interacts_with DB01407?
Synaptic vesicular monoamine transporter expression : distribution and pharmacologic profile . The human vesicular monoamine transporter ( hSVMT ) cDNA predicts a protein of 515 amino acids that shares 92 % amino acid identity with the rat cDNA . Northern analyses reveal expression of 4.3 kb Q05940 mRNAs in rat hypothalamus , midbrain and brainstem , a 3 kb hSVMT mRNA in human brainstem and a 4.8 kb hSVMT mRNA in human hypothalamus . In situ hybridization documents significant Q05940 expression in human nigra compacta neurons and in rat hypothalamic neurons whose distribution patterns are identical to those previously reported to display histaminergic markers . COS cell hSVMT expression yielded nanomolar affinities for tetrabenazine and reserpine , micromolar affinities for haloperidol , GBR12909 , serotonin , mazindol , nomifensin and DB01576 , while dopamine , epinephrine , norepinephrine and histamine each displayed millimolar affinities . These observations extend the pharmacological characterization of hSVMT and studies of its distribution , and indicate likely physiological roles for Q05940 in packaging monoamine transmitters including histamine . Intercellular adhesion molecule-1 ( P05362 ) expression and soluble P05362 ( sICAM-1 ) production by cytokine-activated human aortic endothelial cells : a possible role for P05362 and sICAM-1 in atherosclerotic aortic aneurysms . The interactions of inflammatory cells , cytokines , and cell adhesion molecules ( P62158 ) may be important in the pathogenesis of vascular diseases such as abdominal aortic aneurysms ( AAA ) , in which inflammation plays a role . The aim of this study was to investigate the pathogenic role of P05362 , a molecule involved in leucocyte-endothelial interactions , in vascular inflammation . ELISA of human explant culture supernatants revealed a four-fold increase in sICAM-1 production by AAA ( n = 9 ) versus normal ( n = 8 ) aortic explants . Human aortic endothelial cell ( hAEC ) culture was used for further studies as an in vitro model for aortic inflammatory conditions . Tumour necrosis factor-alpha ( P01375 ) or P01584 treatment of hAEC resulted in an up to 1.8-fold significant increase in sICAM-1 production compared with resting cells . In addition , the expression of P05362 on cytokine-stimulated versus resting hAEC was measured by radioimmunoassay . P01375 significantly induced P05362 expression on these cells . These results suggest that different forms of P05362 , present on or released by the activated aortic endothelium , may be involved in leucocyte adhesion to and migration into the vessel wall . Comparison of the novel antipsychotic ziprasidone with clozapine and olanzapine : inhibition of dorsal raphe cell firing and the role of P08908 receptor activation . Ziprasidone is a novel antipsychotic agent which binds with high affinity to P08908 receptors ( Ki = 3.4 nM ) , in addition to P28221 , 5-HT2 , and D2 sites . While it is an antagonist at these latter receptors , ziprasidone behaves as a P08908 agonist in vitro in adenylate cyclase measurements . The goal of the present study was to examine the P08908 properties of ziprasidone in vivo using as a marker of central P08908 activity the inhibition of firing of serotonin-containing neurons in the dorsal raphe nucleus . In anesthetized rats , ziprasidone dose-dependently slowed raphe unit activity ( ED50 = 300 micrograms/kg i.v. ) as did the atypical antipsychotics clozapine ( ED50 = 250 micrograms/kg i.v. ) and olanzapine ( ED50 = 1000 micrograms/kg i.v. ) . Pretreatment with the P08908 antagonist WAY-100,635 ( 10 micrograms/kg i.v. ) prevented the ziprasidone-induced inhibition ; the same dose of WAY-100,635 had little effect on the inhibition produced by clozapine and olanzapine . Because all three agents also bind to alpha 1 receptors , antagonists of which inhibit serotonin neuronal firing , this aspect of their pharmacology was assessed with desipramine ( DB01151 ) , a NE re-uptake blocker previously shown to reverse the effects of alpha 1 antagonists on raphe unit activity . DB01151 ( 5 mg/kg i.v. ) failed to reverse the inhibitory effect of ziprasidone but produced nearly complete reversal of that of clozapine and olanzapine . These profiles suggest a mechanism of action for each agent , P08908 agonism for ziprasidone and alpha 1 antagonism for clozapine and olanzapine . The P08908 agonist activity reported here clearly distinguishes ziprasidone from currently available antipsychotic agents and suggests that this property may play a significant role in its pharmacologic actions . Effect of isoproterenol and dexamethasone on the lipopolysaccharide induced expression of CD11b on bovine neutrophils . The present experiments investigate the changes in expression of CD11b on bovine neutrophils and its modulation by isopropylnoradrenaline ( IPN , isoproterenol ) , dexamethasone ( DX ) , phenylephrine ( alpha-agonist ) and clenbuterol ( beta-agonist ) . Both IPN and DX caused a dose-dependent inhibition of LPS-induced CD11b expression . A combination of IPN and DX elicited a synergistical decrease of the CD11b expression . DB01407 mimicked the effect of IPN , whereas phenylephrine did not . The effect of IPN and DX could at least partly be mediated through a decreased P01375 production by monocytes since tumor necrosis factor-alpha ( P01375 ) is shown to mediate a dose-dependent CD11b up-regulation . Stimulation of stress hormone receptors partly immuno-suppresses neutrophil functions by inhibition of CD11b expression on the neutrophil surface upon LPS stimulation . This inhibition is probably related to a decrease in P01375 production . A similar mechanism of immuno-suppression could contribute to the higher susceptibility of cattle to Gram-negative bacterial infections of the udder and lung during periods of stress . Implantation of P15692 transfected preadipocytes improves vascularization of fibrin implants on the cylinder chorioallantoic membrane ( P62158 ) model . The successful substitution or augmentation of soft tissues by implantation of three dimensional cell constructs , consisting of human preadipocytes and fibrin glue as a carrier matrix , requires a rapid and homogeneous vascularization of the whole implant in order to provide a sufficient blood supply of centrally situated cells . Previous investigations have shown that under in vivo conditions primary human preadipocytes induce vascularization of fibrin matrices by secretion of several growth factors , such as P15692 and P09038 . The current study investigates whether vascularization of implants can be improved by transplantation of preadipocytes following transfection with a P15692 -vector . Transfection was performed by electroporation with an pCMX-GFP and pCMX-VEGF165 vector . Transfection efficiency ( GFP expression ) and P15692 expression were determined in vitro by FACS analysis and P15692 immunoassay , respectively . In vivo investigations to determine the vascularization of the implants were performed on the cylinder chorioallantoic membrane ( P62158 ) . Four million P15692 transfected cells were transferred within a fibrin matrix onto the P62158 on the 7(th) day of incubation and after 8 days the vascularization of the implant was histologically examined and evaluated by means of a computer-assisted image analysis program . Transfection of preadipocytes with the GFP vector by electroporation yielded transfection efficiencies between 12 % and 41 % of surviving cells . Results of the P15692 immunoassay demonstrated that P15692 expression was significantly higher following transfection . Investigations on the P62158 outlined a significantly higher rate of vascularization in the transfected vs. control population . Our investigations demonstrate that primary human preadipocytes can be successfully transfected by electroporation with a P15692 vector . The enhanced P15692 expression on transfected cells results in an increase of vascularization of the cell constructs on the P62158 . Upregulation of cell-surface-associated plasminogen activation in cultured keratinocytes by interleukin-1 beta and tumor necrosis factor-alpha . Keratinocytes synthesize and secrete urokinase-type plasminogen activator ( uPA ) which is bound in an autocrine manner to a specific receptor ( uPA-R ) at the keratinocyte surface . P00747 that is also bound to specific membrane binding sites is readily activated by uPA-R-bound uPA . Thus , plasmin is provided for proteolysis of pericellular glycoproteins . The expression of uPA and the uPA-R is confined to migrating keratinocytes during epidermal wound healing , rather than to keratinocytes of the normal epidermis . The regulatory factors of uPA/uPA-R expression in keratinocytes remained largely elusive . Proinflammatory cytokines , such as tumor necrosis factor-alpha ( P01375 ) or interleukin-1 beta ( P01584 ) , are present in epidermal wounds . We have therefore tested P01584 and P01375 for their influence on surface-associated plasminogen activation in a human keratinocyte cell line ( HaCaT ) as well as in primary cultures of normal human epidermal keratinocytes . Both cytokines induced the secretion of uPA into the culture supernatants and a concomitant increase in uPA activity as well as in uPA and uPA-R antigen at the cell surface . The increase was preceded by an increase in specific mRNA . The induction was accompanied by an accelerated uPA-dependent and plasmin-mediated detachment of HaCaT cells from the culture substratum . Taken together , the proinflammatory cytokines P01584 and P01375 induced a coordinated increase in uPA and uPA-R as well as increased pericellular plasmin-mediated proteolysis in human epidermal keratinocytes . This function might be an element of the molecular cell biological events during epidermal wound healing . In vitro and in vivo evidence for a role of the Q99572 receptor in the release of P01584 in the murine brain . The P2X(7) receptor ( P2X(7)R ) is a purinoceptor expressed predominantly