interacts_with DB00013?
DB00013 induces stromal cell-derived factor-1 expression in human hepatocellular carcinoma cells . Both the urokinase-type plasminogen activator ( uPA ) and the uPA receptor ( Q03405 ) play important roles with regard to hepatocellular carcinoma ( HCC ) progression and metastasis . Notably , the stromal cell-derived factor-1 ( P48061 ) is an important chemokine involved in HCC pathology . However , the influence of uPA on P48061 expression in human HCC cells remains unknown . We investigated the mechanisms underlying the modulation of P48061 expression through uPA stimulation in human HCC SK-Hep-1 cells . SK-Hep-1 cells stimulation with uPA induced increases in the expression and secretion of P48061 . By using specific inhibitors and small interfering RNA , we have demonstrated that the activation of extracellular signal-related kinase ( P29323 ) and c-Jun-NH(2)-terminal kinase ( JNK ) pathways are critical for uPA-induced P48061 expression . Transcription factor ELISA and chromatin immunoprecipitation assays suggest that uPA increase Sp1- and AP-1-DNA-binding activities in SK-Hep-1 cells . Inhibition of Sp1 and AP-1 activations by specific siRNAs blocked the uPA-induced P48061 promoter activity and expression . The effect of uPA on SK-Hep-1 signaling and P48061 expression is mediated by Q03405 . In summary , our findings serve to elucidate the uPA/ Q03405 downstream signaling , providing new insight into the function of uPA in HCC cells . 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 . Red meat and poultry , cooking practices , genetic susceptibility and risk of prostate cancer : results from a multiethnic case-control study . Red meat , processed and unprocessed , has been considered a potential prostate cancer ( DB11245 ) risk factor ; epidemiological evidence , however , is inconclusive . An association between meat intake and DB11245 may be due to potent chemical carcinogens that are generated when meats are cooked at high temperatures . We investigated the association between red meat and poultry intake and localized and advanced DB11245 taking into account cooking practices and polymorphisms in enzymes that metabolize carcinogens that accumulate in cooked meats . We analyzed data for 1096 controls , 717 localized and 1140 advanced cases from the California Collaborative Prostate Cancer Study , a multiethnic , population-based case-control study . We examined nutrient density-adjusted intake of red meat and poultry and tested for effect modification by 12 SNPs and 2 copy number variants in 10 carcinogen metabolism genes : P09211 , P35354 , P05177 , P05181 , P07099 , Q16678 , P19224 , NAT2 , P09488 and P30711 . We observed a positive association between risk of advanced DB11245 and high intake of red meat cooked at high temperatures ( trend P = 0.026 ) , cooked by pan-frying ( trend P = 0.035 ) , and cooked until well-done ( trend P = 0.013 ) . An inverse association was observed for baked poultry and advanced DB11245 risk ( trend P = 0.023 ) . A gene-by-diet interaction was observed between an SNP in the P35354 gene and the estimated levels of meat mutagens ( interaction P = 0.008 ) . Our results support a role for carcinogens that accumulate in meats cooked at high temperatures as potential DB11245 risk factors , and may support a role for heterocyclic amines ( HCAs ) in DB11245 etiology . Blocking dopamine D2 receptors by haloperidol curtails the beneficial impact of calorie restriction on the metabolic phenotype of high-fat diet induced obese mice . Calorie restriction is the most effective way of expanding life-span and decreasing morbidity . It improves insulin sensitivity and delays the age-related loss of dopamine receptor D(2) ( P14416 ) expression in the brain . Conversely , high-fat feeding is associated with obesity , insulin resistance and a reduced number of P14416 binding sites . We hypothesised that the metabolic benefit of calorie restriction involves the preservation of appropriate P14416 transmission . The food intake of wild-type C57Bl6 male mice was restricted to 60 % of ad lib. intake while they were treated with the P14416 antagonist haloperidol or vehicle using s.c. implanted pellets . Mice with ad lib. access to food receiving vehicle treatment served as controls . All mice received high-fat food throughout the experiment . After 10 weeks , an i.p. glucose tolerance test was performed and , after 12 weeks , a hyperinsulinaemic euglycaemic clamp . Hypothalamic P14416 binding was also determined after 12 weeks of treatment . Calorie-restricted ( CR ) vehicle mice were glucose tolerant and insulin sensitive compared to ad lib . ( AL ) fed vehicle mice . CR mice treated with haloperidol were slightly heavier than vehicle treated CR mice . DB00502 completely abolished the beneficial impact of calorie restriction on glucose tolerance and partly reduced the insulin sensitivity observed in CR vehicle mice . The metabolic differences between AL and CR vehicle mice were not accompanied by alterations in hypothalamic P14416 binding . In conclusion , blocking P14416 curtails the metabolic effects of calorie restriction . Although this suggests that the dopaminergic system could be involved in the metabolic benefits of calorie restriction , restricting access to high-fat food does not increase ( hypothalamic ) P14416 binding capacity , which argues against this inference . Protective effects of metallothionein on isoniazid and rifampicin-induced hepatotoxicity in mice . Isoniazid ( DB00951 ) and DB01045 ( RFP ) are widely used in the world for the treatment of tuberculosis , but the hepatotoxicity is a major concern during clinical therapy . Previous studies showed that these drugs induced oxidative stress in liver , and several antioxidants abated this effect . Metallothionein ( MT ) , a member of cysteine-rich protein , has been proposed as a potent antioxidant . This study attempts to determine whether endogenous expression of MT protects against DB00951 and RFP-induced hepatic oxidative stress in mice . Wild type ( MT+/+ ) and MT-null ( MT-/- ) mice were treated intragastrically with DB00951 ( 150 mg/kg ) , RFP ( 300 mg/kg ) , or the combination ( 150 mg/kg DB00951 +300 mg/kg RFP ) for 21 days . The results showed that MT-/- mice were more sensitive than MT+/+ mice to DB00951 and RFP-induced hepatic injuries as evidenced by hepatic histopathological alterations , increased serum Q9NRA2 levels and liver index , and hepatic oxidative stress as evidenced by the increase of MDA production and the change of liver antioxidant status . Furthermore , DB00951 increased the protein expression of hepatic P05181 and DB00951 /RFP ( alone or in combination ) decreased the expression of hepatic P05177 . These findings clearly demonstrate that basal MT provides protection against DB00951 and RFP-induced toxicity in hepatocytes . The P05181 and P05177 were involved in the pathogenesis of DB00951 and RFP-induced hepatotoxicity . DB00013 receptor is necessary for bacterial defense against pneumonia-derived septic melioidosis by facilitating phagocytosis . DB00013 receptor ( urokinase-type plasminogen activator receptor [ Q03405 ] , CD87 ) , a P06744 -anchored protein , is considered to play an important role in inflammation and fibrinolysis . The Gram-negative bacterium Burkholderia pseudomallei is able to survive and replicate within leukocytes and causes melioidosis , an important cause of pneumonia-derived community-acquired sepsis in Southeast Asia . In this study , we investigated the expression and function of Q03405 both in patients with septic melioidosis and in a murine model of experimental melioidosis . Q03405 mRNA and surface expression was increased in patients with septic melioidosis in/on both peripheral blood monocytes and granulocytes as well as in the pulmonary compartment during experimental pneumonia-derived melioidosis in mice . Q03405 -deficient mice intranasally infected with B. pseudomallei showed an enhanced growth and dissemination of B. pseudomallei when compared with wild-type mice , corresponding with increased pulmonary and hepatic inflammation . Q03405 knockout mice demonstrated significantly reduced neutrophil migration toward the pulmonary compartment after inoculation with B. pseudomallei . Further in vitro experiments showed that Q03405 -deficient macrophages and granulocytes display a markedly impaired phagocytosis of B. pseudomallei . Additional studies showed that Q03405 deficiency did not influence hemostatic and fibrinolytic responses during severe melioidosis . These data suggest that Q03405 is crucially involved in the host defense against sepsis caused by B. pseudomallei by facilitating the migration of neutrophils toward the primary site of infection and subsequently facilitating the phagocytosis of B. pseudomallei . DB00013 induces proliferation of human ovarian cancer cells : characterization of structural elements required for growth factor function . Ovarian cancer metastasis is associated with an increase in the urokinase-type plasminogen activator ( uPA ) and its receptor Q03405 . We present evidence that binding of uPA to Q03405 provokes a mitogenic response in the human ovarian cancer cell line OV-MZ-6 in which endogenous uPA production had been significantly reduced by stable uPA ' antisense ' transfection . High molecular weight ( HMW ) uPA , independent of its enzymatic activity , produced an up to 95 % increase in cell number concomitant with 2-fold elevated [3H]thymidine incorporation as did the catalytically inactive but Q03405 binding amino-terminal fragment of uPA , P39905 . uPA-induced cell proliferation was significantly decreased by blocking uPA/ Q03405 interaction by the monoclonal antibody IIIF10 and by soluble Q03405 . The efficiency of the Q03405 binding synthetic peptide cyclo19,31 uPA19-31 to enhance OV-MZ-6 cell growth proved this molecular domain to be the minimal structural determinant for uPA mitogenic activity . Dependence of uPA-provoked cell proliferation on Q03405 was further demonstrated in Raji cells which do not express Q03405 and were thus not induced by uPA . However , upon transfection with full-length Q03405 , Raji cells acquired a significant growth response to HMW uPA and P39905 . Comparison of expression profiles induced by dust mite in airway epithelia reveals a common pathway . BACKGROUND : Airway epithelial cells have shown to be active participants in the defense against pathogens by producing signaling and other regulatory molecules in response to the encounter . METHODS : In previous manuscripts , we have studied the effect of house dust mite ( HDM ) extract on both an epithelial cell-line ( H292 ) and primary nasal epithelial cell . When we compare these responses we conclude that the H292 cells more closely resemble nasal epithelium of healthy controls ( share 107 probe-sets ) than of allergic individuals ( share 17 probe-sets ) . RESULTS : Interestingly , probably because of an absent intraindividual variation between samples , more probe-sets ( 8280 ) change expression significantly in H292 than in either healthy ( 555 ) or allergic ( 401 ) epithelium . CONCLUSIONS : A direct comparison of all the responses in these epithelial cells reveals a core-response to HDM of just 29 genes . These genes ( P78556 , P10145 , P19875 , P09341 , IL-1B , P15514 , P21580 , Q99075 , P35354 , P12643 , P01130 , Q03405 , P00749 , Q00653 , P19838 , P05412 , P18847 , P18146 , O15118 , Q8IUC6 , P29317 , P29279 , P28562 , O43609 , TLR-3 , complement factor P01024 , Q9Y6Y0 , SerpinB3 , and Q9Y617 ) have described links with allergy or inflammation and may even describe the well-established relationship between viral infections and allergic exacerbations or allergy development . DB00741 is a suppressor of apoptosis in bovine corpus luteum . Glucocorticoid ( GC ) acts as a modulator of physiological functions in several organs . In the present study , we examined whether GC suppresses luteolysis in bovine corpus luteum ( CL ) . DB00741 ( an active GC ) reduced the mRNA expression of caspase 8 ( Q14790 ) and caspase 3 ( P42574 ) and reduced the enzymatic activity of P42574 and cell death induced by tumor necrosis factor ( P01375 ) and interferon gamma ( P01579 ) in cultured bovine luteal cells . mRNAs and proteins of GC receptor ( P04150 ) , 11beta-hydroxysteroid dehydrogenase type 1 ( P28845 ) , and P80365 were expressed in CL