interacts_with DB00031?
Secretagogue-stimulated pancreatic secretion is differentially regulated by constitutive NOS isoforms in mice . DB00435 ( NO ) and NO synthase ( NOS ) play controversial roles in pancreatic secretion . NOS inhibition reduces CCK-stimulated in vivo pancreatic secretion , but it is unclear which NOS isoform is responsible , because NOS inhibitors lack specificity and three NOS isoforms exist : neuronal ( P29475 ) , endothelial ( P29474 ) , and inducible ( P35228 ) . Mice having individual NOS gene deletions were used to clarify the NOS species and cellular interactions influencing pancreatic secretion . In vivo secretion was performed in anesthetized mice by collecting extraduodenal pancreatic duct juice and measuring protein output . Nonselective NOS blockade was induced with N(omega)-nitro-L-arginine ( DB04223 ; 10 mg/kg ) . In vivo pancreatic secretion was maximal at 160 pmol.kg(-1).h(-1) CCK octapeptide ( CCK-8 ) and was reduced by NOS blockade ( 45 % ) and P29474 deletion ( 44 % ) . Secretion was unaffected by P35228 deletion but was increased by P29475 deletion ( 91 % ) . To determine whether the influence of NOS on secretion involved nonacinar events , in vitro CCK-8-stimulated secretion of amylase from isolated acini was studied and found to be unaltered by NOS blockade and P29474 deletion . Influence of NOS on in vivo secretion was further examined with carbachol . Protein secretion , which was maximal at 100 nmol.kg(-1).h(-1) carbachol , was reduced by NOS blockade and P29474 deletion but unaffected by P29475 deletion . NOS blockade by DB04223 had no effect on carbachol-stimulated amylase secretion in vitro . Thus constitutive NOS isoforms can exert opposite effects on in vivo pancreatic secretion . P29474 likely plays a dominant role , because P29474 deletion mimics NOS blockade by inhibiting CCK-8 and carbachol-stimulated secretion , whereas P29475 deletion augments CCK-8 but not carbachol-stimulated secretion . P11511 inhibitors and cyclooxygenase-2 ( P35354 ) inhibitors in endometriosis : new questions -- old answers ? The medical treatment of endometriosis needs to be optimized . Therapeutic management strategies for endometriosis-associated pain or recurrent disease are primarily aimed at downregulating ovarian function or antagonizing the effect of estrogen in ectopic endometrial implants . In this context , basic research is providing important results for the development of new , specific treatment modalities . P11511 overexpression has recently been detected in endometriotic tissue . P11511 ( p450arom ) is responsible for converting C19 androgens into estrogen in several types of human tissue . P11511 activity causes local estrogen biosynthesis , which , in turn , stimulates prostaglandin E2 production by upregulating cyclooxygenase-2 ( P35354 ) . Thus , a positive feedback cycle develops between the two systems . Another abnormality in endometriosis , the deficient 17beta-hydroxysteroiddehydrogenase type II ( 17beta-HSD-Type-II ) expression , impairs the inactivation of estradiol to estrone . In contrast to the eutopic endometrium , these molecular aberrations increase the amount of local estradiol and prostaglandin E2 in endometriosis . In several human cell lines , prostaglandin and estrogen concentrations are associated with proliferation , migration , angiogenesis , apoptosis resistance and even invasiveness . Consequently , aromatase and P35354 are thought to be promising new therapeutic targets . Thus , specific aromatase inhibitors ( e.g. DB01006 / DB01006 , DB01217 /Arimidex or Exemestan/Aromasin ) or selective P35354 inhibitors ( e.g. Celecoxib/ DB00482 , DB00533 /Vioxx , DB00580 /Bextra ) are of great interest and should be studied in clinical trials in premenopausal woman with endometriosis to expand the spectrum of currently available treatment options . Inhibitors of the interaction between P04275 and platelet GPIb/IX/V . The formation of platelet-rich thrombi , a critical step in the pathogenesis of atherothrombotic events , is a multistep process involving several components , among which von Willebrand Factor ( P04275 ) plays a central role . Ruptured atherosclerotic plaques expose subendothelial matrix proteins which bind P04275 that represents a bridge between the injured blood vessel and activated platelets , playing a crucial role in platelet adhesion and aggregation , especially in conditions of high-shear rate . Due to these peculiarities , the binding of P04275 to GPIbα is an attractive drug target . Here we summarize the present knowledge on the different classes of drugs targeting the P04275 -GPIb interaction and we give an account of their level of clinical development . In particular , the following compounds are discussed : AJW200 , an IgG4 humanized monoclonal antibody against P04275 -A1 ; 82D6A3 , a monoclonal antibody against P04275 -A3 ; Q96JZ2 -0081 and Q96JZ2 -0681 , bivalent humanized nanobodies targeting the P04275 -A1 domain ; DB05202 and its advanced formulation ARC15105 , second-generation aptamers that bind the P04275 -A1 domain ; h6B4-Fab , a murine monoclonal antibody , and GPG-290 , a recombinant chimeric protein , both directed against GPIbα . DB00107 and vasopressin receptor polymorphisms interact with circulating neuropeptides to predict human emotional reactions to stress . DB00107 ( OT ) and a polymorphism ( rs53576 ) in the oxytocin receptor gene ( P30559 ) have been independently associated with stress reactivity , whereas oxytocin 's sister peptide , arginine vasopressin ( AVP ) and polymorphisms in the vasopressin receptor gene ( P37288 ) have been independently associated with aggressive behavior . In this study , 68 men and 98 women were genotyped for the P30559 rs53576 polymorphism and the P37288 O15537 polymorphism . Baseline and poststressor levels of plasma OT , plasma AVP , positive affect , and anger were assessed . Women , but not men , with high levels of poststressor OT and the GG genotype of rs53576 felt the most positive affect after the stressor . Men , but not women , with high levels of poststressor AVP and the 320 allele of the O15537 polymorphism reported more poststressor anger than noncarriers . These data constitute the first evidence that oxytocin and vasopressin receptor genes interact with levels of OT and AVP to predict sex-specific emotional stress responses . A pleiotropic antiatherogenic action of ibuprofen . Ibuprofen is a cyclooxygenase ( P23219 and P35354 ) inhibitor known to reduce the production of prostaglandins that play prominent role in inflammation . Other properties of the drug , aside from its anti-inflammatory effects , have been recently studied . In this paper we shall discuss several properties of ibuprofen that making the drug interesting for treatment of conditions associated with atherosclerosis . Ibuprofen exerts pleiotropic effects such as inhibition of adhesion and transendothelial migration of leukocytes , suppressing intracellular production of reactive oxygen species and oxidative modification of LDL . Interestingly , ibuprofen increased HDL cholesterol levels and reduced the level of triglicerides . Ibuprofen can also modulate efficiency of fibrynolisis by inhibiting production of plasminogen activator inhibitor ( P05121 ) . This properties of ibuprofen may be due to changing the activity of transcription factors . Ibuprofen inhibits the activation of NF-kB and activates PPARa and PPARg . Direct anti-inflammatory mechanisms contribute to attenuation of experimental allograft arteriosclerosis by statins . BACKGROUND : Despite the development of effective immunosuppressive therapy , transplant graft arterial disease ( Q99259 ) remains the major limitation to long-term graft survival . The interplay between host inflammatory cells and donor vascular wall cells results in an intimal hyperplastic lesion , which leads to ischemia and graft failure . P04035 inhibitors ( statins ) reduce Q99259 in human cardiac allografts , although it is unclear whether this is secondary to cholesterol lowering or other mechanisms . This study tested the hypothesis that statins can suppress Q99259 by cholesterol-independent pathways . METHODS AND RESULTS : We performed heterotopic murine cardiac transplants in total allogeneic or major histocompatibility complex class II-mismatched combinations . Transplanted animals received either control chow , chow containing 25 ppm cerivastatin ( low dose ) , or chow containing 125 ppm cerivastatin ( high dose ) . Mean plasma cerivastatin concentrations were 0.0 ( control ) , 10.1 ( low dose ) , and 21.9 ( high dose ) nmol/L , respectively . Plasma cholesterol levels were the same in all groups . Q99259 scores decreased in low-dose ( P < 0.05 ) and high-dose ( P < 0.0001 ) cerivastatin groups compared with controls , with concomitant reduction in graft-infiltrating cells and significantly decreased intragraft RANTES and monocyte chemotactic protein-1 mRNA expression . DB00439 , as well as other statins , also reduced RANTES and monocyte chemotactic protein-1 production in mouse endothelial cells stimulated with interferon-gamma and tumor necrosis factor-alpha in vitro . CONCLUSIONS : Clinically achievable levels of an P04035 inhibitor attenuate Q99259 in murine heart transplants , diminish host inflammatory cell recruitment , and do not alter cholesterol levels . These results indicate that statins can affect arterial biology and inflammation independently of their effects on cholesterol metabolism . Acute renal failure from hemoglobinuric and interstitial nephritis secondary to iodine and mefenamic acid . DB00784 ingestion , usually in excess and over prolonged period is known to produce interstitial nephritis , or less commonly papillary necrosis , with acute renal failure . However , it is not dose-dependent for the induction of tubulointerstitial damage . Excess iodine ingestion is known to produce toxicity and possible death , but acute renal failure is rare . There is evidence from clinical and experimental data that iodine has toxic effect on tubular epithelial cells . Iodine has not been documented to produce red cell hemolysis and hemoglobinuria . We present a unique case of acute renal failure from hemoglobinuric and acute interstitial nephritis secondary to suicidal ingestion of potassium iodide solution and also ingestion of a few mefenamic acid tablets . These agents led to potentiation of the renal injury from hemoglobinuric tubulopathy , probably from the iodine , and renal dysfunction from alteration of renal perfusion by selective P23219 inhibition of prostaglandin production , and induction of acute interstitial nephritis from mefenamic acid , leading to acute renal failure which was reversible by hemodialysis and supportive therapy . DB02010 -induced growth inhibition of glioma cells is accompanied by altered expression of cyclins , CDKs and CDK inhibitors . DB02010 was found to bring about complete growth inhibition of human glioma cell lines . U87 MG cells were arrested in S phase while U373 MG cells in G2/M phase on staurosporine treatment . Consistent with this observation , no change in P55008 phase regulators viz. , P12004 D1 , D3 and P11802 was seen on staurosporine treatment . The levels of P24941 , P06493 , P12004 A and P12004 B proteins decreased , while the levels of CDK inhibitors viz. , P38936 and p27 were found to increase on staurosporine treatment . The mRNA levels of P24941 and P06493 genes were also found to decrease on staurosporine treatment . Thus apart from staurosporine 's known direct inhibitory effect on P24941 and P06493 activities , staurosporine was found to down-regulate activities of these two kinases by modulating the expression of the kinases themselves as well that of their activating partners ( Cyclins ) and their inhibitors . Comparison of low fat and low carbohydrate diets on circulating fatty acid composition and markers of inflammation . Abnormal distribution of plasma fatty acids and increased inflammation are prominent features of metabolic syndrome . We tested whether these components of metabolic syndrome , like dyslipidemia and