interacts_with DB06684?
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 . Heme oxygenase-1 attenuates glucose-mediated cell growth arrest and apoptosis in human microvessel endothelial cells . Heme oxygenase-1 ( P09601 ) is a stress protein that has been suggested to participate in defense mechanisms against agents that may induce oxidative injury , such as heme and inflammatory molecules . Incubation of endothelial cells in a high-glucose ( 33 mmol/L ) medium for 7 days resulted in a decrease of HO activity by 34 % and a decrease in P09601 and P30519 proteins compared with cells exposed to low glucose ( 5 mmol/L ) ( P < 0.05 ) or cells exposed to mannitol ( 33 mmol/L ) . Overexpression of P09601 was coupled with an increase in HO activity and carbon monoxide synthesis , decreased cellular heme , and acceleration in all phases of the cell cycle ( P < 0.001 ) . The rate of cell cycle or cell birth rate was increased by 29 % ( P < 0.05 ) in cells overexpressing P09601 but decreased by 23 % ( P < 0.05 ) in cells underexpressing P09601 compared with control cells . Exposure to high glucose significantly decreased cell-cycle progression in control cells and in cells underexpressing P09601 but did not decrease cell-cycle progression in cells overexpressing P09601 . High glucose induced P38936 and p27 in control cells but not in cells overexpressing P09601 . The addition of DB04912 ( DB04912 ) , an inhibitor of HO activity , reversed the P09601 -mediated decrease of P38936 and p27 in cells overexpressing P09601 . These findings identify a novel effect of P09601 on endothelial cell growth and indicate that heme metabolism and P09601 expression regulate signaling systems in cells exposed to high glucose , which controls cell-cycle progression . Correcting human mitochondrial mutations with targeted RNA import . Mutations in the human mitochondrial genome are implicated in neuromuscular diseases , metabolic defects , and aging . An efficient and simple mechanism for neutralizing deleterious mitochondrial DNA ( mtDNA ) alterations has unfortunately remained elusive . Here , we report that a 20-ribonucleotide stem-loop sequence from the H1 RNA , the RNA component of the human RNase P enzyme , appended to a nonimported RNA directs the import of the resultant RNA fusion transcript into human mitochondria . The methodology is effective for both noncoding RNAs , such as tRNAs , and mRNAs . The RNA import component , polynucleotide phosphorylase ( Q8TCS8 ) , facilitates transfer of this hybrid RNA into the mitochondrial matrix . In addition , nucleus-encoded mRNAs for mitochondrial proteins , such as the mRNA of human mitochondrial ribosomal protein P28222 ( O15235 ) , contain regulatory sequences in their 3'-untranslated region ( UTR ) that confers localization to the mitochondrial outer membrane , which is postulated to aid in protein translocation after translation . We show that for some mitochondrial-encoded transcripts , such as P35354 , a 3'-UTR localization sequence is not required for mRNA import , whereas for corrective mitochondrial-encoded tRNAs , appending the 3'-UTR localization sequence was essential for efficient fusion-transcript translocation into mitochondria . In vivo , functional defects in mitochondrial RNA ( mtRNA ) translation and cell respiration were reversed in two human disease lines . Thus , this study indicates that a wide range of RNAs can be targeted to mitochondria by appending a targeting sequence that interacts with Q8TCS8 , with or without a mitochondrial localization sequence , providing an exciting , general approach for overcoming mitochondrial genetic disorders . Role of presynaptic serotonergic receptors on the mechanism of action of P08908 and P28222 agonists on masculine sexual behaviour : physiological and pharmacological implications . In order to establish whether the P08908 or the 5HT1B agonists , 8-OH-DPAT or TFMPP , produce their facilitatory or inhibitory actions on masculine sexual behaviour via a mechanism involving : ( a ) the serotonin synthesis or release ; ( b ) the stimulation of presynaptic receptors , or ( c ) the stimulation of somatodendritic receptors , three series of experiments were performed . The administration of the serotonin synthesis inhibitor , p-chlorophenylalanine ( p- P15085 , 300 mg/kg x 3 