfected P13671 glial/ P28221 beta cells was determined by reverse transcription-polymerase chain reaction using primers specific for rat P08908 , rat P28222 , rat P28221 alpha , human P28221 beta , and rat 5- Q13049 receptor genes . Constitutive mRNA for 5- Q13049 receptors was present in control and transfected P13671 glial/ P28221 beta cells , whereas mRNA for P28221 beta receptor sites was only present in the transfected P13671 glial/ P28221 beta cell line . 5-HT inhibited forskolin-stimulated cyclic AMP formation and promoted cell growth , in contrast to the absence of any measurable effect in pcDNA3 plasmid-transfected and nontransfected P13671 glial cells . The 5-HT effects could be mimicked by sumatriptan ( EC50 = 44-76 nM ) and were totally and partially blocked by methiothepin ( IC50 = 9 nM ) and GR 127,935 ( 2'-methyl-4'-(5-methyl[1,2,4]oxadiazol-3-yl)-biphenyl-4-carbox yli c acid [4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]amide ; IC50 = 97 pM ) , respectively . No effect on cell growth was measured with the 5-HT2 receptor agonist DOI [ 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane ; 10 microM ] , suggesting that 5- Q13049 receptors are not involved in the 5-HT-stimulated P13671 glial/ P28221 beta cell growth . Dibutyryl-cyclic AMP ( 0.3 mM ) -treated cultures did not show sumatriptan-promoted cell growth , indicating an inhibitory role for cyclic AMP in the cell growth mediated by P28221 beta receptor sites. ( ABSTRACT TRUNCATED AT 250 WORDS ) P35367 occupancy in human brains after single oral doses of histamine H1 antagonists measured by positron emission tomography . 1. P35367 occupancy in the human brain was measured in 20 healthy young men by positron emission tomography ( PET ) using [ 11C ] -doxepin . 2 . (+)- DB01114 , a selective and classical antihistamine , occupied 76.8 +/- 4.2 % of the averaged values of available histamine H1 receptors in the frontal cortex after its administration in a single oral dose of 2 mg . Intravenous administration of 5 mg (+)-chlorpheniramine almost completely abolished the binding of [ 11C ] -doxepin to H1 receptors ( H1 receptor occupancy : 98.2 +/- 1.2 % ) . 3 . Terfenadine , a nonsedative antihistamine , occupied 17.2 +/- 14.2 % of the available H1 receptors in the human frontal cortex after its administration in a single oral dose of 60 mg . 4 . There was no correlation between H1 receptor occupancy by terfenadine and the plasma concentration of the active acid metabolite of terfenadine in each subject . 5 . PET data on human brain were essentially compatible with those on H1 receptor occupancy in guinea-pig brain determined by in vivo binding techniques , although for the same H1 receptor occupancy the dose was less in human subjects than in guinea-pigs . 6 . The PET studies demonstrated the usefulness of measuring H1 receptor occupancy with classical and second-generation antihistamines in human brain to estimate their unwanted side effects such as sedation and drowsiness quantitatively . Effect of milk hydrolysates on inflammation markers and drug-induced transcriptional alterations in cell-based models . Nonsteroidal anti-inflammatory drugs ( NSAID ) are associated with gastrointestinal inflammation and subsequent damage to the intestinal tissue . Earlier studies in our laboratory have found that specific casein hydrolysates ( CH ) might be useful in the treatment of gastrointestinal wounds . The underlying mechanisms that support inflammation and wound healing are not completely understood , but transcriptional alterations may be used as markers for inflammation and wound healing . The bioactivity of 3 CH prepared by treatment of commercial casein with pepsin ( 60 min ) followed by corolase ( 0 , 10 , or 60 min ) were investigated in intestinal epithelial cells treated with the NSAID indomethacin . The bioactivity was evaluated as transcriptional alterations of transforming growth factor-β1 ( TGF-β1 ) , cyclooxygenase-2 ( P35354 ) , peroxisome proliferator-activated receptor-γ ( Q07869 -γ ) and nuclear factor κB ( NFκB ) by real-time PCR . Furthermore , the effect of CH on lipopolysaccharide-induced inflammation was evaluated in macrophages by measuring PG E(2) levels . Casein hydrolysates treated with corolase for 10 or 60 min after pepsin treatment downregulated