glycemia , are responsive to carbohydrate restriction . Overweight men and women with atherogenic dyslipidemia consumed ad libitum diets very low in carbohydrate ( VLCKD ) ( 1504 kcal : % CHO:fat:protein = 12:59:28 ) or low in fat ( LFD ) ( 1478 kcal : % CHO:fat:protein = 56:24:20 ) for 12 weeks . In comparison to the LFD , the VLCKD resulted in an increased proportion of serum total n-6 PUFA , mainly attributed to a marked increase in arachidonate ( 20:4n-6 ) , while its biosynthetic metabolic intermediates were decreased . The n-6/n-3 and arachidonic/eicosapentaenoic acid ratio also increased sharply . Total saturated fatty acids and 16:1n-7 were consistently decreased following the VLCKD . Both diets significantly decreased the concentration of several serum inflammatory markers , but there was an overall greater anti-inflammatory effect associated with the VLCKD , as evidenced by greater decreases in P01375 , P05231 , P10145 , P13500 , P16581 , I- P62158 , and P05121 . Increased 20:4n-6 and the ratios of 20:4n-6/20:5n-3 and n-6/n-3 are commonly viewed as pro-inflammatory , but unexpectedly were consistently inversely associated with responses in inflammatory proteins . In summary , a very low carbohydrate diet resulted in profound alterations in fatty acid composition and reduced inflammation compared to a low fat diet . DB00107 attenuates NADPH-dependent superoxide activity and P05231 secretion in macrophages and vascular cells . DB00107 is synthesized and released in the heart and vasculature , tissues that also express oxytocin receptors . Although it has been established this intrinsic cardiovascular oxytocin system is important in normal homeostatic cardiac and vascular regulation , a role for this system in cardiovascular pathophysiology has not been investigated . The current study examined the influence of oxytocin on mechanisms in atherogenesis , oxidative stress , and inflammation in cultured human vascular cells , THP-1 monocytes , and macrophages . P30559 protein and mRNA expression , NADPH-dependent superoxide activity , and interleukin-6 secretion were measured . Results demonstrated oxytocin receptor protein and mRNA in THP-1 monocytes and macrophages . Incubation of cells at physiological levels of oxytocin significantly decreased basal and stimulated NADPH-dependent superoxide activity in vascular cells , monocytes , and macrophages by 24-48 % . DB00107 also attenuated interleukin-6 secretion from stimulated THP-1 macrophages and endothelial cells by 56 and 26 % , respectively . These findings suggest that oxytocin attenuates vascular oxidative stress and inflammation , two important pathophysiological processes in atherosclerosis . The fact that oxytocin receptors are found in monocytes and macrophages , and oxytocin decreases both superoxide production and release of a proinflammatory cytokine from these cells , suggests a potentially larger role for oxytocin in the attenuation of disease . BIO5192 , a small molecule inhibitor of VLA-4 , mobilizes hematopoietic stem and progenitor cells . Here we show that interruption of the P19320 /VLA-4 axis with a small molecule inhibitor of VLA-4 , BIO5192 , results in a 30-fold increase in mobilization of murine hematopoietic stem and progenitors ( HSPCs ) over basal levels . An additive affect on O14818 mobilization ( 3-fold ) was observed when plerixafor ( DB06809 ) , a small molecule inhibitor of the P61073 / P48061 axis , was combined with BIO5192 . Furthermore , the combination of granulocyte colony-stimulating factor ( DB00099 ) , BIO5192 , and plerixafor enhanced mobilization by 17-fold compared with G- P04141 alone . HSPCs mobilized by BIO5192 or the combination of BIO5192 and plerixafor mobilized long-term repopulating cells , which successfully engraft and expand in a multilineage fashion in secondary transplantation recipients . Splenectomy resulted in a dramatic enhancement of G- P04141 -induced mobilization while decreasing both plerixafor- and BIO5192-induced mobilization of HSPCs . These data provide evidence for the utility of small molecule inhibitors of VLA-4 either alone or in combination with G- P04141 or DB06809 for mobilization of hematopoietic stem and progenitor cells . Increase in proinflammatory cytokines in peripheral blood without haemostatic changes after LPS inhalation . INTRODUCTION : Bronchoalveolar fibrin deposition is a characteristic of various lung disorders including acute lung injury , acute respiratory distress syndrome and sepsis . It is secondary to the activation of coagulation and inhibition of fibrinolysis in the alveolar space , and can be stimulated by lipopolysaccharide ( LPS ) inhalation . The aim of this study was to determine the relation between compartmental stress in the lung and systemic response after LPS inhalation by measuring haemostatic parameters . PATIENTS AND METHODS : 12 healthy subjects underwent a bronchial challenge test with LPS ; sequential dosages were performed for 5 biological markers ( P05231 ( P05231 ) , C-Reactive Protein ( CRP ) , P00734 Fragments 1 and 2 ( F 1+2 ) , cortisol and P00747 Activator Inhibitor 1 ( P05121 ) before endotoxin inhalation and 2 , 4 , 6 , 8 and 24 hours afterwards . RESULTS : P05231 and CRP levels in the peripheral blood were higher after LPS inhalation ; there was no activation of coagulation and no increase in P05121 level . CONCLUSION : This study confirms that despite systemic release of proinflammatory cytokines , LPS inhalation does not induce systemic haemostatic response to LPS challenge . Targeting P04275 as a novel anti-platelet therapy ; application of DB05202 , an Anti- P04275 aptamer , against thrombotic risk . Excessive activation of platelets is a causative factor for thrombotic diseases such as acute coronary syndrome or stroke , and various anti-platelet drugs were developed . DB00945 and clopidogrel have been used as gold standards for anti-platelet therapies , however , their clinical limitations including bleeding problem have increased the demand driving development of novel anti-platelet drugs