days ) , facilitated sexual behaviour but does not interfere neither with the inhibitory nor with the facilitatory effects of TFMPP ( 0.5 mg/kg ) or 8-OH-DPAT ( 0.5 mg/kg ) , respectively . The icv or the intraraphé administration of the serotonergic neurotoxin , 5,7-dihydroxytryptamine ( 5,7- DB02901 ) , slightly stimulated masculine sexual behaviour and produced a decrease in serotonin and its metabolite levels . In lesioned animals TFMPP ( 0.5 mg/kg ) resulted in an inhibitory effect reflected as a prolongation of the ejaculation latency . The inhibitory effect of this drug on mounting behaviour was not observed in 5,7- DB02901 treated rats . In lesioned animals 8-OH-DPAT ( 0.5 mg/kg ) produced the same facilitatory effect . Present data indicate that serotonergic postsynaptic receptors mediate both the inhibitory and the facilitatory actions of TFMPP or 8-OH-DPAT in copulation . All data further support the idea that endogenous serotonin acts via the stimulation of P28222 receptors to induce its inhibitory effects on masculine sexual behaviour . Effects of external calcium on the biotransformation of DB06749 to ginsenoside Rd by Paecilomyces bainier 229-7 . DB01373 is a known signalling molecule in eukaryotic cells and plays a central role in the regulation of many cellular processes . In the following study , we report on the effect of external calcium treatments on the biotransformation of DB06749 to ginsenoside Rd by Paecilomyces bainier 229-7 . We observed that the intracellular calcium content of P. bainier 229-7 mycelia was increased in response to exposure to high external Ca(2+) concentrations . Both ginsenoside Rd biotransformation and β-glucosidase activity were both found to be dependent on the external calcium concentration . At an optimal Ca(2+) concentration of 45 mM , maximal ginsenoside Rd bioconversion rate of 92.44 % was observed and maximal β-glucosidase activity of 0.1778 U was reached in a 72-h biotransformation . The Ca(2+) channel blocker Verapamil blocked the trans-membrane influx of calcium and decreased ginsenoside Rd biotransformatiom . In addition , β-glucosidase activity and ginsenoside Rd content decreased by 36.0 and 29.2 % respectively after a 72-h incubation in the presence of 0.05 mM P62158 ( P62158 ) antagonist DB00850 . These results suggest that both Ca(2+) channels and P62158 are involved in ginsenoside Rd biotransformation via regulation of β-glucosidase activity . This is the first report regarding the effects of calcium signal transduction on biotransformation and enzyme activity in fungi . Design and rationale for novel antifolates . The goals of new antifolate development are : 1 ) improved selectivity , 2 ) improved penetration into pharmacologic sanctuaries , and 3 ) effectiveness vs. tumors either with intrinsic or acquired resistance to methotrexate ( MTX ) . The major target for antifolate development has been dihydrofolate reductase ( P00374 ) , but other critical folate-dependent enzymes , i.e. , thymidylate synthase , methionine synthetase , and folylpolyglutamate synthetase are also important targets for new antifolate development . The possibility that P00374 from tumor tissue differs significantly from normal tissue P00374 now seems improbable , and the ideas of the late Bill Baker to design specific inhibitors of the tumor enzyme vs. the normal tissue P00374 are unlikely to succeed . However , the experience with triazinate ( Baker 's antifol ; TZT ) indicates that transport of antifols could be exploited to provide selective toxicity , as well as to provide agents effective vs. MTX-resistant cells . This work led to a second generation of " nonclassical " folate antagonists , of which trimetrexate ( JB-11 ; DB01157 ) is now in clinical trial . Uptake of DB01157 is via an MTX-independent membrane system , and extremely high intracellular levels of this drug are achieved in human leukemia cells . Effects of systemic injections of vilazodone , a selective serotonin reuptake inhibitor and serotonin 1A receptor agonist , on anxiety induced by predator stress in rats . We examined the effect of DB06684 , a selective serotonin reuptake inhibitor ( SSRI ) and serotonin 1A ( 5-HT(1A) ) receptor agonist [ Bartoszyk , G.D. , Hegenbart , R. , Ziegler , H. , 1997. P50402 68843 , a serotonin reuptake inhibitor with selective presynaptic P08908 receptor agonistic properties. Eur. J. Pharmacol. 