throughout the estrous cycle . Moreover , the protein expression and the enzymatic activity of P28845 were high at the early and the midluteal stages compared to the regressed luteal stage . These results suggest that cortisol suppresses P01375 - P01579 -induced apoptosis in vitro by reducing apoptosis signals via Q14790 and P42574 in bovine CL and that the local increase in cortisol production resulting from increased P28845 at the early and midluteal stages helps to maintain CL function by suppressing apoptosis of luteal cells . DB00013 plasminogen activator augments cell proliferation and neointima formation in injured arteries via proteolytic mechanisms . DB00013 plasminogen activator ( uPA ) has been implicated in the healing responses of injured arteries , but the importance of its various properties that influence smooth muscle cell ( SMC ) proliferation and migration in vivo is unclear . We used three recombinant ( r- ) forms of uPA , which differ markedly in their proteolytic activities and abilities to bind to the uPA receptor ( Q03405 ) , to determine , which property most influences the healing responses of balloon catheter injured rat carotid arteries . After injury , uPA and Q03405 expression increased markedly throughout the period when medial SMCs were rapidly proliferating and migrating to form the neointima . Perivascular application of uPA neutralizing antibodies immediately after injury attenuated the healing response , significantly reducing neointima size and neointimal SMC numbers . Perivascular application of r-uPAwt ( wild type uPA ) or r-uPA/GDF ( r-uPA with multiple mutations in its growth factor-like domain ) doubled the size of the neointima . Four days after injury these two uPAs nearly doubled neointimal and medial SMC numbers in the vessels , and induced greater reductions in lumen size than injury alone . Proteolytically inactive r-uPA/H/Q ( containing glutamine rather than histidine-204 in its catalytic site ) did not affect neointima or lumen size . Also , in contrast to the actions of proteolytically active uPAs , tissue plasminogen activator ( tPA ) did not affect the rate of neointima development . We conclude that uPA is an important factor regulating the healing responses of balloon catheter injured arteries , and its proteolytic property , which can not be mimicked by tPA , greatly influences SMC proliferation and early neointima formation . Development of peptidomimetic ligands of Pro- DB00149 - DB00145 -NH(2) as allosteric modulators of the dopamine D(2) receptor . A variety of stable , small-molecule peptidomimetic ligands have been developed to elucidate the mechanism by which the neuropeptide Pro- DB00149 - DB00145 -NH(2) ( P00747 ) modulates dopaminergic neurotransmission . Photoaffinity labeling ligands based upon P00747 peptidomimetics have been used to establish that P00747 binds to the P14416 at a site that is different from the orthosteric site , thus making P00747 and its peptidomimetics allosteric modulators of the dopamine receptor . Through the design , synthesis and pharmacological evaluation of conformationally constrained peptidomimetics containing lactam , bicyclic , and spiro-bicyclic scaffolds , support was provided for the hypothesis that the bioactive conformation of P00747 is a type II β-turn . In addition , studies with peptidomimetics designed to mimic either a type VI β-turn or polyproline II helix conformation yielded molecules that were able to modulate dopamine receptors because of their ability to place the carboxamide NH(2) pharmacophore in the same topological space as that seen in the type II β-turn . Extensive studies with the spiro-bicyclic P00747 peptidomimetics also established that both positive and negative modes of modulation were possible for the same series of peptidomimetics simply as a result of minor differences in the stereochemistry about the bridgehead carbon within the scaffold . This information was used to transform existing positive modulators into negative modulators , which demonstrated that small structural changes in the spiro-bicyclic dopamine receptor modulators are capable of causing major changes in the modulatory activity of P00747 peptidomimetics . A human seminoma xenograft model with regional lymph node metastasis . PURPOSE : To establish a seminoma orthotopic model with lymph node metastasis to investigate the factors related to the lymphophilic behavior of seminoma cells . MATERIALS AND METHODS : Testicular seminoma xenografts were established by the inoculation of small fragments from subcutaneous ( s.c. ) xenografts that had previously been established in severe combined immunodeficient ( SCID ) mice with a supraclavicular lymph node metastasis from a human seminoma . Hematologic dissemination of tumor cells was analyzed by polymerase chain reaction ( PCR ) amplification of the human beta-globin gene . Xenograft messenger RNA levels of metastasis-related genes were examined by reverse transcription ( RT ) -PCR . RESULTS : Testicular seminoma xenografts grew in 32/32 ( 100 % ) of the inoculated mice , of which 15 mice ( 47 % ) developed macroscopic metastasis to the renal hilar lymph node . Circulating tumor cells and tumor cell shedding in the lung and liver were detectable by PCR assay in 25/32 ( 78 % ) , 32/32 ( 100 % ) , and 27/32 ( 84 % ) mice , respectively , although metastatic foci were not histologically evident in these organs . Increased expression of matrix metalloproteinase-2 ( P08253 ) , membrane-type 3 matrix metalloproteinase ( P51512 ) and vascular endothelial growth factor ( P15692 ) , and reduction in expression of plasminogen activator inhibitor-2 ( P05120 ) were demonstrated by RT-PCR assay in the testicular xenografts as compared with the s.c. xenografts . CONCLUSIONS : This model mimics the lymphophilic behavior of seminoma and may help in elucidating the molecular mechanism of tumor spread via the lymphatics . P10275 as a therapeutic target . Androgens function as sex hormone primarily via activation of a single androgen receptor ( AR , or P10275 ) . AR is an important therapeutic target for the treatment of diseases such as hypogonadism and prostate cancer . AR ligands of different chemical structures and/or pharmacological properties are widely used for these therapeutic applications , and all of the AR ligands currently available for therapy modulate AR function via direct binding to the ligand-binding pocket ( P18428 ) of the receptor . In the past ten years , our understanding of AR structure and molecular mechanism of action has progressed extensively , which has encouraged the rapid development of newer generation of AR ligands , particularly tissue-selective AR ligands . With improved tissue selectivity , future generations of AR ligands are expected to greatly expand the therapeutic applications of this class of drugs . This review will provide an overview of the common therapeutic applications of currently available AR ligands , and discussion of the major challenges as well as novel therapeutic strategies proposed for future drug development . Smad6s regulates plasminogen activator inhibitor-1 through a protein kinase C-beta-dependent up-regulation of transforming growth factor-beta . P00747 activator inhibitor-1 ( P05121 ) is a serpin class protease inhibitor that plays a central role in the regulation of vascular function and tissue remodeling by modulating thrombosis , inflammation , and the extracellular matrix . A central mediator controlling P05121 is transforming growth factor-beta ( TGF-beta ) , which induces its expression and promotes fibrosis . We have found that a unique member of the Smad family of signal transduction molecules , Smad6s , modulates the expression of P05121 . Overexpression of Smad6s in endothelial cells increases promoter activity and P05121 secretion , and an antisense to Smad6s suppresses the induction of P05121 by TGF-beta . The effect of Smad6s on the P05121 promoter appeared to be the result of increase binding of the forkhead winged helix factor FoxD1 to a TGF-beta-responsive element . Furthermore , the effect of Smad6s on P05121 up-regulation and on FoxD1 binding was found to result from up-regulation of TGF-beta and could be inhibited by the blocking TGF-beta signaling with O15105 . The ability of Smad6s to regulate the TGF-beta promoter and subsequent P05121 induction was suppressed by a selective protein kinase C-beta ( P05771 ) inhibitor . Consistent with the in vitro data , we found that increased Smad6s in diseased vessels correlated with increased TGF-beta and P05121 levels . Overall , our results demonstrate that the level of Smad6s can alter the level of TGF-beta and the subsequent induction of P05121 via a FoxD1 transcription site . Furthermore , our data suggest that this process , which is up-regulated in diseased vessels , can be modulated by the inhibition of P05771 . DB00013 plasminogen activator receptor promotes macrophage infiltration into the vascular wall of ApoE deficient mice . The urokinase plasminogen activator receptor ( Q03405 ) regulates macrophage adhesion and migration by binding directly to matrix proteins and signaling through integrin complexes . In this study , we examined the role of Q03405 on macrophage infiltration into the vascular wall . Stable murine macrophage ( Raw264.7 ) cell lines expressing high levels of human Q03405 , human urokinase plasminogen activator ( uPA ) , or both were established using expression vectors driven by the human P34810 promoter . Stimulation with human uPA specifically induced phosphorylation of early response regulated kinase ( P29323 ) in cells expressing human Q03405 but not in sham transfected cells . The human Q03405 expressing Raw264.7 cells showed increased adhesion to both human uPA and vitronectin ( Vn ) . Raw264.7 cells expressing human Q03405 or both human Q03405 and uPA , but not uPA alone , were detected in the aortic wall of ApoE(-/-) mice , and no cells were detected in that of age-matched C57BL/6J mice after intravenous infusion of the cells . Blocking of Mac-1/ P05362 interaction by anti-alphaM antibody ( M1/70 ) significantly reduced the infiltration of huPAR-expressing Raw264.1 cells into aorta of ApoE(-/-) mice . Treatment of C57BL/6J mice with angiotensin II resulted in infiltration of Raw264.7 cells expressing human Q03405 . These data demonstrate that Q03405 plays a key role in promoting macrophage infiltration into the arterial wall of ApoE(-/-) mice . DB00013 plasminogen activator ( uPA ) and its receptor ( Q03405 ) in gestational tissues ; Measurements and clinical implications . BACKGROUND : DB00013 plasminogen activator ( uPA ) and urokinase plasminogen activator receptor ( Q03405 ) are central molecules for uPA/ Q03405 /plasmin-dependent proteolysis , which is thought to play a significant role in the development of pregnancy , as well as its many complications . OBJECTIVE : To measure the levels of uPA and Q03405 in the placenta and myometrium , as well as in the foetal membranes and amniotic fluid . STUDY DESIGN : The study group consisted of 35 women with normal course of pregnancy , but with complications arising during delivery , which led to Caesarean section . Samples of placenta , myometrium , foetal membranes , amniotic fluid and blood were obtained at the time of operation . Tissue extracts were prepared . Measurements were made by the ELISA method . RESULTS : uPA and Q03405 concentration in gestational tissues , including amniotic fluid , is 100-200 times higher than in plasma . Among tissues , the highest uPA level was found in placenta ( 1.32 +/- 0.48 ng/mg of protein ) , and the highest Q03405 level in foetal membranes ( 3.33 +/- 1.20 ng/mg of protein ) . CONCLUSIONS : uPA and Q03405 are present in all gestational tissues , in some in relatively high concentrations . Our results support the modern clinical hypothesis that fibrinolytic system can participate in mechanisms of such obstetric complications as pre-term pre-mature rupture of foetal membranes and placental abruption . Differential expression of the urokinase receptor in fibroblasts from normal and fibrotic human lungs . Binding of urokinase-type plasminogen activator ( uPA ) to a specific receptor ( Q03405 ) on human lung fibroblasts enables it to regulate cellular proteolysis and remodeling of the extracellular matrix . Binding studies with radiolabeled uPA indicated that both