interacts_with DB08864?
Effects of systemic injections of vilazodone , a selective serotonin reuptake inhibitor and serotonin 1A receptor agonist , on anxiety induced by predator stress in rats . We examined the effect of DB06684 , a selective serotonin reuptake inhibitor ( SSRI ) and serotonin 1A ( 5-HT(1A) ) receptor agonist [ Bartoszyk , G.D. , Hegenbart , R. , Ziegler , H. , 1997. P50402 68843 , a serotonin reuptake inhibitor with selective presynaptic P08908 receptor agonistic properties. Eur. J. Pharmacol. 322 , 147-153. ] , on change in affect following predator stress . DB06684 and vehicle injection ( intraperitoneal ) occurred either 10 min after predator stress ( prophylactic testing ) , or 90 min prior to behavioral testing for the effects of predator stress ( therapeutic testing ) . Predator stress involved unprotected exposure of rats to a domestic cat . Behavioral effects of stress were evaluated with hole board , plus-maze , and acoustic startle tests 1 week after stress . Predator stress increased anxiety-like behavior in the plus-maze and elevated response to acoustic startle . In prophylactic testing , DB06684 affected stress potentiation of startle at doses above 5 mg/kg . DB06684 increased stress elevation of startle at 10 mg/kg . Higher doses of DB06684 ( 20 and 40 mg/kg ) blocked stress potentiation of startle . In contrast , DB06684 had no effect on stress potentiation of anxiety in the plus-maze . In therapeutic testing , DB06684 increased stress elevation of startle at all doses . In contrast , therapeutic DB06684 had no effect on stress potentiation of anxiety in the plus-maze . Taken together , the data suggest a prophylactic potential for DB06684 in the treatment of changes in hypervigilance following severe stress . P00734 in normal human cerebrospinal fluid originates from the blood . In spite of the fact that prothrombin is produced by cells within the central nervous system , its presence in the cerebrospinal fluid ( P04141 ) has not been investigated . We determined the concentration of prothrombin in P04141 with reference to the concentration in plasma in paired samples from 18 " normal " control patients and 4 patients with relapsing-remitting type of multiple sclerosis ( MS ) . The newly developed ELISA was very specific ( no cross-reactivity with thrombin ) and sensitive ( detection limit -- 0.7 ng/ml ) with an imprecision of CV = 8.3 % ( intraseries ) and 7.0 % ( interassay ) . The mean prothrombin concentration in normal P04141 was 0.55 mg/l ( CV +/- 33 % , range : 0.28-0.93 mg/l ) , in normal plasma 121.8 mg/l +/- 21 % , resulting in a mean P04141 /plasma concentration quotient ( Q(Proth) -- 4.5 x 10(-3) ( CV +/- 35 % , range : 2.1-8.3 x 10(-3) ) corresponding to a mean albumin quotient in this group of subjects of Q(Alb) = 5.8 x 10(-3) . Due to the Q(Proth) and the molecular weight of prothrombin ( 72 kDa ) -- similar to that of albumin -- we conclude that prothrombin in normal human P04141 originates predominantly ( > 95 % ) from blood . The enzymatic activity in P04141 is conserved . Comparable results obtained in MS patients with only few small Q9BWK5 lesions suggest that local chronic inflammatory disease of the central nervous system does not influence prothrombin concentration in the P04141 if the blood- P04141 barrier function is normal . Matrix metalloproteinases are differentially expressed in adipose tissue during obesity and modulate adipocyte differentiation . Matrix metalloproteinases ( MMPs ) are essential for proper extracellular matrix remodeling , a process that takes place during obesity-mediated adipose tissue formation . Here , we examine expression profiles and the potential role of MMPs and their tissue inhibitors ( TIMPs ) in adipose tissue remodeling during obesity . Expression patterns are studied by Northern blot and real-time PCR in two genetic models of obesity ( ob/ob and db/db mice ) and in a diet-induced model of obesity ( AKR mice ) . Of the MMPs and TIMPs studied , mRNA levels for P08253 , P08254 , P39900 , P50281 , Q99542 , and P01033 are strongly induced in obese adipose tissues compared with lean tissues . In contrast , P09237 and P35625 mRNAs are markedly decreased in obesity . Interestingly , enzymatic activities of P39900 and of a new identified adipocyte-derived 30-kDa metalloproteinase are enhanced in obese adipose tissue fractions , demonstrating that MMP/ P01033 balance is shifted toward increased matrix degradation in obesity . Finally , we analyze the modulation of P08253 , Q99542 , and P01033 during 3T3- Q9NUQ9 preadipocyte differentiation , and we explore the effect of inhibition of MMP activity on in vitro adipogenesis . We find that the synthetic MMP inhibitor BB-94 ( DB03880 ) decreases adipose conversion of 3T3- Q9NUQ9 and primary rat preadipocytes . BB-94 represses differentiation without affecting mitotic clonal expansion but prevents the early expression of P17676 , a transcription factor that is thought to play a major role in the adipogenic program . Such findings support a role for the MMP/ P01033 system in the control of proteolytic events and adipogenesis during obesity-mediated fat mass development . Serotonergic mechanisms in human allergic contact dermatitis . Expression of serotonin ( 5-hydroxytryptamine ; 5-HT ) , 5-HT receptors 1A ( 5-HT1AR ) and 2A , and serotonin transporter protein ( P31645 ) was studied in positive epicutaneous reactions to nickel sulphate in nickel-allergic patients , at 72 h post-challenge with the antigen . In addition , the effects of 5-HT2AR agonist 2,5-dimethoxy-4-iodoamphetamine ( DOI ) , and the selective serotonin reuptake inhibitors ( SSRIs ) citalopram and fluoxetine , were tested on nickel-stimulated peripheral blood mononuclear cells from nickel-allergic patients , regarding their proliferation and interleukin ( IL ) -2 production , as well as the effect of these SSRIs on a murine Langerhans ' cell-like line ( XS52 ) , regarding its IL-1beta production . Serotonin-positive platelets were increased in the inflamed skin compared with control skin . A decrease ( p < 0.01 ) in 5-HT1AR-positive mononuclear cells was evident in the eczematous skin compared with control skin , whereas 5-HT2AR- and P31645 -positive cells were increased ( p < 0.001 for both ) in the eczematous skin . Treatment of nickel-stimulated peripheral blood mononuclear cells with 5x10(-5) mol/l of DOI inhibited ( p < 0.01 ) the proliferation of nickel-stimulated peripheral blood mononuclear cells , while no effect was found regarding P60568 production . DB00215 at 10(-6) mol/l tended to inhibit the production of IL-1beta by the XS52 cell line . These results indicate the implication of the serotonergic system in the contact allergic reaction . P10275 is the key transcriptional mediator of the tumor suppressor O43791 in prostate cancer . Somatic missense mutations in the substrate-binding pocket of the E3 ubiquitin ligase adaptor O43791 are present in up to 15 % of human prostate adenocarcinomas , but are rare in other malignancies , suggesting a prostate-specific mechanism of action . O43791 promotes ubiquitination and degradation of several protein substrates , including the androgen receptor ( AR ) coactivator Q9Y6Q9 . However , the relative contributions that O43791 substrates may make to the pathophysiology of O43791 -mutant ( mt ) prostate adenocarcinomas are unknown . Using an unbiased bioinformatics approach , we determined that the gene expression profile of prostate adenocarcinoma cells engineered to express mt- O43791 overlaps greatly with the gene signature of both Q9Y6Q9 and AR transcriptional output , with a stronger similarity to AR than Q9Y6Q9 . This finding suggests that in addition to its Q9Y6Q9 -mediated effects , O43791 also exerts Q9Y6Q9 -independent effects that are AR-mediated . Indeed , we found that wild-type ( wt ) but not prostate adenocarcinoma-associated mutants of O43791 promoted AR ubiquitination and degradation , acting directly through a O43791 -binding motif in the hinge region of AR . In support of these results , tumor xenografts composed of prostate adenocarcinoma cells expressing mt- O43791 exhibited higher AR protein levels and grew faster than tumors composed of prostate adenocarcinoma cells expressing wt- O43791 . Furthermore , genetic ablation of O43791 was sufficient to increase AR protein levels in mouse prostate . Examination of public human prostate