322 , 147-153. ] , on change in affect following predator stress . DB06684 and vehicle injection ( intraperitoneal ) occurred either 10 min after predator stress ( prophylactic testing ) , or 90 min prior to behavioral testing for the effects of predator stress ( therapeutic testing ) . Predator stress involved unprotected exposure of rats to a domestic cat . Behavioral effects of stress were evaluated with hole board , plus-maze , and acoustic startle tests 1 week after stress . Predator stress increased anxiety-like behavior in the plus-maze and elevated response to acoustic startle . In prophylactic testing , DB06684 affected stress potentiation of startle at doses above 5 mg/kg . DB06684 increased stress elevation of startle at 10 mg/kg . Higher doses of DB06684 ( 20 and 40 mg/kg ) blocked stress potentiation of startle . In contrast , DB06684 had no effect on stress potentiation of anxiety in the plus-maze . In therapeutic testing , DB06684 increased stress elevation of startle at all doses . In contrast , therapeutic DB06684 had no effect on stress potentiation of anxiety in the plus-maze . Taken together , the data suggest a prophylactic potential for DB06684 in the treatment of changes in hypervigilance following severe stress . Q07869 gamma ligands , rosiglitazone and pioglitazone , inhibit P09038 - and P15692 -mediated angiogenesis . OBJECTIVE : To study the effect of peroxisome proliferator-activated receptor-gamma ( Q07869 gamma ) agonists , pioglitazone and rosiglitazone , on vascular endothelial growth factor ( P15692 ) - and basic fibroblast growth factor ( P09038 ) -induced angiogenesis and on endothelial cell migration . METHODS : Chick chorioallantoic membrane ( P62158 ) model was used to evaluate the efficacy of pioglitazone and rosiglitazone on P15692 - and P09038 -induced angiogenesis . In addition , the effect of pioglitazone and rosiglitazone on endothelial cell migration was evaluated using 8 mm pore filter to a feeder layer containing vitronectin as chemoattractant . RESULTS : Pioglitazone and rosiglitazone inhibited the pro-angiogenic effects of P09038 and P15692 in the P62158 model significantly ( P < 0.001 ) to the same extent . Endothelial cell migration was also inhibited by both pioglitazone and rosiglitazone ( P < 0.001 ) . CONCLUSIONS : These results suggest that Q07869 gamma ligands , pioglitazone and rosiglitazone , in addition to their important regulatory role in adipogenesis and inflammation , possess anti-angiogenic properties . Thus , Q07869 gamma ligands may be useful in the treatment of diabetic retinopathy , macular degeneration , and other ocular disorders and may lower the risk to develop cancer in diabetic patients . DB00055 attenuates coagulation-associated over-expression of fibrinolytic activity by suppressing the thrombin-dependent inactivation of P05121 . Several activated coagulation factors have been reported to enhance fibrinolysis by neutralizing plasminogen activator inhibitor type 1 ( P05121 ) activity . We evaluated the physiological relevance of this mechanism using the euglobulin clot lysis time ( ECLT ) assay in the presence and absence of Ca2+ , which is controlled by P05121 and mimics physiological thrombolysis . We found that the ECLT ( 18.5 +/- 0.6 h ) was shortened by Ca2+ ( 5 mm ) ( 6.6 +/- 0.1 h ) . A significant difference was observed in thrombin generation by the presence of Ca2+ in the euglobulin fraction . P00734 was almost fully converted to thrombin within 15 min in the presence of Ca2+ , whereas essentially no conversion was observed without Ca2+ . The presence of activated protein C ( aPC ) suppressed thrombin generation , and attenuated the shortening of ECLT in a dose-dependent manner , an effect enhanced by phospholipid and protein S . In the absence of Ca2+ , aPC did not prolong the ECLT . After addition of biotin-labeled recombinant P05121 to the euglobulin fraction , P05121 was cleaved to lower molecular weight forms only in the presence of Ca2+ . This cleavage did not occur in the presence of aPC , suggesting that thrombin was the catalyst for P05121 cleavage . The cleavage and inactivation of P05121 by generated thrombin is proposed to be responsible for the shortening of ECLT by Ca2+ and