normal and fibrotic lung fibroblasts express the receptor , but cells from fibrotic tissues bound significantly more uPA ( P < 0.001 ) . Phorbol myristate acetate , lipopolysaccharide , transforming growth factor-beta ( TGF-beta ) , and tumor necrosis factor-alpha ( P01375 ) increased uPA binding and plasminogen activation at the cell surface , with a greater maximal effect on fibrotic than on normal fibroblasts . Excess unlabeled uPA , specific antibody , or antisense oligonucleotides inhibited uPA binding . Ribonuclease ( RNase ) protection assays showed higher levels of Q03405 messenger ribonuleic acid ( mRNA ) in each of the five fibrotic cell lines than in normal fibroblasts . uPA was mitogenic for normal as well as fibrotic fibroblasts , indicating that receptor binding concurrently localizes cellular proteolytic activity and stimulates mitogenesis . Morphometry and immunohistochemical analysis showed that Q03405 , as well as uPA , was increased in fibroblasts in fibrotic lung tissue . Increased expression of Q03405 by fibrotic lung fibroblasts and enhanced urokinase binding induced by proinflammatory cytokines suggest a novel mechanism by which fibroblast-mediated matrix remodeling and proliferation may be regulated in interstitial lung diseases . Release of mediators of systemic inflammatory response syndrome in the course of a severe delayed hemolytic transfusion reaction caused by anti-D . BACKGROUND : In vitro studies suggest that mediators of systemic inflammatory response syndrome are generated in the course of hemolytic transfusion reactions . Evidence for the in vivo significance of these findings is given by the present clinical and laboratory analysis of a severe delayed hemolytic transfusion reaction ( P10275 ) . CASE REPORT : A 67-year-old patient ( blood group O , D-negative ) with a negative pretransfusion antibody screen received a massive transfusion because of arterial bleeding ( Day 1 ) . The transfusion of group O , D-positive red cell concentrates was unavoidable because of limited supplies . At Day 10 , the patient developed a P10275 with symptoms of septic-toxic syndrome and signs of hemolysis ; he received an exchange transfusion . Serologic markers , as well as proinflammatory and anti-inflammatory mediators , were monitored at the onset of the P10275 and during the exchange transfusion . RESULTS : At Day 10 , the direct antiglobulin test was positive ; anti-D was present , most likely as the result of an anamnestic immune response . Interleukin ( IL ) -1 was not detectable ; all other mediators monitored were elevated : IL-1 receptor antagonist , tumor necrosis factor , P05231 , P10145 , P22301 , neopterin , elastase , C3a-desArg , P02741 , and fibrinogen . Most of the values declined during the exchange transfusion , which was followed by an improvement of the clinical presentation . CONCLUSIONS : Mediators of systemic inflammatory response syndrome were released in the course of a P10275 caused by anti-D . Severe clinical symptoms could be treated successfully by exchange transfusion . Effects of addition of tissue-type plasminogen activator in in vitro fertilization medium on bovine embryo development and quality . P00747 activators/Plasmin system plays pivotal role in regulating reproductive functions of mammals . Here , we examined the effects of modification of in vitro fertilization medium ( IVF medium ) with the addition of tissue-type plasminogen activator ( t-PA ) , on bovine embryo development and quality , assessed by quantification of expression of various genes related to metabolism , oxidation , implantation and apoptosis . In addition , plasminogen activator activity ( PAA ) and plasminogen activator inhibition ( P05121 ) were measured in the spent media . After conventional IVM , 2016 cumulus-oocyte complexes ( COCs ) were divided into four groups with modified composition of the IVF medium containing t-PA and/or its inhibitor epsilon-aminocaproic acid ( control , t-PA , t-PA+ε-ACA , ε-ACA ) . Presumptive zygotes were cultured for 8 days in synthetic oviductal fluid ( SOF ) medium ; gene expression studies were carried out on morulae and blastocysts . t-PA alone significantly suppressed cleavage and blastocyst formation rates , but this effect was neutralized by the addition of ε-ACA . PAA in the treated group was significantly reduced by ε-ACA , but without total elimination . Significant differences were detected in the expression of genes related to apoptosis and/or cell cycle arrest ( Q07812 , Q07817 , Q92831 ) between embryos produced in t-PA-modified media and controls , giving an overall notion that the inferior developmental competence of treated embryos may be attributed to apoptotic phenomena induced by t-PA . In conclusion , it appears that excessive t-PA content in the IVF media , suppresses blastocyst formation rate , possibly due to induction of apoptotic phenomena . DB00013 stimulates human vascular smooth muscle cell migration via a phosphatidylinositol 3-kinase-Tyk2 interaction . Janus kinases Jak1 and Tyk2 play an important role in urokinase-type plasminogen activator ( uPA ) -dependent signaling . We have recently demonstrated that both kinases are associated with the uPA receptor ( Q03405 ) and mediate uPA-induced activation of signal transducers and activators of transcription ( Stat1 , Stat2 , and Stat4 ) in human vascular smooth muscle cells ( VSMC ) . Janus kinases are not only required for Stat activation but may also interfere with other intracellular signaling pathways . Here we report that in VSMC , Tyk2 interacts with a downstream signaling cascade involving phosphatidylinositol 3-kinase ( P19957 -K ) . We demonstrate that uPA induces P19957 -K activation , which is abolished in VSMC expressing the dominant negative form of Tyk2 . The regulatory subunit p85 of P19957 -K co-immunoprecipitates with Tyk2 but not with Jak1 , Jak2 , or Jak3 , and uPA stimulation increases the P19957 -K activity in Tyk2 immunoprecipitates . Tyk2 directly binds to either of the two Src homology 2(SH2)p85 domains in a uPA-dependent fashion . We provide evidence that the Tyk2-mediated P19957 -K activation in response to uPA is required for VSMC migration . Thus , two unrelated structurally distinct specific inhibitors of P19957 -K , wortmannin and LY294002 , prevent VSMC migration induced by uPA . No migratory effect of uPA was observed in VSMC expressing the dominant negative form of Tyk2 . Our results underscore the versatile function of Tyk2 in uPA-related intracellular signaling and indicate that P19957 -K plays a selective role in the regulation of VSMC migration . The effect of antisense inhibition of urokinase receptor in human squamous cell carcinoma on malignancy . Concomitant expression of urokinase type plasminogen activator ( uPA ) and its surface receptor ( Q03405 ) has been shown to correlate strongly with a more invasive tumor cell phenotype . A highly malignant human epidermoid carcinoma cell line ( HEp3 ) was transfected with a vector capable of expressing an antisense transcript complementary to 300 bases of the 5' end of Q03405 , including the ATG codon . Six stably transfected antisense ( AS-2 , 3 , 5 , 9 , 10 , 12 ) and eight control clones were characterized . All clones produced high levels of uPA activity . Examination of collagenase production and doubling time showed that all of the clones tested produced similar activities . The antisense clones showed a 20-74 % reduction in the Q03405 sites ; the Q03405 mRNA level was also reduced . A test of the invasive ability of all clones in a modified chorioallantoic membrane ( P62158 ) showed that invasiveness of the antisense-inhibited clones was directly proportional to the density of surface Q03405 . The AS-2 clone , which expressed the lowest number of uPARs showed a significantly reduced level of invasion . The invasiveness of additional AS-inhibited clones was also reduced . Seven control and four AS-inhibited clones were tested for tumorigenicity on CAMs of chick embryos . Inoculation of control cells produced large tumors , while the As clones were non-tumorigenic . AS-2 did not produce tumors even if kept in vivo for up to 10 weeks. ( ABSTRACT TRUNCATED AT 250 WORDS ) DB00013 plasminogen activator receptor ( Q03405 ) and plasminogen activator inhibitor-1 ( P05121 ) are potential predictive biomarkers in early stage oral squamous cell carcinomas ( OSCC ) . Oral squamous cell carcinoma ( OSCC ) is often associated with metastatic disease and a poor 5 year survival rate . Patients diagnosed with small tumours generally have a more favourable outcome , but some of these small tumours are aggressive and lead to early death . To avoid harmful overtreatment of patients with favourable prognosis , there is a need for predictive biomarkers that can be used for treatment stratification . In this study we assessed the possibility to use components of the plasminogen activator ( PA ) system as prognostic markers for OSCC outcome and compared this to the commonly used biomarker Ki-67 . A tissue-micro-array ( TMA ) based immunohistochemical analysis of primary tumour tissue obtained from a North Norwegian cohort of 115 patients diagnosed with OSCC was conducted . The expression of the biomarkers was compared with clinicopathological variables and disease specific death . The statistical analyses revealed that low expression of Q03405 ( p = 0.031 ) and P05121 ( p = 0.021 ) in the tumour cells was significantly associated with low disease specific death in patients with small tumours and no lymph node metastasis ( T1N0 ) . The commonly used biomarker , Ki-67 , was not associated with disease specific death in any of the groups of patients analysed . The conclusion is that Q03405 and P05121 are potential predictive biomarkers in early stage tumours and that this warrants further studies on a larger cohort of patients . DB00013 mediates endothelial cell survival via induction of the P98170 . P00749 ( uPA ) additionally elicits a whole array of pro-angiogenic responses , such as differentiation , proliferation , and migration . In this study , we demonstrate that in endothelial cells uPA also protects against apoptosis by transcriptional up-regulation and partially by mRNA stabilization of inhibitor of apoptosis proteins , most prominently the P98170 ( P98170 ) . The antiapoptotic activity of uPA was dependent on its protease activity , the presence of uPA receptor ( Q03405 ) and low-density lipoprotein receptor-related protein ( Q14764 ) , but independent of the phosphatidylinositol 3 ( P19957 ) kinase pathway , whereas vascular endothelial growth factor ( P15692 ) -induced antiapoptosis was P19957 kinase dependent . uPA-induced cell survival involved phosphorylation of Q13153 ( Pak1 ) and the O15111 alpha that leads to nuclear factor kappaB ( NF-kappaB ) p52 activation . Indeed , blocking NF-kappaB activation by using specific NF-kappaB inhibitors abolished uPA-induced cell survival as it blocked uPA-induced P98170 up-regulation . Furthermore , down-regulating P98170 expression by small interfering RNA ( siRNA ) significantly reduced uPA-dependent endothelial cell survival . This mechanism is also important for P15692 -induced antiapoptosis because P15692 -dependent up-regulation of P98170 was found defective in uPA(-/-) endothelial cells . This led us to conclude that uPA is part of a novel NF-kappaB-dependent cell survival pathway . Regulation of the Q03405 /uPA system expressed on monocytes by the deactivating cytokines , P05112 , P22301 and P35225 : consequences on cell adhesion to vitronectin and fibrinogen . DB00013 ( uPA ) and its receptor ( Q03405 ) have been proposed to be involved in monocyte migration by inducing degradation of matrix proteins . In addition , Q03405 is also implicated in cell adhesion to the vascular wall . The adhesive function of Q03405 depends on a direct interaction with vitronectin which is increased by uPA and by modification of cell surface integrin ( such as CD11b- P05107 ) when associated to Q03405 . In this study we analysed the role of three deactivating cytokines , P05112 , P22301 and P35225 , on the surface expression of uPA , Q03405 and CD11b by monocytes and their consequences on monocyte adhesion to immobilized fibrinogen and vitronectin . P22301 induced a decrease in uPA and CD11b after 18 h incubation and a delayed decrease in Q03405 which was only significant after 48 h