adenocarcinoma datasets confirmed a strong link between transcriptomic profiles of mt- O43791 and AR . Overall , our studies highlight the AR axis as the key transcriptional output of O43791 in prostate adenocarcinoma and provide an explanation for the prostate-specific tumor suppressor role of wt- O43791 . Microenvironmental regulation of membrane type 1 matrix metalloproteinase activity in ovarian carcinoma cells via collagen-induced P18146 expression . Late stage ovarian cancer is characterized by disseminated intraperitoneal metastasis as secondary lesions anchor in the type I and III collagen-rich submesothelial matrix . Ovarian carcinoma cells preferentially adhere to interstitial collagen , and collagen-induced integrin clustering up-regulates the expression of the transmembrane collagenase membrane type 1 matrix metalloproteinase ( P50281 ) . Collagenolytic activity is important in intraperitoneal metastasis , potentiating invasion through the mesothelial cell layer and colonization of the submesothelial collagen-rich matrix . The objective of this study was to elucidate a potential mechanistic link between collagen adhesion and P50281 expression . Our results indicate that culturing cells on three-dimensional collagen gels , but not thin layer collagen or synthetic three-dimensional hydrogels , results in rapid induction of the transcription factor P18146 . Integrin signaling through a P12931 kinase-dependent pathway is necessary for P18146 induction . Silencing of P18146 expression using small interfering RNA abrogated collagen-induced P50281 expression and inhibited cellular invasion of three-dimensional collagen gels . These data support a model for intraperitoneal metastasis wherein collagen adhesion and clustering of collagen binding integrins activates integrin-mediated signaling via P12931 kinases to induce expression of P18146 , resulting in transcriptional activation of the P50281 promoter and subsequent P50281 -catalyzed collagen invasion . This model highlights the role of unique interactions between ovarian carcinoma cells and interstitial collagens in the ovarian tumor microenvironment in inducing gene expression changes that potentiate intraperitoneal metastatic progression . Astaxanthin functions differently as a selective peroxisome proliferator-activated receptor γ modulator in adipocytes and macrophages . Astaxanthin ( ASX ) , an oxygenated carotenoid ( xanthophyll ) , has previously been shown to exert ameliorative effects on obesity and insulin resistance , but the underlying mechanisms were not clearly elucidated . In the present study , we investigated whether ASX serves as a novel selective peroxisome proliferator-activated receptor ( Q07869 ) γ modulator . Analyses of PPARγ binding by DB01992 -BAP assays revealed that ASX bound to PPARγ in a dose-dependent manner . However , ASX was unable to activate transcription in PPARγ reporter assays , although it antagonized transcriptional activation by the PPARγ agonist rosiglitazone ( RGZ ) . When the molecular interactions between PPARγ and three coactivators were examined , ASX increased the interactions of PPARγ with transcriptional intermediary factor 2 ( Q15596 ) and steroid receptor coactivator-1 ( Q15788 ) , but not DB02527 responsive element-binding protein ( CREB ) -binding protein ( CBP ) . In addition , ASX effectively blocked the increase in CBP recruitment to PPARγ mediated by RGZ . ASX alone did not stimulate 3T3- Q9NUQ9 cell differentiation , although it antagonized 3T3- Q9NUQ9 cell differentiation and lipid accumulation induced by RGZ , similar to the PPARγ antagonist GW9662 . When the effects of cotreatment of 3T3- Q9NUQ9 cells with ASX and RGZ were determined based on the mRNA levels of PPARγ target genes , ASX effectively reduced the mRNA levels of aP2 and lipoprotein lipase , but not P16671 . Intriguingly , ASX was capable of inducing PPARγ target genes such as liver X receptor , P16671 and O95477 in thioglycollate-elicited peritoneal macrophages . Collectively , the present findings indicate that ASX is a novel selective PPARγ modulator that acts as an antagonist or agonist depending on the cell context . P22681 mutation-related patterns of phosphorylation