MH_dev_297

8 - OH-DPAT ( P08908 REA 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 REA ) . 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 REA receptor agonist ; 0.25 , 0.5 and 1mg / kg , IP for 10 days ) . P04141 REA samples were collected on the tenth day of 8 - OH-DPAT administration and analyzed by ELISA method to measure levels of P01375 REA - α , IL - 1β and P05231 REA . 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 REA - α in P04141 REA increased three weeks after 6 - OHDA injection while there was a significant decrease in P01375 REA - α level of parkinsonian animals treated with 8 - OH-DPAT ( 1 mg / kg , IP for 10 days ) . IL - 1β and P05231 REA 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 REA 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 REA ) 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 REA and P30519 REA 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 REA 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 REA but decreased by 23 % ( P < 0.05 ) in cells underexpressing P09601 REA compared with control cells . Exposure to high glucose significantly decreased cell-cycle progression in control cells and in cells underexpressing P09601 REA but did not decrease cell-cycle progression in cells overexpressing P09601 REA . High glucose induced P38936 REA and p27 in control cells but not in cells overexpressing P09601 REA . The addition of DB04912 MEN ( DB04912 MEN ) , an inhibitor of HO activity , reversed the P09601 REA - mediated decrease of P38936 REA and p27 in cells overexpressing P09601 REA . These findings identify a novel effect of P09601 REA on endothelial cell growth and indicate that heme metabolism and P09601 REA 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 REA ( O15235 REA ) , 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 REA , 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 REA and P28222 REA agonists on masculine sexual behaviour : physiological and pharmacological implications . In order to establish whether the P08908 REA 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 REA 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 MENMAX DB00850 MEN . 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 REA ) , 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 REA from tumor tissue differs significantly from normal tissue P00374 REA now seems improbable , and the ideas of the late Bill Baker to design specific inhibitors of the tumor enzyme vs . the normal tissue P00374 REA 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 MEN ) is now in clinical trial . Uptake of DB01157 MEN 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 SUB , a selective serotonin reuptake inhibitor ( SSRI ) and serotonin 1A ( 5 - HT ( 1A ) ) receptor agonist [ Bartoszyk , G . D . , Hegenbart , R . , Ziegler , H . , 1997 . P50402 REA 68843 , a serotonin reuptake inhibitor with selective presynaptic P08908 REA receptor agonistic properties . Eur . J . Pharmacol . 322 , 147-153 . ] , on change in affect following predator stress . DB06684 SUB 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 SUB affected stress potentiation of startle at doses above 5 mg / kg . DB06684 SUB increased stress elevation of startle at 10 mg / kg . Higher doses of DB06684 SUB ( 20 and 40 mg / kg ) blocked stress potentiation of startle . In contrast , DB06684 SUB had no effect on stress potentiation of anxiety in the plus-maze . In therapeutic testing , DB06684 SUB increased stress elevation of startle at all doses . In contrast , therapeutic DB06684 SUB had no effect on stress potentiation of anxiety in the plus-maze . Taken together , the data suggest a prophylactic potential for DB06684 SUB in the treatment of changes in hypervigilance following severe stress .

Q07869 REA gamma ligands , rosiglitazone and pioglitazone , inhibit P09038 REA - and P15692 REA - mediated angiogenesis . OBJECTIVE : To study the effect of peroxisome proliferator-activated receptor-gamma ( Q07869 REA gamma ) agonists , pioglitazone and rosiglitazone , on vascular endothelial growth factor ( P15692 REA ) - and basic fibroblast growth factor ( P09038 REA ) - 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 REA - and P09038 REA - 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 REA and P15692 REA 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 REA gamma ligands , pioglitazone and rosiglitazone , in addition to their important regulatory role in adipogenesis and inflammation , possess anti-angiogenic properties . Thus , Q07869 REA 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 MEN attenuates coagulation-associated over-expression of fibrinolytic activity by suppressing the thrombin-dependent inactivation of P05121 REA . Several activated coagulation factors have been reported to enhance fibrinolysis by neutralizing plasminogen activator inhibitor type 1 ( P05121 REA ) 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 REA 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 REA 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 REA to the euglobulin fraction , P05121 REA 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 REA cleavage . The cleavage and inactivation of P05121 REA 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 REA ) 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 REA 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 REA obtained from leaves of transgenic S . miltiorrhiza lines was 272 ng / fresh weight . Aqueous extracts from transgenic S . miltiorrhiza exhibited P05230 REA activity approximately 19.2- fold greater than that of the standard P05230 REA . Compared to the standard P05230 REA 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 REA as well as the medicinal properties of the plant . The extracts from transgenic S . miltiorrhiza combines the therapeutic functions of P05230 REA 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 REA ) acting through direct phosphorylation of P17752 REA , 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 REA receptor , and may contribute to the progress of molecular mechanism of PTSD .