incubation . These results may explain the decrease in monocyte adhesion , which was observed after an 18 h incubation with P22301 , on immobilized vitronectin and fibrinogen . In contrast , P05112 and P35225 induced a decrease in Q03405 after 18 h and a significant increase in uPA both in the cell lysates and at the cell surface , as well as an increase in cell surface associated CD11b . These cytokines did not modify cell adhesiveness to vitronectin or fibrinogen despite the increase in CD11b- P05107 . This could be due to the decrease in Q03405 because CD11b- P05107 / Q03405 forms a cell adhesion complex . In addition , the increase in uPA induced by P05112 could counterbalance the direct interaction of Q03405 with vitronectin . The increase in uPA suggests that P05112 and P35225 could induce plaque fissuring by monocytes , whereas P22301 may induce protection against matrix protein degradation by decreasing uPA . DB00013 mediates fibrinolysis in the pulmonary microvasculature . The role of urokinase-type plasminogen activator ( uPA ) and its receptor ( Q03405 ) in fibrinolysis remains unsettled . The contribution of uPA may depend on the vascular location , the physical properties of the clot , and its impact on tissue function . To study the contribution of urokinase within the pulmonary microvasculature , a model of pulmonary microembolism in the mouse was developed . Iodine 125 ( (125)I ) -labeled fibrin microparticles injected intravenously through the tail vein lodged preferentially in the lung , distributing homogeneously throughout the lobes . Clearance of (125)I-microemboli in wild type mice was rapid and essentially complete by 5 hours . In contrast , uPA(-/-) and tissue-type plasminogen activator tPA(-/-) mice , but not Q03405 (-/-) mice , showed a marked impairment in pulmonary fibrinolysis throughout the experimental period . The phenotype in the uPA(-/-) mouse was rescued completely by infusion of single chain uPA ( scuPA ) . The increment in clot lysis was 4-fold greater in uPA(-/-) mice infused with the same concentration of scuPA complexed with soluble recombinant Q03405 . These data indicate that uPA contributes to endogenous fibrinolysis in the pulmonary vasculature to the same extent as tPA in this model system . Binding of scuPA to its receptor promotes fibrinolytic activity in vivo as well as in vitro . The physical properties of fibrin clots , including size , age , and cellular composition , as well as heterogeneity in endothelial cell function , may modify the participation of uPA in endogenous fibrinolysis . ( Blood. 2000;96:1820-1826 ) Signalling pathways involved in retinal endothelial cell proliferation induced by advanced glycation end products : inhibitory effect of gliclazide . AIM : We have previously demonstrated that advanced glycation end products ( AGEs ) stimulate bovine retinal endothelial cell ( BREC ) proliferation through induction of vascular endothelial growth factor ( P15692 ) production by these cells . We have also shown that gliclazide , a sulfonylurea which decreases oxidative stress , inhibits this effect . The aim of the present study was to characterize the signalling pathways involved in P51606 -induced BREC proliferation and P15692 production and mediating the inhibitory effect of gliclazide on these biological events . METHODS : BRECs were treated or not treated with AGEs in the presence or absence of gliclazide , antioxidants , protein kinase C ( PKC ) , mitogen-activated protein kinase ( MAPK ) or nuclear factor-kappaB ( NF-kappaB ) inhibitors . BREC proliferation was assessed by measuring [ 3H ] -thymidine incorporation into DNA . Activation of PKC , MAPK and NF-kappaB signal transduction pathways and determination of P15692 expression were assessed by Western blot analysis using specific antibodies . MAPK activity was also determined by an in vitro kinase assay . RESULTS : Treatment of BRECs with AGEs significantly increased cell proliferation and P15692 expression . AGEs induced P05771 translocation , extracellular signal-regulated protein kinase 1/2 and NF-kappaB activation in these cells . Pharmacological inhibition of these signalling pathways abolished P51606 effects on cell proliferation and P15692 expression . Exposure of BRECs to gliclazide or antioxidants such as vitamin E or N-acetyl-l-cysteine resulted in a significant decrease in P51606 -induced activation of PKC- , MAPK- and NF-kappaB-signalling pathways . CONCLUSIONS : Our results demonstrate the involvement of PKC , MAPK and NF-kappaB in P51606 -induced BREC proliferation and P15692 expression . DB01120 inhibits BREC proliferation by interfering with these intracellular signal transduction pathways . Examining the genetic and neural components of cognitive flexibility using mice . This commentary summarizes the research presented during the symposium " Examining the genetic and neural components of cognitive flexibility using mice " at the annual meeting of the International Behavioral Neuroscience Society 2011 . Research presented includes examining : 1 ) Corticostriatal networks underlying reversal learning using Q13224 knockout mice , cFos expression , and in vivo electrophysiological recording ; 2 ) Cerebellar contribution to reversal learning using mutants with Purkinje cell loss and in vivo electrochemical recording ; 3 ) Parvalbumin contribution to reversal learning and set-shifting using Q03405 mutants and in vitro recording to examine fast-spiking interneurones ; and 4 ) Alpha 7 nAChR contribution to reversal learning , set-shifting , motivation , and the ' eureka moment ' of rule acquisition . It is proposed that these studies revealed more about the neurobiology underlying these behaviors than could be discovered using pharmacological techniques alone . Together , the research presented stressed the importance of exploring the genetic contribution to neuropsychiatric disease and the important role that the mouse , coupled with robust behavioral measures , can play in understanding neurobiology underlying cognitive flexibility . Helicobacter pylori-induced interleukin-12 p40 expression . Interleukin-12 ( IL-12 ) is a heterodimeric cytokine produced by antigen-presenting cells that promotes the development of T-helper lymphocyte 1 ( Th1 ) . Chronic gastritis induced by Helicobacter pylori is considered a Th1-mediated process . IL-12 levels in gastric biopsy samples of H. pylori-infected patients are higher than in those of uninfected individuals , but the cellular source of IL-12 remains elusive . IL-12 staining was detected in mucosal epithelial cells , lymphocytes , and macrophages in specimens of patients with H. pylori-positive gastritis . Therefore , we investigated IL-12 p40 mRNA induction by H. pylori in gastric epithelial cells and T cells . Although cag pathogenicity island ( P05121 ) -positive H. pylori induced IL-12 p40 mRNA expression , an isogenic mutant of the cag P05121 failed to induce it in both cell types . Supernatants from H. pylori cultures and H. pylori VacA induced IL-12 p40 mRNA expression in T cells but not in epithelial cells . The activation of the IL-12 p40 promoter by H. pylori was mediated through NF-kappaB . The transfection of O15111 and NF-kappaB-inducing kinase dominant-negative mutants inhibited H. pylori-induced IL-12 p40 activation . Inhibitors of NF-kappaB , phosphatidylinositol 3-kinase , p38 mitogen-activated protein kinase , and Hsp90 suppressed H. pylori- and VacA-induced IL-12 p40 mRNA expression . The results indicate that H. pylori induces IL-12 p40 expression by the activation of NF-kappaB , phosphatidylinositol 3-kinase , and p38 mitogen-activated protein kinase . Hsp90 is also a crucial regulator of H. pylori-induced IL-12 p40 expression . In addition to the cag P05121 , VacA might be relevant in the induction of IL-12 expression and a Th1-polarized response only in T cells . Analysis of breast cancer related gene expression using natural splines and the Cox proportional hazard model to identify prognostic associations . Many studies correlating gene expression data to clinical parameters assume a linear increase or decrease of the clinical parameter under investigation with the expression of a gene . We have studied genes encoding important breast cancer-related proteins using a model for survival-type data that is based on natural splines and the Cox proportional hazard model , thereby removing the linearity assumption . Expression data of 16 genes were studied in relation to metastasis-free probability in a cohort of 295 consecutive breast cancer patients treated at The Netherlands Cancer Institute . The independent predictive power for disease outcome of the 16 individual genes was tested in a multivariable model with known clinical and pathological risk factors . There is a linear relationship between increasing expression and a higher or lower hazard for distant metastasis for P03372 , Q15303 , P15692 , O96020 , Q15910 , and Q96NZ9 ; for P04626 , P21860 , P24385 , P24864 , O75530 , P61073 , P32248 , P48061 , and P05121 there is no clear increase or decrease ; and for P00533 there seems to be a non-linear relation . Multivariable analysis showed that the 70-gene prognosis profile outperforms all the other variables in the model ( hazard-rate 5.4 , 95 % CI 2.5-11.7 ; P = 0.000018 ) . P00533 -expression seems to have a non-linear relation with disease outcome , indicating that lower but also higher expression of P00533 are associated with worse outcome compared to intermediate expression levels ; the other genes show no or a linear relation . DB00502 induces neurotoxicity by the DB01221 receptor downstream signaling pathway , alternative from glutamate excitotoxicity . The DB01221 receptor is believed to be important in a wide range of nervous system functions including neuronal migration , synapse formation , learning and memory . In addition , it is involved in excitotoxic neuronal cell death that occurs in a variety of acute and chronic neurological disorders . Besides of agonist/coagonist sites , other modulator sites , including butyrophenone site may regulate the N-methyl-D-aspartate receptor . It has been shown that haloperidol , an antipsychotic neuroleptic drug , interacts with the Q13224 subunit of DB01221 receptor and inhibits DB01221 response in neuronal cells . We found that DB01221 receptor was co-immunoprecipitated by anti-Ras antibody and this complex , beside NR2 subunit of DB01221 receptor contained haloperidol-binding proteins , P29475 and Ras- P01286 . Furthermore , we have shown that haloperidol induces neurotoxicity of neuronal cells via DB01221 receptor complex , accompanied by dissociation of Ras- P01286 from membranes and activation of c-Jun-kinase . Inclusion of insulin prevented relocalization of Ras- P01286 and subsequent neuronal death . DB00502 -induced dissociation of Ras- P01286 leads to inhibition of membrane-bound form of Ras protein and changes downstream regulators activity that results in the initiation of the apoptotic processes via the mitochondrial way . Our results suggest that haloperidol induces neuronal cell death by the interaction with DB01221 receptor , but through the alternative from glutamate excitotoxicity signaling pathway . DB00013 binds to a plasminogen activator inhibitor type-2-like molecule in placental microvillous membranes . Placental microvillous membranes exhibited saturable binding of urokinase-type plasminogen activator with plateau achieved by 30 min at 4 degrees C and 10 min at 37 degrees C . The binding was essentially irreversible . The capacity was about 8 pmol urokinase per mg membrane protein . Half-maximal displacement of 125I-labelled urokinase was achieved with about 1.0 nM unlabelled urokinase when using 75 micrograms membrane protein/ml . 