transcription of TGF-β1 and NFκB ( P < 0.05 ) compared with the hydrolysate treated with pepsin only . Hydrolysate prepared by corolase treatment for 60 min after pepsin hydrolysis downregulated transcription of P35354 ( P < 0.05 ) compared with hydrolysate treated with corolase for only 10 min whereas transcription of Q07869 -γ was not affected ( P > 0.05 ) . Additionally , the hydrolysate prepared by pepsin treatment only ( 0 min corolase ) had a pro-inflammatory effect on macrophages via PG E(2) stimulation ( P < 0.05 ) . In conclusion , CH produced by a combination of pepsin and corolase treatments downregulated the transcription levels of TGF-β1 , P35354 , and NFκB . Leukotriene D4-induced increases in cytosolic calcium in THP-1 cells : dependence on extracellular calcium and inhibition with selective leukotriene D4 receptor antagonists . Agonist-induced changes in intracellular calcium ion concentration ( [Ca++]i ) were examined in human monocytic leukemia THP-1 cells loaded with fura 2/acetoxymethyl ester ( fura 2/AM ) . Leukotriene (LT)D4 induced a concentration-dependent biphasic response consisting of a transient phase ( up to 5-fold peak increase ) followed by a sustained phase , showing characteristics of a receptor-operated calcium channel . Homologous desensitization to LTD4 was observed . The responses to LTD4 were reduced by 80 to 90 % in calcium-free buffer . The responses to LTD4 in a calcium-free buffer were dependent upon the duration of prior exposure of the cells to a calcium-free environment . The response at 30 or 60 min after exposure to calcium-free buffer was greater than that at earlier time points ( time-dependent sensitization ) . Similar responses were obtained with THP-1 cells exposed to DB00974 -containing buffer . It is speculated that such time-dependent sensitization is a result of changes at the receptor level . The responses to LTD4 were blocked by two specific LTD4 antagonists , MK-0571 and DB00549 , in a concentration-dependent manner . When given after addition of LTD4 , MK-0571 or DB00549 reversed the sustained phase of the LTD4-induced response , suggesting that maintenance of the response requires persistent activation of the Q9Y271 . DB00549 was 5 to 10 times more potent than MK-0571 ( IC50 values of 1.1 and 9.3 nM , respectively ) , in agreement with results from radioligand binding studies reported separately . Beyond statins : new lipid lowering strategies to reduce cardiovascular risk . Statins are the first-line therapy in LDL- DB04540 ( LDL-C ) reduction and its clinical use has contributed to significant prevention and treatment of atherosclerotic vascular disease . Yet , a significant proportion of patients remain at high risk . Recently , a number of new therapies have been developed to further lower LDL-C . These agents may provide clinical benefit on top of statin therapy in patients with high residual risk , severe hypercholesterolemia or as an alternative for patients who are intolerant to statins . We review four novel approaches based on the inhibition of proprotein convertase subtilisin/kexin type 9 ( Q8NBP7 ) , apolipoprotein-B100 ( apoB ) , Cholesteryl ester transport protein ( P11597 ) and microsomal triglyceride transfer protein ( P55157 ) . ApoB and P55157 inhibitors ( DB05528 and DB08827 ) are indicated only for homozygous familial hypercholesterolemia patients . The results of ongoing trials with P11597 and Q8NBP7 inhibitors may warrant a wider employment in different categories of patients at high risk for cardiovascular disease . Does increased leukotriene B4 in type 1 diabetes result from elevated cholesteryl ester transfer protein activity ? Elevated cholesteryl ester transfer protein ( P11597 ) activity has been reported in type 1 diabetic subjects and may be one cause of the high incidence of macrovascular complications in these patients . LDL delivers arachidonic acid ( AA ) , in the form of cholesteryl ester ( CE ) , to cells such as monocytes and fibroblasts , as precursor for eicosanoid synthesis . We discovered that AA content in LDL CE was significantly correlated with P11597 activity , even after controlling for P11597 concentration , in type 1 diabetic children . The production of Q06643 (4) , a potent chemotactic and pro-inflammatory factor which plays a role in