interacts_with DB08889?
Acute renal failure from hemoglobinuric and interstitial nephritis secondary to iodine and mefenamic acid . DB00784 ingestion , usually in excess and over prolonged period is known to produce interstitial nephritis , or less commonly papillary necrosis , with acute renal failure . However , it is not dose-dependent for the induction of tubulointerstitial damage . Excess iodine ingestion is known to produce toxicity and possible death , but acute renal failure is rare . There is evidence from clinical and experimental data that iodine has toxic effect on tubular epithelial cells . Iodine has not been documented to produce red cell hemolysis and hemoglobinuria . We present a unique case of acute renal failure from hemoglobinuric and acute interstitial nephritis secondary to suicidal ingestion of potassium iodide solution and also ingestion of a few mefenamic acid tablets . These agents led to potentiation of the renal injury from hemoglobinuric tubulopathy , probably from the iodine , and renal dysfunction from alteration of renal perfusion by selective P23219 inhibition of prostaglandin production , and induction of acute interstitial nephritis from mefenamic acid , leading to acute renal failure which was reversible by hemodialysis and supportive therapy . Potential effects of tetrodotoxin exposure to human glial cells postulated using microarray approach . Sodium channels play an important role in many neurological disorders and also in prostate cancer . DB05232 ( TTX ) , a blocker of voltage-gated sodium channels has been chiefly used as a molecular probe for the study and characterization of these channels . The regulation of gene expression in response for the exposure of TTX to glial cells which are reported to be involved in neurodegenerative process is poorly understood . Therefore , the present study aims to develop a repository of genes and map it on a few pivotal neurodegenerative pathways to speculate the effect of TTX . Using Affymetrix GeneChip ( HG-U133A ) , we have selected a subset of 692 differentially expressed genes , several of which are-cullin 4A ( Q13619 ) , ubiquitin carrier protein ( Q16763 ) , proteasome ( prosome , macropain ) subunit , beta type , 8 ( large multifunctional protease 7 ) ( P28062 ) , protein tyrosine phosphatase type IVA ( Q93096 ) , intercellular adhesion molecule 1 ( P05362 ) , prostaglandin-endoperoxide synthase 2 ( P35354 ) , and caspase 1 ( P29466 ) . These genes , which facilitate some of the neurodegenerative pathways , such as ubiquitin , proteasome , inflammation and kinases , were identified to be up- or down-regulated for the TTX treatment . Thus , the selected genes were further examined on ubiquitin-proteasome mediated inflammatory responses pathway as ample evidence for the role of glial cell-mediated inflammation in the neurodegenerative process are available . In summary , our result provides a basic understanding of the differentially expressed genes along with one of the possible pathway which may have been modulated by the exposure of TTX . DB00588 -induced regulation of the balance within macrophage subpopulations . In asthma , treatment with inhaled corticosteroids reduces chronic peribronchial inflammation and restores the balance within macrophage subpopulations . This study investigates whether corticosteroids can regulate monocyte differentiation in vitro and thereby influence the balance of functionally distinct macrophages . Graded doses of fluticasone propionate ( FP ) were added to cultures of normal peripheral blood monocytes in the presence or absence of P05112 . Cells were harvested after 7 days ' culture . Double immunofluorescence studies were performed on cytospins of differentiated macrophages using the MoAbs RFD1 and RFD7 to distinguish inductive and suppressive macrophages by their respective phenotypes . Macrophage function was determined by quantifying allostimulation in a mixed leucocyte reaction and by measuring tumour necrosis factor-alpha ( P01375 ) production . FP reduced the number of mature cells with a D1+ antigen-presenting phenotype and up-regulated the development of cells with the D1/D7+ and D7+ phenotypes . Functionally , this was associated with reduced stimulation of T cell proliferation in a mixed leucocyte reaction ( P08235 ) . DB00588 also reversed the increase in both D1+ expression and P01375 production induced by P05112 . The effect of FP persisted for 24 h after removal of FP from the culture medium . These