by cells of immune origin , including microglial cells . P2X(7)R has a role in the release of biologically active proinflammatory cytokines such as P01584 , P05231 and TNFalpha . Here we demonstrate that when incubated with lipopolysaccharide ( LPS ) , glial cells cultured from brain of P2X(7)R(-/-) mice produce less P01584 compared to glial cells from brains of wild-type mice . This is not the case for TNFalpha and P05231 . Our results indicate a selective effect of the P2X7R gene deletion on release of P01584 release but not of P05231 and TNFalpha . In addition , we confirm that only microglial cells produce IL-1beta , and this release is dependent on P2X(7)R and ABC1 transporter . Because P01584 is a key regulator of the brain cytokine network and P2X(7)R is an absolute requirement for P01584 release , we further investigated whether response of brain cytokines to LPS in vivo was altered in P2X(7)R(-/-) mice compared to wild-type mice . P01584 and TNFalpha mRNAs were less elevated in the brain of P2X(7)R(-/-) than in the brain of wild-type mice in response to systemic LPS . These results show that P2X7R plays a key role in the brain cytokine response to immune stimuli , which certainly applies also to cytokine-dependent alterations in brain functions including sickness behavior . Resistance to killing by tumor necrosis factor in an adipocyte cell line caused by a defect in arachidonic acid biosynthesis . We have found that Q96RJ0 -R6 , which are resistant to the cytotoxic effects of tumor necrosis factor ( P01375 ) in the presence of cycloheximide ( Reid , T. R. , Torti , F. , and Ringold , G. M. ( 1989 ) J. Biol. Chem. 264 , 4583-4589 ) , have reduced ability to release arachidonic acid ( 20:4 ) from membrane phospholipids in response to either P01375 or the calcium ionophore A23187 treatment . However , no defect in the activity of phospholipase A2 , the principal enzyme responsible for the release of 20:4 from phospholipids , was observed in these cells . Detailed biochemical characterization of these P01375 -resistant cells has revealed that these cells are unable to synthesize 20:4 endogenously because of a defect in delta 6-desaturase , the rate-limiting enzyme of 20:4 biosynthesis . This deficiency leads to a marked decrease in the steady-state levels of 20:4 present in choline-containing phospholipid ( PC ) and ethanolamine-containing phospholipid ( PE ) . The Q96RJ0 -R6 cells , however , are capable of incorporating exogenous 20:4 into PC and PE , and when loaded in such manner they become significantly more sensitive to the cytotoxic effects of P01375 in the presence of cycloheximide . Therefore , the release of arachidonic acid from phospholipids appears to be a critical element in the signaling pathway utilized by P01375 and is essential to the rapid cytotoxic response elicited by P01375 in the absence of protein synthesis in wild-type Q96RJ0 cells . [ 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 . DB03404 upregulates Egr-1 expression in vascular smooth muscle cells via reactive oxygen species P27361 /2-Elk-1 and NF-kappaB . Reactive oxygen species ( ROS ) and oxidant stress are important mediators of cardiovascular pathologies including atherosclerosis . One source of ROS in the vasculature is free heme released from hemoglobin . Because Egr-1 , the regulator of cell proliferation and apoptosis , is also induced by oxidant stress and is likewise implicated in atherosclerosis , we examined the regulation of Egr-1 by heme in vascular smooth muscle cells ( SMCs ) . DB03404 increased Egr-1 expression ( mRNA , protein ) within 30 minutes and P27361 /2 phosphorylation and nuclear translocation within 5 minutes . Inhibiting hemin-induced P27361 /2 activation by U0126 ( MAPK-inhibitor ) , the antioxidant N-acetyl cysteine , the NADPH oxidase inhibitors apocynin and diphenyleneiodonium chloride , the superoxide scavenger tiron , or tricarbonyldichlororuthenium(II)-dimer ( carbon-monoxide donor ; CORM-2 ) blocked hemin-induced Egr-1 expression . DB03404 activated Elk-1 , P11831 , and NF-kappaB and promoted their interaction with the Egr-1 promoter . Downregulating Elk-1 ( via siRNA ) or blocking NF-kappaB activation ( via BAY-11-7082 ) abolished hemin induction of Egr-1 . Finally , hemin-induced Egr-1 bound the promoters of tissue factor ( TF ) , P00747 Activator Inhibitor ( P05121 ) -1 , and P01138 -1A Binding ( NAB ) -2 , upregulating their expression , and increased the biochemical activity of TF and P05121 . Upregulation of Egr-1 and its target genes by heme-induced oxidant stress may be an important event in the initiation and progression of inflammatory vascular diseases such as atherosclerosis . Regulatory effect of nerve growth factor in alpha9beta1 integrin-dependent progression of glioblastoma . In the present study we described the role of alpha9beta1 integrin in glioblastoma progression following its interaction with nerve growth factor ( P01138 ) . The level of expression of alpha9beta1 on astrocytomas is correlated with increased grade of this brain tumor and is highest on glioblastoma , whereas normal astrocytes do not express this integrin . Two glioblastoma cell lines , LN229 and LN18 , that are alpha9beta1 integrin positive and negative , respectively , were used for alpha9beta1 integrin-dependent P01138 -induced tumor progression . P01138 was a significant promoter of promigratory and pro-proliferative activities of glioblastoma cells through direct interaction with alpha9beta1 integrin and activation of MAPK Erk1/2 pathway . The level of P01138 increases approximately threefold in the most malignant glioma tissue when compared with normal brain . This increase is related to secretion of P01138 by tumor cells . Specific inhibitors of alpha9beta1 integrin or gene silencing inhibited P01138 -induced proliferation of LN229 cell line to the level shown by LN18 cells . VLO5 promoted alpha9beta1-dependent programmed cell death by induction of intrinsic apoptosis pathway in cancer cells . LN229 cells were rescued from proapoptotic effect of VLO5 by the presence of P01138 . This disintegrin significantly inhibited tumor growth induced by implantation of LN229 cells to the chorioallantoic membrane ( P62158 ) of quail embryonic model , and this inhibitory effect was significantly abolished by the presence of P01138 . alpha9beta1 integrin appears to be an interesting target for blocking the progression of malignant gliomas , especially in light of the stimulatory effect of P01138 on the development of these tumors and its ability to transfer proapoptotic signals in cancer cells . [ Functional characteristics of calcium-sensitive adenylyl cyclase of ciliate Tetrahymena pyriformis ] . DB01373 -sensitive forms of adenylyl cyclase ( AC ) were revealed in most vertebrates and invertebrates and also in some unicellular organisms , in particular ciliates . We have shown for the first time that calcium cations influence the AC activity of ciliate Tetrahymena pyriformis . These cations at the concentrations of 0.2-20 microM stimulated the enzyme activity , and maximum of catalytic effect was observed at 2 microM Ca2+ . DB01373 cations at a concentrations of 100 microM or higher inhibited the AC activity . P62158 antagonists W-5 and W-7 at the concentrations of 20-100 microM inhibited the catalytic effect induced by 5 microM Ca2+ and blocked the effect at higher concentrations of Ca2+ . DB00477 , another calmodulin antagonist , reduced Ca2+-stimulated AC activity only at the concentrations of 200-1000 microM . AC stimulating effects of serotonin , P01133 and DB02527 increased in the presence of 5 microM Ca2+ . AC stimulating effects of P01133 , DB02527 and insulin decreased in the presence of 100 microM Ca2+ , and AC stimulating effect of DB02527 decreased also in the presence of calmodulin antagonists ( 1 mM ) . At the same time , stimulating effect of D-glucose in the presence of Ca2+ and calmodulin antagonists did not change essentially . The data obtained speak in favor of the presence of calcium-sensitive forms of AC in ciliate T. pyriformis which mediate enzyme stimulation by P01133 , DB02527 , insulin , and serotonin . DB01032 reduces infection and inflammation in acute Pseudomonas aeruginosa pneumonia . The activation of inflammasome signaling mediates pathology of acute Pseudomonas aeruginosa pneumonia . This suggests that the inflammasome might represent a target to limit the pathological consequences of acute P. aeruginosa lung infection . Q96RD7 ( Px1 ) channels mediate the activation of caspase-1 and release of IL-1β induced by Q99572 receptor activation . The approved drug probenecid is an inhibitor of Px1 and DB00171 release . In this study , we demonstrate that probenecid reduces infection and inflammation in acute P. aeruginosa pneumonia . Treatment of mice prior to infection with P. aeruginosa resulted in an enhanced clearance of P. aeruginosa and reduced levels of inflammatory mediators , such as IL-1β . In addition , probenecid inhibited the release of inflammatory mediators in murine alveolar macrophages and human U937 cell-derived macrophages upon bacterial infection but not in human bronchial epithelial cells . Thus , Px1 blockade via probenecid treatment may be a therapeutic option in P. aeruginosa pneumonia by improving bacterial clearance and reducing negative consequences of inflammation . [ Relationship between basic fibroblast growth factor ( P09038 ) and cell proliferation , invasion in pituitary adenoma ] . P09038 ( P09038 ) and proliferating cell nuclear antigen ( P12004 ) were examined by immunohistochemistry in fifty-one pituitary adenomas . The results showed that the intensity of P09038 expression was strong or intermediate in twenty-nine adenomas , which was positively related to cell proliferation , there was positive relationship between P09038 expressin and tumor invasion in non-functional adenomas . The data suggest that P09038 may play some role in the origin and progression of pituitary adenomas . Induction of nerve growth