atherogenesis , has been shown to be increased in type 1 diabetic patients . We hypothesized that in these subjects , increased AA content in LDL CE , resulting from increased P11597 activity and transient hyperinsulinemia , may lead to enhanced synthesis of Q06643 (4) and subsequently the higher incidence of cardiovascular disease . Determination of fenofibric acid concentrations by HPLC after anion exchange solid-phase extraction from human serum . Triglycerides are increasingly being recognized as a risk factor for cardiovascular disease . Research efforts to identify sources of variability in triglyceride-lowering response to the lipid-lowering drug fenofibrate require quantification of the active acidic form of this Q07869 agonist . Anion-exchange solid-phase extraction , in combination with reverse-phase high-performance liquid chromatography ( HPLC ) , rapidly and accurately determines steady-state fenofibric acid serum concentrations . Chromatographic separation under isocratic conditions , with use of ultraviolet detection at 285 nm , provides clean baseline and sharp peaks for clofibric acid , 1-napthyl acetic acid ( internal standards ) , and fenofibric acid . Commonly prescribed and over-the-counter nonsteroidal anti-inflammatory drugs ( NSAIDs ) were screened for assay interference , and the assay was employed to quantify fenofibric acid in more than 800 human subject specimens . DB01039 analysis was found to be linear over the range of 0.5 to 40 mg/L and was validated with either internal standard . Accuracies ranged from 98.65 % to 102.4 % , whereas the within- and between-day precisions ranged from 1.0 % to 2.2 % and 2.0 % to 6.2 % , respectively . NSAIDs had minimal interference with the assay , which succeeded in quantifying fenofibric acid in more than 843 of 846 serum samples from human subjects , many taking a variety of coadministered medications . Anion-exchange solid-phase extraction in combination with reverse-phase HPLC accurately determines steady-state fenofibric acid serum concentrations in humans without interference from NSAIDs or commonly administered medications . This method is suitable for quantification of fenofibric acid for clinical pharmacokinetic studies in patients with dyslipidemia . Q9Y271 promoter polymorphism and requirement for leukotriene receptor antagonist in aspirin-intolerant asthma patients . OBJECTIVES : Leukotriene receptor antagonists ( LTRA ) , such as montelukast , have been used as a first-line treatment for patients with aspirin-intolerant asthma ( AIA ) . This study evaluated associations between the clinical requirement for LTRA and genetic polymorphisms of the P09917 , Q16873 , P35354 , Q9Y271 and P21731 genes in the arachidonic acid cascade in the long-term management of 89 AIA patients from a Korean population . METHODS : Asthma control status was monitored for 1 year with maintenance medications of inhaled corticosteroid and oral LTRA , and AIA patients were classified into three groups according to the mean montelukast dose required per month to maintain asthma control for 1 year : group I ( > or = 200 mg montelukast/month ; n = 37 ) , group II ( 5-150 mg/month ; n = 25 ) and group III ( < 5 mg/month ; n = 27 ) . Genetic polymorphisms in the arachidonic acid cascade were determined using a single-base extension method . RESULTS : We found that there was a significant difference in the genotype frequency of the Q9Y271 promoter polymorphism -634C > T among the three groups ( p = 0.007 for group I vs group II , p = 0.017 for group I vs group III ) , while there were no significant associations between LTRA requirements and polymorphisms of the other genes . The patients with the variant genotype ( CT or TT ) of the -634C = T Q9Y271 promoter polymorphism showed a higher expression level than those with the common genotype ( CC ) . CONCLUSION : These findings indicate that the Q9Y271 promoter polymorphism is a useful genetic marker for predicting LTRA requirements in the long-term management of AIA patients . DB00501 enhances antigen-specific IgE and Th2 cytokine production . BACKGROUND : Treatment with anti-ulcer drugs has been shown to enhance IgE production against food antigens . However , little is known about the immunological effects of cimetidine , a histamine receptor type 2 ( P25021 ) antagonist that is widely used as an anti-ulcer drug , in allergy . Therefore , the present study investigated the role of cimetidine in Th2 immune responses in mice . METHODS : BALB/c mice were immunized intraperitoneally with ovalbumin ( OVA ) with and without cimetidine . The levels of cytokines in supernatants of spleen cells cultured in the presence of OVA for 4 days and the levels of total and OVA-specific IgG(1) , IgG(2a) and/or IgE in sera from these mice were determined by ELISA . RESULTS : Administration of cimetidine to OVA-sensitized BALB/c mice promoted Th2 cytokine secretion by OVA-stimulated spleen cells in vitro and increased serum levels of OVA-specific IgE , IgG(1) and IgG(2a) . CONCLUSIONS : These results indicate that cimetidine can enhance Th2 responses , suggesting that cimetidine may contribute to IgE production in allergies . Statin Modulation of Human T-Cell Proliferation , IL-1β and Q16552 Production , and IFN-γ T Cell Expression : Synergy with Conventional Immunosuppressive Agents . P04035 inhibitors ( statins ) have been demonstrated to be immunomodulatory for human immune-mediated disease and in experimental models . The aim of this study was to compare statin-mediated immunosuppressive effects on human T-cell responses in vitro with those of conventional immunosuppressives ( dexamethasone , cyclosporin A ( DB00091 ) , mycophenolate , and rapamycin ) . Statins ( atorvastatin , lovastatin , and simvastatin ) were investigated for their modulatory effects on human PBMC viability , cytokine profiles , and T-cell proliferation . At concentrations that inhibited anti-CD3/28-stimulated T-cell proliferation ( P < 0.01 ) , simvastatin significantly decreased intracellular P01730 (+) T-cell expression of IFN-γ ( P < 0.01 ) to levels similar to those induced by conventional immunosuppressives . DB01076 and lovastatin also decreased IFN-γ expression , although to a lesser degree ( P < 0.05 ) . All three statins reduced levels of Q16552 production ( P < 0.01 ) . However , in response to anti-CD3/28 stimulation , simvastatin significantly upregulated IL-1β production ( P < 0.05 ) . The profile of cytokines produced in response to anti-CD3/28 stimulation was similar when both atorvastatin and dexamethasone were added as compared with dexamethasone alone , suggesting that atorvastatin can synergise with dexamethasone with respect to immunomodulation of cytokines . This data supports the hypothesis of selective statin-mediated immunomodulatory effects on human immune cells . 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 . Pharmacological investigation of the role of leukotrienes in the pathogenesis of experimental NSAID gastropathy . The role of leukotrienes in the pathogenesis of acute gastric ulceration induced by nonsteroidal antiinflammatory drugs was investigated using a rat model . One part of the study involved oral pretreatment with a leukotriene synthesis inhibitor 1 h prior to administration of indomethacin ( 20 mg/kg per os ) . Three hours after indomethacin , the extent of macroscopically visible gastric damage was determined , and gastric LTB4 synthesis was determined . The compounds tested were PF-5901 , A-64077 , nordihydroguaiaretic acid , and L-698,037 . Each compound produced dose-related inhibition of gastric LTB4 synthesis and a parallel reduction in the severity of indomethacin-induced damage . The antioxidant properties of these compounds was assessed using an in vitro assay . There was no correlation between the antioxidant properties of the compounds and their ability to reduce the severity of indomethacin-induced gastric damage . In the second part of the study , the effects of intravenous , administration of LTD4 and LTB4 receptor antagonists on indomethacin-induced gastric epithelial damage ( measured by permeability to [51Cr] DB00974 ) were assessed . The two Q9Y271 antagonists ( MK-571 and DB00549 ) significantly reduced the permeability changes induced by indomethacin , while the two LTB4 antagonists ( SC-41930 and LY-255,283 ) were without significant effect . Despite the reduction of gastric epithelial injury , blockade of LTD4 receptors did not markedly affect the extent of macroscopically visible injury . These data are consistent with the hypothesis that leukotrienes contribute to the epithelial injury and macroscopically visible damage induced by NSAIDs . However , it remains unclear to what extent leukotrienes are involved in the initiation of the injury , as opposed to its amplification . 