results suggest that FP treatment of asthmatics may have a direct beneficial effect by normalizing the macrophage subset imbalance that contributes to the chronic peribronchial inflammation present in this condition . Polyamines and membrane transporters . In recent years , our understanding of the importance of membrane transporters ( MTs ) in the disposition of and response to drugs has increased significantly . MTs are proteins that regulate the transport of endogenous molecules and xenobiotics across the cell membrane . In mammals , two super-families have been identified : DB00171 -binding cassette ( DB01048 ) and solute carrier ( O00585 ) transporters . There is evidence that MTs might mediate polyamines ( PA ) transport . PA are ubiquitous polycations which are found in all living cells . In mammalian cells , three major PA are synthesised : putrescine , spermidine and spermine ; whilst the decarboxylated arginine ( agmatine ) is not produced by mammals but is synthesised by plants and bacteria . In addition , research in the PA field suggests that PA are transported into cells via a specific transporter , the polyamine transport system(s) ( Q03393 ) . Although the Q03393 has not been fully defined , there is evidence that some of the known MTs might be involved in PA transport . In this mini review , eight O00585 transporters will be reviewed and their potential to mediate PA transport in human cells discussed . These transporters are O15245 , O15244 , O75751 , Q96FL8 , P30825 , P08195 , SLC12A8A , and Q86VW1 . Preliminary data from our laboratory have revealed that O15245 might be involved in the PA uptake ; in addition to one member of ABC superfamily ( P08183 protein ) might also mediate the efflux of polyamine like molecules . P00734 in normal human cerebrospinal fluid originates from the blood . In spite of the fact that prothrombin is produced by cells within the central nervous system , its presence in the cerebrospinal fluid ( P04141 ) has not been investigated . We determined the concentration of prothrombin in P04141 with reference to the concentration in plasma in paired samples from 18 " normal " control patients and 4 patients with relapsing-remitting type of multiple sclerosis ( MS ) . The newly developed ELISA was very specific ( no cross-reactivity with thrombin ) and sensitive ( detection limit -- 0.7 ng/ml ) with an imprecision of CV = 8.3 % ( intraseries ) and 7.0 % ( interassay ) . The mean prothrombin concentration in normal P04141 was 0.55 mg/l ( CV +/- 33 % , range : 0.28-0.93 mg/l ) , in normal plasma 121.8 mg/l +/- 21 % , resulting in a mean P04141 /plasma concentration quotient ( Q(Proth) -- 4.5 x 10(-3) ( CV +/- 35 % , range : 2.1-8.3 x 10(-3) ) corresponding to a mean albumin quotient in this group of subjects of Q(Alb) = 5.8 x 10(-3) . Due to the Q(Proth) and the molecular weight of prothrombin ( 72 kDa ) -- similar to that of albumin -- we conclude that prothrombin in normal human P04141 originates predominantly ( > 95 % ) from blood . The enzymatic activity in P04141 is conserved . Comparable results obtained in MS patients with only few small Q9BWK5 lesions suggest that local chronic inflammatory disease of the central nervous system does not influence prothrombin concentration in the P04141 if the blood- P04141 barrier function is normal . P49146 deletion attenuates the type 2 diabetic syndrome of ob/ob mice . Hypothalamic neuropeptide Y ( P01303 ) is implicated in the regulation of a variety of physiological functions , notably energy homeostasis and reproduction . Chronically elevated P01303 levels in the hypothalamus , as in genetically obese ob/ob mice , are associated with obesity , a syndrome of type 2 diabetes , and infertility . However , it is not known which of the five cloned Y receptors mediate these effects . Here , we show that crossing the P49146 knockout mouse ( P28062 (-/-) ) onto the ob/ob background attenuates the increased adiposity , hyperinsulinemia , hyperglycemia , and increased hypothalamo-pituitary-adrenal ( Q9Y251 ) axis activity of ob/ob mice . Compared with lean controls , ob/ob mice had elevated expression of P01303 and agouti-related protein ( AgRP ) mRNA in the arcuate nucleus and decreased expression of proopiomelanocortin ( P01189 ) and cocaine- and amphetamine-regulated transcript ( Q16568 ) mRNA . P28062 deletion in ob/ob mice significantly increased the hypothalamic P01189 mRNA expression , with no effect on P01303 , AgRP , or Q16568 expression . [ P28062 (-/-)ob/ob ] mice were no different from ob/ob littermates with respect to food intake and body weight , and P49146 deficiency had no beneficial effect on the infertility or the reduced hypothalamo-pituitary-gonadotropic function of ob/ob mice . These data demonstrate that P28062 receptors mediate the obese type 2 diabetes phenotype of ob/ob mice , possibly via alterations in melanocortin tonus in the arcuate nucleus and/or effects on the Q9Y251 axis . Neuropeptide Y induces ischemic angiogenesis and restores function of ischemic skeletal muscles . Previously we showed that neuropeptide Y ( P01303 ) , a sympathetic vasoconstrictor neurotransmitter , stimulates endothelial cell migration , proliferation , and differentiation in vitro . Here , we report on P01303 's actions , receptors , and mediators in ischemic angiogenesis . In rats , hindlimb ischemia stimulates sympathetic P01303 release ( attenuated by lumbar sympathectomy ) and upregulates P01303 - P28062 ( P28062 ) receptor and a peptidase forming P28062 /Y5-selective agonist . Exogenous P01303 at physiological concentrations also induces Q15761 , stimulates neovascularization , and restores ischemic muscle blood flow and performance . P01303 -mediated ischemic angiogenesis is not prevented by a selective Q03519 receptor antagonist but is reduced in P28062 (-/-) mice . Nonischemic muscle vascularity is also lower in P28062 (-/-) mice , whereas it is increased in P01303 -overexpressing rats compared with their WT controls . Ex vivo , P01303 -induced aortic sprouting is markedly reduced in P28062 (-/-) aortas and spontaneous sprouting is severely impaired in P01303 (-/-) mice . P01303 -mediated aortic sprouting , but not cell migration/proliferation , is blocked by an antifetal liver kinase 1 antibody and abolished in mice null for P29474 . Thus , P01303 mediates neurogenic ischemic angiogenesis at physiological concentrations by activating P28062 /Y5 receptors and P29474 , in part due to release of P15692 . P01303 's effectiveness in revascularization and restoring function of ischemic tissue suggests its therapeutic potential in ischemic conditions . Enhancement of cytotoxicity of natural product drugs against multidrug resistant variant cell lines of human head and neck squamous cell carcinoma and breast carcinoma by tesmilifene . N,N-diethyl-2-[4-(phenylmethyl)phenoxyl]ethanamine ( tesmilifene ) , a tamoxifen derivative with antihistamine activity , greatly enhanced the survival of doxorubicin-treated , advanced stage breast cancer patients in a phase III trial . However , the molecular basis of tesmilifene action is not firmly established . The effects of tesmilifene on activity of several anticancer drugs was investigated using human head and neck squamous cell carcinoma ( HNSCC ) and breast carcinoma cell lines as a model system . Multidrug resistant ( MDR ) variants of an HNSCC cell line , HN-5a/V15e , and a breast carcinoma cell line , MCF-7/V25a , both highly overexpressed mdr1 ( P08183 ) mRNA and the proteins P-glycoprotein and glutathione transferase-pi . Drug sensitivities were measured by a vital stain after 4 days of continuous exposure to anticancer drug in the absence and presence of tesmilifene at a concentration that alone had no antiproliferative effect . DB04905 had minimal effect on drug cytotoxicity against the parental cell lines . However , the same tesmilifene treatment enhanced cytotoxicity of docetaxel , paclitaxel , epirubicin , doxorubicin , and vinorelbine against both MDR cell lines by up to 50 % . Flow cytometric measurement of annexin V/propidium iodide staining demonstrated that tesmilifene increased the killing of HN-5a/V15e cells caused by docetaxel after 24 and 48h exposure . DB04905 increased accumulation of radiolabelled vincristine in HN-5a/V15e cells , over 4h , by up to 100 % . The results suggest that tesmilifene might be effective in the treatment of tumors that are resistant to natural product drugs . The mechanism of enhancement appears to be related to expression of an ABC pump-dependent , MDR phenotype . Establishment and characterization of an immature human megakaryoblastic cell line , P29074 -A2 . We have established a novel human megakaryoblastic cell line , designated as P29074 -A2 , from a patient with megakaryoblastic crisis of Philadelphia ( Ph ) chromosome positive chronic myelogenous leukemia . P29074 -A2 cells showed positive phenotypes for periodic acid Schiff and alpha-naphthylbutyrate esterase reactions , but were