DB02342 MEN 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-P 450-1 A1 ( P04798 REA ) and catechol-O-methyl transferase ( P21964 REA ) in CL and the action of 2 - ME on P , vascular endothelial growth factor ( P15692 REA ) 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 REA and P21964 REA were assessed by immunohistochemistry and Western blot . P and P15692 REA 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 REA and P21964 REA expression in all CL . In physiological doses , 2 - ME inhibited basal P15692 REA by granulosa lutein cells and diminished the angiogenic activity in conditioned media but did not prevent P and P15692 REA 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 REA . 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 MEN ( SOS ) , a chemical analogue of heparin , has been demonstrated to activate FGF signalling pathways . The structure of rat P05230 REA crystallized in the presence of SOS has been determined at 2.2 A resolution . SOS-mediated dimerization of P05230 REA was observed , which was further supported by gel-filtration experiments . The major contributors to the sulfate-binding sites in rat P05230 REA are Lys 113 , Lys 118 , Arg 122 and Lys 128 . An arginine at position 116 is a consensus residue in mammalian FGF molecules ; however , it is a serine in rat P05230 REA . This difference may be important for SOS-mediated P05230 REA dimerization in rat .

Xaliproden ( SR57746A ) induces P08908 REA 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 REA agonist are very poorly understood . Xaliproden does not activate the Trk receptor but causes a rapid increase in the activities of the P27361 REA and P28482 REA isoforms of Q96HU1 kinase , which then rapidly decrease to the basal level . We demonstrate that isoforms of the P29353 REA 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 REA antagonist , pindobind , and pertussis toxin abolished the Xaliproden-induced P29323 REA stimulation suggested that Xaliproden activates the Q96HU1 kinase pathways by stimulating the G protein-coupled receptor , P08908 REA . 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 REA receptors , P38936 REA 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 REA ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 REA remain incompletely defined . In this work , we present evidence that stimulation of the 5 - hydroxytryptamine 1A ( P08908 REA ) receptor results in the formation of a signaling complex that includes activated O60674 REA ( Jak 2 ) , Ca2 + / calmodulin ( P62158 ) , and P19634 REA , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist-induced association of P62158 and P19634 REA as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 REA is activated through this pathway : P08908 REA receptor --> G ( i2 ) alpha and / or G ( i3 ) alpha --> Jak 2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 REA --> induction of a conformational change in P19634 REA that unmasks an obscured proton-sensing and / or proton-transporting region of P19634 REA --> activation of P19634 REA . The G ( i / o ) - coupled P08908 REA 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 REA 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 :p rotein = 12:59 : 28 ) or low in fat ( LFD ) ( 1478 kcal : % CHO : fat :p rotein = 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 ( 20:4 n - 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 16:1 n - 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 REA , P05231 REA , P10145 REA , P13500 REA , P16581 REA , I - P62158 , and P05121 REA . Increased 20:4 n - 6 and the ratios of 20:4 n -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 REA ) in the actions of antidepressant treatment in two key areas . First , by determining the requirement for P15692 REA 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 REA receptor subtype in the regulation of P15692 REA , and the cellular localization of antidepressant regulation of P15692 REA expression . The results show that pharmacological inhibition of P15692 REA 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 REA - 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 REA receptors is sufficient to induce P15692 REA expression and that a P08908 REA antagonist blocks both the increase in P15692 REA and behavioral effects induced by fluoxetine . Finally , double labeling studies show that chronic fluoxetine administration increases P15692 REA expression in both neurons and endothelial cells in the hippocampus . Taken together these studies show that P15692 REA 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 REA 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 REA / P35354 REA ) . Several studies indicate that P35354 REA is overexpressed in actinic keratosis in humans and dogs . DB09217 MEN is a P35354 REA - selective inhibitor that blocks the biochemical activity of P35354 REA . 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 MEN 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 REA 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 REA might thus be hypothesized in the pathogenesis of canine solar dermatitis .