125I-labelled urokinase did not bind when treated with diisopropylfluorophosphate to block the catalytic activity . Single-chain urokinase ( prourokinase ) , devoid of catalytic activity , did not bind . Catalytically active tissue-type plasminogen activator did compete with 125I-labelled urokinase for binding although less efficiently than urokinase . Binding activity remained in the 100,000 x g pellet after treatment of the membranes with 3 M DB00761 , alkaline stripping at pH 12 or extraction by the detergent Triton X-100 . The binding was essentially blocked by antibodies against plasminogen activator inhibitor-type-2 ( P05120 ) . DB00815 polyacrylamide gel electrophoresis of solubilized membranes with bound 125I-labelled urokinase showed that the urokinase- P05120 complexes largely migrated in fractions corresponding to a very large Mr although no clearly defined peaks were observed . It is suggested that P05120 occurs in a form anchored to syncytiotrophoblast microvilli , possibly to the cytoskeleton . aChE and BuChE inhibition by rivastigmin have no effect on peripheral insulin resistance in elderly patients with Alzheimer disease . BACKGROUND : P01308 resistance ( IR ) may play a role in most pathogenic processes that promote the development of Late Onset Alzheimer Disease ( LOAD ) . This study was designed to determine the interaction between inhibition of both butyrylcholinesterase ( BuChE ) and acetylcholinesterase ( P22303 ) with rivastigmine and peripheral insulin resistance ( IR ) in LOAD . METHODS : Seventy-Nine consecutive elderly patients , 31 late onset AD and 48 non-demented patients were evaluated . IR was calculated with HOMA . All of the patients were evaluated through comprehensive geriatric assessments at baseline and in the 6th and 12th months . RESULTS : End of the study , compared to the baseline values , there was a significant increase in the 6th month in both MMSE and IADL scores ( t =2.200 , p = 0.036 for MMSE and t =2.724 , p= 0.011 for IADL , respectively ) . DB00989 was improved both the scores of MMSE and IADL in elderly patients with LOAD , but there was no significance or correlation between HOMA scores and cognitive status . CONCLUSION : In conclusion , inhibition of both BuChE and P22303 with rivastigmine was improved the cognition without affecting on the peripheral IR in the elderly patients with LOAD by HOMA . Due to the complexity of disease pathogenesis , it is too early to make general comments , and further longitudinal and long-term studies on this issue are needed . Modulation of leukocyte transendothelial migration by integrin-associated glycosyl phosphatidyl inositol ( P06744 ) -anchored proteins . Leukocyte transendothelial migration is an essential process in inflammation and the immune response . The mechanisms involved in leukocyte adhesion to the endothelium , forming the first step in leukocyte extravasation , have been fairly well documented . However , subsequent steps , which include de-adhesion , coupled with locomotion , remain largely unknown . As part of our efforts to study leukocyte transendothelial migration , we previously established a monoclonal antibody ( mAb ) that sequentially up-regulates and down-regulates beta2 integrin-dependent adhesion of human neutrophils , as well as transendothelial migration in vitro . The molecule recognized by this mAb is a glycosyl phosphatidyl inositol , ( P06744 ) -anchored glycoprotein . This protein may prove to be a new member of the family of integrin-associated , P06744 -anchored proteins , which includes urokinase-type plasminogen activator receptor ( Q03405 ) , lipopolysaccharide ( LPS ) /LPS binding protein ( P18428 ) receptor ( P08571 ) , and Fcgamma receptor IIIB ( CD16b ) ; all of which are regulators of integrin function . The mechanisms involved in beta2 integrin regulation by this new P06744 -anchored glycoprotein are discussed . P00747 activator inhibitor type 1 ( P05121 ) is a valuable biomarker for predicting the metabolic syndrome ( MS ) in institutionalized elderly residents in Taiwan . Circulating levels of inflammatory and prothrombotic factors are elevated in the metabolic syndrome ( MS ) and linked with the occurrence of cardiovascular events . The aim of our study was to investigate the relationship between inflammatory and prothrombotic markers and the MS in elderly institutionalized residents . A total of 326 non-diabetic residents of Chuang-Hua Veterans Care Home ( age : 79.9+/-4.1 years ; 100 % males ) were enrolled . MS was diagnosed according to the DB00551 /NHLBI Scientific Statement criteria . Body fat percentage was measured by bioelectrical impedance analysis . P01308 resistance was calculated by homeostasis model assessment for insulin resistance ( HOMA-IR ) . Inflammatory markers , including tumor necrosis factor-a ( P01375 ) , high sensitivity P02741 ( hsCRP ) , and plasminogen activator inhibitor-1 ( P05121 ) , were determined using ELISA . Elderly residents with the MS had higher systolic and diastolic blood pressures ( both p < 0.001 ) and higher HOMA-IR ( p < 0.001 ) , hsCRP ( p = 0.008 ) , and P05121 levels ( p < 0.001 ) than those without the MS . On multivariate logistic regression analysis , P05121 was an independent risk factor for the MS . Of the MS components , elderly residents with higher waist circumferences and higher levels of plasma fasting glucose , and triglyceride ( TG ) , and lower levels of high density lipoprotein ( HDL ) had higher P05121 levels than those without the above components . An anti-urokinase plasminogen activator receptor antibody ( ATN-658 ) blocks prostate cancer invasion , migration , growth , and experimental skeletal metastasis in vitro and in vivo . DB00013 plasminogen activator receptor ( Q03405 ) is a multidomain protein that plays important roles in the growth , invasion , and metastasis of a number of cancers . In the present study , we examined the effects of administration of a monoclonal anti- Q03405 antibody ( ATN-658 ) on prostate cancer progression in vitro and in vivo . We examined the effect of treatment of ATN-658 on human prostate cancer cell invasion , migration , proliferation , and regulation of intracellular signaling pathways . For in vivo studies , PC-3 cells ( 1 x 10(6) ) were inoculated into the right flank of male Balb C nu/nu mice through subcutaneous or through intratibial route ( 2 x 10(5) ) of male Fox Chase severe combined immunodeficient mice to monitor the effect on tumor growth and skeletal metastasis . Treatment with ATN-658 resulted in a significant dose-dependent decrease in PC-3 cell invasion and migration without affecting cell doubling time . Western blot analysis showed that ATN-658 treatment decreased the phosphorylation of serine/threonine protein kinase B ( AKT ) , mitogen-activated protein kinase ( MAPK ) , and focal adhesion kinase ( Q05397 ) without affecting AKT , MAPK , and Q05397 total protein expression . In in vivo studies , ATN-658 caused a significant decrease in tumor volume and a marked reduction in skeletal lesions as determined by Faxitron x-ray and micro-computed tomography . Immunohistochemical analysis of subcutaneous and tibial tumors showed a marked decrease in the levels of expression of pAKT , pMAPK , and pFAK , consistent with the in vitro observations . Results from these studies provide compelling evidence for the continued development of ATN-658 as a potential therapeutic agent for the treatment of prostate and other cancers expressing Q03405 . Reduced plasminogen activator content of the endometrium in oral contraceptive users . Human endometrium was found to contain two different plasminogen activators , urokinase and tissue activator . DB00013 was released in higher amounts from endometrial tissue explants obtained in the midcycle phase than from those obtained in the luteal phase . P00747 activator activity of the culture medium followed the same pattern . Treatment of postmenopausal patients with ethinylestradiol resulted in liberation of urokinase and tissue activator from endometrial explants in concentrations similar to those found in the normal midcycle phase . In contrast , treatment with oral contraceptives ( OCs ) , containing ethinylestradiol and a progestagen , resulted in lowered release of both activators , even lower than was found during the normal luteal phase . Also the amounts of extractable urokinase from endometrial tissue samples were significantly lower in OC-users than in non-users . Estradiol seems to have a stimulatory effect on the release of plasminogen activators from the endometrium ; whereas , gestagens depress the content and release of activators . The low content of plasminogen activators in the endometrium explains the reduced menstrual bleedings found in OC-users . Serotonin induces the expression of tissue factor and plasminogen activator inhibitor-1 in cultured rat aortic endothelial cells . Serotonin ( 5-hydroxytryptamine , or 5-HT ) , released from activated platelets , not only accelerates aggregation of platelets but also is known to promote mitosis , migration , and contraction of vascular smooth muscle cells ( VSMCs ) . These effects are considered to contribute to thrombus formation and atherosclerosis . The aim of this study was to investigate the effects of 5-HT on the expressions of coagulative and fibrinolytic factors in rat aortic endothelial cells . Endothelial cells were stimulated with various concentrations of 5-HT ( 0.1 approximately 10 microM ) , and the expressions of tissue factor ( TF ) , tissue factor pathway inhibitor ( P10646 ) , plasminogen activator inhibitor-1 ( P05121 ) , and tissue-type plasminogen activator ( TPA ) messenger RNAs ( mRNAs ) were evaluated by Northern blot analysis . The activities of TF and P05121 were also measured . TF and P05121 mRNA were increased significantly in a concentration- and time-dependent manner . However , P10646 and TPA mRNA expression did not change . The inductions of TF and P05121 mRNAs were inhibited by a 5-HT1/5-HT2 receptor antagonist ( methiothepin ) and a selective 5- Q13049 receptor antagonist ( D6RGH6 -9042 ) . These results indicate that 5-HT increases procoagulant activity and reduces fibrinolytic activities of endothelial cells through the 5- Q13049 receptor . It was concluded that the modulation of procoagulant and hypofibrinolytic activities of endothelial cells by 5-HT synergistically promotes thrombus formation at the site of vessel injury with the platelet aggregation , VSMC contraction , and VSMC proliferation . [ DB00013 therapy of deep vein thrombosis ( author 's transl ) ] . 30 patients with deep vein thrombosis were treated with a combination of urokinase and heparin . Clinically relevant improvement was achieved in 2/3 of them with appr . 40,000 IU/h ( 1,000,000 IU/d ) urokinase administered over a period of several days . This indicates that urokinase at this dosage offers a valuable alternative or supplementation to fibrinolytic therapy with streptokinase . With the dosage employed , routine blood coagulation tests are only minimally affected , although a strong enhancement of fibrinolytic activity can be demonstrated by the euglobulin clot lysis time . P00747 depletion - as is usually observed with streptokinase therapy - does not occur . DB00013 is well tolerated and there is only a very moderate bleeding tendency . The cost per day of urokinase therapy at the dosage employed is approximately twice that of customary streptokinase therapy . P00747 activation by airway smooth muscle is regulated by type I collagen . Plasmin , the activated protease product of plasminogen , is involved in collagen remodeling , and is strongly implicated in asthma pathophysiology by recent genome-wide association studies . This study examines plasminogen " activation " by airway smooth muscle cells , and its regulation in a fibrotic environment created by culture on type I collagen and incubation with transforming growth factor ( TGF ) -β . DB00013 plasminogen activator ( uPA ) activity was detected in the supernatants of human airway smooth muscle cell cultures maintained in serum-free conditions . Incubation with plasminogen ( 1.5-50.0 μg/ml , 24 h ) increased plasmin activity in a concentration-dependent manner ( P < 0.001 ) . uPA activity was higher in cultures maintained on fibrillar type I collagen substrata than in those on plastic , as was plasmin activity after incubation with plasminogen ( 20 μg/ml ) . Pretreatment with TGF-β ( 100 pM ) for 18 hours inhibited plasminogen activation by airway smooth muscle cells maintained on plastic , but not on collagen . TGF-β stimulated an increase in the level of uPA mRNA in airway smooth muscle cells grown on collagen , but not on plastic . Reducing the levels of β1-integrin collagen receptor , using interference RNA , attenuated plasmin formation by airway smooth muscle cells grown on collagen , and restored the inhibitory effect of TGF-β . This study shows that airway smooth muscle activation of plasminogen by uPA is accelerated in a collagen-rich environment