negative for myeloperoxidase and naphthol P51689 chloroacetate esterase reactions . Flow cytometric analyses of cell surface markers revealed that P29074 -A2 cells had a low level of GP IIb/IIIa expression as well as apparent expressions of P01730 , P09564 , P15144 , P20138 and P28906 antigens , but no expression of GP Ib nor glycophorin A . Stimulation with phorbol 12-myristate 13-acetate ( PMA ) dramatically increased the expression of megakaryocyte-related markers such as P09382 -3 , J15 , Pit-1 , P28062 /51 and AN51 in P29074 -A2 cells . The PMA-stimulation also induced expression of platelet peroxidase ( P50336 ) in P29074 -A2 cells on electromicroscopic observation . Proliferative responses to granulocyte-macrophage colony-stimulating factor ( GM- P04141 ) , interleukin-3 ( P08700 ) or erythropoietin were observed , and the expression of GP IIb/IIIa was increased by stimulation with GM- P04141 , P08700 , erythropoietin and interleukin-6 ( P05231 ) . Protein S mRNA expression was seen in cultured cells on Northern blot analysis . Expression of platelet factor 4 mRNA was induced in PMA-stimulated cells , and a marked accumulation of protein was observed in the culture medium . In conclusion , a new cell line , P29074 -A2 , belongs to the relatively immature megakaryocytic lineage and has markedly increased megakaryocytic characteristics with PMA stimulation . DB00819 inhibits stimulated feline liver and gallbladder bicarbonate secretion . Bile acidification is a key factor in preventing calcium carbonate precipitation and gallstone formation . P00918 ( CA II ) , that is inhibited by acetazolamide , plays a role in regulation of the acid-base balance in many tissues . This study examines the effect of acetazolamide on secretin- and vasoactive intestinal peptide ( P01282 ) -stimulated gallbladder mucosal bicarbonate and acid secretion . Gallbladders in anaesthetized cats were perfused with a bicarbonate buffer bubbled with CO2 in air . In 20 experiments P01282 ( 10 microg kg(-1) h(-1) ) and in 10 experiments secretin ( 4 microg kg(-1) h(-1) ) were infused continuously intravenous ( i.v. ) . Hepatic bile and samples from the buffer before and after perfusion of the gallbladder were collected for calculation of ion and fluid transport . During basal conditions a continuous secretion of H+ by the gallbladder mucosa was seen . Intravenous infusion of vasoactive intestinal peptide ( P01282 ) and secretin caused a secretion of bicarbonate from the gallbladder mucosa ( P < 0.01 ) . This secretion was reduced by intraluminal ( i.l. ) acetazolamide ( P < 0.01 ) . Bile flow was enhanced by infusion of P01282 and secretin ( P < 0.01 ) but this stimulated outflow was not affected by i.v. acetazolamide . The presence of CA II in the gallbladder was demonstrated by immunoblotting . Biliary CA activity has an important function in the regulation of P01282 - and secretin-stimulated bicarbonate secretion across the gallbladder mucosa . Influence of in-situ synthesized exopolysaccharides on the quality of gluten-free sorghum sourdough bread . The majority of gluten-free breads on the market are of poor sensory and textural quality . Exopolysaccharides ( EPS ) formed from sucrose during sourdough fermentation can improve the technological properties of gluten-free breads and potentially replace hydrocolloids . In this study , the influence of in situ formed EPS on dough rheology and quality of gluten-free sorghum bread was investigated . DB09255 forming Weissella cibaria MG1 was compared to reuteran producing Lactobacillus reuteri P01282 and fructan forming L. reuteri P28062 . EPS containing bread batters were prepared by adding 10 % and 20 % of sourdough . As control served batters and bread containing sourdoughs fermented without sucrose and batters and bread without sourdough addition . The amount of EPS formed in situ ranged from 0.6 to 8.0 g/kg sourdough . EPS formed during sourdough fermentation were responsible for the significant decrease in dough strength and elasticity , with in situ formed dextran exhibiting the strongest impact . Increased release of glucose and fructose from sucrose during fermentation enhanced CO₂ production of yeast . Organic acids in control sourdough breads induced hardening of the bread crumb . EPS formed during sourdough fermentation masked the effect of the organic acids and led to a softer crumb in the fresh and stored sorghum bread . Among EPS , dextran showed the best shelf life improvements . In addition to EPS , all three strains produced oligosaccharides during sorghum sourdough fermentation contributing to the nutritional benefits of gluten-free sorghum bread . Results of this study demonstrated that EPS formed during sourdough fermentation can be successfully applied in gluten-free sorghum flours to improve their bread-making potentials . Investigation of the binding of isoform-selective inhibitors to prostaglandin endoperoxide synthases using fluorescence spectroscopy . Prostaglandin endoperoxide synthase ( PGHS ) is a heme protein that catalyzes the committed step in prostaglandin and thromboxane biosynthesis . Two isoforms of PGHS exist , a constitutive form termed P23219 and an inducible form termed P35354 . We report here fluorescence resonance energy transfer analysis of isoform-selective inhibitors interacting with P23219 and P35354 . By measuring fluorescence quenching due to the energy transfer of the inhibitor fluorescence to the heme prosthetic group of PGHS , we determined these inhibitors bind in the arachidonic acid substrate access channel with an R0 of 35 A for P23219 with the P23219 inhibitor and an R0 of 21 A for P35354 with the P35354 inhibitor . The observed fluorescence quenching is completely dynamic and dominated by quenching by the heme . Time-resolved results combined with molecular modeling determine the distance from the inhibitor to the heme moiety to be 20 A in P23219 and 18 A in P35354 . Preliminary stopped-flow kinetic studies reveal that the rate of quenching is limited by a first-order protein transition , which is slow , and that bound inhibitor undergoes rapid exchange . Desmopressin ( DB00035 ) induces NO production in human endothelial cells via V2 receptor- and DB02527 -mediated signaling . The hemostatic agent desmopressin ( DB00035 ) also has strong vasodilatory effects . DB00035 is a selective agonist for the vasopressin V2 receptor ( P30518 ) , which is coupled to DB02527 -dependent signaling . DB00035 -induced vasodilation may be due to endothelial NO synthase ( P29474 ) activation . This hypothesis implies DB02527 -mediated P29474 activation . It also implies wide extrarenal , endothelial P30518 expression . We show that in human umbilical vein endothelial cells ( HUVECs ) the DB02527 -raising agents forskolin and epinephrine increase NO production , as measured by a l-NMMA-inhibitable rise in cellular cGMP content . They also increase P29474 enzymatic activity , in a partly calcium-independent manner . DB02527 -mediated P29474 activation is associated with phosphorylation of residue Ser1177 , in a phosphatidyl inositol 3-kinase ( PI3K ) -independent manner . HUVECs do not express P30518 . However , after heterologous P30518 expression , DB00035 induces DB02527 -dependent P29474 activation via Ser1177 phosphorylation . We have previously found P30518 expression in cultured lung endothelial cells . By real time quantitative RT-PCR , we now find a wide P30518 distribution notably in heart , lung and skeletal muscle . These results indicate that DB00035 and other DB02527 -raising agents can activate P29474 via PI3K-independent Ser1177 phosphorylation in human endothelial cells . This mechanism most likely accounts for DB00035 -induced vasodilation . DB00278 -coupled Affi-Gel matrix for the purification of thrombin from plasma . Sometimes it is necessary to obtain thrombin from limited amounts of human plasma for laboratory assay . None of the available purification methods easily deals with this subject . The procedure described in the present paper uses a readily available pharmaceutical agent , argatroban , to construct an affinity matrix . DB00278 has a high affinity for thrombin and its thrombin binding is reversible . P00734 derived from a Ba(2+) precipitate of human plasma is used as the starting material . The crude prothrombin can be bulk activated to thrombin using taipan-snake ( Oxyuranus scutellatus ) venom and bound to the argatroban-coupled matrix without further processing steps . The thrombin product eluted from the argatroban matrix is very pure as judged by high specific activity and by electrophoresis . This purification scheme is rapid , yielding purified thrombin within 2 days . DB08889 can induce tumor cell death through selective inhibition of the chymotrypsin-like activity of the proteasome . DB08889 is a proteasome inhibitor in clinical development that primarily targets the chymotrypsin-like ( CT-L ) subunits in both the constitutive proteasome ( c20S ) and the