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 . Is Q13304 a P2Y/leukotriene receptor ? examination of uracil nucleotides , nucleotide sugars , and cysteinyl leukotrienes as agonists of Q13304 . The orphan receptor Q13304 has been reported to be activated by UDP , UDP-sugars , and cysteinyl leukotrienes , and coupled to intracellular Ca(2+) mobilization and inhibition of DB02527 accumulation , but other studies have reported either a different agonist profile or lack of agonist activity altogether . To determine if Q13304 is activated by uracil nucleotides and leukotrienes , the hemagglutinin-tagged receptor was expressed in five different cell lines and the signaling properties of the receptor were investigated . In P13671 , 1321N1 , or Chinese hamster ovary ( CHO ) cells stably expressing Q13304 , UDP , UDP-glucose , DB03501 , and cysteinyl leukotriene C4 ( LTC4 ) all failed to promote inhibition of forskolin-stimulated DB02527 accumulation , whereas both UDP and UDP-glucose promoted marked inhibition ( > 80 % ) of forskolin-stimulated DB02527 accumulation in P13671 and CHO cells expressing the Q15391 receptor . Likewise , none of these compounds promoted accumulation of inositol phosphates in COS-7 or human embryonic kidney 293 cells transiently transfected with Q13304 alone or cotransfected with Gαq/i5 , which links Gi-coupled receptors to the Gq-regulated phospholipase C ( P98160 ) signaling pathway , or PLCε , which is activated by the Gα12/13 signaling pathway . Moreover , none of these compounds promoted internalization of Q13304 in 1321N1- Q13304 cells . Consistent with previous reports , coexpression experiments of Q13304 with cysteinyl leukotriene receptor 1 ( Q9Y271 ) suggested that Q13304 acts as a negative regulator of Q9Y271 . Taken together , these data suggest that UDP , UDP-glucose , DB03501 , and LTC4 are not the cognate ligands of Q13304 . Leukotriene pathway genetics and pharmacogenetics in allergy . Leukotrienes ( LT ) are biologically active lipid mediators known to be involved in allergic inflammation . Leukotrienes have been shown to mediate diverse features of allergic conditions including inflammatory cell chemotaxis/activation and smooth muscle contraction . Cysteinyl leukotrienes ( LTC(4) , LTD(4) and , LTE(4) ) and the dihydroxy leukotriene Q06643 (4) are generated by a series of enzymes/proteins constituting the LT synthetic pathway or P09917 ( P09917 ) pathway . Their function is mediated by interacting with multiple receptors . Leukotriene receptor antagonists ( LTRA ) and LT synthesis inhibitors ( LTSI ) have shown clinical efficacy in asthma and more recently in allergic rhinitis . Despite growing knowledge of leukotriene biology , the molecular regulation of these inflammatory mediators remains to be fully understood . Genes encoding enzymes of the P09917 pathway ( i.e. P09917 , Q16873 and P09960 ) and encoding for LT receptors ( Q9Y271 /2 and LTB4R1/2 ) provide excellent candidates for disease susceptibility and severity ; however , their role remains unclear . Preliminary data also suggest that P09917 pathway/receptor gene polymorphism can predict patient responses to LTSI and LTRA ; however , the exact mechanisms require elucidation . The aim of this review was to summarize the recent advances in the knowledge of these important mediators , focusing on genetic and pharmacogenetic aspects in the context of allergic phenotypes . 5-Lipoxygenase mediates O14788 -induced osteoclast formation via the cysteinyl leukotriene receptor 1 . 