for coagulation-associated over-expression of fibrinolysis . Under such conditions , aPC appeared to suppress thrombin generation and to normalize highly activated fibrinolysis . Ectopic expression of human acidic fibroblast growth factor 1 in the medicinal plant , Salvia miltiorrhiza , accelerates the healing of burn wounds . BACKGROUND : Healing of burns is a complex process and very few effective treatments exist to facilitate the burn recovery process . Human acidic fibroblast growth factor 1 ( P05230 ) plays an important role in a variety of biological processes , including angiogenesis , and tissue repair . Salvia miltiorrhiza is widely used in traditional Chinese medicine as an herb for the treatment of various diseases , including cardiovascular and cerebrovascular diseases , and traumatic injuries . We present that expression of P05230 in S. miltiorrhiza significantly accelerates the healing of burn wounds . RESULTS : The human fgf-1 gene was fused with a barley α-amylase signal peptide DNA sequence and driven by a 35S promoter for constitutive expression in transgenic S. miltiorrhiza plants . The highest yield of recombinant P05230 obtained from leaves of transgenic S. miltiorrhiza lines was 272 ng/fresh weight . Aqueous extracts from transgenic S. miltiorrhiza exhibited P05230 activity approximately 19.2-fold greater than that of the standard P05230 . Compared to the standard P05230 or the extracts obtained from non-transgenic plants , it stimulated proliferation of Balb/c 3 DB00279 mouse fibroblast cells assessed with the standard MTT assay and promoted angiogenesis in the chicken embryo chorioallantoic membrane ( P62158 ) assay . Topical application of the extract significantly accelerated the burn wound healing process . CONCLUSIONS : The product appears to retain the biological activity of both P05230 as well as the medicinal properties of the plant . The extracts from transgenic S. miltiorrhiza combines the therapeutic functions of P05230 and the medicinal plant , S. miltiorrhiza . Topical application of the product can reduce the costs associated with extraction , purification , and recovery . Single-prolonged stress induce changes of P62158 /CaMKIIα in the rats of dorsal raphe nucleus . Ca2+/calmodulin-dependent protein kinase IIα ( CaMKIIα ) is identified as a Ca2+-dependent kinase in brain involved in the activation of DB00150 hydroxylase ( P17752 ) acting through direct phosphorylation of P17752 , and playing key roles in the signaling pathways initiated by various G protein-coupled 5-HT receptors . The goal of this study is to detect whether there are changes of P62158 and CaMKIIα in dorsal raphe nucleus in the rats exposed to single-prolonged stress ( P49903 ) , which is a model employed in post-traumatic stress disorder ( PTSD ) study extensively . A total of 90 male Wistar rats were randomly divided into a normal control group and P49903 groups of 7d , 14d . The changes of P62158 /CaMKIIα were detected by immunohistochemistry , reverse transcription-polymerase chain reaction and western blot . Our results demonstrate that both expressions of P62158 and CaMKIIα significantly increase ( P < 0.001 ) in the P49903 7d group than that in the control group , and then decreased dramatically ( P < 0.001 ) 14 days after P49903 . Our results confirm that P49903 induce changes of P62158 /CaMKIIα in the dorsal raphe nucleus . Changes of P62158 /CaMKIIα may be associated with the activation of P08908 receptor , and may contribute to the progress of molecular mechanism of PTSD . DB02342 in the human corpus luteum throughout the luteal phase and its influence on lutein cell steroidogenesis and angiogenic activity . OBJECTIVE : To quantitate 2-methoxyestradiol ( 2-ME ) in human corpus luteum ( CL ) of different ages and to determine the expression of cytochrome-P450-1A1 ( P04798 ) and catechol-O-methyl transferase ( P21964 ) in CL and the action of 2-ME on P , vascular endothelial growth factor ( P15692 ) secretion , and luteal angiogenesis . DESIGN : Experimental study . SETTING : University division of reproductive endocrinology . PATIENT(S) : Twenty-four women of reproductive age . INTERVENTION(S) : CL was collected from 15 women during the minilaparotomy for tubal sterilization . Granulosa lutein cells were harvested 36 hours after hCG administration