factor and basic fibroblast growth factor mRNA following clenbuterol : contrasting anatomical and cellular localization . RNase protection assay and in situ hybridization were used to analyze the temporal and cellular changes in nerve growth factor ( P01138 ) and basic fibroblast growth factor ( P09038 ) mRNA content evoked by the lipophilic beta-adrenergic receptor agonist clenbuterol in adult rat brain . DB01407 elicited a threefold increase in P01138 mRNA expression which was limited to the cerebral cortex . This increase was maximal at 5 h , still evident by 10 h , and declined to control levels by 24 h . By 10 h P01138 protein was also increased . Elevated P01138 mRNA hybridization following clenbuterol was localized in the superficial cortical layers II and III in large Nissl-pale cells , suggesting that P01138 mRNA induction occurs in neurons . In the same animals , clenbuterol induced a twofold increase in the levels of P09038 mRNA in cerebral cortex and hippocampus . This increase was localized primarily in glial cells as demonstrated by P09038 mRNA hybridization over all cortical regions and by labeling of the stratum lacunosum moleculare of the hippocampus . Our results suggest that enhanced noradrenergic tone regulates expression of these two trophic factors by different synaptic mechanisms and suggest that neurotransmitter(s) can coordinate trophic influences on different cell populations . P01138 regulates the PC12 cell cycle machinery through specific inhibition of the Cdk kinases and induction of cyclin D1 . We have examined the effects of P01138 on components of the PC12 cell cycle machinery . We show that P01138 represses over 6-8 d the levels of specific cdk kinase proteins and the G2-M phase specific cyclin B1 and the S phase marker P12004 as well as the level of phosphorylation of the retinoblastoma ( P06400 ) protein . All of these changes may provide a basis for a P01138 block to cell cycling . Unexpectedly , the P55008 phase-specific cyclin D1 was dramatically increased by inducers of differentiation ( P01138 and FGF ) , but not by inducers of proliferation ( P01133 and insulin ) . Although the levels of cyclin D1/cdk2 and cyclin D1/cdk4 complexes increased following P01138 treatment , as did cyclin D1/ P06400 complexes , the associated kinase activities declined , indicating that P01138 also induces an inhibitor of cdk kinase activity . In agreement , P01138 induced the cdk inhibitory protein , P38936 , which was found in cyclin D1/cdk kinase complexes after P01138 treatment . We show that vector over expression of cyclin D1 in PC12 is sufficient on its own to arrest the cells in P55008 phase and inhibit expression of P12004 . These results indicate that P01138 induction of cyclin D1 and inactivation of cdk kinases , the latter possibly by increase of P38936 , play a central role in the P01138 block of PC12 cell cycling . c- P05412 promotes P11274 - P00519 -induced lymphoid leukemia by inhibiting methylation of the 5' region of Cdk6 . The transcription factor c- P05412 and its upstream kinase P45983 have been implicated in P11274 - P00519 -induced leukemogenesis . P45983 has been shown to regulate P10415 expression , thereby altering leukemogenesis , but the impact of c- P05412 remained unclear . In this study , we show that P45983 and c- P05412 promote leukemogenesis via separate pathways , because lack of c- P05412 impairs proliferation of p185( P11274 - P00519 )-transformed cells without affecting their viability . The decreased proliferation of c-Jun(Δ/Δ) cells is associated with the loss of cyclin-dependent kinase 6 ( Q00534 ) expression . In c-Jun(Δ/Δ) cells , Q00534 expression becomes down-regulated upon P11274 - P00519 -induced transformation , which correlates with CpG island methylation within the 5' region of Cdk6 . We verified the impact of Cdk6 deficiency using Cdk6(-/-) mice that developed P11274 - P00519 -induced B-lymphoid leukemia with significantly increased latency and an attenuated disease phenotype . In addition , we show that reexpression of Q00534 in P11274 - P00519 -transformed c-Jun(Δ/Δ) cells reconstitutes proliferation and tumor formation in Nu/Nu mice . In summary , our study reveals a novel function for the activating protein 1 ( AP-1 ) transcription factor c- P05412 in leukemogenesis by antagonizing promoter methylation . Moreover , we identify Q00534 as relevant and critical target of AP-1-regulated DNA methylation on P11274 - P00519 -induced transformation , thereby accelerating leukemogenesis . The P08908 receptor agonist Bay x 3702 inhibits apoptosis induced by serum deprivation in cultured neurons . We examined whether the highly selective P08908 receptor agonist (-)-(R)-2- [ 4- [ [ (3,4-dihydro-2H-1-benzopyran-2-yl)methyl ] -amino ] butyl ] -11 , 2-benz-isothiazol-3(2H)-one 1,1-dioxide monohydrochloride ( Bay x 3702 ) could inhibit neuronal apoptosis induced by serum deprivation . In primary cultures of chick embryonic neurons and in mixed neuronal/glial cultures from neonatal rat hippocampus , Bay x 3702 ( 1 microM ) rescued serum-deprived neurons from apoptosis . The antiapoptotic effect of Bay x 3702 ( 1 microM ) was blocked in chick neurons by the selective P08908 receptor antagonists 4-iodo-N-[2-[4-(methoxyphenyl)-1-piperazin]ethyl]-N-2-pyridinyl-be nzamide hydrochloride ( p-MPPI , 10 microM ) and 4-[3-benzotriazol-1-propyl]-1-(2-methoxyphenyl)-piperazine ( BPMP , 10 microM ) as well as by anti-nerve growth factor ( anti- P01138 ) antibodies and in rat neurons by N-[2-4-(2-methoxy)-1-piperazinyl]ethyl ] -N-(2-pyridinyl)cyclohexane-carbo xamide trihydrochloride ( WAY 100635 , 10 microM ) . We found only under control conditions ( medium with serum ) , but not in serum-deprived cultures , that P01138 secretion was 6-fold increased by Bay x 3702 ( 1 microM ) compared to untreated cultures . Additionally , Bay x 3702 ( 4 microg/kg i.v. ) , infused within a period of 4 h , significantly increased the P01138 content of the rat hippocampus , but not of the striatum . In summary , our data suggest that Bay x 3702 inhibited growth factor withdrawal-induced apoptosis by the stimulation of P08908 receptors and that the P01138 signalling pathway is involved in the mechanism of action . P11362 - 5-hydroxytryptamine 1A heteroreceptor complexes and their enhancement of hippocampal plasticity . BACKGROUND : The hippocampus and its 5-hydroxytryptamine transmission plays an important role in depression related to its involvement in limbic circuit plasticity . METHODS : The analysis was made with bioluminescence resonance energy transfer , co-immunoprecipitation , in situ proximity ligation assay , binding assay , in cell western and the forced swim test . RESULTS : Using bioluminescence resonance energy transfer analysis , fibroblast growth factor receptor 1 ( P11362 ) -5-hydroxytryptamine 1A ( P08908 ) receptor complexes have been demonstrated and their specificity and agonist modulation characterized . Their presence based on co-immunoprecipitation and proximity ligation assay has also been indicated in hippocampal cultures and rat dorsal hippocampal formation showing a neuronal location . In vitro assays on extracellular signal-regulated kinases 1 and 2 phosphorylation have shown synergistic increases in signaling on coactivation with fibroblast growth factor 2 ( P09038 ) and a P08908 agonist , and dependent on the heteroreceptor interface . In vitro and in vivo studies also revealed a P08908 agonist induced phosphorylation of P11362 and extracellular signal-regulated kinase 1/2 in rat hippocampus without changing P09038 levels . Co-activation of the heteroreceptor also resulted in synergistic increases in extensions of PC12 cells and neurite densities and protrusions in primary hippocampal cultures dependent on the receptor interface . The combined acute and repeated intracerebroventricular treatment with P09038 and 8-OH-DPAT was found to produce evidence of highly significant antidepressant actions in the forced swim test . CONCLUSIONS : The findings indicate that neurotrophic and antidepressant effects of 5-HT in brain may , in part , be mediated by activation of the P08908 receptor protomer in the hippocampal P11362 - P08908 receptor complex enhancing the P11362 signaling . 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 . The β2-adrenoceptor agonist clenbuterol elicits neuroprotective , anti-inflammatory and neurotrophic actions in the kainic acid model of excitotoxicity . Excitotoxicity is a mechanism of neuronal cell death implicated in a range of neurodegenerative conditions . Systemic administration of the excitotoxin kainic acid ( KA ) induces inflammation and apoptosis in the hippocampus , resulting in neuronal loss . Evidence indicates that stimulation of glial β(2)-adrenoceptors has anti-inflammatory and neurotrophic properties that could result in neuroprotection . Consequently , in this study we examined the effect of the β(2)-adrenoceptor agonist clenbuterol on KA-induced inflammation , neurotrophic factor expression and apoptosis in the hippocampus . DB01407 ( 0.5mg/kg ) was administered to rats one hour prior to KA ( 10mg/kg ) . Epileptic behaviour induced by KA was assessed for three hours following administration using the Racine scale . Twenty-four hours later TUNEL staining in the P07451 hippocampal subfield and hippocampal caspase-3 activity was assessed to measure KA-induced apoptosis . In addition , expression of inflammatory cytokines ( IL-1β and IFN-γ ) , inducible nitric oxide synthase ( P35228 ) , kynurenine pathway enzymes indolamine 2,3-dioxygenase ( P14902 ) and kynurenine monooxygenase ( O15229 ) , the microglial activation marker CD11b , and the neurotrophins P23560 and P01138 were quantified in the hippocampus using real-time PCR . Whilst clenbuterol treatment did not significantly alter KA-induced epileptic behavior it ameliorated KA-induced apoptosis , and this neuroprotective effect was accompanied by reduced inflammatory cytokine expression , reduced expression of P35228 , P14902 , O15229 and CD11b , coupled with increased P23560 and P01138 expression in KA-treated rats . In conclusion , the β(2)-adrenoceptor agonist clenbuterol has anti-inflammatory and neurotrophic actions and elicits a neuroprotective effect in the KA model of neurodegeneration . Neuroprotection mediated via neurotrophic factors and induction of neurotrophic factors . Neurotrophins and other neurotrophic factors have been shown to support the survival and differentiation of many neuronal populations of the central and peripheral nervous system . Therefore , administering neurotrophic factors could represent an alternative strategy for the treatment of acute and chronic brain disorders . However , the delivery of neurotrophic factors to the brain is one of the largest obstacles in the development of effective therapy for neurodegenerative disorders , because these proteins are not able to cross the blood-brain barrier . The induction of growth factor synthesis in the brain tissue by systemically administered lipophilic drugs , such as beta-adrenoceptor agonists , shown to increase endogenous nerve growth factor ( P01138 ) synthesis in the brain , would be an elegant way to overcome these problems of application . Stimulation of beta-adrenoceptors with clenbuterol led to increased P01138 synthesis in cultured central nervous system ( CNS ) cells and rat brain tissue . DB01407 -induced P01138 expression was reduced to the control levels by coadministration of beta-adrenoceptor antagonist propranolol . Furthermore , clenbuterol protected rat hippocampal neurons subjected to excitotoxic damage . The neuroprotective effect of clenbuterol in vitro depended on increased P01138 synthesis , since the neuroprotection was abolished by P01138 antisense oligonucleotide as well as by antibodies directed against P01138 itself . In vivo , clenbuterol protected rat hippocampus in a model of transient forebrain ischemia and reduced the infarct volume in a rat model of permanent middle cerebral artery occlusion ( MCAo ) . The neuroprotective effect of clenbuterol in vivo was accompanied by enhanced P01138 synthesis in brain tissue . These findings support our hypothesis that orally active P01138 inducers may have a potential as therapeutic agents for the treatment of neurodegenerative disorders and stroke . 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 . Endotoxin-induced liver damage in rats is minimized by beta 2-adrenoceptor stimulation . OBJECTIVE AND DESIGN : To investigate the effects of beta(2)-adrenoceptor ( beta(2)-AR ) stimulation on endotoxin-induced liver damage and systemic cytokine levels in rats . SUBJECTS : Standard male Wistar rats . TREATMENT : A disease-model of lipopolysaccharide ( LPS ) -induced acute systemic inflammation was used . The beta(2)-selective AR agonist clenbuterol was administered before , during , and after LPS-challenge to investigate its effects on the acute inflammatory response and associated liver-failure . METHODS : The following parameters have been measured in plasma : P01375 alpha , P01584 , P05231 , P22301 , Q9NRA2 , ALT , and Bilirubin . Liver histological examination was performed to look for changes in tissue morphology . RESULTS : Administration of clenbuterol ( p.o. ) one hour before , or intravenous at the same time as LPS-challenge resulted in a marked reduction of plasma levels of P01375 alpha , P01584 , and P05231 . A change both in plasma-level and in time-concentration profile of the anti-inflammatory cytokine P22301 was found . DB01407 minimized LPS-induced liver damage , as represented by significantly lowered concentrations of several parameters for liver-failure ( Q9NRA2 , ALT , Bilirubin ) , and improved hepatic tissue morphology . DB01407 administration after LPS challenge failed to inhibit P01375 alpha-release but reduced liver-damage . Simultaneous use of the beta(2)-AR antagonist propranolol augmented LPS-induced liver failure , suggesting a role of endogenous adrenoceptor-agonists in prevention of organ-failure during systemic inflammation . CONCLUSIONS : The results indicate that a selective beta(2)-AR agonist might be used as an additional therapeutic agent in the clinic for the treatment of ( acute ) systemic inflammatory disorders in order to reduce or prevent subsequent liver failure . DB01407 induces growth factor mRNA , activates astrocytes , and protects rat brain tissue against ischemic damage . The induction of growth factor synthesis in brain tissue by beta2-adrenoceptor agonists , such as clenbuterol , is a promising approach to protect brain tissue from ischemic damage . DB01407 ( 0.01-0.5 mg/kg ) reduced the cortical infarct volume in Long-Evans rats as measured 7 days after permanent occlusion of the middle cerebral artery . Dosages of clenbuterol higher than 1 mg/kg showed no cerebroprotective effect due to a decrease in blood pressure and an increase in plasma glucose level . The increase in the mRNA level of nerve growth factor ( P01138 ) , basic fibroblast growth factor ( basic FGF ) , and transforming growth factor-beta1 ( TGF-beta1 ) mRNA in cortical and hippocampal tissue occurred earlier after middle cerebral artery occlusion and was more pronounced in animals treated with clenbuterol than in controls . In addition , glial fibrillary acidic protein ( P14136 ) mRNA expression was enhanced in astrocytes 6 h after ischemia in clenbuterol-treated animals . The results suggest that growth factor synthesis is enhanced in activated astrocytes and that this could be the mechanism of clenbuterol-induced cerebroprotection after ischemia . 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 . Q99572 receptor-dependent intestinal afferent hypersensitivity in a mouse model of postinfectious irritable bowel syndrome . The DB00171 -gated P2X(7) receptor ( P2X(7)R ) was shown to be an important mediator of inflammation and inflammatory pain through its regulation of IL-1β processing and release . Trichinella spiralis-infected mice develop a postinflammatory visceral hypersensitivity that is reminiscent of the clinical features associated with postinfectious irritable bowel syndrome . In this study , we used P2X(7)R knockout mice ( P2X(7)R(-/-) ) to investigate the role of P2X(7)R activation in the in vivo production of IL-1β and the development of postinflammatory visceral hypersensitivity in the T. spiralis-infected mouse . During acute nematode infection , IL-1β-containing cells and P2X(7)R expression were increased in the jejunum of wild-type ( WT ) mice . Peritoneal and serum IL-1β levels were also increased , which was indicative of elevated IL-1β release . However , in the P2X(7)R(-/-) animals , we found that infection had no effect upon intracellular , plasma , or peritoneal IL-1β levels . Conversely , infection augmented peritoneal P01375 -α levels in both WT and P2X(7)R(-/-) animals . Infection was also associated with a P2X(7)R-dependent increase in extracellular peritoneal lactate dehydrogenase , and it triggered immunological changes in both strains . Jejunal afferent fiber mechanosensitivity was assessed in uninfected and postinfected WT and P2X(7)R(-/-) animals . Postinfected WT animals developed an augmented afferent fiber response to mechanical stimuli ; however , this did not develop in postinfected P2X(7)R(-/-) animals . Therefore , our results demonstrated that P2X(7)Rs play a pivotal role in intestinal inflammation and are a trigger for the development of visceral hypersensitivity . 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 . Evaluation of human astrocytoma and glioblastoma cell lines for nerve growth factor release . Nerve growth factor ( P01138 ) prevents degeneration of cholinergic neurons in the central nervous system ( CNS ) , and has potential as a therapeutic treatment for Alzheimer 's disease . The inability of P01138 to cross the blood-brain barrier has prompted pharmacological approaches investigating peripherally administered compounds that stimulate release of endogenous P01138 . This study describes the P01138 -releasing properties of six human astrocytoma and glioblastoma cell lines ( SW 1088 , SW 1783 and CRL 1718 astrocytomas , and U-138 , U-373 , and T98G glioblastomas ) . Using a highly specific two-site ELISA for human P01138 , basal P01138 release could be detected in all cell lines , with the lowest level in the T98G line ( approximately 80 pg P01138 /ml ) . Cell lines tested with a variety of compounds for 24 h in serum-free media demonstrated stimulation of P01138 release by distinct mechanisms . P01138 levels were markedly elevated ( up to 8-fold above vehicle-treated cells ) when stimulated with the cytokine interleukin-1 beta ( P01584 ) . Phorbol ester stimulated P01138 release 4-fold . DB01407 , 4-methyl catechol , and propentofylline had little activity , while 6-(4-hydroxybutyl)-2,3,5,-trimethyl-1,4,benzoquinone ( DB01157 ) , dexamethasone and 1,25-dihydroxyvitamin D3 elevated P01138 levels 3-fold . These data indicate differences in the ability of human astrocytoma and glioblastoma cells to release P01138 when stimulated with mechanistically distinct compounds . The role of tumor suppressor dysregulation in prostate cancer progression . P10275 activity is essential for prostate cancer development and progression . While there are classically defined roles for the retinoblastoma ( P06400 ) and p53 tumor suppressor pathways in maintenance of cell cycle control and the DNA damage response , recent studies have demonstrated a direct role of these two pathways in regulating AR expression and function . While the role of Pten deregulation in prostate cancer has provided much insight in to the mechanisms underlying prostate cancer initiation and progression , emerging roles for P06400 and p53 are likely to further expand upon our understanding of tumor suppressor/nuclear receptor interaction . As disconnecting mitogenic signaling from AR-mediated gene transcription underlies the progression to castrate resistant prostate cancer ( CRPC ) , functional inactivation of these