immunoproteasome ( i20S ) . To investigate the impact of inhibiting the CT-L activity with carfilzomib , we set out to quantitate the levels of CT-L subunits beta5 from the c20S and P28062 from the i20S in normal and malignant hematopoietic cells . We found that the i20S is a major form of the proteasome expressed in cells of hematopoietic origin , including multiple myeloma ( MM ) CD138+ tumor cells . Although specific inhibition of either P28062 or beta5 alone was insufficient to produce an antitumor response , inhibition of all proteasome subunits was cytotoxic to both hematologic tumor cells and peripheral blood mononuclear cells . However , selective inhibition of both beta5 and P28062 was sufficient to induce an antitumor effect in MM , non-Hodgkin lymphoma , and leukemia cells while minimizing the toxicity toward nontransformed cells . In MM tumor cells , CT-L inhibition alone was sufficient to induce proapoptotic sequelae , including proteasome substrate accumulation , Noxa and caspase 3/7 induction , and phospho-eIF2alpha suppression . These data support a hypothesis that hematologic tumor cells are uniquely sensitive to CT-L inhibition and provide a mechanistic understanding of the clinical safety profile and antitumor activity of proteasome inhibitors . Design and synthesis of an orally bioavailable and selective peptide epoxyketone proteasome inhibitor ( PR-047 ) . Proteasome inhibition has been validated as a therapeutic modality in the treatment of multiple myeloma and non-Hodgkin 's lymphoma . DB08889 , an epoxyketone currently undergoing clinical trials in malignant diseases , is a highly selective inhibitor of the chymotrypsin-like ( CT-L ) activity of the proteasome . A chemistry effort was initiated to discover orally bioavailable analogues of carfilzomib , which would have potential for improved dosing flexibility and patient convenience over intravenously administered agents . The lead compound , 2-Me-5-thiazole- DB00133 (OMe)- DB00133 (OMe)- DB00120 -ketoepoxide ( 58 ) ( PR-047 ) , selectively inhibited CT-L activity of both the constitutive proteasome ( beta5 ) and immunoproteasome ( P28062 ) and demonstrated an absolute bioavailability of up to 39 % in rodents and dogs . It was well tolerated with repeated oral administration at doses resulting in > 80 % proteasome inhibition in most tissues and elicited an antitumor response equivalent to intravenously administered carfilzomib in multiple human tumor xenograft and mouse syngeneic models . The favorable pharmacologic profile supports its further development for the treatment of malignant diseases . P35557 contributes to glucose phosphorylation in D-lactic acid production by Sporolactobacillus inulinus P28062 -8 . Sporolactobacillus inulinus , a homofermentative lactic acid bacterium , is a species capable of efficient industrial D-lactic acid production from glucose . DB09341 phosphorylation is the key step of glucose metabolism , and fine-tuned expression of which can improve D-lactic acid production . During growth on high-concentration glucose , a fast induction of high glucokinase ( Q8IVH8 ) activity was observed , and paralleled the patterns of glucose consumption and D-lactic acid accumulation , while phosphoenolpyruvate phosphotransferase system ( Q03393 ) activity was completely repressed . The transmembrane proton gradient of 1.3-1.5 units was expected to generate a large proton motive force to the uptake of glucose . This suggests that the Q8IVH8 pathway is the major route for glucose utilization , with the uptake of glucose through Q03393 -independent transport systems and phosphorylation of glucose by Q8IVH8 in S. inulinus D-lactic acid production . The gene encoding Q8IVH8 was cloned from S. inulinus and expressed in Escherichia coli . The amino acid sequence revealed significant similarity to Q8IVH8 sequences from Bacillaceae . The recombinant Q8IVH8 was purified and shown to be a homodimer with a subunit molecular mass of 34.5 kDa . Strikingly , it demonstrated an unusual broad substrate specificity , catalyzing phosphorylation of DB08831 , mannitol , maltose , galactose and glucosamine , in addition to glucose . This report documented the key step concerning glucose phosphorylation of S. inulinus , which will help to understand the regulation of glucose metabolism and D-lactic acid production . Neuropeptide Y selectively inhibits slow synaptic potentials in rat dorsal raphe nucleus in vitro by a presynaptic action . Neuropeptide Y ( P01303 ) has been