in which the inhibitory effect of TGF-β is attenuated in association with greater uPA expression induced via β1-integrin signaling . These findings suggest that the plasminogen-activation system involving uPA has the potential to contribute to airway wall remodeling in asthma . Targeting the urokinase plasminogen activator receptor enhances gene transfer to human airway epithelia . Developing gene therapy for cystic fibrosis has been hindered by limited binding and endocytosis of vectors by human airway epithelia . Here we show that the apical membrane of airway epithelia express the urokinase plasminogen activator receptor ( Q03405 ) . DB00013 plasminogen activator ( uPA ) , or a 7-residue peptide derived from this protein ( u7-peptide ) , bound the receptor and stimulated apical endocytosis . Both ligands enhanced gene transfer by nonspecifically bound adenovirus and adeno-associated virus vectors and by a modified adenovirus vector that had been coupled to the u7-peptide . These data provide the first evidence that targeting an apical receptor can circumvent the two most important barriers to gene transfer in airway epithelia . Thus , the uPA/ Q03405 system may offer significant advantages for delivering genes and other pharmaceuticals to airway epithelia . DB00989 improves hippocampal neurogenesis and depression-like behaviors via P08908 receptor stimulation in olfactory bulbectomized mice . DB00989 is a non-competitive inhibitor of both acetylcholinesterase ( P22303 ) and butylcholinesterase ( BuChE ) used to treat mild to moderate dementia in Alzheimer 's disease ( AD ) patients . Although rivastigmine reportedly ameliorates cognitive dysfunction in these patients , its ability to improve Behavioral and Psychological Symptoms of Dementia ( BPSD ) remains unclear . To determine whether rivastigmine treatment antagonizes depression-like behaviors , we chronically administered rivastigmine ( 0.1-1.0mg/kg ) to olfactory bulbectomized ( OBX ) mice once a day for 2weeks , starting 2weeks after bulbectomy . Chronic treatment at 0.3 or 1.0mg/kg dose dependently and significantly improved depression-like behaviors , as assessed by tail suspension ( Q16762 ) , forced swim ( P19883 ) , locomotion and novelty-suppressed feeding ( NSFT ) tests . Importantly , co-administration with WAY-100635 ( 1.0mg/kg ) , a P08908 receptor antagonist , but not ketanserin ( 1.0mg/kg , ) , a 5- Q13049 receptor antagonist , completely blocked rivastigmine-induced anti-depressive effects , suggesting that P08908 receptor stimulation mediates this activity . Consistent with this observation , rivastigmine treatment significantly rescued impaired neurogenesis observed in OBX mice in a P08908 receptor-dependent manner . Furthermore , enhanced protein kinase B ( Akt ) and extracellular signal-regulated kinase ( P29323 ) phosphorylation seen following rivastigmine treatment was closely associated with improved neurogenesis . These effects were blocked by WAY-100635 but not ketanserin treatment . Finally , we confirmed that P08908 but not 5- Q13049 receptor stimulation by specific agonists mimicked rivastigmine-induced anti-depression activity and promoted hippocampal neurogenesis . We conclude that , in addition to enhancing the cholinergic system , rivastigmine treatment restores normal function of the hippocampal serotonergic system , an activity that likely ameliorates depressive behaviors in AD patients . DB00013 plasminogen activator is a central regulator of macrophage three-dimensional invasion , matrix degradation , and adhesion . DB00013 plasminogen activator ( uPA ) and its receptor ( Q03405 ) coordinate a plasmin-mediated proteolytic cascade that has been implicated in cell adhesion , cell motility , and matrix breakdown , for example , during inflammation . As part of their function during inflammatory responses , macrophages move through tissues and encounter both two-dimensional ( 2D ) surfaces and more complex three-dimensional ( 3D ) interstitial matrices . Based on approaches employing uPA gene-deficient macrophages , plasminogen supplementation , and neutralization with specific protease inhibitors , it is reported in this study that uPA activity is a central component of the invasion of macrophages through a 3D Matrigel barrier ; it also has a nonredundant role in macrophage-mediated matrix degradation . For murine macrophages , matrix metalloproteinase-9 activity was found to be required for these uPA-mediated effects . Evidence for a unique role for uPA in the inverse relationship between macrophage adhesion and 2D migration was also noted : macrophage adhesion to vitronectin was enhanced by uPA and blocked by plasminogen activator inhibitor-1 , the latter approach also able to enhance in turn the 2D migration on this matrix protein . It is therefore proposed that uPA can have a key role in the inflammatory response at several levels as a central regulator of macrophage 3D invasion , matrix remodeling , and adhesion . DB00013 receptor interacts with alpha(v)beta5 vitronectin receptor , promoting urokinase-dependent cell migration in breast cancer . Perturbation of adhesive interactions at cell-substratum and cell-cell contact sites is a critical event in the multistep process of cancer invasion . Recent studies indicate that the urokinase receptor ( Q03405 ) is associated in large molecular complexes with other molecules , such as integrins . To test the possibility that Q03405 may physically and functionally interact with vitronectin ( Vn ) receptors , we determined the expression level of Q03405 , alpha(v)beta3 , and alpha(v)beta5 Vn receptors in 10 human breast carcinomas . Here , we show the ability of Q03405 to physically associate with alpha(v)beta5 in the breast carcinomas examined . The functional effects of this interaction were studied using HT1080 human fibrosarcoma and MCF-7 human breast carcinoma cell lines , both exhibiting a urokinase-dependent physical association between Q03405 and alpha(v)beta5 . Both cell lines respond to urokinase or to its noncatalytic amino-terminal fragment by exhibiting remarkable cytoskeletal rearrangements that are mediated by alpha(v)beta5 and require protein kinase C activity . On the contrary , binding of Vn to alpha(v)beta5 results in the protein kinase C-independent formation of F-actin containing microspike-type structures . Furthermore , alpha(v)beta5 is required for urokinase-directed , receptor-dependent MCF-7 and HT1080 cell migration . These data show that Q03405 association with alpha(v)beta5 leads to a functional interaction of these receptors and suggest that Q03405 directs cytoskeletal rearrangements and cell migration by altering alpha(v)beta5 signaling specificity . P10275 rediscovered : the new biology and targeting the androgen receptor therapeutically . Discoveries over the past decade suggest that castration-resistant prostate cancer ( CRPC ) is sensitive , but not resistant to , further manipulation of the androgen-androgen receptor ( AR ) axis . Several new therapies that target this axis have demonstrated clinical activity . In this article , preclinical and clinical findings occurring in the field of AR-targeted therapies are reviewed . Reviews of scientific and clinical development are divided into those occurring prereceptor ( androgen production and conversion ) and at the level of the receptor ( AR aberrations and therapies targeting AR directly ) . Intracrine androgen production and AR amplification , among others , are among the principal aberrancies driving CRPC growth . Phase III data with abiraterone acetate and phase II data with DB08899 , along with other similar therapies , confirm for the clinician that the scientific findings related to persistent AR signaling in a castrate milieu can be harnessed to produce significant clinical benefit for patients with the disease . Studies aimed at optimizing the timing of their use and exploring the mechanisms of resistance to these therapies are under way . The clinical success of therapies that directly target androgen synthesis as well as the most common aberrancies of the AR confirm that prostate cancer retains dependence on AR signaling , even in the castrate state . Effect of valproic acid through regulation of DB01221 receptor- P29323 signaling in sleep deprivation rats . Although the effect of mood stabilizer valproic acid ( DB00313 ) through multiple signaling pathways has been shown , its therapeutic mechanism is still largely unknown . We investigated the effect of DB00313 ( 200 mg/kg , every 12 h ) in sleep deprivation ( SD ) rats ( 72 h ) , the manic-like animal model , focusing on the N-methyl-D : -aspartic acid ( DB01221 ) receptor and signaling mediators of synaptic plasticity such as extracellular signal-regulated protein kinase ( P29323 ) , DB02527 response element-binding protein ( CREB ) , B cell chronic lymphocytic leukemia/lymphoma 2 ( P10415 ) , and brain-derived neurotrophic factor ( P23560 ) . SD reduced the expression of the Q13224 subunit of the DB01221 receptor in the frontal cortex and hippocampus but did not affect the expression of Q9UHB4 and Q12879 subunits . In comparison , DB00313 inhibited the SD-induced reduction of Q13224 expression in both brain regions . In addition , SD attenuated P29323 phosphorylation in the frontal cortex and hippocampus , whereas DB00313 prevented the attenuation . DB00313 also protected the SD-induced decrease of CREB phosphorylation , P10415 expression , and P23560 expression in the frontal cortex but not in the hippocampus . These results indicate that DB00313 could regulate DB01221 receptor- P29323 signaling in SD rats , preventing the SD-induced decrease of the expression of Q13224 subunit and the activation of P29323 signaling mediators such as P29323 , CREB , P10415 , and P23560 . Differential roles of Q03405 in peritoneal ovarian carcinomatosis . Epithelial ovarian cancer is the fourth leading cause of death from gynecologic malignancies in the United States . Most cases are diagnosed at late stages , with the solid tumor masses growing as peritoneal implants , or floating within the ascitic fluid ( peritoneal ovarian carcinomatosis ) . Despite aggressive surgical " debulking , " recurrence of recalcitrant disease is frequent with poor patient survival . Efforts to improve survival rates are hindered by lack of biomarkers that can detect and effectively treat ovarian cancer in its early stages . DB00013 plasminogen activator receptor ( Q03405 ) is a multifunctional receptor involved in a myriad of tumor cell processes . However , the role of host Q03405 in ovarian cancer is still elusive . To define the potential proinflammatory role of Q03405 in ovarian cancer , first , using a syngeneic murine model in Q03405 (-/-) mice , we found that ablation of Q03405 restrained tumor take and peritoneal implants and prolonged the survival of Q03405 (-/-) mice compared with their Q03405 (+/+) counterparts . Ascitic fluid accumulation was significantly decreased in Q03405 (-/-) mice with decreased macrophage infiltration . Second , in vitro mechanistic studies revealed that host Q03405 is involved in the multiple steps of peritoneal metastatic cascade . Third , we evaluated the prognostic utility of tumor and stromal Q03405 in human ovarian cancer tissue microarray . In summary , our studies indicated that Q03405 plays a significant role in ovarian cancer cell-stromal crosstalk and contributes to increased vascular permeability and inflammatory ovarian cancer microenvironment . This provides a rationale for targeting the Q03405 with either specific neutralizing antibodies or targeting its downstream inflammatory effectors in patients with ovarian cancer . P09486 -induced migration of glioblastoma cell lines via uPA- Q03405 signaling and activation of small GTPase RhoA . P09486 ( P09486 ) is highly expressed in human gliomas where it promotes invasion and delays tumor growth , both in vitro and in vivo . P09486 , which interacts at the cell surface , has an impact on intracellular signaling and downstream gene expression changes , which might account for some of its effects on invasion and growth . Additionally in vitro studies demonstrated that P09486 delays growth , increases attachment , and modulates migration of tumor cells in an extracellular matrix-specific and concentration-dependent manner . Because the signaling aspect of this migration is neither well