Suppression of tumor growth and metastasis by a P17948 REA antagonizing peptide identified from a phage display library . Although the P15692 REA - Flk - 1 - pathway has been known as the major driving force of angiogenesis , new evidence has shown that P17948 REA / 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 REA receptor Flt - 1 , of which peptide F56 ( WHSDMEWWYLLG ) almost abolished P15692 REA binding to receptor Flt - 1 in vitro . In vivo , F56 fused with P00374 REA ( P00374 REA - F56 ) inhibited angiogenesis in a P62158 assay . Moreover , P00374 REA - 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 REA - F56 . In the severe combined immunodeficiency disease ( SCID ) mouse model for studying metastasis of the human breast cancer cell line BICR-H 1 , 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 REA and receptor Flt - 1 . Thus , short peptide F56 may have clinical potential in tumor therapy .

Impact of the Pro 12Ala polymorphism of the Q07869 REA - gamma 2 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 Pro 12Ala polymorphism of the peroxisome proliferator-activated receptor-gamma 2 ( Q07869 REA - gamma 2 ) 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 ( 3.6 g n - 3 fatty acids / day containing 2.4 g of EPA and DB01708 MEN ) or placebo capsules containing olive oil for 3 months . At baseline , the Pro 12Ala 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 Ala 12 allele presented a greater decrease in serum triacylglycerol concentration in response to n - 3 fatty acid supplementation than did subjects with the Pro 12Pro 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 Pro 12Ala polymorphism of the Q07869 REA - gamma 2 gene may modify the inter-individual variability in serum triacylglycerol response to n - 3 fatty acid supplementation .

Monoclonal antibodies targeting P01584 REA reduce biomarkers of atherosclerosis in vitro and inhibit atherosclerotic plaque formation in P02649 REA - 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 MEN , might inhibit the secretion of pro-atherogenic cytokines from macrophages in vitro and affect a positive outcome in the P02649 REA - deficient mouse ( ApoE ( - / - ) ) model of atherosclerosis in vivo . METHODS AND RESULTS : In an in vitro co-culture model , DB06062 MEN inhibited macrophage-induced secretion of key atherogenic cytokines from EC and SMC , including P05231 REA , P10145 REA , P13500 REA and TNFα . The release of degradative enzymes , such as the matrix metalloproteinases P08254 REA and P14780 REA , was also decreased by DB06062 MEN . In addition , DB06062 MEN inhibited the secretion of P13232 REA from EC and P05112 REA from SMC , cytokines not previously reported to be driven by IL - 1β in this context . In vivo , XMA 052 MG1K , a chimeric murine version of DB06062 MEN , 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 serotonin 1A - 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 REA 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 SUB - 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 REA receptor blocker N - [ 2 - ( 4 - { 2 - methoxyphenyl } - 1 - piperazinyl ) - ethyl ] - N - 2 - pyridinylcyclohexanecarboxamide ( WAY 100635 ) . In contrast to fluoxetine , vilazodone exhibited intrinsic P08908 REA 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 REA receptor-related since endogenous 5 - HT is lacking in the reserpine-depleted animal . CONCLUSIONS : In spite of high intrinsic P08908 REA activity in reserpinized rats , the net effect of vilazodone at release-regulating P08908 REA autoreceptors must be inhibitory , leading to markedly increased 5 - HT output . Another possibility is that vilazodone rapidly desensitizes autoinhibitory P08908 REA receptors by an unknown mechanism .