with new targets . Among several activating pathways leading to platelet aggregation , the interaction between P04275 ( P04275 ) and glycoprotein Ib , which mainly occurs under high shear stress in arterioles , is recently suggested to be a new promising target . The anti-thrombotic efficacy of anti- P04275 agents , such as DB05202 , has been proved in several preclinical and clinical studies . Here , we will discuss the potential benefits of targeting P04275 as a novel antiplatelet therapy , providing an insight into the role of P04275 in increased thrombotic risk . DB01373 -calmodulin suppresses the filamentous actin-binding activity of a 135-kilodalton actin-bundling protein isolated from lily pollen tubes . We have isolated a 135-kD actin-bundling protein ( P-135- P04278 ) from lily ( Lilium longiflorum ) pollen tubes and have shown that this protein is responsible for bundling actin filaments in lily pollen tubes ( E. Yokota , K. Takahara , T. Shimmen [ 1998 ] Plant Physiol 116 : 1421-1429 ) . However , only a few thin actin-filament bundles are present in random orientation in the tip region of pollen tubes , where high concentrations of Ca(2+) have also been found . To elucidate the molecular mechanism for the temporal and spatial regulation of actin-filament organization in the tip region of pollen tubes , we explored the possible presence of factors modulating the filamentous actin ( F-actin ) -binding activity of P-135- P04278 . The F-actin-binding activity of P-135- P04278 in vitro was appreciably reduced by Ca(2+) and calmodulin ( P62158 ) , although neither Ca(2+) alone nor P62158 in the presence of low concentrations of Ca(2+) affects the activity of P-135- P04278 . A micromolar order of Ca(2+) and P62158 were needed to induce the inhibition of the binding activity of P-135- P04278 to F-actin . An antagonist for P62158 , W-7 , cancelled this inhibition . W-5 also alleviated the inhibition effect of Ca(2+)- P62158 , however , more weakly than W-7 . These results suggest the specific interaction of P-135- P04278 with Ca(2+)- P62158 . In the presence of both Ca(2+) and P62158 , P-135- P04278 organized F-actin into thin bundles , instead of the thick bundles observed in the absence of P62158 . These results suggest that the inhibition of the P-135- P04278 activity by Ca(2+)- P62158 is an important regulatory mechanism for organizing actin filaments in the tip region of lily pollen tubes . Predictive value of circulating interleukin-6 and heart-type fatty acid binding protein for three months clinical outcome in acute cerebral infarction : multiple blood markers profiling study . INTRODUCTION : There is no single blood marker for predicting the prognosis in ischemic stroke . A combination of multiple blood markers may enhance the ability to predict long-term outcome following ischemic stroke . METHODS : Blood concentrations of neuronal markers ( neuron-specific enolase , visinin-like protein 1 , heart type fatty acid binding protein ( hFABP ) and neuroglobin ) , astroglial markers ( P04271 and glial fibrillary acidic protein ) , inflammatory markers ( P05231 , P01375 -α , and P02741 ) , blood-brain barrier marker ( matrix metalloproteinase 9 ) , and haemostatic markers ( D-dimer and P05121 ) were measured within 24 hours after stroke onset . The discrimination and reclassification for favorable and poor outcome were compared after adding individual or a combination of blood markers to the clinical model of stroke outcome . RESULTS : In multivariate analysis , natural log-transformed ( log ) P05231 ( odds ratio ( OR ) : 1.75 , 95 % CI : 1.25 to 2.25 , P=0.001 ) and loghFABP ( OR : 3.23 , 95 % CI : 1.44 to 7.27 , P=0.005 ) were independently associated with poor outcome . The addition of a single blood marker to the clinical model did not improve the discriminating ability of the clinical model of stroke outcome . However , the addition of the combination of logIL-6 and loghFABP to the clinical model showed improved discrimination ( area under receiver operating characteristic ( AUROC ) curve : 0.939 versus 0.910 , P=0.03 ) and reclassification performance ( net reclassification improvement index : 0.18 , P=0.005 ) . CONCLUSIONS : A combination of circulating P05231 and hFABP level has an additive clinical value for the prediction of stroke outcome . Novel mechanism of endothelial nitric oxide synthase activation mediated by caveolae internalization in endothelial cells . Q03135 , the caveolae scaffolding protein , binds to and negatively regulates P29474 activity . As caveolin-1 also regulates caveolae-mediated endocytosis after activation of the 60-kDa albumin-binding glycoprotein gp60 in endothelial cells , we addressed the possibility that endothelial NO synthase ( P29474 ) -dependent NO production was functionally coupled to caveolae internalization . We observed that gp60-induced activation of endocytosis increased NO production within 2 minutes and up to 20 minutes . NOS inhibitor N(G)-nitro-L-arginine ( DB04223 ) prevented the NO production . To determine the role of caveolae internalization in the mechanism of NO production , we expressed dominant-negative dynamin-2 mutant ( K44A ) or treated cells with methyl-beta-cyclodextrin . Both interventions inhibited caveolae-mediated endocytosis and NO generation induced by gp60 . We determined the role of signaling via Src kinase in the observed coupling of endocytosis to P29474 activation . Src activation induced the phosphorylation of caveolin-1 , Akt and P29474 , and promoted dissociation of P29474 from caveolin-1 . Inhibitors of Src kinase and Akt also prevented NO production . In isolated perfused mouse lungs , gp60 activation induced NO-dependent vasodilation , whereas the response was attenuated in P29474 (-/-) or caveolin-1(-/-) lungs . Together , these results demonstrate a critical role of caveolae-mediated endocytosis in regulating P29474 activation in endothelial cells and thereby the NO-dependent vasomotor tone . P55008 arrest and down-regulation of cyclin E/cyclin-dependent kinase 2 by the protein kinase inhibitor staurosporine are dependent on the retinoblastoma protein in the bladder carcinoma cell line 5637 . The protein kinase inhibitor staurosporine has been shown to induce P55008 phase arrest in normal cells but not in most transformed cells . DB02010 did not induce P55008 phase arrest in the bladder carcinoma cell line 5637 that lacks a functional retinoblastoma protein ( pRB- ) . However , when infected with a pRB-expressing retrovirus [ Goodrich , D. W. , Chen , Y. , Scully , P. & Lee , W.