understood nor characterized , we overexpressed P09486 in both the minimally-invasive U87 cell line and in the most aggressive invasive cell line , SNB19 . We first performed RT-PCR analysis and observed an upregulation of uPA and its receptor , Q03405 . We also observed increased expression levels of matrix metalloproteinase-2 and -9 ( P08253 and P14780 ) . Western blot analysis confirmed these results , and the enzymatic activity of the metalloproteinases and uPA was further supported by zymography . Downstream of the uPA- Q03405 interaction , upregulation of P19957 -K occurred in cells overexpressing P09486 . Using Q86UG4 -TRBD , we showed the upregulation of active GTP-bound RhoA , but neither Rac1 nor Cdc42 were activated . The inhibition of uPA and Q03405 downregulated P19957 -K activity and cell migration , as shown by matrigel invasion assay . A dorsal skin-fold chamber model revealed the high angiogenic activity of P09486 , though the proliferation of P09486 overexpressing cells was unaffected . Our results show that the small GTPase RhoA was a critical mediator of invasion or migration in the uPA- Q03405 / P19957 -K signaling pathway . miR-17-5p targets the p300/CBP-associated factor and modulates androgen receptor transcriptional activity in cultured prostate cancer cells . BACKGROUND : P10275 ( AR ) signalling is critical to the initiation and progression of prostate cancer ( PCa ) . Transcriptional activity of AR involves chromatin recruitment of co-activators , including the p300/CBP-associated factor ( Q92831 ) . Distinct miRNA expression profiles have been identified in PCa cells during the development and progression of the disease . Whether miRNAs regulate Q92831 expression in PCa cells to regulate AR transcriptional activity is still unclear . METHODS : Expression of Q92831 was investigated in several PCa cell lines by qRT-PCR , Western blot , and immunocytochemistry . The effects of Q92831 expression on AR-regulated transcriptional activity and cell growth in PCa cells were determined by chromatin immunoprecipitation , reporter gene construct analysis , and MTS assay . Targeting of Q92831 by miR-17-5p was evaluated using the luciferase reporter assay . RESULTS : Q92831 was upregulated in several PCa cell lines . Upregulation of Q92831 promoted AR transcriptional activation and cell growth in cultured PCa cells . Expression of Q92831 in PCa cells was associated with the downregulation of miR-17-5p . Targeting of the 3'-untranslated region of Q92831 mRNA by miR-17-5p caused translational suppression and RNA degradation , and , consequently , modulation of AR transcriptional activity in PCa cells . CONCLUSIONS : Q92831 is upregulated in cultured PCa cells , and upregulation of Q92831 is associated with the downregulation of miR-17-5p . Targeting of Q92831 by miR-17-5p modulates AR transcriptional activity and cell growth in cultured PCa cells . Effect of glial cell line-derived neurotrophic factor on behavior and key members of the brain serotonin system in mouse strains genetically predisposed to behavioral disorders . The effect of glial cell line-derived neurotrophic factor ( P39905 ) on behavior and on the serotonin ( 5-HT ) system of a mouse strain predisposed to depressive-like behavior , ASC/Icg ( Antidepressant Sensitive Cataleptics ) , in comparison with the parental " nondepressive " CBA/Lac mice was studied . Within 7 days after acute administration , P39905 ( 800 ng , i.c.v. ) decreased cataleptic immobility but increased depressive-like behavioral traits in both investigated mouse strains and produced anxiolytic effects in ASC mice . The expression of the gene encoding the key enzyme for 5-HT biosynthesis in the brain , tryptophan hydroxylase-2 ( Tph-2 ) , and P08908 receptor gene in the midbrain as well as 5- Q13049 receptor gene in the frontal cortex were increased in P39905 -treated ASC mice . At the same time , P39905 decreased P08908 and 5- Q13049 receptor gene expression in the hippocampus of ASC mice . P39905 failed to change Tph2 , P08908 , or 5- Q13049 receptor mRNA levels in CBA mice as well as 5-HT transporter gene expression and P08908 and 5- Q13049 receptor functional activity in both investigated mouse strains . The results show 1 ) a P39905 -induced increase in the expression of key genes of the brain 5-HT system , Tph2 , P08908 , and 5- Q13049 receptors , and 2 ) significant genotype-dependent differences in the 5-HT system response to P39905 treatment . The data suggest that genetically defined cross-talk between neurotrophic factors and the brain 5-HT system underlies the variability in behavioral response to P39905 . Suppression of NF-kappaB activity by sulfasalazine is mediated by direct inhibition of IkappaB kinases alpha and beta . BACKGROUND & AIMS : Activation of NF-kappaB/Rel has been implicated in the pathogenesis of inflammatory bowel disease ( Q9UKU7 ) . Various drugs used in the treatment of Q9UKU7 , such as glucocorticoids , DB00244 , and sulfasalazine , interfere with NF-kappaB/Rel signaling . The aim of this study was to define the molecular mechanism by which sulfasalazine inhibits NF-kappaB activation . METHODS : The effects of sulfasalazine and its moieties on NF-kappaB signaling were evaluated using electromobility shift , transfection , and immune complex kinase assays . The direct effect of sulfasalazine on O15111 ( IKK ) activity was investigated using purified recombinant O15111 and -beta proteins . RESULTS : NF-kappaB/Rel activity induced by tumor necrosis factor alpha , 12-O-tetradecanoylphorbol-13-acetate , or overexpression of NF-kappaB-inducing kinase , O15111 , O14920 , or constitutively active O15111 and O14920 mutants was inhibited dose dependently by sulfasalazine . Sulfasalazine inhibited tumor necrosis factor alpha-induced activation of endogenous IKK in Jurkat T cells and SW620 colon cells , as well as the catalytic activity of purified O15111 and O14920 in vitro . In contrast , the moieties of sulfasalazine , DB00244 , and sulfapyridine or DB00233 had no effect . Activation of extracellular signal-related kinase ( P29323 ) 1 and 2 , c-Jun-N-terminal kinase ( JNK ) 1 , and p38 was unaffected by sulfasalazine . The decrease in substrate phosphorylation by O15111 and -beta is associated with a decrease in autophosphorylation of IKKs and can be antagonized by excess adenosine triphosphate . CONCLUSIONS : These data identify sulfasalazine as a direct inhibitor of O15111 and -beta by antagonizing adenosine triphosphate binding . The suppression of NF-kappaB activation by inhibition of the IKKs contributes to the well-known anti-inflammatory and immunosuppressive effects of sulfasalazine . Synthesis and biological evaluation of novel pyrrolidine-2,5-dione derivatives as potential antidepressant agents . Part 1 . A series of 3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives was synthesized and their biological activity was evaluated . The chemical structures of the newly prepared compounds were confirmed by (1)H NMR , (13)C NMR and P19957 -HRMS spectra data . All tested compounds proved to be potent P08908 receptor and serotonin transporter protein ( P31645 ) ligands . Among them , compounds 15 , 18 , 19 and 30 showed significant affinity for P08908 and P31645 . Computer docking simulations carried out for compounds 15 , 31 and 32 to models of P08908 receptor and P31645 confirm the results of biological tests . Due to high affinity for the P08908 receptor and moderate affinity for P31645 , compounds 31 , 32 , 35 , and 37 were evaluated for their affinity for D2L , P50406 , P34969 and 5- Q13049 receptors . In vivo tests , in turn , resulted in determining the functional activity of compounds 15 , 18 , 19 and 30 to the P08908 receptor . The results of these tests indicate that all of the ligands possess properties characteristic of P08908 receptor agonists . DB00013 plasminogen activator cleaves its cell surface receptor releasing the ligand-binding domain . The cellular receptor for urokinase-type plasminogen activator ( Q03405 ) is a glycolipid-anchored three-domain membrane protein playing a central role in pericellular plasminogen activation . We have found that urokinase ( uPA ) can cleave its receptor between domains 1 and 2 generating a cell-associated Q03405 variant without ligand-binding properties . In extracts of U937 cells there are two Q03405 variants which after complete deglycosylation have apparent molecular masses of 35,000 and 27,000 . Analysis with monoclonal antibodies showed that these variants represented the intact Q03405 and a two-domain form , Q03405 (2+3) , lacking ligand-binding domain 1 . Trypsin treatment showed that both variants are present on the outside of the cells . Addition to the culture medium of an anticatalytic monoclonal antibody to uPA inhibited the formation of the Q03405 (2+3) , indicating that uPA is involved in its generation . Purified Q03405 can be cleaved directly by uPA as well as by plasmin . The uPA-catalyzed cleavage does not require binding of the protease to the receptor through its epidermal growth factor-like receptor-binding domain , since low molecular weight uPA that lacks this domain also cleaves Q03405 . This unusual reaction in which a specific binding protein is proteolytically inactivated by its own ligand may represent a regulatory step in the plasminogen activation cascade . The effectiveness of lurasidone as an adjunct to lithium or divalproex in the treatment of bipolar disorder . The majority of patients with bipolar disorder spend a lot of time in depressive episodes that impose a great burden on patients , caregivers , and society and accounts for the largest part of the morbidity-mortality of the illness . DB08815 is an atypical antipsychotic with a potent binding affinity as antagonist for D2 , 5- Q13049 , P34969 , and partial agonist at P08908 receptors . Affinity for other receptors as H1 and muscarinic were negligible . DB08815 was approved in 2010 for the treatment of schizophrenia and recently , 2013 , for bipolar depression in monotherapy and an adjunct to lithium or valproate . Clinical trials have established that lurasidone adjuvant to lithium or valproate has more efficacy than the placebo and is associated with minimal weight gain and no clinically meaningful alterations in glucose , lipids , or the QT interval . Additional studies are desirable to know the clinical profile of lurasidone in long-term treatment , in patients with bipolar II disorders , and versus other antipsychotic agents . Induction of c-fos Gene Expression by DB00013 -Type P00747 Activator in Human Ovarian Cancer Cells . The ability to fractionate nucleic acids and to determine which of them has sequences complementary to an array of DNA or RNA molecules is one of the most powerful tools of molecular biology . The Southern blot , named for its inventor , is a method for transferring size-fractionated DNA from a gel matrix to a solid support followed by hybridization to a labeled probe ( 1. The identical process for RNA became known as ) the Northern blot i2 1i The identical process for RNA became known as the Northern blot ( 2 ) . Both are , then , often key elements in establishing the identity of nucleic acids of interest . Northern blot analysis was used by us as a tool in order to answer the question whether or not the nuclear transcripitional apparatus of human ovarian cancer cells might be activated in response to the urokinase . P00747 activators , venous leg ulcers and reepithelialization . BACKGROUND AND OBJECTIVE : The pathogenesis of leg ulcers due to chronic venous hypertension ( CVH ) seems to be related to perivenular fibrin-film formation due to decreased cutaneous fibrinolytic activity dependent on reduced release of tissue-type plasminogen activator that leads to tissue anoxia and ulcer formation . The purpose of the work is a spectrophotometric evaluation of urokinase ( Q96NZ9 ) at the edge , the floor and in the periulcerous skin of leg ulcers . METHODS : We examined a group of 10 patients with chronic leg ulcers caused by CVH . The biopsies from each patient were taken : ( 1 ) from the edge of the ulcer ; ( 2 ) from the perilesional skin and ( 3 ) from the floor of the ulcer . DB00013 levels were evaluated in the same areas in 10 control subjects . The Q96NZ9 activity was determined spectrophotometrically at 405 nm . RESULTS : The results of our study showed that Q96NZ9 is