and sensitivity to tyrosine kinase inhibitors . Recurrent homozygous P22681 -inactivating mutations in myeloid malignancies decrease ubiquitin ligase activity that inactivates P12931 family kinases ( SFK ) and receptor tyrosine kinases ( RTK ) . However , the most important SFK and RTK affected by these mutations , and hence , the most important therapeutic targets , have not been clearly characterized . We compared SFK and RTK pathway activity and inhibitors in acute myeloid leukemia cell lines containing homozygous R420Q mutation ( GDM-1 ) , heterozygous deletion ( MOLM13 ) and wild-type ( WT ) P22681 ( THP1 , U937 ) . As expected with P22681 loss , GDM-1 displayed high P10721 expression and granulocyte-macrophage colony-stimulating factor ( GM- P04141 ) hypersensitivity . Ectopic expression of WT P22681 decreased GDM-1 proliferation but not cell lines with WT P22681 . GDM-1 , but not the other cell lines , was highly sensitive to growth inhibition by dasatinib ( dual SFK and RTK inhibitor , LD50 50 nM ) ; there was less or no selective inhibition of GDM-1 growth by sunitinib ( RTK inhibitor ) , imatinib ( P00519 , P10721 inhibitor ) , or Q99463 ( SFK inhibitor ) . Phosphoprotein analysis identified phosphorylation targets uniquely inhibited by dasatinib treatment of GDM-1 , including a number of proteins in the P10721 and GM- P04141 receptor pathways ( for example , P10721 Tyr721 , P40763 Tyr705 ) . In conclusion , the promiscuous effects of P22681 loss on SFK and RTK signaling appear to be best targeted by dual SFK and RTK inhibition . DB09341 -6-phosphate dehydrogenase and Q9NPH5 control P40763 activity in melanoma cells through a pathway involving reactive oxygen species , c- P12931 and SHP2 . BACKGROUND : DB09341 -6-phosphate dehydrogenase ( P11413 ) participates in glucose utilization by catalysing the first step of the pentose-phosphate pathway in mammalian cells . Previous studies have shown that changes in P11413 levels can promote tumor cell proliferation or apoptosis via the P40763 /5 pathway in a human melanoma xenograft model . P11413 cooperates with Q9NPH5 ( Q9NPH5 ) in the cellular metabolism of reactive oxygen species ( ROS ) and in maintaining the intracellular redox state . METHODS : In this study , the effect of P11413 or Q9NPH5 silencing in the melanoma line A375 was examined in terms of redox state , proto-oncogene tyrosine-protein kinase Src ( c-Src ) and the tyrosine-specific protein phosphatase SHP2 expression as well as cell cycle progression . RESULTS : The results demonstrate that : ( 1 ) Downregulation of cyclin D1 and P11802 and up-regulation of p53 and P38936 occurred in response to silencing of P11413 and Q9NPH5 thus resulting in P55008 /S cell cycle arrest and inhibition of A375 cell proliferation . ( 2 ) The blockade of cell proliferation is primarily due to a reduced DNA-binding activity of P40763 . ( 3 ) The DNA-binding activity of P40763 was regulated by the upstream factors , c- P12931 and SHP2 . Silencing of Q9NPH5 in A375 cells inhibited c- P12931 and SHP2 regulated P40763 activity . CONCLUSION : The data are consistent with a novel P11413 - Q9NPH5 -NADPH-ROS-c- P12931 /SHP2 pathway controlling P40763 activity in A375 melanoma cells . Sex steroid receptors , secondary bile acids and colorectal cancer . A possible mechanism of interaction . AIM : The aim of the work was to study in colon-rectum cancer mucosae the binding charateristics , as sex steroid receptors . METHODS : Specific androgen ( AR ) , estrogen ( ER ) and progesterone ( PgR ) receptors were measured in the tissue samples of 35 patients ( 15 males , 20 females ) undergoing colectomy or coloproctectomy for adenocarcinoma . The characteristics of androgen receptor ( AR , DB02901 -R : dihydrotestosterone receptor ) were also investigated using competitive activity of cyproterone acetate , cortisol , aldosterone and steroid-like substances such as deoxycholic and lithocholic acid , present in the milieu of the considered organ . Binding assays and competition tests were conducted using a charcoal dextran method . RESULTS : When present ( 50 % ) , ER and PgR receptors showed very low levels and no difference was noted between cancerous and the