-H. ( 1992 ) Cancer Res. 52 , 1968-1973 ] , these cells , now pRB+ , were arrested by staurosporine in P55008 phase . This arrest was accompanied by the accumulation of hypophosphorylated pRB . In both the pRB+ and pRB- cells , cyclin D1-associated kinase activities were reduced on staurosporine treatment . In contrast , cyclin-dependent kinase ( CDK ) 2 and cyclin E/ P24941 activities were inhibited only in pRB+ cells . DB02010 treatment did not cause reductions in the protein levels of P11802 , cyclin D1 , P24941 , or cyclin E . The CDK inhibitor proteins P38936 (Waf1/Cip1) and p27 ( Kip1 ) levels increased in staurosporine-treated cells . Immunoprecipitation of P24941 , cyclin E , and p2l from staurosporine-treated pRB+ cells revealed a 2.5- to 3-fold higher ratio of p2l bound to P24941 compared with staurosporine-treated pRB- cells . In pRB+ cells , p2l was preferentially associated with Thrl6O phosphorylated active P24941 . In pRB- cells , however , p2l was bound preferentially to the unphosphorylated , inactive form of P24941 even though the phosphorylated form was abundant . This is the first evidence suggesting that P55008 arrest by 4 nM staurosporine is dependent on a functional pRB protein . Cell cycle arrest at the pRB- dependent checkpoint may prevent activation of cyclin E/ P24941 by stabilizing its interaction with inhibitor proteins p2l and p27 . Dysregulation of leukocyte gene expression in women with medication-refractory depression versus healthy non-depressed controls . BACKGROUND : Depressive Disorders ( DD ) are a great financial and social burden . Females display 70 % higher rate of depression than males and more than 30 % of these patients do not respond to conventional medications . Thus medication-refractory female patients are a large , under-served , group where new biological targets for intervention are greatly needed . METHODS : We used real-time quantitative polymerase chain reaction ( qPCR ) to evaluate mRNA gene expression from peripheral blood leukocytes for 27 genes , including immune , Q9Y251 -axis , ion channels , and growth and transcription factors . Our sample included 23 females with medication refractory DD : 13 with major depressive disorder ( MDD ) , 10 with bipolar disorder ( BPD ) . Our comparison group was 19 healthy , non-depressed female controls . We examined differences in mRNA expression in DD vs. controls , in MDD vs. BPD , and in patients with greater vs. lesser depression severity . RESULTS : DD patients showed increased expression for P22301 , P05231 , P30559 , Q99572 , P47900 , and Q8NER1 . BPD patients showed increased P05067 , P16220 , P19838 , P04150 , and P09486 and decreased P01375 expression . Depression severity was related to increased P22301 , P47900 , P51575 , and Q9HBA0 expression . CONCLUSIONS : These results support prior findings of dysregulation in immune genes , and provide preliminary evidence of dysregulation in purinergic and other ion channels in females with medication-refractory depression , and in transcription and growth factors in those with BPD . If replicated in future research examining protein levels as well as mRNA , these pathways could potentially be used to explore biological mechanisms of depression and to develop new drug targets . Normal and perturbed endothelial cells from canine femoral arteries and femoral veins exhibit heterogeneity in hemostatic properties and growth characteristics . BACKGROUND : We sought to examine the heterogeneity of endothelial cells from the same anatomic site but different vascular systems and described P04275 ( P04275 ) release and morphological change in response to injury-associated factor in femoral vessels from canine in vitro . METHODS : Levels of hemostatic factors ( P04275 , plasminogen activator inhibitor type 1( P05121 ) , antithrombin III ( P01008 ) , in tissue sections and cultured endothelial cells of canine femoral arteries and canine femoral veins were compared by the immunohistochemistry technique . In addition to comparing cell growth density and cell protein contents , cultured femoral arterial endothelial cells ( FAECs ) and cultured femoral venous endothelial cells ( FVECs ) were incubated with a series concentration of basic fibroblast factor ( P09038 ) ( 1 , 10 , 100 ng/ml ) for up to 48 hours to test the amount of P04275 secretion and morphological change . RESULTS : Both in tissue sections and cultured cells , the levels of P04275 are higher in FVECs than in FAECs . We were unable to differentiate the level of P05121 and P01008 difference between FAECs and FVECs. P09038 ( 10 ng/ml ) significantly increased P04275 secretion from cultured FAECs but not from FVECs . The size of cultured FAECs is smaller than of FVECs ; however , FAECs have higher amounts of protein contents than FVECs . CONCLUSIONS : These comparative studies provide evidence indicating that the characteristics of FVECs differ from those of FAECs . These differences may be indicated heterogeneity with either inherited or acquired thrombotic disease . Possible regulation of migration of intrahepatic cholangiocarcinoma cells by interaction of P61073 expressed in carcinoma cells with tumor necrosis factor-alpha and stromal-derived factor-1 released in stroma . Intrahepatic cholangiocarcinoma ( ICC ) is highly fatal because of early invasion , widespread metastasis , and lack of an effective therapy . We examined roles of P61073 and its ligand , stromal cell-derived factor ( SDF ) -1 , in migration of ICC with respect to tumor-stromal interaction by using two ICC cell lines , a