detectable in the center of the ulcer , on the edge , in the perilesional skin , as well as in the controls . Data are statistically significant . The highest levels of Q96NZ9 are found at the edge of the ulcer ; they were lower in the center and in the periulcerous skin . CONCLUSION : A chemoattracting effect of Q96NZ9 on human keratinocytes has been documented and this study showed significantly higher levels of Q96NZ9 at the edge and on the floor of the ulcers , suggesting a possible role of an Q96NZ9 gradient that could promote mobilization of keratinocytes from the edge to the floor , thus inducing reepithelialization . Moreover , Q96NZ9 could play some role in neoangiogenesis and fibroblast chemoattraction , thus contributing in various ways to wound healing . P00747 activator inhibitor type-1 inhibits insulin signaling by competing with alphavbeta3 integrin for vitronectin binding . Functional cooperation between integrins and growth factor receptors has been reported for several systems , one of which is the modulation of insulin signaling by alphavbeta3 integrin . P00747 activator inhibitor type-1 ( P05121 ) , competes with alphavbeta3 integrin for vitronectin ( VN ) binding . Here we report that P05121 , in a VN-dependent manner , prevents the cooperation of alphavbeta3 integrin with insulin signaling in NIH3T3 fibroblasts , resulting in a decrease in insulin-induced protein kinase B ( P31749 ) phosphorylation , vascular endothelial growth factor ( P15692 ) expression and cell migration . P01308 -induced HUVEC migration and angiotube formation was also enhanced in the presence of VN and this enhancement is inhibited by P05121 . By using specific P05121 mutants with either VN binding or plasminogen activator ( PA ) inhibiting activities ablated , we have shown that the P05121 -mediated interference with insulin signaling occurs through its direct interaction with VN , and not through its PA neutralizing activity . Moreover , using cells deficient for uPA receptor ( Q03405 ) we have demonstrated that the inhibition of P05121 on insulin signaling is independent of Q03405 -VN binding . These results constitute the first demonstration of the interaction of P05121 with the insulin response . DB04946 binding to human and rat dopamine and 5-HT receptors . DB04946 ( DB04946 ; 1- [ 4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy] -3- methoxyphenyl ] ethanone ) is a compound currently in clinical trials for the treatment of schizophrenia . DB04946 displays affinity for dopamine D2 receptors and for 5- Q13049 receptors and has a variety of in vivo activities suggestive of an atypical antipsychotic . Here we present an examination of the affinity of iloperidone to a variety of human and rat homologs of dopamine and 5-HT receptor subtypes . We employed receptor binding assays using membranes from cells stably expressing human dopamine D1 , D2S , D2L , D3 , D4 and D5 and 5- Q13049 and P28335 receptors and rat P50406 and P34969 receptors . DB04946 displayed higher affinity for the dopamine D3 receptor ( Ki = 7.1 nM ) than for the dopamine D4 receptor ( Ki = 25 nM ) . DB04946 displayed high affinity for the P50406 and P34969 receptors ( Ki = 42.7 and 21.6 nM , respectively ) , and was found to have higher affinity for the 5- Q13049 ( Ki = 5.6 nM ) than for the P28335 receptor ( Ki = 42.8 nM ) . The potential implications of this receptor binding profile are discussed in comparison with data for other antipsychotic compounds . Genetic polymorphisms , the metabolism of estrogens and breast cancer : a review . Breast cancer is the most common female cancer and the second cause of cancer death in women . Despite recent breakthroughs , much of the etiology of this disease is unknown and the most important risk factor , i.e. , exposure to endogenous and exogenous estrogen throughout life can not explain the heterogeneity of prognosis nor clinical features of patients . Recently , many gene polymorphisms in the metabolism of breast cancer have been described as possible neoplasm etiologic factors . This review is an attempt to summarize the current knowledge about these polymorphisms and to determine new target genes for diagnosis and treatment of the disease . Polymorphisms in the genes P05093 , P11511 , P04798 , P05177 , Q16678 , P22309 , P50225 , 17-hydroxysteroid-dehydrogenase , P21964 , Q86UG4 , P03372 , and Q92731 are described . DB00013 and its receptor in follicular and inflammatory cysts of the jaws . OBJECTIVE : Proteases are considered critical in peri-cystic tissue degradation required in jaw cyst expansion . We studied the expression of the plasminogen activation system ( plasminogen activators ; their inhibitor type-1 , P05121 ; the receptor for the urokinase-type plasminogen activator , Q03405 ) in follicular and inflammatory cysts of the jaw , to identify a possible role of this system in jaw cyst enlargement . MATERIALS AND METHODS : Jaw cysts were collected by therapeutic enucleation . ELISA and casein zymography were used to measure and characterize plasminogen activators in cyst fluid . By immunohistochemistry we examined the presence of Q03405 in cyst walls and inflammatory cells , and by Western blotting the molecular forms of Q03405 within the cyst fluid . RESULTS : Inflammatory cysts fluid contained higher amounts of plasminogen activators of the urinary-type ( uPA ) , and lower amounts of P05121 , when compared to follicular cysts fluid . Epithelial layers of both types of cysts and inflammatory cells expressed Q03405 . Native 3-domain Q03405 was scarcely detectable within cysts , where its cleavage was accounted for by uPA . CONCLUSION : These data suggest a plasminogen activation-dependent mechanism of cyst enlargement , where only the outward Q03405 expressed on epithelial cells and on inflammatory cells direct the peri-cystic protease cascade , in a way similar to tumor enlargement within tissues . Expression of the urokinase-type plasminogen activator receptor in human articular chondrocytes : association with caveolin and beta 1-integrin . The urokinase-type plasminogen activator ( uPA ) in concert with other proteolytic enzymes plays a critical role in cartilage degradation during osteoarthritis . DB00013 receptor ( Q03405 ) , a glycosyl-phosphatidylinositol-linked glycoprotein present on the cell surface of various cell types such as cancer cells , fibroblasts , synoviocytes , and chondrocytes , is a key regulator of the plasmin-mediated pericellular proteolysis . Recently , in arthritic synovial tissue increased Q03405 expression has been detected . By immunohistochemical analysis we observed , in addition , enhanced expression of Q03405 in chondrocytes of arthritic samples of human cartilage compared to non-arthritic controls . Using in vitro cultured human chondrocytes , we analyzed whether Q03405 is associated with structural proteins , which are known to be involved in cell signaling and activation . Q03405 in phorbol-12-myristate-13-acetate-stimulated chondrocytes colocalized with caveolin as well as beta 1-integrin , as demonstrated by double immunostaining with specific antibodies . Furthermore , Q03405 was present in caveolae-like structures of chondrocytes as detected by immunoelectron microscopy . Finally , both caveolin and beta 1-integrin were coprecipitated with Q03405 -specific antibodies from cell extracts suggesting that these proteins may form functional complexes in human chondrocytes . The localization of Q03405 in caveolae and its close association with caveolin and beta 1-integrin points to a significance of Q03405 -mediated signaling pathways in human chondrocytes . Transforming growth factor-beta is a strong and fast acting positive regulator of the level of type-1 plasminogen activator inhibitor mRNA in WI-38 human lung fibroblasts . We have studied the mechanism of a transforming growth factor-beta ( TGF-beta ) -stimulated production of type-1 plasminogen activator inhibitor ( P05121 ) in WI-38 human lung fibroblasts . TGF-beta causes an early increase in the P05121 mRNA level which reaches a maximal 50-fold enhancement after 8 h . Blocking of protein synthesis with cycloheximide causes an equally strong increase in the level of P05121 mRNA . Quantitative studies of the effect of TGF-beta on P05121 protein levels in cell extracts and culture media by using monoclonal antibodies are consistent with the effect on P05121 mRNA . The results suggest a primary effect of TGF-beta on P05121 gene transcription , and also suggest the possibility that the transcription of this gene in non-induced cells may be suppressed by a short-lived negatively regulating protein . DB00013 -type ( u-PA ) and tissue-type ( t-PA ) plasminogen activators are decreased in the culture media of TGF-beta-treated cells concomitantly with the increase in P05121 accumulation . These findings show that a primary and important biological effect of TGF-beta may be an overall decreased extracellular proteolytic activity , and give an insight into the molecular mechanisms underlying TGF-beta action at the genetic level . Association between urokinase-plasminogen activator gene T4065C polymorphism and risk of mitral valve prolapse . BACKGROUND : Abnormalities of collagen and elastic fibers were found in floppy mitral valves ( FMV ) . DB00013 -plasminogen activator ( P00749 ) was suggested to be involved in the pathogenesis of elastin and collagen degradation in arterial aneurysm . The role of P00749 genetic variant in mitral valve prolapse ( Q14764 ) has not been studied . We , therefore , performed a case-controlled study investigating the possible relation between the P00749 gene polymorphisms and risk of Q14764 in Taiwan Chinese . METHODS : We studied 100 patients with Q14764 diagnosed by echocardiography and 106 age- and sex-matched normal control subjects . The T4065C and T3995C polymorphisms of the P00749 gene were identified by polymerase chain reaction ( PCR ) -based restriction analysis . RESULTS : There was a significant difference in either the genotype distribution or allelic frequencies between Q14764 cases and controls for P00749 gene T4065C polymorphism ( P = 0.0001 and 0.0002 , respectively ) . An odds ratio for risk of Q14764 associated with P00749 T4065C TC genotype was 6.03 ( 95 % confidence interval 2.11-14.83 ) . An odds ratio for risk of Q14764 associated with P00749 T4065C T allele was 4.99 ( 95 % confidence interval 1.93-12.91 ) . There was no significant difference in either the genotype distribution or allelic frequencies between Q14764 cases and controls for P00749 T3995C polymorphism . Further categorization of the Q14764 patients into mild and severe subgroups revealed no statistical difference between these two subgroups for P00749 T4065C and T3995C polymorphisms . CONCLUSIONS : This study shows that patients with Q14764 have a higher frequency of P00749 T4065C TC genotype and T allele that supports a role of the P00749 T4065C polymorphism in determining the risk of Q14764 among the Chinese population in Taiwan . O43609 promotes the degradation of Q03405 and inhibits Q03405 -mediated cell adhesion and proliferation . DB00013 plasminogen activator receptor ( Q03405 ) is a P06744 anchored cell surface protein that is closely associated with invasion , migration , and metastasis of cancer cells . Many functional extracellular proteins and transmembrane receptors interact with Q03405 . However , few studies have examined the association of Q03405 with cytoplasm proteins . We previously used yeast two-hybrid screening to isolate several novel Q03405 -interacting cytoplasmic proteins , including Sprouty1 ( O43609 ) , an inhibitor of the ( Ras-mitogen-activated protein kinase ) MAPK pathway . In this study , we show that O43609 interacts with Q03405 and directs it toward lysosomal-mediated degradation . Overexpression of O43609 decreased the cell surface and cytoplasmic Q03405 protein level . Moreover , O43609 overexpression augmented Q03405 -induced cell adhesion to vitronectin as well as proliferation of cancer cells . Our results also further support the critical role of O43609 contribution to tumor growth . In a subcutaneous tumor model , overexpression of O43609 in HCT116 or A549 xenograft in athymic nude mice led to great suppression of tumor growth . These results show that O43609 may affect tumor cell function through direct interaction with Q03405 and promote its lysosomal degradation .