in patients undergoing IVF . MAIN OUTCOMES MEASURE(S) : Levels of 2-ME were determined by high-performance liquid chromatography in CL . P04798 and P21964 were assessed by immunohistochemistry and Western blot . P and P15692 were measured by radioimmunoassay and ELISA . The angiogenic potential was analyzed using EA.hy926 cells . RESULT(S) : Plasma levels of E₂ decreased in the late luteal phase in association with an increase in luteal tissue of 2-ME concentrations . Concomitantly , there was a significant reduction of angiogenic activity in late CL . There was no significant variation in P04798 and P21964 expression in all CL . In physiological doses , 2-ME inhibited basal P15692 by granulosa lutein cells and diminished the angiogenic activity in conditioned media but did not prevent P and P15692 production stimulated by hCG . CONCLUSION(S) : These data suggest the participation of 2-ME in physiological luteolysis by reducing angiogenesis . However , 2-ME did not prevent in vitro hCG stimulation of P biosynthesis , providing a mechanism for CL rescue in the cycle of conception . Dimerization effect of sucrose octasulfate on rat P05230 . Fibroblast growth factors ( FGFs ) constitute a family of at least 23 structurally related heparin-binding proteins that are involved in regulation of cell growth , survival , differentiation and migration . DB01901 ( SOS ) , a chemical analogue of heparin , has been demonstrated to activate FGF signalling pathways . The structure of rat P05230 crystallized in the presence of SOS has been determined at 2.2 A resolution . SOS-mediated dimerization of P05230 was observed , which was further supported by gel-filtration experiments . The major contributors to the sulfate-binding sites in rat P05230 are Lys113 , Lys118 , Arg122 and Lys128 . An arginine at position 116 is a consensus residue in mammalian FGF molecules ; however , it is a serine in rat P05230 . This difference may be important for SOS-mediated P05230 dimerization in rat . Xaliproden ( SR57746A ) induces P08908 receptor-mediated Q96HU1 kinase activation in PC12 cells . Neurotrophic growth factors are involved in cell survival . However , natural growth factors have a very limited therapeutic use because of their short half-life . In the present study , we investigated the mechanism of action of a non-peptidic neurotrophic drug , Xaliproden , a potential molecule for the treatment of motoneuron diseases , since the transduction pathways of this synthetic P08908 agonist are very poorly understood . Xaliproden does not activate the Trk receptor but causes a rapid increase in the activities of the P27361 and P28482 isoforms of Q96HU1 kinase , which then rapidly decrease to the basal level . We demonstrate that isoforms of the P29353 adapter protein are phosphorylated independently of each other and are probably not the source of the Xaliproden-induced Q96HU1 kinases activation . The inhibitor of Ras farnesylation , FPT-1 , and the protein kinase C inhibitors , GF 109203X and chelerythrine , inhibited the Xaliproden-induced Q96HU1 kinase activation , suggesting p21Ras and PKC involvement . Moreover , the observations that the P08908 antagonist , pindobind , and pertussis toxin abolished the Xaliproden-induced P29323 stimulation suggested that Xaliproden activates the Q96HU1 kinase pathways by stimulating the G protein-coupled receptor , P08908 . These results demonstrate clearly that the non-peptidic compound , Xaliproden , exerts its neurotrophic effects through a mechanism of action differing from that of neurotrophins . These findings suggest that this compound does not involve MAPK activation by TrkA receptor stimulation but acts by Q96HU1 kinase pathway by a pertussis toxin-sensitive mechanism involving P08908 receptors , P38936 Ras and MEK-1 and by PKC and Akt pathways . Ca2+-calmodulin and janus kinase 2 are required for activation of sodium-proton exchange by the Gi-coupled 5-hydroxytryptamine 1a receptor . The type 1 sodium-proton exchanger ( P19634 ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 remain incompletely defined . In this work , we present evidence that stimulation of the 5-hydroxytryptamine 1A ( P08908 ) receptor results in the formation of a signaling complex that includes activated O60674 ( Jak2 ) , Ca2+/calmodulin ( P62158 ) , and