two tumor suppressor pathways represents one mechanism through which AR protein levels can be upregulated and AR-mediated gene transcription can become aberrant . Importantly , recent advances in small molecule inhibitor design and discovery have led to the identification of agents capable of targeting these two prominent pathways and restoring the function of deregulated wild-type P06400 and p53 protein . While such agents have undergone extensive study in many solid tumor types , the additional importance of P06400 and p53 in restraining transcription of the AR gene within the prostate provides impetus for examining how loss of these two tumor suppressor proteins can facilitate transition of prostate cancers to CRPC . As will be reviewed in this article , restoration of P06400 and p53 functions are not only important in regard to shortterm cell cycle regulation and response to genomic stresses , but likely have direct implications for deregulation of the AR locus . Basal cell carcinoma and variants in genes coding for immune response , DNA repair , folate and iron metabolism . Basal cell carcinoma ( BCC ) is one of the most common neoplasms in the world and its incidence has been increasing worldwide in recent years . BCCs are caused by an interplay between genetic and environment factors . We conducted a case-control association study in BCC patients and controls from Sweden and Finland . Fifteen single nucleotide polymorphisms ( SNPs ) , P05231 -174G/C , -634G/C , and -597G/A ; P22301 -1082G/A and -592C/A ; IL-1beta-511C/T ; NBS1 exon 5 Glu185Gln ; Q01831 exon 15 Lys939Gln ; P18074 exon 23 Lys751Gln ; P18887 exon 10 Arg399Gln ; O43542 exon 7 Thr241Met ; cyclin D1 exon 4 G870A ; P42898 exon 4 Ala222Val and exon 7 Glu429Ala ; Q30201 exon 4 C282Y were performed by Pyrosequencing and RFLP techniques . Most of the genotype distributions were in accordance with the Hardy-Weinberg equilibrium ( HWE ) , except for P22301 -1082G/A , where cases with BCC showed a significant deviation from HWE ( P = 0.04 ) . Linkage disequilibrium was observed between the -174 and -597 alleles in the P05231 gene in the present populations . No difference between BCC and controls appeared in any of the SNPs analyzed . Only the combined distributions of TT/AA genotypes in P42898 exon 4 ( C/T ) and exon 7 ( A/C ) showed slight increase in BCC compared to controls ( P < 0.07 , OR : 1.94 ; 95 % CI : 0.96-3.89 ) . Bayesian analysis and the GUSTO trial . Global Utilization of DB00086 and Tissue P00747 Activator in Occluded Arteries . Role of the androgen receptor axis in prostate cancer . P10275 ( AR ) is expressed in nearly all prostate cancers , including treatment-refractory disease . The role of this receptor in the molecular endocrinology of prostate cancer has become increasingly clear in recent years . The AR is now known to participate in tumor progression through 3 mechanisms : expression ( activation and upregulation of receptor activity ) , point mutations , and ligand-independent activation . With regard to the latter mechanism , interleukin-6 ( P05231 ) is among the most important nonsteroidal regulators of AR activity . In the absence of androgen , P05231 causes activation of AR that is approximately 50 % of the maximal activity induced by androgen . At low concentrations of androgen , P05231 and androgen synergistically activate AR . Nonsteroidal antiandrogens usually antagonize this activation , but they switch to an agonist effect in the presence of oncostatin M , an P05231 -related cytokine . The growth of parental LNCaP cells is initially inhibited by exposure to P05231 , but long-term treatment renders the cells resistant to such inhibition and confers a growth advantage . Both P05231 and oncostatin M stimulate AR activity , but only oncostatin M is associated with strong acquisition of the agonist properties of nonsteroidal antiandrogens . It is hoped that continuing research on AR expression and function in prostate cancer will pave the way for new therapeutic strategies . P10275 stimulates bone sialoprotein ( BSP ) gene transcription via DB02527 response element and activator protein 1/glucocorticoid response elements . Bone sialoprotein ( BSP ) is an early marker of osteoblast differentiation . Androgens are steroid hormones that are essential for skeletal development . The androgen receptor ( AR ) is a transcription factor and a member of the steroid receptor superfamily that plays an important role in male sexual differentiation and prostate cell proliferation . To determine the molecular mechanism involved in the stimulation of bone formation , we have analyzed the effects of androgens and AR effects on BSP gene transcription . AR protein levels were increased after AR overexpression in ROS17/2.8 cells . BSP mRNA levels were increased by AR overexpression . However , the endogenous and overexpressed BSP mRNA levels were not changed by DB02901 ( 10(-8) M , 24 h ) . Whereas luciferase ( LUC ) activities in all constructs , including a short construct ( nts -116 to +60 ) , were increased by AR overexpression , the basal and LUC activities enhanced by AR overexpression were not induced by DB02901 ( 10(-8)M , 24 h ) . The effect of AR overexpression was abrogated by 2 bp mutations in either the DB02527 response element ( CRE ) or activator protein 1 ( P05412 ) /glucocorticoid response element ( GRE ) . Gel shift analyses showed that AR overexpression increased binding to the CRE and P05412 /GRE elements . Notably , the CRE-protein complexes were supershifted by phospho-CREB antibody , and CREB , c-Fos , c-Jun , and AR antibodies disrupted the complexes formation . The P05412 /GRE-protein complexes were supershifted by c-Fos antibody and c-Jun , and AR antibodies disrupted the complexes formation . These studies demonstrate that AR stimulates BSP gene transcription by targeting the CRE and P05412 /GRE elements in the promoter of the rat BSP gene . Molecular and biologic characterization of a newly established Philadelphia-positive acute lymphoblastic leukemia cell line ( Z-33 ) with an autocrine response to GM- P04141 . We have recently established a new Philadelphia chromosome ( Ph1 ) -positive acute lymphoblastic leukemia ( ALL ) cell line , designated Z-33 . This line has Q401N2 morphology , ultrastructural characteristics of lymphoblasts and typical B lineage surface markers identical to those observed in the Ph1-positive ALL patient from whom the line was derived . In addition , a rearranged immunoglobulin heavy-chain gene ( JH ) band was found in Z-33 cells by Southern blot analysis , confirming B cell clonality . Cytogenetic analysis of the cell line revealed t(9;22)(q34;q11.2) . Polymerase chain reaction ( PCR ) -amplified cDNA from Z-33 cells demonstrated an e1-az P11274 - P00519 junction , and the p190BCR- P00519 protein was detected in them by the immune complex kinase assay . Z-33 cells produce interleukin ( IL ) -1 beta , P05231 , granulocyte colony-stimulating factor ( DB00099 ) , granulocyte-macrophage P04141 ( GM- P04141 ) , tumor necrosis factor ( P01375 ) -alpha , and transforming growth factor ( TGF ) -beta , Neither P01584 , DB00099 , P01375 , nor their corresponding antibodies affected the cell line 's growth . In contrast , anti-GM- P04141 neutralizing antibodies suppressed Z-33 colony formation , and GM- P04141 stimulated it in a dose-dependent fashion . In addition , receptor studies with biotinylated GM- P04141 demonstrated specific binding to Z-33 cells , indicating that the cells express GM- P04141 receptors . Taken together , our data suggest that the Ph1-positive Z-33 ALL cells produce GM- P04141 , express GM- P04141 receptors , and show an autocrine proliferative response to this cytokine . P10275 coregulator Q96L73 -alpha interacts with death receptor-6 revealed by the yeast two-hybrid . Q96L73 -alpha is a newly identified androgen receptor coactivator . In order to further elucidate its precise role in cells , using the Q96L73 -alpha fragment containing four P20941 and one Q01105 conserved domains as bait we revealed an Q96L73 -alpha- P20941 - Q01105 -interacting protein , death receptor-6 ( O75509 ) , in the yeast two-hybrid screening . O75509 is the member of P01375 receptor family and has a death domain in its intracellular cytoplasmic portion ( DR6cp ) to mediate the cell apoptosis . The interaction between Q96L73 -alpha- P20941 - Q01105 and DR6cp was confirmed in vitro and in vivo . Our finding implied that androgen signaling pathway might cross talk with apoptosis signaling pathway through the interaction between Q96L73 -alpha and O75509 . Extracellular DB00171 and nerve growth factor intensify hypoglycemia-induced cell death in primary neurons : role of P2 and NGFRp75 receptors . In this study , we monitored the direct expression of P2 receptors for extracellular DB00171 in cerebellar granule neurons undergoing metabolism impairment . DB09341 deprivation for 30-60 min inhibited P47900 receptor protein , only weakly modulated P51575 , Q9UBL9 and P56373 , and up-regulated by about two-fold Q99571 , Q99572 and P51582 . The P2X/Y antagonist basilen blue , protecting cerebellar neurons from hypoglycemic cell death , maintained within basal levels only the expression of Q99572 and P51582 proteins , but not Q99571 or P47900 . DB09341 starvation transiently increased ( up to three-fold ) the expression of NGFRp75 receptor protein and strongly stimulated the extracellular release of nerve growth factor ( P01138 ; about 10-fold ) . Exogenously added P01138 then augmented hypoglycemic neuronal death by about 60 % , increasing the percentage of Höechst-positive nuclei ( from approximately 62 to 95 % ) , reducing lactate dehydrogenase ( LDH ) release ( from about 50 to 14 % ) and significantly overstimulating the hypoglycemia-induced expression of Q99572 and P51582 . Conversely , extracellular DB00171 augmented hypoglycemic neuronal death by about 80 % , reducing the number of Höechst-positive nuclei ( from approximately 62 % to 14 % ) , augmenting LDH outflow ( by about 30 % ) and further increasing the hypoglycemia-induced expression of NGFRp75 . Our results indicate that P2 and NGFRp75 receptors are modulated during glucose starvation and that extracellular DB00171 and P01138 drive features of , respectively , necrotic and apoptotic hypoglycemic cell death , aggravating the consequences of metabolism impairment in cerebellar primary neurons . Intermediate phenotype analysis of patients , unaffected siblings , and healthy controls identifies Q05940 as a candidate gene for psychotic disorder and neurocognition . Psychotic disorders are associated with neurocognitive alterations that aggregate in unaffected family members , suggesting that genetic vulnerability to psychotic disorder impacts neurocognition . The aim of the present study was to investigate whether selected schizophrenia candidate single nucleotide polymorphisms ( SNPs ) are associated with ( 1 ) neurocognitive functioning across populations at different genetic risk for psychosis ( 2 ) and psychotic disorder . The association between 152 SNPs in 43 candidate genes and a composite measure of neurocognitive functioning was examined in 718 patients with psychotic disorder . Follow-up analyses were carried out in 750 unaffected siblings and 389 healthy comparison subjects . In the patients , 13 associations between SNPs and cognitive functioning were significant at P < .05 , situated in P21728 , P35462 , Q01959 , P23560 , P09038 , Q05940 , Q13451 , and Q9UBC3 . Follow-up of these SNPs revealed a significant and directionally similar association for Q05940 ( alternatively Q05940 ) rs363227 in siblings ( B = -0.13 , P = .04 ) and a trend association in control subjects ( B = -0.10 , P = .12 ) . This association was accompanied by a significantly increased risk for psychotic disorder associated with the T allele ( linear OR = 1.51 , 95 % CI 1.10-2.07 , P = .01 ) , which was reduced when covarying for cognitive performance ( OR = 1.29 , 95 % CI 0.92-1.81 , P = .14 ) , suggesting mediation . Genetic variation in Q05940 may be linked to alterations in cognitive functioning underlying psychotic disorder , possibly through altered transport of monoamines into synaptic vesicles . Repeated , intermittent treatment with amphetamine induces neurite outgrowth in rat pheochromocytoma cells ( PC12 cells ) . Repeated , intermittent treatment with amphetamine ( P49418 ) leads to long-term neurobiological adaptations in rat brain including an increased number and branching of dendritic spines . This effect depends upon several different cell types in the intact brain . Here we demonstrate that repeated , intermittent P49418 treatment induces neurite outgrowth in cultured PC12 cells without the requirement for integrated synaptic pathways . PC12 cells were treated with 1 micro M P49418 for 5 min a day , for 5 days . After 10 days of withdrawal , there was an increase in the percentage of cells with neurites ( approximately 30 % ) and the length of neurites as well as an increase in the level of P20936 -43 and neurofilament-M . Neurite outgrowth was enhanced as withdrawal time was increased . Neurite outgrowth was much greater following repeated , intermittent treatment with P49418 compared to continuous or single treatment with P49418 . Pretreatment with cocaine , a monoamine transporter blocker , inhibited the P49418 -mediated increase in neurite outgrowth . Neither P01138 antibody nor DA receptor antagonists blocked P49418 -induced neurite outgrowth , demonstrating that P49418 -induced neurite outgrowth is not dependent on endogenous P01138 release or DA receptors . Thus we have demonstrated that repeated , intermittent treatment with P49418 has a neurotrophic effect in PC12 cells . The effect requires the action of P49418 on the norepinephrine transporter , and shares characteristics in its development with other forms of sensitization but does not require an intact neuroanatomy . Nerve growth factor and receptors are significantly affected by histamine stimulus through H1 receptor in pancreatic carcinoma cells . Nerve growth factor ( P01138 ) as an autocrine or paracrine growth factor plays a critical role in the pathogenesis and progression of human pancreatic cancer . P01138 is synthesized as a proform ( proNGF ) that , when cleaved , releases mature ligand (mNGF). proNGF and mNGF bind to high-affinity tyrosine kinase receptor A ( TrkA ) and low-affinity receptor p75 to different extents . DB11320 is a potent stimulator of P01138 in the inflammatory lesion as determined by ELISA . This has generally been attributed to the accumulation of mNGF . To determine the effect of histamine on nerve growth factor/receptor expression in human pancreatic cancer , the present study explored intracellular and extracellular P01138 production and p75 and TrkA membrane receptor expression in the PANC-1 , KMP-6 and PK-1 cell lines . DB11320 enhanced P01138 secretion and mRNA expression in PANC-1 and KMP-6 cells , but not in PK-1 cells . proNGF was revealed using Western blotting to be the predominant form of P01138 , but was significantly reduced by histamine . p75 receptor binding was increased with histamine treatement , but no significant alteration was observed for TrkA . P12004 ( P12004 ) , an important indicator of cell proliferation , was significantly reduced by histamine stimulation . H1 and H2 receptors were both observed in the pancreatic cancer cells , and the alterations induced by histamine were counteracted by H1 receptor antagonist DB06691 ; however , the H2 receptor subtype was excluded from this process . These results suggest that histamine induces distinct nerve growth factor/receptor responsiveness via H1 receptor-induced signaling , thus affecting pancreatic cancer cell proliferation . Evaluation of cytokine production by equine alveolar macrophages exposed to lipopolysaccharide , Aspergillus fumigatus , and a suspension of hay dust . OBJECTIVE : To evaluate cytokine production by equine alveolar macrophages after exposure to lipopolysaccharide ( LPS ) , Aspergillus fumigatus , and hay dust , and determine the effect of clenbuterol on the cytokine response . ANIMALS : 6 horses . PROCEDURE : Alveolar macrophages were exposed to PBS solution ( negative control ) , LPS , hyphae and conidia of Aspergillus fumigatus ( AF ) , or a suspension of hay dust ( Q86SQ9 ) and incubated for 24 hours at 37 degrees C . Concentrations of tumor necrosis factor ( P01375 ) -alpha and interleukin ( IL ) -1beta were measured in the supernatant . The procedure was repeated with cells that were concurrently incubated with 0.5 microM clenbuterol . RESULTS : Exposure to Q86SQ9 and AF significantly increased production of P01375 by equine alveolar macrophages . The increase in P01375 produced in response to Q86SQ9 and AF was 5 and 7 times as great , respectively , as the increase measured in response to LPS . The concentration of IL-1beta in the supernatant was significantly increased after exposure of cells to AF . DB01407 was effective at inhibiting P01375 production by cells exposed to LPS , Q86SQ9 , or AF . CONCLUSIONS AND CLINICAL RELEVANCE : Increased production of P01375 and IL-1 indicated that the pro-inflammatory cytokines produced by alveolar macrophages in response to allergens may play a role in recurrent airway obstruction ( O75106 ) in horses . Equine alveolar macrophages are not only a primary pulmonary defense mechanism but may also influence the pathogenesis of equine O75106 . The beta2-adrenoceptor agonist clenbuterol , a drug that is commonly used for treatment of equine O75106 , promotes immediate bronchodilation and may also contribute to downward modulation of the inflammatory response . Sex steroid receptors , secondary bile acids and colorectal cancer . A possible mechanism of interaction . AIM : The aim of the work was to study in colon-rectum cancer mucosae the binding charateristics , as sex steroid receptors . METHODS : Specific androgen ( AR ) , estrogen ( ER ) and progesterone ( PgR ) receptors were measured in the tissue samples of 35 patients ( 15 males , 20 females ) undergoing colectomy or coloproctectomy for adenocarcinoma . The characteristics of androgen receptor ( AR , DB02901 -R : dihydrotestosterone receptor ) were also investigated using competitive activity of cyproterone acetate , cortisol , aldosterone and steroid-like substances such as deoxycholic and lithocholic acid , present in the milieu of the considered organ . Binding assays and competition tests were conducted using a charcoal dextran method . RESULTS : When present ( 50 % ) , ER and PgR receptors showed very low levels and no difference was noted between cancerous and the surrounding healthy mucosa . AR were found in all samples from both neoplastic and non neoplastic surrounding mucosa , with no significant difference . P10275 however exhibited an altered binding activity in cancer specimens . DB04839 did not displace DB02901 from AR while significant displacing activity was elicited by DB02901 , testosterone , as well as by lithocholic acid , but not by deoxycholic acid . CONCLUSION : In cancerous large bowel mucosa , androgen receptors show altered binding characteristics . The selective binding of lithocholic acid to AR supports the hypothesis that diet-related endoluminal substances may play a role in cancer development model where molecular alterations such as DNA damage or mutation is the 1st event . [ DB01407 in amyotrophic lateral sclerosis. No indication for a positive effect ] . The anabolic effects of clenbuterol have been recognized for a long time . DB01407 augments the expression of specific muscle proteins with a differential effect on type I and type II fibres . Furthermore , clenbuterol induces the synthesis of endogenous nerve growth factor ( P01138 ) and may itself be a myotrophic factor released by neuron endings . Side effects include tremor and headache and dose dependent abnormalities of laboratory values ( hypokalemia , hypoglycemia ) . After long-term medication increasing fatigue