5-Lipoxygenase ( P09917 ) catalyzes the formation of two major groups of leukotrienes , leukotriene B4 and cysteinyl leukotrienes ( CysLTs ) , and it has been implicated as a promising drug target to treat various inflammatory diseases . However , its role in osteoclastogenesis has not been investigated . In this study , we used mouse bone marrow-derived macrophages ( BMMs ) to show that P09917 inhibitor suppresses O14788 -induced osteoclast formation . Inhibition of P09917 was associated with impaired activation of multiple signaling events downstream of Q9Y6Q6 , including P29323 and p38 phosphorylation , and IκB degradation , followed by a decrease in O95644 expression . Ectopic overexpression of a constitutively active form of O95644 partly rescued the antiosteoclastogenic effect of P09917 inhibitor . The knockdown of P09917 in BMMs also resulted in a significant reduction in O14788 -induced osteoclast formation , accompanied by decreased expression of O95644 . Similar effects were shown with CysLT receptor (CysLTR)1/2 antagonist and small RNA for Q9Y271 in BMMs , indicating the involvement of CysLT and Q9Y271 in P09917 -mediated osteoclastogenesis . Finally , P09917 inhibitor suppressed LPS-induced osteoclast formation and bone loss in the in vivo mouse experiments , suggesting a potential therapeutic strategy for treating diseases involving bone destruction . Taken together , the results of this study demonstrate that P09917 is a key mediator of O14788 -induced osteoclast formation and possibly a novel therapeutic target for bone-resorption diseases . Leukotriene B4 modulates in vivo expression of delayed-type hypersensitivity by a receptor-mediated mechanism : regulation by lipoxin A4 . Leukotriene B4 ( LTB4 ) is a potent proinflammatory arachidonic acid metabolite whose actions are mediated by specific receptors . Recent characterization of a high-affinity LTB4 receptor on the surface of guinea pig P01730 + T lymphocytes prompted examination of a possible role of LTB4 in modulating in vivo expression of delayed-type hypersensitivity ( DTH ) to tuberculin ( PPD ) . In the absence of PPD , intradermal injections of LTB4 or LTB4/ Q9Y271 antagonists did not elicit delayed-onset erythema at 24 h . When injected together with PPD , LTB4 ( 1 fmol to 1 pmol ) caused a significant 25 to 30 % decrease in DTH expression , whereas LTB4 receptor antagonists SC-41930 , LY-223982 , ONO-4057 ( 0.1-10 nmol ) , caused a highly significant ( P < .01 ) 25 to 50 % increase . The effect of SC-41930 on DTH expression was inhibited by a 10-fmol dose of LTB4 . Q9Y271 antagonist LY-171883 had no effect on DTH expression . Lipoxin A4 ( LXA4 ) interferes with binding of LTB4 to T lymphocytes or neutrophils by reducing LTB4 receptor density . It caused a small but significant enhancement of DTH expression at 1-nmol doses when injected with PPD . Lipoxin B4 had no effect . Enhancement or inhibition of grossly visible delayed skin responses to PPD by LTB4 . LTB4 receptor antagonists or LXA4 was not associated with qualitative or quantitative changes in superficial or deep dermal mononuclear cell infiltrates at the reaction site . We conclude that LTB4 modulates visible expression of DTH in vivo by a receptor-mediated mechanism . DB00472 induces preventive and complex effects against colon cancer development in epithelial and stromal areas in rats . DB00472 ( FLX ) is a drug commonly used as antidepressant . However , its effects on tumorigenesis remain controversial . Aiming to evaluate the effects of FLX treatment on early malignant changes , we analyzed serotonin ( 5-HT ) metabolism and recognition , aberrant crypt foci ( Q9NQ94 ) , proliferative process , microvessels , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase-2 ( P35354 ) expression in colon tissue . Male Wistar rats received a daily FLX-gavage ( 30mgkg(-1) ) and , a single dose of 1,2 dimethylhydrazine ( Q03001 ; i.p. , 125mgkg(-1) ) . After 6 weeks of FLX-treatment , our results revealed that FLX and nor-fluoxetine ( N-FLX ) are present in colon tissue , which was related to significant increase in serotonin ( 5-HT ) levels ( P < 0.05 ) possibly through a blockade in P31645 mRNA ( serotonin reuptake transporter ; P < 0.05 ) resulting in lower 5-hydroxyindoleacetic acid ( 5-HIAA ) levels ( P < 0.01 ) and , P28335 receptor mRNA expressions . FLX-treatment decreased dysplastic Q9NQ94 development ( P < 0.01 ) and proliferative process ( P < 0.001 ) in epithelia . We observed a significant decrease in the development of malignant microvessels ( P < 0.05 ) , P15692 ( P < 0.001 ) , and P35354 expression ( P < 0.01 ) . These findings suggest that FLX may have oncostatic effects on carcinogenic colon tissue , probably due to its modulatory activity on 5-HT metabolism and/or its ability to reduce colonic malignant events . 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 .