P19634 , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist-induced association of P62158 and P19634 as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 is activated through this pathway : P08908 receptor --> G(i2)alpha and/or G(i3)alpha --> Jak2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 --> induction of a conformational change in P19634 that unmasks an obscured proton-sensing and/or proton-transporting region of P19634 --> activation of P19634 . The G(i/o)-coupled P08908 receptor now joins a handful of Gq-coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2+ . We have also shown for the first time that the association of P62158 with P19634 in living cells is a dynamic process . Comparison of low fat and low carbohydrate diets on circulating fatty acid composition and markers of inflammation . Abnormal distribution of plasma fatty acids and increased inflammation are prominent features of metabolic syndrome . We tested whether these components of metabolic syndrome , like dyslipidemia and glycemia , are responsive to carbohydrate restriction . Overweight men and women with atherogenic dyslipidemia consumed ad libitum diets very low in carbohydrate ( VLCKD ) ( 1504 kcal : % CHO:fat:protein = 12:59:28 ) or low in fat ( LFD ) ( 1478 kcal : % CHO:fat:protein = 56:24:20 ) for 12 weeks . In comparison to the LFD , the VLCKD resulted in an increased proportion of serum total n-6 PUFA , mainly attributed to a marked increase in arachidonate ( 20:4n-6 ) , while its biosynthetic metabolic intermediates were decreased . The n-6/n-3 and arachidonic/eicosapentaenoic acid ratio also increased sharply . Total saturated fatty acids and 16:1n-7 were consistently decreased following the VLCKD . Both diets significantly decreased the concentration of several serum inflammatory markers , but there was an overall greater anti-inflammatory effect associated with the VLCKD , as evidenced by greater decreases in P01375 , P05231 , P10145 , P13500 , P16581 , I- P62158 , and P05121 . Increased 20:4n-6 and the ratios of 20:4n-6/20:5n-3 and n-6/n-3 are commonly viewed as pro-inflammatory , but unexpectedly were consistently inversely associated with responses in inflammatory proteins . In summary , a very low carbohydrate diet resulted in profound alterations in fatty acid composition and reduced inflammation compared to a low fat diet . Vascular endothelial growth factor signaling is required for the behavioral actions of antidepressant treatment : pharmacological and cellular characterization . This study extends earlier work on the role of vascular endothelial growth factor ( P15692 ) in the actions of antidepressant treatment in two key areas . First , by determining the requirement for P15692 in the actions of a 5-HT selective reuptake inhibitor ( SSRI ) , fluoxetine in behavioral models of depression/antidepressant response ; and second , by examining the role of the P08908 receptor subtype in the regulation of P15692 , and the cellular localization of antidepressant regulation of P15692 expression . The results show that pharmacological inhibition of P15692 receptor signaling blocks the behavioral actions of fluoxetine in rats subjected to chronic unpredictable stress . Infusions of SU5416 or SU1498 , two structurally dissimilar inhibitors of P15692 -Flk-1 receptor signaling , block the antidepressant effects of fluoxetine on sucrose preference , immobility in the forced swim test , and latency to feed in the novelty suppressed feeding paradigm . We also show that activation of P08908 receptors is sufficient to induce P15692 expression and that a P08908 antagonist blocks both the increase in P15692 and behavioral effects induced by fluoxetine . Finally , double labeling studies show that chronic fluoxetine administration increases P15692 expression in both neurons and endothelial cells in the hippocampus . Taken together these studies show that P15692 is necessary for the behavioral effects of the SSRI fluoxetine , as well as norepinephrine selective reuptake inhibitor , and that these effects may be mediated by P08908 receptors located on neurons and endothelial cells . Clinical outcome and cyclo-oxygenase-2 expression in five dogs with solar dermatitis/actinic keratosis treated with firocoxib . BACKGROUND : The conversion of arachidonic acid into