fibroblast cell line ( WI-38 ) , and 28 human ICC tissues . The two ICC cell lines expressed P61073 mRNA and protein , and WI-38 fibroblasts expressed P48061 mRNA and protein . Migration of cultured ICC cells in Matrigel was induced by co-culture with WI-38 fibroblasts and by incubation with P48061 . Anti- P48061 antibody suppressed migration , demonstrating that P48061 released from WI-38 fibroblasts was responsible for this migration . P01375 ( P01375 ) -alpha pretreatment of ICC cells up-regulated P61073 mRNA and protein expression in a concentration-dependent manner . Administration of P48061 and P01375 increased synergistically ICC cell migration , which was suppressed by the P61073 antagonist DB06809 . In ICC tissue , P01375 was mainly expressed in infiltrated macrophages , P61073 in ICC cells , and P48061 in stromal fibroblasts . In conclusion , the interaction of P48061 released from fibroblasts and P61073 expressed on ICC cells may be actively involved in ICC migration , and P01375 may enhance ICC cell migration by increasing P61073 expression . P61073 could be a therapeutic target to prevent ICC invasion . Amelioration of nephropathy with apoA-1 mimetic peptide in apoE-deficient mice . BACKGROUND : There is mounting evidence that dyslipidaemia may contribute to development and progression of renal disease . For instance , hyperlipidaemia in apolipoprotein E-deficient ( apoE(-/-) ) mice is associated with glomerular inflammation , mesangial expansion and foam cell formation . ApoA-1 mimetic peptides are potent antioxidant and anti-inflammatory compounds which are highly effective in ameliorating atherosclerosis and inflammation in experimental animals . Given the central role of oxidative stress and inflammation in progression of renal disease , we hypothesized that apoA-1 mimetic peptide , D-4F , may attenuate renal lesions in apoE(-/-) mice . METHODS : Twenty-five-month-old female apoE(-/-) mice were treated with D-4F ( 300 µg/mL in drinking water ) or placebo for 6 weeks . Kidneys were harvested and examined for histological and biochemical characteristics . RESULTS : Compared with the control mice , apoE(-/-) mice showed significant proteinuria , tubulo-interstitial inflammation , mesangial expansion , foam cell formation and up-regulation of oxidative [ NAD(P)H oxidase subunits ] and inflammatory [ NF-κB , P13500 , P05121 and P35354 ] pathways . D-4F administration lowered proteinuria , improved renal histology and reversed up-regulation of inflammatory and oxidative pathways with only minimal changes in plasma lipid levels . CONCLUSIONS : The apoE(-/-) mice develop proteinuria and glomerular and tubulo-interstitial injury which are associated with up-regulation of oxidative and inflammatory mediators in the kidney and are ameliorated by the administration of apoA-1 mimetic peptide . These observations point to the role of oxidative stress and inflammation in the pathogenesis of renal disease in hyperlipidaemic animals and perhaps humans . Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism (PE). tPA has not been replaced by third generation plasminogen activators , e.g. DB00015 ( Ret ) and DB00031 ( TNK ) that circulate with longer life-spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor-1 ( e.g. P05121 ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility . G- P04141 increases secretion of urokinase-type plasminogen activator by human lung cancer cells . We reported previously that granulocyte colony-stimulating factor ( DB00099 ) can promote the invasion of human lung cancer cell lines in vitro . However , the exact mechanism of its stimulatory effect on invasion remains to be elucidated . In the present study we mainly focused our attention on the components of the plasminogen activation system in human lung cancer cell lines , because of the central role that plasminogen activators play in regulating extracellular proteolysis . We showed that G- P04141 induced a dose-dependent increase in the urokinase-type plasminogen activator ( uPA ) activity in the conditioned medium of a PC-9 lung cancer cell line . When the amounts of uPA activity were quantitated by densitometry , we found that even at a concentration of 0.01 microg/ml , G- P04141 had a stimulatory effect on the uPA release , while high concentrations caused a 3.6-fold increase at a maximum concentration of 1 microg/ml . A Western blot analysis of the conditioned medium confirmed the findings observed in a zymographic analysis . The observed increase in uPA protein was paralleled by a significant increase in the uPA mRNA levels after treatment with DB00099 . However , our experiments failed to identify any alteration in the plasminogen activator inhibitor ( P05121 ) secretion caused by DB00099 . In addition , we also found the expression of Q99062 by PC-9 cells , suggesting the possible pathway activated by DB00099 . Oxidative stress-responsive transcription factor P18847 potentially mediates diabetic angiopathy . Previous results of our cDNA microarray analysis to look for genes whose expression level correlates well with in vitro tubulogenesis by NP31 endothelial cells revealed the transcription factor P18847 known to be responsive to stress such as reactive oxygen species ( ROS ) . Anti- P18847 small interfering RNA gave an inhibitory influence on tube formation by NP31 cells expressing an activated form of the vascular endothelial growth factor receptor 1 ( P17948 ) kinase . When expression of P18847 was regulated under the control of tetracycline system in NP31 cells , they acquired the tubulogenic ability upon P18847 induction . While P18847 failed to induce expressions of P15692 and VEGFR , it regulated those of P24941 , P11802 , p8 , plasminogen activator inhibitor 1 , integrin alpha1 , subunit and matrix metalloprotease P45452 . In H2O2-stimulated NP31 cells as well as endothelial cells of glomerulus and aorta of Otsuka-Long-Evans-Tokushima-Fatty diabetic model rats , concomitantly enhanced expressions of P18847 , P05121 , and p8 were observed . Given the proposed hypothesis of