surrounding healthy mucosa . AR were found in all samples from both neoplastic and non neoplastic surrounding mucosa , with no significant difference . P10275 however exhibited an altered binding activity in cancer specimens . DB04839 did not displace DB02901 from AR while significant displacing activity was elicited by DB02901 , testosterone , as well as by lithocholic acid , but not by deoxycholic acid . CONCLUSION : In cancerous large bowel mucosa , androgen receptors show altered binding characteristics . The selective binding of lithocholic acid to AR supports the hypothesis that diet-related endoluminal substances may play a role in cancer development model where molecular alterations such as DNA damage or mutation is the 1st event . The T11(3) epitope of the P06729 molecule , sheep erythrocytes , and the alternative T-cell activation pathway . In this study , results are presented showing that the T11(3) epitope of the P06729 molecule is expressed on unfractionated peripheral blood mononuclear cells , resting T cells and activated T cells . T11(3) is not therefore , an activation-specific P06729 epitope . Sheep erythrocytes ( P12931 ) which present a cell-surface ligand for P06729 could not effectively replace anti-T11(2) in initiating proliferation of resting T cells , stimulated by anti-T11(3) . P12931 with either of these anti- P06729 monoclonal antibodies did activate resting T cells , but proliferation required the presence of added P60568 . Agonism of human pregnane X receptor by rilpivirine and etravirine : comparison with first generation non-nucleoside reverse transcriptase inhibitors . DB08864 and etravirine are second generation non-nucleoside reverse transcriptase inhibitors approved recently by the United States Food and Drug Administration for the treatment of human immunodeficiency virus-1 infection . O75469 ( O75469 ) is a member of the superfamily of nuclear receptors that regulate the expression of various genes controlling diverse biological functions . The present study investigated the effects of rilpivirine and etravirine on the activity of human O75469 ( hPXR ) , including the mode of activation , and compared them to those of efavirenz , nevirapine , and delavirdine , which are first generation non-nucleoside reverse transcriptase inhibitors . In transiently transfected HepG2 cells , rilpivirine , etravirine , and efavirenz , but not nevirapine or delavirdine , activated human , mouse , and rat O75469 . Results from mechanistic studies indicated that rilpivirine , etravirine , and efavirenz , but not nevirapine or delavirdine , bound to the ligand-binding domain of hPXR , as assessed by a transactivation assay and by a competitive ligand-binding assay using time-resolved fluorescence resonance energy transfer ; triggered nuclear translocation of a green fluorescence protein-tagged hPXR , as visualized by confocal imaging ; and recruited steroid receptor coactivator-1 ( Q15788 ) , P12931 -2 , and Q9Y6Q9 to hPXR , as demonstrated by mammalian two-hybrid assays . DB08864 , etravirine , and efavirenz , but not nevirapine or delavirdine , increased hPXR target gene ( P08684 ) expression in primary cultures of human hepatocytes . In summary , select non-nucleoside reverse transcriptase inhibitors activated human and rodent O75469 . DB08864 , etravirine , and efavirenz , but not nevirapine or delavirdine , were identified as agonists of hPXR , as assessed in mechanistic experiments , and inducers of P08684 , as determined in primary cultures of human hepatocytes . Neural cell adhesion molecules modulate tyrosine phosphorylation of tubulin in nerve growth cone membranes . Triggering neural cell adhesion molecules of the immunoglobulin superfamily with specific ligands or antibodies inhibited the phosphorylation of tryosyl residues in a subpopulation of alpha- and beta-tubulin associated with membranes from a subcellular fraction of nerve growth cones from fetal rat brain . Preincubation of these membranes with purified extracellular fragments of Q9NUQ9 , N- P62158 , or myelin-associated glycoprotein , or with antibodies directed against the extracellular domains of Q9NUQ9 or N- P62158 , inhibited P12931 -dependent phosphorylation of