of muscles has been observed . Decreased expression of beta 2-adrenergic receptors may limit the expected functional improvement . The efficacy of clenbuterol as symptomatic treatment of amyotrophic lateral sclerosis has not been proved . Controlled treatment trials are warranted to assess this question . Stimulation of central β2-adrenoceptors suppresses NFκB activity in rat brain : a role for IκB . In this study we examined the impact of systemic treatment with the long-acting brain penetrant β2-adrenoceptor agonist clenbuterol on NFκB activity and IκB expression in rat brain . DB01407 decreased NFκB activity ( p65 DNA binding ) in nuclear extracts prepared from rat cortex and hippocampus for up to 8h following a single treatment . This was accompanied by increased expression of IκBα mRNA and protein . The temporal increase in IκB protein expression paralleled the suppression of NFκB activity , suggesting that IκBα mediates the suppression NFκB activity observed . These actions of clenbuterol were prevented by pre-treatment with the non-selective β-adrenoceptor antagonist propranolol , the β2-adrenoceptor antagonist ICI-118,551 , but not the β1-adrenoceptor antagonist metoprolol , suggesting that the effects of clenbuterol on IκBα expression and NFκB activity are mediated specifically by the β2-adrenoceptor . In addition , the actions of clenbuterol were mimicked by systemic administration of another highly selective long-acting β2-adrenoceptor agonist formoterol . As neurodegenerative diseases are associated with inflammation we determined if clenbuterol could suppress NFκB activation that occurs in response to an inflammatory stimulus . In this regard we demonstrate that clenbuterol inhibited IκB phosphorylation and IκB degradation and inhibited NFκB activity in hippocampus and cortex of rats following a central injection of the inflammagen bacterial lipopolysaccharide ( LPS ) . In tandem , clenbuterol blocked expression of the NFκB-inducible genes P01375 -α and P05362 following LPS administration . Our finding that clenbuterol and formoterol inhibit NFκB activity in the CNS further supports the idea that β2-adrenoceptors may be an attractive target for treating neuroinflammation and combating inflammation-related neurodegeneration . Tyrosine phosphorylation of Q92835 promotes its proteasomal degradation . OBJECTIVE : The activity of the SH2-containing-phosphatidylinositol-5'-phosphatase ( Q92835 , also known as Q92835 ) , a critical hematopoietic-restricted negative regulator of the P19957 kinase ( PI3K ) pathway , is regulated in large part via its protein levels . We sought to determine the mechanism(s) involved in its downregulation by P11274 - P00519 and by interleukin ( IL ) -4 . MATERIALS AND METHODS : We used Ba/ P13726 ( Q92817 -tetOFF) cells to study the downregulation of Q92835 by P11274 - P00519 and bone marrow-derived macrophages to study Q92835 's downregulation by P05112 . RESULTS : We show herein that P11274 - P00519 downregulates Q92835 , but not O15357 or P60484 , and this can be blocked with the Src kinase inhibitor Q99463 , which inhibits the tyrosine phosphorylation of Q92835 , or with the proteasomal inhibitor MG-132 . We also show , using anti- Q92835 immunoprecipitates , that c-Cbl and Cbl-b are associated with Q92835 and that P11274 - P00519 induces Q92835 's polyubiquitination . This ubiquitination can be blocked with Q99463 , consistent with the tyrosine phosphorylation of Q92835 acting as a signal for its ubiquitination . In bone marrow-derived macrophages , P05112 also leads to the proteasomal degradation of Q92835 but , unlike in Ba/ P13726 ( Q92817 -tetOFF) cells , O15357 is also proteasomally degraded and the degradation of both inositol phosphatases can be prevented with Q99463 or MG-132 . CONCLUSION : Our results suggest that Q92835 protein levels can be reduced via P11274 - P00519 and/or Src family member-induced tyrosine phosphorylation of Q92835 because this triggers its polyubiquitination and degradation within the proteasome . [ Genetic polymorphisms and cancer risk ] . While hereditary disease genes have a high lifelong cumulative incidence rate ( penetrance ) , the penetrance for polymorphism genotypes is not high . Polymorphisms relating to cancer incidence are classified into 1. carcinogen metabolizing enzymes ( CYPs , GSTs , P15559 , etc. ) , 2 . DNA repair enzymes ( O15527 , P18887 , P18074 , etc. ) , 3 . DNA synthesis and methylation ( P42898 , MS , etc. ) , 4. cytokines and inflammation-related enzymes ( IL-1B , P01375 -A , P05164 , etc. ) , and 5. sex hormone metabolizing enzymes and the receptors ( P11511 , P31213 , ER , etc. ) . Since genotypes can not be manipulated , they are not the factors subject to prevention . However , the finding that the strength of association between lifestyle and disease occurrence is influenced by genotypes ( gene-environment interaction ) , opens the door to genotype applications for disease prevention practice . 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 . Characterization of plant P18887 and its interaction with proliferating cell nuclear antigen . In plants , there are no P06746 ( Pol beta ) and P49916 ( Lig3 ) genes . Thus , the plant short-patch base excision repair ( short-patch BER ) pathway must differ considerably from that in mammals . We characterized the rice ( Oryza Sativa L. cv. Nipponbare ) homologue of the mammalian X-ray repair cross complementing 1 ( P18887 ) , a well-known BER protein . The plant P18887 lacks the N-terminal domain ( NTD ) which is required for Pol beta binding and is essential for mammalian cell survival . The recombinant rice P18887 ( OsXRCC1 ) protein binds single-stranded DNA ( ssDNA ) as well as double-stranded DNA ( dsDNA ) and also interacts with rice proliferating cell nuclear antigen ( OsPCNA ) in a pull-down assay . Through immunoprecipitation , we demonstrated that OsXRCC1 forms a complex with P12004 in vivo . OsXRCC1 mRNA was expressed in all rice organs and was induced by application of bleomycin , but not of MMS , H(2)O(2) or UV-B . DB00290 also increased the fraction of OsXRCC1 associated with chromatin . These results suggest that OsXRCC1 contributes to DNA repair pathways that differ from the mammalian BER system . DB00227 -stimulated superinduction of P16581 , P05362 and P19320 in P01375 activated human vascular endothelial cells . Inhibitors of P04035 ( statins ) reveal important pharmacological effects in addition to reducing the plasma LDL cholesterol level . In the pathogenesis of arteriosclerosis , transendothelial migration of various leukocytes including monocytes is a crucial step . We , therefore , investigated the expression of P16581 , intercellular cell adhesion molecule-1 ( P05362 ) and vascular cell adhesion molecule-1 ( P19320 ) in vascular endothelial cells as influenced by lovastatin . Human umbilical vein endothelial cells ( HUVECs ) express significant amounts of selectins and cell adhesion molecules ( CAMs ) within a few hours after stimulation with P01375 . This effect is potentiated by 100-200 % when the cells are pretreated with 0.1-2.5 microM lovastatin . The lovastatin-mediated increase in the cytoplasm and at the cell surface is dose-dependent and significant at lovastatin concentrations comparable to plasma levels in patients under lovastatin treatment . The lovastatin-potentiated increase of P16581 and CAMs is correlated with a corresponding increase of selectin- and P62158 -specific mRNA . We conclude that , in vivo , statin treatment could trigger an enhanced recruitment of macrophages that might support the cholesteryl ester efflux from the arteriosclerotic plaque . Dopamine modulating drugs influence striatal (+)-[11C]DTBZ binding in rats : Q05940 binding is sensitive to changes in vesicular dopamine concentration . Binding of (+)-[11C]DTBZ ( dihydrotetrabenazine ) to the striatal vesicular monoamine transporter ( Q05940 ) is widely considered to be a stable marker of dopamine neurone integrity . However , we now find that specific binding of a tracer dose of (+)-[11C]DTBZ is modestly increased in rat striatum following dopamine depletion with alpha-methyl-p-tyrosine ( alpha-MPT , +14 % ) or DB01576 ( d- P49418 , 20 mg/kg , +12 % ) and decreased following dopamine elevation with gamma-hydroxybutyrate ( DB01440 , -16 % ) or levodopa ( -20 % ) . We suggest that in vivo (+)-[11C]DTBZ binding in imaging studies is subject to competition by vesicular dopamine and , in this respect , is not a " stable " dopamine biomarker as is generally assumed . DB01407 affects the expression of messenger RNA for interleukin 10 in peripheral leukocytes from horses challenged intrabronchially with lipopolysaccharides . On four occasions , four horses with heaves and four horses with small airway inflammatory diseases inhaled 0.9 % saline based aerosol mixtures with or without lipopolysaccharides ( LPS ) . Prior to the first saline and LPS inhalation , horses were untreated , while three and a half days prior to the third and forth inhalation horses had received 0.8 microg/kg clenbuterol intravenously twice daily . The messenger RNA ( mRNA ) expression of tumour necrosis factor-alpha ( P01375 ) , interleukin ( IL ) -1beta , P05112 , P05231 , P10145 , P22301 and interferon- gamma ( IFN- gamma ) was investigated by RT-PCR , all of which were expressed in the white blood cells of samples collected . Inhalation of LPS only changed the cytokine expression profile of P22301 , P05112 and P01375 mRNA which were higher after challenge with LPS . However in those horses that were treated with clenbuterol the LPS-induced P22301 mRNA expression was shown to be suppressed . Further changes in P05112 and P01375 were not significant . Thus the results of this study indicated that clenbuterol can modulate the expression of P22301 mRNA in peripheral white blood cells in those horses with small airway diseases that have been exposed to LPS . Effect of olopatadine and other histamine H1 receptor antagonists on the skin inflammation induced