the close linkage between diabetic angiopathy and ROS , those data suggest that ROS-associated diabetic complication may involve P18847 -mediated pathological angiogenesis . Coadministrating luteolin minimizes the side effects of the aromatase inhibitor letrozole . P11511 inhibitors ( AIs ) have been used as adjuvant therapeutic agents for breast cancer . Their adverse side effect on blood lipid is well documented . Some natural compounds have been shown to be potential AIs . In the present study , we compared the efficacy of the flavonoid luteolin to the clinically approved AI letrozole ( DB01006 ; Novartis Pharmaceuticals , East Hanover , NJ ) in a cell and a mouse model . In the in vitro experimental results for aromatase inhibition , the Ki values of luteolin and letrozole were estimated to be 2.44 µM and 0.41 nM , respectively . Both letrozole and luteolin appeared to be competitive inhibitors . Subsequently , an animal model was used for the comparison . P11511 -expressing MCF-7 cells were transplanted into ovariectomized athymic mice . Luteolin was given by mouth at 5 , 20 , and 50 mg/kg , whereas letrozole was administered by intravenous injection . Similar to letrozole , luteolin administration reduced plasma estrogen concentrations and suppressed the xenograft proliferation . The regulation of cell cycle and apoptotic proteins-such as a decrease in the expression of Bcl-xL , cyclin-A/D1/E , P24941 /4 , and increase in that of Bax-was about the same in both treatments . The most significant disparity was on blood lipids . In contrast to letrozole , luteolin increased fasting plasma high-density lipoprotein concentrations and produced a desirable blood lipid profile . These results suggested that the flavonoid could be a coadjuvant therapeutic agent without impairing the action of AIs . DB00439 , an inhibitor of P04035 , inhibits urokinase/urokinase-receptor expression and P14780 secretion by peripheral blood monocytes -- a possible protective mechanism against atherothrombosis . It is now recognised that acute myocardial infarction results from the rupture of atherosclerotic plaques . Lymphocytes and macrophages , which infiltrate rupture sites , contribute to plaque degradation by expressing urokinase ( u-PA ) bound to cell membrane by urokinase receptor ( u-PAR ) and by secreting metalloproteinase P14780 . We have previously demonstrated that the uptake of oxidised LDL ( ox-LDL ) by monocytes induces an increase of u-PA and u-PAR expression . The present study shows that the expression of u-PA and u-PAR induced by ox-LDL on monocyte surface is suppressed by cerivastatin ( a synthetic inhibitor of P04035 , Bayer ) from 2 nM . This leads to reduced plasmin generation and monocyte adhesion to vitronectin . Furthermore , higher concentrations of cerivastatin ( 50-100 nM ) reduce the expression of u-PA and u-PAR on unstimulated monocytes . It also inhibits P14780 secretion but has no effect on P01033 secretion , suggesting that the decrease in P14780 has a real protective effect on plaque stabilisation . The inhibitory effect of cerivastatin on u-PA expression and P14780 secretion can be explained by the inhibition of NF-kappa B translocation into the nucleus , as shown by immunofluorescence . As farnesyl-pyrophosphate reverses the effect of cerivastatin , it is postulated that these effects could also be due to the inhibition of Ras prenylation . This was confirmed by confocal microscopy , which shows the Ras delocalisation from the monocyte membrane . The cerivastatin-induced effects on monocyte functions could explain , at least in part , the protective effect of this drug against atherothrombotic events . The conformational plasticity of calmodulin upon calcium complexation gives a model of its interaction with the oedema factor of Bacillus anthracis . We analyzed the conformational plasticity of calmodulin ( P62158 ) when it is bound to the oedema factor ( EF ) of Bacillus anthracis and its response to calcium complexation with molecular dynamics ( MD ) simulations . The EF- P62158 complex was simulated during 15 ns for three different levels of calcium bound to P62158 . They were respectively no calcium ion ( EF-(Apo- P62158 ) ) , two calcium ions bound to the C-terminal domain of P62158 ( EF-(2Ca- P62158 ) ) , and four calcium ions bound to P62158 ( EF-(4Ca- P62158 ) ) . Calculations were performed using AMBER package . The analysis of the MD simulations illustrates how P62158 forces EF in an open conformation to form the adenylyl cyclase enzymatic site , especially with the two calcium form of P62158 , best suited to fit the open conformation of EF . By contrast , P62158 encounters bending and unwinding of its flexible interlinker in EF-(Apo- P62158 ) and EF-(4Ca- P62158 ) . DB01373 binding to one domain of P62158 affects the other one , showing a transmission of information along the protein structure . The analysis of the P62158 domains conformation along the simulations brings an atomistic and dynamic explanation for the instability of these complexes . Indeed the EF-hand helices of the N-terminal domain tend to open upon calcium binding ( EF-(4Ca- P62158 ) ) , although the domain is locked by EF . By contrast , the C-terminal domain is strongly locked in the open conformation by EF , and the removal of calcium induces a collapse of EF catalytic site ( EF-(Apo- P62158 ) ) . Multiplex protein signature for the detection of bladder cancer in voided urine samples . PURPOSE : Accurate urine assays for bladder cancer detection would benefit patients and health care systems . Through extensive genomic and proteomic profiling of urine components we previously identified a panel of 8 biomarkers that can facilitate the detection of bladder cancer in voided urine samples . In this study we confirmed this diagnostic molecular signature in a diverse multicenter cohort . MATERIALS AND METHODS : We performed a case-control , phase II study in which we analyzed voided urine from 102 subjects with bladder cancer and 206 with varying urological disorders . The urinary concentration