shown to modulate synaptic transmission in both peripheral and central tissues via both pre- and postsynaptic mechanisms . In this study , we examined the effect of P01303 and its analog , peptide YY ( P10082 ) , on slow synaptic potentials in the dorsal raphe nucleus in vitro using intracellular recording and single-microelectrode voltage-clamp techniques . P01303 and P10082 inhibited both the slow P08908 receptor-mediated IPSP and the alpha 1-adrenoceptor-mediated slow EPSP while not affecting the fast , amino acid-mediated synaptic responses . P10082 also inhibited pharmacologically isolated slow synaptic responses . P01303 / P10082 appear to mediate the observed inhibitions via a presynaptic mechanism , as the postsynaptic conductances mediated by activation of P08908 receptors or alpha 1-adrenoceptors were unaffected by the peptides . P01303 / P10082 act via a different mechanism than presynaptic P28222 receptors . P01303 / P10082 probably act via presynaptic P28062 receptors , as the C-terminal fragment P01303 13-36 and the P28062 -selective agonist P06681 - P01303 are effective . Since P01303 and its receptors are present in the dorsal raphe nucleus , this peptide may act as an endogenous modulator of the state of activity of neurons in this region and may thus have a role in the modulation of neuronal output from this nucleus . 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 . Leptin resistance in vagal afferent neurons inhibits cholecystokinin signaling and satiation in diet induced obese rats . BACKGROUND AND AIMS : The gastrointestinal hormone cholecystokinin ( CCK ) plays an important role in regulating meal size and duration by activating CCK1 receptors on vagal afferent neurons ( Q15025 ) . Leptin enhances CCK signaling in Q15025 via an early growth response 1 ( P18146 ) dependent pathway thereby increasing their sensitivity to CCK . In response to a chronic ingestion of a high fat diet , Q15025 develop leptin resistance and the satiating effects of CCK are reduced . We tested the hypothesis that leptin resistance in Q15025 is responsible for reducing CCK signaling and satiation . RESULTS : Lean Zucker rats sensitive to leptin signaling , significantly reduced their food intake following administration of CCK8S ( 0.22 nmol/kg , i.p. ) , while obese Zucker rats , insensitive to leptin , did not . CCK signaling in Q15025 of obese Zucker rats was reduced , preventing CCK-induced up-regulation of P49146 and down-regulation of melanin concentrating hormone 1 receptor ( Q99705 ) and cannabinoid receptor ( P21554 ) . In Q15025 from diet-induced obese ( DIO ) Sprague Dawley rats , previously shown to become leptin resistant , we demonstrated that the reduction in P18146 expression resulted in decreased sensitivity of Q15025 to CCK and reduced CCK-induced inhibition of food intake . The lowered sensitivity of Q15025 to CCK in DIO rats resulted in a decrease in P28062 expression and increased P21554 and Q99705 expression . These effects coincided with the onset of hyperphagia in DIO rats . CONCLUSIONS : Leptin signaling in Q15025 is required for appropriate CCK signaling and satiation . In response to high fat feeding , the onset of leptin resistance reduces the sensitivity of Q15025 to CCK thus reducing the satiating effects of CCK . Bipartite regulation of different components of the MHC class I antigen-processing machinery during dendritic cell maturation . Dendritic cells ( DC ) are professional antigen-presenting cells ( P25054 ) which proceed from immature to a mature stage during their final differentiation . Immature DC are highly effective in terms of antigen uptake and processing , whereas mature DC become potent immunostimulatory cells . Until now , the expression profiles of the major components of the MHC class I antigen-processing machinery ( APM ) during DC development have not been well characterized . In this study , the mRNA and protein expression levels of the P01579 inducible proteasome subunits , of the proteasome activators PA28 , and of key components required for peptide transport and MHC class I-peptide complex assembly have been evaluated in immature and mature stages of human monocyte-derived DC using semiquantitative RT-PCR and Western blot analyses . The P01579 -responsive immunoproteasome subunits P28065 , P28062 and P40306 are up-regulated in immature DC , whereas the other components of the MHC class I presentation machinery , such as PA28 , TAP , tapasin , and HLA heavy and light chains , were found to be more abundant in mature DC . These findings support the hypothesis that immature DC produced by the differentiation of monocytes in response to P05112 and granulocyte macrophage colony stimulating factor first increase their capacity to capture antigens and process them into peptides , thereby switching from housekeeping to immunoproteasomes , while mature DC rather up-regulate the components required for peptide translocation and MHC class I-peptide complex formation , and thus specialize in antigen presentation . Our results establish that MHC class I , like MHC class II surface expression , is markedly regulated during DC development and maturation . Chronic daily tadalafil prevents the corporal fibrosis and veno-occlusive dysfunction that occurs after cavernosal nerve resection . OBJECTIVES : To determine whether a long-term single daily oral dose of a longer half-life phosphodiesterase-5 ( O76074 ) inhibitor , tadalafil , has a similar effect to that of the shorter half-life O76074 inhibitors sildenafil and vardenafil , and can prevent the fibrosis and resultant corporal veno-occlusive dysfunction ( CVOD ) occurring after cavernosal nerve ( CN ) injury . MATERIALS AND METHODS : Male rats ( 10 per group ) had either a sham operation , unilateral CN resection ( P21554 ) or bilateral P21554 , and were left untreated or given retrolingually 5 mg/kg per day of tadalafil . After 45 days , CVOD was assessed via cavernosometry , and the underlying corporal tissue changes were examined by immunohistochemistry and histochemistry ( followed by quantitative image analysis ) , Western blots , and ad hoc methods . RESULTS : DB00820 treatment normalized the low response to papaverine and high drop rate in the intracavernosal pressure measured by cavernosometry after P21554 compared with sham-operated rats . DB00820 also normalized the increase in penile shaft collagen content , and the reduction in corporal smooth muscle cell ( SMC ) content , SMC/collagen , and replication index , and improved the lower collagen III/I ratio and the increase in apoptotic index , caused by P21554 , compared with sham operation . There were no effects of tadalafil on increased transforming growth factor beta1 , inducible nitric oxide synthase and xanthine oxidoreductase levels . CONCLUSIONS : A long-term single daily dose of tadalafil prevented CVOD and the underlying corporal fibrosis in the rat caused by CN damage , as effectively as the previously reported continuous treatment with vardenafil or sildenafil , through a cGMP-related mechanism that appears to be independent of inducible nitric oxide synthase induction . Nongenomic , glucocorticoid receptor-mediated regulation of serotonin transporter cell surface expression in embryonic stem cell derived serotonergic neurons . Depressive disorders have been linked to the combined dysregulation of the hypothalamus-pituitary-adrenal ( Q9Y251 ) -axis and the serotonergic system . The Q9Y251 -axis and serotonergic ( 5-HT ) neurons exert reciprocal regulatory actions . It has been reported that glucocorticoid-glucocorticoid receptor ( GR ) signaling influences serotonin transporter ( 5-HTT ) transcription but data also points to the fact that 5-HTT expression is regulated nongenomically via redistribution of 5-HTT from the cell surface into intracellular compartments . In order to analyze the acute effects of glucocorticoids on 5-HTT cell surface localization we differentiated serotonergic neurons from mouse embryonic stem ( ES ) cells derived from the C57BL/6N blastocysts . These postmitotic 5-HT neurons express all relevant serotonergic markers following the application of a growth factor-based differentiation protocol . Increasing concentrations of the GR agonist dexamethasone ( DB00514 ) resulted in enhanced , dose-dependent 5-HTT cell surface localization in the presence of the protein synthesis inhibitor cycloheximide already 1h after incubation . Inhibition of GR function by the specific GR-antagonist mifepristone abolished the increase in 5-HTT cell surface localization . Hence , our data account for a nongenomic upregulation of 5-HTT cell surface expression by glucocorticoid-GR interaction which likely constitutes a rapid physiological response to increased levels of glucocorticoids as seen during stress . Taken together , we provide a cellular model to analyze and dissect glucocorticoid- P31645 interactions on a molecular level that corresponds to in vivo animal models using C57BL/6N mice .