by repeated topical application of oxazolone in mice . P35367 antagonists have long been prescribed for atopic dermatitis as an adjuvant therapy with topical therapy by local applied steroids . Olopatadine is one of the second-generation histamine H1 receptor antagonists that are treated for allergic disorders . We investigated that the effect of olopatadine on oxazolone-induced chronic contact hypersensitivity response in BALB/c mice compared with other histamine H1 receptor antagonists loratadine , cetirizine and fexofenadine . The chronic contact hypersensitivity induced by repeated application of oxazolone was treated with olopatadine and other histamine H1 receptor antagonists at the effective doses on histamine-induced paw edema in mice . The effects of these drugs in the oxazolone-induced model were quantified by measurements of ear swelling , and levels of cytokines in the lesioned ear . Olopatadine significantly inhibited the ear swelling and the increased production of P05112 , IL-1beta , P05231 , GM- P04141 and P01138 in the lesioned ear . On the other hand , the other histamine H1 receptor antagonists did not significantly suppress the increase in ear thickness . Moreover , they did not affect the production of cytokines in the lesioned ear . These results indicate that olopatadine appears to exert additional biological effects besides its blockade of the histamine H1 receptor . Pharmacological modulation of nerve growth factor synthesis : a mechanistic comparison of vitamin D receptor and beta(2)-adrenoceptor agonists . Increasing nerve growth factor ( P01138 ) in the PNS is a rational strategy for treating certain neurodegenerative disorders . The present studies were undertaken to compare two compounds , a vitamin D(3) analogue ( CB1093 ) with minimal calcaemic effects , and clenbuterol , a long-acting beta(2)-adrenoceptor agonist , both of which induce P01138 synthesis in vivo . DB01407 caused significant increases in both P01138 mRNA and protein in 3T3 cells ; with maxima at 10 nM and at 8-12 h exposure . Effects of clenbuterol on P01138 mRNA were antagonized by propranolol . Mobility shift assays on whole cell extracts showed that clenbuterol increased P05412 binding in 3T3 cells prior to increasing P01138 synthesis . DB01407 was without effect on P01138 mRNA levels in L929 cells , whereas CB1093 caused significant increases in both P01138 mRNA and protein levels in both 3T3 and L929 cells . Stimulation was almost maximal at 24 h exposure and was sustained for at least 72 h . The magnitude of the increase was much greater in L929 ( 700 % increase ) than in 3T3 cells ( 80 % ) . Binding to the vitamin D nuclear receptor ( P11473 ) , which acts as a transcription factor itself , was increased as early as 30 min after exposure to of CB1093 and maintained up to 24 h . Increased P11473 binding preceded increased P01138 mRNA . A 150 % increase in AP-1 binding was also evident . This study demonstrates that CB1093 and clenbuterol stimulate P01138 levels in vitro and that AP-1 binding could be a commonality between the mechanism of P01138 induction of these two compounds . Augmentation of methamphetamine-induced behaviors in transgenic mice lacking the trace amine-associated receptor 1 . The trace amine-associated receptor 1 ( Q96RJ0 ) is a G protein-coupled receptor that is functionally activated by amphetamine-based psychostimulants , including amphetamine , methamphetamine and DB01454 . Previous studies have shown that in transgenic mice lacking the Q96RJ0 gene ( Q96RJ0 knockout ; KO ) a single injection of amphetamine can produce enhanced behavioral responses compared to responses evoked in wild-type ( WT ) mice . Further , the psychostimulant effects of cocaine can be diminished by selective activation of Q96RJ0 . These findings suggest that Q96RJ0 might be implicated in the rewarding properties of psychostimulants . To investigate the role of Q96RJ0 in the rewarding effects of drugs of abuse , the psychomotor stimulating effects of amphetamine and methamphetamine and the conditioned rewarding effects of methamphetamine and morphine were compared between WT and Q96RJ0 KO mice . In locomotor activity studies , both single and repeated exposure to DB01576 or methamphetamine generated significantly higher levels of total distance traveled in Q96RJ0 KO mice compared to WT mice . In conditioned place preference ( CPP ) studies , Q96RJ0 KO mice acquired methamphetamine-induced CPP earlier than WT mice and retained CPP longer during extinction training . In morphine-induced CPP , both WT and KO genotypes displayed similar levels of CPP . Results from locomotor activity studies suggest that Q96RJ0 may have a modulatory role in the behavioral sensitization to amphetamine-based psychostimulants . That methamphetamine-but not morphine-induced CPP was augmented in Q96RJ0 KO mice suggests a selective role of Q96RJ0 in the conditioned reinforcing effects of methamphetamine . Collectively , these findings provide support for a regulatory role of Q96RJ0 in methamphetamine signaling . P11274 - P00519 induces neurite-like structures and P11274 lacking the SH2-binding domain induces cell rounding in PC12 cells . The activated tyrosine kinase oncoprotein P11274 - P00519 is responsible for pathogenesis of Philadelphia chromosome-positive human leukemias . Because P11274 carries a P20936 ( P20936 ) activity toward cytoskeleton-related small GTP-binding proteins , we utilized a neuronal PC12 cell system to test morphogenic potentials of P11274 - P00519 or P11274 . We report here unique morphological phenotypes of PC12 cells expressing either P11274 - P00519 or a P11274 mutant which lacks the SH2-binding domain ( P11274 Delta162-413 ) . Although Q96HU1 kinase was not activated in PC12 cells expressing P11274 - P00519 , they showed incomplete neurite extensions even in the absence of the nerve growth factor ( P01138 ) . Overproduction of P11274 Delta162-413 in PC12 cells , on the other hand , induced cell rounding in the absence of P01138 . Interestingly , those cells could hardly make terminal differentiation in the presence of P01138 and continued to grow without changing their round shape , although P08138 as well as Q96HU1 kinase appeared to be activated . Interestingly , the botulinum P01024 toxin induced neurite-like structures in PC12 cells overexpressing P11274 Delta162-413 without P01138 . P10275 expression induces P09038 , FGF-binding protein production , and P09038 release in prostate carcinoma cells : role of P09038 in growth , survival , and androgen receptor down-modulation . BACKGROUND : Alterations in fibroblast growth factors ( FGFs ) production and/or FGF receptors expression have been described to play key roles in prostate tumor progression , particularly in androgen-independent tumors . However , the role of androgen receptor ( AR ) in altering FGF-mediated growth and survival of prostatic neoplastic cells has not been completely defined . In this study , we investigated the alterations in P09038 production and utilization by the PC3 cell line , after transfection with a full-length AR . METHODS : P05230 ,2,7 , FGF-binding protein ( Q14512 ) production and FGF receptor ( FGFR ) 1-4 expression were investigated by polymerase chain reaction ( PCR ) and Western blot analysis . RESULTS : De novo AR expression by PC3 cells restores P21802 IIIb isoform expression and sensitivity to P21781 and P09038 . Androgen stimulation induces AR+ PC3 clones to secrete Q14512 , likely responsible for activation and mobilization from the extracellular matrix of the high amounts of P09038 produced by the same cells . In addition to the effects on cell proliferation , P09038 maintains the survival of AR+ PC3 clones through a positive modulation of the Bcl-2 protein and down-modulates AR protein expression , allowing the escape of selected clones from androgen regulation . CONCLUSION : In the presence of an active AR , the combined production of P09038 and Q14512 may play an important role in the progression of prostate cancer through the selection of AR- clones expressing high levels of Bcl-2 . Combined anti-inflammatory effects of β2-adrenergic agonists and DB05876 inhibitors on astrocytes by upregulation of intracellular DB02527 . Inflammation is an important hallmark of all neurodegenerative diseases and activation of different glial populations may be involved in the progression of some of these disorders . Especially , the activation of astroglia can lead to long-term detrimental morphological changes , such as scar formation . Therefore , improved strategies to modulate inflammation in these cells are currently being investigated . We investigated the interaction of phosphodiesterase ( PDE ) 4 inhibitors , such as rolipram , with other agents raising cellular DB02527 levels . When used alone , none of the DB05876 inhibitors increased DB02527 levels . The adenylate cyclase activator forskolin , the β(2)-adrenergic agonist clenbuterol and the mixed β(1)/β(2)-adrenergic agonist isoproterenol increased intracellular DB02527 levels of cortical murine astrocytes . This increase was synergistically elevated by rolipram or the DB05876 inhibitor RO-201724 , but not by inhibition of PDE3 . Inflammatory stimulation of the cells with the cytokines P01375 -α , IL-1β and IFN-γ strongly induced Q07343 and augmented overall DB05876 activity , while PDE3 activity was low . DB01407 and forskolin caused downregulation of cytokines and chemokines such as P05231 and P13500 . This effect was further enhanced by rolipram , but not by the PDE3 inhibitor milrinone . The DB02527 -raising drug combinations attenuated the upregulation of P01375 -α and P05231 mRNA and the secretion of P05231 , but did not affect initial NF-κB signalling triggered by the stimulating cytokines . These results indicate that DB05876 may be a valuable anti-inflammatory target in brain diseases , especially under conditions associated with stimulation of DB02527 -augmenting astrocyte receptors as is observed by clenbuterol treatment .