of 8 biomarkers ( P10145 , P14780 and 10 , P05121 , P15692 , P03950 , Q16790 and P02649 ) was assessed by enzyme-linked immunosorbent assay . Diagnostic performance of the panel of tested biomarkers was evaluated using ROCs and descriptive statistical values , eg sensitivity and specificity . RESULTS : Seven of the 8 urine biomarkers were increased in subjects with bladder cancer relative to those without bladder cancer . The 7 biomarkers were assessed in a new model , which had an AUROC of 0.88 ( 95 % CI 0.84-0.93 ) , and 74 % sensitivity and 90 % specificity . In contrast , the sensitivity of voided urine cytology and the UroVysion® cytogenetic test in this cohort was 39 % and 54 % , respectively . Study limitations include analysis performed on banked urine samples and the lack of voided urine cytology and cytogenetic test data on controls . CONCLUSIONS : The study provides further evidence that the reported panel of diagnostic biomarkers can reliably achieve the noninvasive detection of bladder cancer with higher sensitivity than currently available urine based assays . The effects of pharmacologic plasminogen activator inhibitor-1 inhibition in acute and chronic rejection in murine cardiac allografts . BACKGROUND : Acute rejection and graft arterial disease ( Q99259 ) in cardiac transplantation limit the long-term survival of recipients ; these processes are enhanced by inflammation and thrombus formation . P00747 activator inhibitor ( P05121 ) -1 is critical in the inflammation and thrombus formation . However , little is known about the effect of P05121 in heart transplantation . Thus , the objective was to clarify the role of P05121 in the progression of cardiac rejection . METHODS : Murine hearts were heterotopically transplanted using major mismatch combinations for evaluation of acute rejection and class II mismatch combinations for the Q99259 . We administered the specific P05121 inhibitor ( IMD-1622 ) into murine recipients after cardiac allografts . RESULTS : Nontreated allografts of the major mismatch group were acutely rejected , whereas the P05121 inhibitor prolonged their survival . Although severe cell infiltration and intimal thickening with enhancement of inflammatory factors were observed in untreated allografts of class II mismatch group on day 60 , the P05121 inhibitor attenuated these changes . CONCLUSION : The P05121 inhibitor is potent for the suppression of both acute rejection and Q99259 . Candidate genetic markers and the risk of restenosis after coronary angioplasty . The aim of the present study was to test for possible associations between candidate gene polymorphisms and the risk of restenosis and recurrent restenosis after percutaneous transluminal coronary angioplasty ( PTCA ) without stenting . We followed up 511 PTCA patients , and restenosis and recurrent restenosis were defined according to angiographical criteria . Genotyping of the beta-fibrinogen -455 G/A , glycoprotein ( GP ) IIIa PlA1/PlA2 , plasminogen activator inhibitor-1 ( P05121 ) 4G/5G , factor V Leiden 1691 G/A , tumour necrosis factor alpha ( TNFalpha ) -238 G/A , TNFalpha -308 G/A , interleukin ( IL ) -1alpha -889 C/T , IL-1beta -511 C/T , methylenetetrahydrofolate reductase ( P42898 ) 677 C/T and endothelial nitric oxide synthase ( P29474 ) 4 b/a gene polymorphisms was performed by PCR and restriction-fragment-length-polymorphism-based techniques . One hundred and sixty patients ( 31.3 % ) developed restenosis and in 130 of these patients , of whom 123 were available for analysis , a second PTCA without stenting was performed . Of these patients , 35 ( 28.5 % ) developed recurrent restenosis . None of the investigated genotypes were associated with the risk of restenosis or recurrent restenosis after PTCA . The degree of stenosis before and immediately after PTCA and the severity of the lesion were independent predictors for restenosis after PTCA . In conclusion , there was no association between the beta-fibrinogen -455 G/A , GP IIIa PlA1/A2 , P05121 4G/5G , factor V Leiden 1691 G/A , TNFalpha -238 G/A , TNFalpha -308 G/A , IL-1alpha -889 C/T , the IL-1beta -511 C/T , P42898 677 C/T and P29474 4 b/a gene polymorphisms and the risk of restenosis after PTCA as well as recurrent restenosis after repeated PTCA . Overexpression of SnoN/SkiL , amplified at the 3q26.2 locus , in ovarian cancers : a role in ovarian pathogenesis . High-resolution array comparative genomic hybridization of 235 serous epithelial ovarian cancers demonstrated a regional increase at 3q26.2 encompassing SnoN/SkiL , a coregulator of SMAD/TGFbeta signaling . SnoN RNA transcripts were elevated in approximately 80 % of advanced stage serous epithelial ovarian cancers . In both immortalized normal ( TIOSE ) and ovarian carcinoma cell lines ( OVCA ) , SnoN RNA levels were increased by TGFbeta stimulation and altered by LY294002 and JNK II inhibitor treatment suggesting that the PI3K and JNK signaling pathways may regulate TGFbeta-induced increases in SnoN RNA . In TIOSE , SnoN protein levels were reduced 15min post TGFbeta-stimulation , likely by proteosome-mediated degradation . In contrast , in OVCA , SnoN levels were elevated 3h post-stimulation potentially as a result of inhibition of the proteosome . To elucidate the role of SnoN in ovarian tumorigenesis , we explored the effects of both increasing and decreasing SnoN levels . In both TIOSE and OVCA , SnoN siRNA decreased cell growth between 20 and 50 % concurrent with increased P38936 levels . In TIOSE , transient expression of SnoN repressed TGFbeta induction of P05121 promoters with little effect on the P38936 promoter or resultant cell growth . In contrast to the effects of transient expression , stable expression of SnoN in TIOSE led to growth arrest through induction of senescence . Collectively , these results implicate SnoN levels in multiple roles during ovarian carcinogenesis : promoting cellular proliferation in ovarian cancer cells and as a positive mediator of cell cycle arrest and senescence in non-transformed ovarian epithelial cells .