prostaglandin is catalysed by the cyclo-oxygenases ( P23219 / P35354 ) . Several studies indicate that P35354 is overexpressed in actinic keratosis in humans and dogs . DB09217 is a P35354 -selective inhibitor that blocks the biochemical activity of P35354 . HYPOTHESIS/OBJECTIVES : To evaluate the efficacy of firocoxib ( 5 mg/kg orally once daily ) for the treatment of dogs with solar dermatitis/actinic keratosis . METHODS : DB09217 5 mg/kg was given orally once daily for 180 days to five dogs with clinical signs and histopathological lesions consistent with solar dermatitis/actinic keratosis . On days 0 , 50 and 180 , the severity of erythema , skin shine , induration and the number of comedones were evaluated by a clinical scoring system . On the same days , samples were collected for histopathology from ' target lesions ' and P35354 expression was evaluated by immunohistochemistry . RESULTS : The clinical follow-up showed that four of five dogs improved with the treatment ; improvement in terms of histological findings was correlated with the regularization of the epidermal proliferation rather than the recovery of dermal changes . CONCLUSIONS AND CLINICAL IMPORTANCE : A role for P35354 might thus be hypothesized in the pathogenesis of canine solar dermatitis . Suppression of tumor growth and metastasis by a P17948 antagonizing peptide identified from a phage display library . Although the P15692 -Flk-1-pathway has been known as the major driving force of angiogenesis , new evidence has shown that P17948 /Flt-1 plays important roles during the neovascularization under pathological conditions including tumor , atherosclerosis and arthritis . In search of Flt-1 receptor antagonizing peptides , we screened a phage display 12-mer-peptide library with recombinant Flt-1 protein . Seven candidate peptides were identified that specifically bound to P15692 receptor Flt-1 , of which peptide F56 ( WHSDMEWWYLLG ) almost abolished P15692 binding to receptor Flt-1 in vitro . In vivo , F56 fused with P00374 ( P00374 -F56 ) inhibited angiogenesis in a P62158 assay . Moreover , P00374 -F56 significantly inhibited the growth of nodules of human gastric cancer cell line MGC-803 in BALB/c nude mice . Histological analyses showed that necrosis of the implanted tumor was markedly enhanced following treatment with P00374 -F56 . In the severe combined immunodeficiency disease ( SCID ) mouse model for studying metastasis of the human breast cancer cell line BICR-H1 , synthetic peptide F56 significantly inhibited tumor growth and lung metastases . Taken together , our results have demonstrated that peptide F56 , as a Flt-1 receptor antagonist , fulfilled the antiangiogenic and antimetastatic effects by specifically interfering with the interaction between P15692 and receptor Flt-1 . Thus , short peptide F56 may have clinical potential in tumor therapy . Impact of the Pro12Ala polymorphism of the Q07869 -gamma2 gene on serum triacylglycerol response to n-3 fatty acid supplementation . Serum lipid responses to dietary modification are partly determined by genetic factors . The objective of the present study was to investigate the influence of the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-gamma2 ( Q07869 -gamma2 ) gene on serum lipid and lipoprotein responses to n-3 fatty acid supplementation . A total of 76 men and 74 women ( age 49+/-8 years , body mass index 26.5+/-3.0 kg/m(2) ) participated in a controlled multi-center study . Subjects were randomly assigned to consume either fish oil supplements ( 3.6g n-3 fatty acids/day containing 2.4 g of EPA and DB01708 ) or placebo capsules containing olive oil for 3 months . At baseline , the Pro12Ala polymorphism was not associated with serum total and lipoprotein lipid concentrations or lipoprotein lipase activity in the fasting state . After the 3-month study period , carriers of the Ala12 allele presented a greater decrease in serum triacylglycerol concentration in response to n-3 fatty acid supplementation than did subjects with the Pro12Pro genotype when the total dietary fat intake was below 37 E % ( p=0.003 ) or the intake of saturated fatty acids was below 10 E % ( p=0.006 ) . Changes in serum total cholesterol , serum LDL cholesterol and HDL cholesterol concentrations were similar among the genotypes in the n-3 fatty acid supplementation group and in the placebo group . In conclusion , the Pro12Ala polymorphism of the Q07869 -gamma2 gene may modify the inter-individual variability in serum triacylglycerol response to n-3 fatty acid supplementation . Monoclonal antibodies targeting P01584 reduce biomarkers of atherosclerosis in vitro and inhibit atherosclerotic plaque formation in P02649 -deficient mice . OBJECTIVE : Atherosclerosis is a condition that is increasingly contributing to worldwide mortality through complications such as stroke and myocardial infarction . IL-1β plays multiple direct , local roles in the formation and stability of the atheroma by eliciting the production of additional cytokines and proteolytic enzymes from macrophages , endothelial cells ( EC ) and smooth muscle cells ( SMC ) . We therefore tested whether an anti-IL-1β antibody , DB06062 , might inhibit the secretion of pro-atherogenic cytokines from macrophages in vitro and affect a positive outcome in the P02649 -deficient mouse ( ApoE(-/-) ) model of atherosclerosis in vivo . METHODS AND RESULTS : In an in vitro co-culture model , DB06062 inhibited macrophage-induced secretion of key atherogenic cytokines from EC and SMC , including P05231 , P10145 , P13500 and TNFα . The release of degradative enzymes , such as the matrix metalloproteinases P08254 and P14780 , was also decreased by DB06062 . In addition , DB06062 inhibited the secretion of P13232 from EC and P05112 from SMC , cytokines not previously reported to be driven by IL-1β in this context . In vivo , XMA052 MG1K , a chimeric murine version of DB06062 , inhibited the formation of atherosclerotic lesions in the ApoE(-/-) model at all three doses tested . This effect was comparable to that reported for complete genetic ablation of IL-1β or IL-1R1 on an ApoE(-/-) background and was associated with decreases in plasma non-HDL/HDL cholesterol ratio and plaque lipid content and macrophage infiltration . CONCLUSIONS : These results demonstrate for the first time that an antibody targeting IL-1β can inhibit the progression of atherosclerosis in vivo , highlighting the importance of this key cytokine in cardiovascular disease . Mechanism of action of the bimodal antidepressant vilazodone : evidence for serotonin1A-receptor-mediated auto-augmentation of extracellular serotonin output . RATIONALE : The recently approved antidepressant vilazodone , a serotonin (5-HT)1A receptor partial agonist/selective 5-HT reuptake inhibitor offers new possibilities to study the underlying mechanisms of depression pharmacotherapy and of 5-HT augmenting antidepressants . OBJECTIVE : The role of the P08908 receptor with respect to the regulation of 5-HT output in the mechanism of action of vilazodone . METHOD : We measured 5-HT levels in two subregions of the rat prefrontal cortex by microdialysis , and 5-hydroxytryptophan ( 5-HTP ) accumulation and tissue 5-HT concentrations ex vivo . RESULTS : DB06684 -induced maximal 5-HT levels were similar in the medial and the lateral cortex and were up to sixfold higher than those induced by paroxetine , citalopram , or fluoxetine tested in parallel . Depolarization/autoreceptor-insensitive 5-HT release by vilazodone could be excluded . The citalopram ( 1 μM , locally infused ) -induced increase of 5-HT was further increased by vilazodone ( 1 mg/kg i.p. ) , but not by citalopram ( 10 mg/kg i.p. ) . Unlike fluoxetine , vilazodone-induced extracellular 5-HT output was not potentiated by cotreatment with the P08908 receptor blocker N-[2-(4-{2-methoxyphenyl}-1-piperazinyl)-ethyl]-N-2-pyridinylcyclohexanecarboxamide ( WAY 100635 ) . In contrast to fluoxetine , vilazodone exhibited intrinsic P08908 agonist activity : it reduced , similar to (±)-8-hydroxy-2-(dipropylamino)-tetralin ( 8-OH-DPAT ) , 5-HTP accumulation in striatum and n. raphe of reserpinized rats . Hence , vilazodone 's agonistic actions must be P08908 receptor-related since endogenous 5-HT is lacking in the reserpine-depleted animal . CONCLUSIONS : In spite of high intrinsic P08908 activity in reserpinized rats , the net effect of vilazodone at release-regulating P08908 autoreceptors must be inhibitory , leading to markedly increased 5-HT output . Another possibility is that vilazodone rapidly desensitizes autoinhibitory P08908 receptors by an unknown mechanism .