tubulin in an endogenous membrane kinase reaction . Other proteins that affect neurite outgrowth ( fibronectin , laminin , antibodies against P19022 ) had no effect . The results suggest that cell adhesion molecules transduce cell surface events to intracellular signals by modulating the activity of protein tyrosine kinases or phosphatases in axonal membranes to influence cytoskeletal dynamics at the growth cone . Stage-dependent inhibition of Plasmodium falciparum by potent Ca2+ and calmodulin modulators . The effects of Ca2+ channel blockers , verapamil , nicardipine and diltiazem , and of potent calmodulin ( P62158 ) inhibitors , trifluoperazine ( Q9HCM9 ) , calmidazolium , W-7 and W-5 , on Plasmodium falciparum in culture were examined . Among Ca2+ blockers , nicardipine was the most potent with the 50 % inhibitory concentration ( IC50 ) of 4.3 microM at 72 h after culture . Parasites were more sensitive to calmidazolium and W-7 with IC50 of 3.4 and 4.5 microM , respectively , than to Q9HCM9 and W-5 . All Ca2+ blockers and P62158 inhibitors suppressed parasite development at later stages . DB00622 , diltiazem , calmidazolium and W-5 also retarded parasite development at earlier stages and/or subsequent growth following pretreatment . Verapamil , nicardipine , Q9HCM9 and calmidazolium reduced erythrocyte invasion by merozoites . Fluorescence microscopy with the cationic fluorescent dye rhodamine 123 revealed that nicardipine , Q9HCM9 and calmidazolium depolarized both the plasma membrane and mitochondrial membrane potentials of the parasite . It is therefore considered that although all Ca2+ and P62158 antagonists tested here influence parasite development at later stages , they are multifunctional , having effects not directly associated with Ca2+ channels or P62158 . p300 mediates functional synergism between P38484 and AF-2 of estrogen receptor alpha and beta by interacting directly with the N-terminal A/B domains . P03372 ( ER ) alpha and beta mediate estrogen actions in target cells through transcriptional control of target gene expression . For 17beta-estradiol-induced transactivation , the N-terminal A/B domain ( P38484 ) and the C-terminal E/F domain ( AF-2 ) of ERs are required . Ligand binding is considered to induce functional synergism between P38484 and AF-2 , but the molecular mechanism remains unknown . To clarify this synergism , we studied the role of reported AF-2 coactivators , p300/CREB binding protein , steroid receptor coactivator-1/transcriptional intermediary factor-2 ( Q15788 / Q15596 ) family proteins and thyroid hormone receptor-associated protein-220/ ( vitamin D3 receptor-interacting protein- 205-( Q15648 / Q15648 ) on the P38484 activity in terms of synergism with the AF-2 function . We found that neither any of the Q15788 / Q15596 family coactivators nor Q15648 / Q15648 is potent , whereas p300 potentiates the P38484 function of both human ERalpha and human ERbeta . Direct interactions of p300 with the A/B domains of ERalpha and ERbeta were observed in an in vitro glutathione S-transferase pull-down assay in accordance with the interactions in yeast and mammalian two-hybrid assays . Furthermore , mutations in the p300 binding sites ( 56-72 amino acids in ERalpha and 62-72 amino acids in ERbeta ) in the A/B domains caused a reduction in ligand-induced transactivation functions of both ERalpha and ERbeta . Thus , these findings indicate that ligand-induced functional synergism between P38484 and AF-2 is mediated through p300 by its direct binding to the A/B regions of ERalpha and ERbeta . Effects of peroxisome proliferator-activated receptor ligands , bezafibrate and fenofibrate , on adiponectin level . OBJECTIVE : Q15848 is adipose-specific secretory protein and acts as anti-diabetic and anti-atherosclerotic molecule . We previously found peroxisome proliferators response element in adiponectin promoter region , suggesting that peroxisome proliferator-activated receptor ( Q07869 ) ligands elevate adiponectin . Fibrates are known to be PPARalpha ligands and were shown to reduce risks of diabetes and cardiovascular disease . Effect of fibrates on adiponectin has not been clarified , whereas thiazolidinediones enhance adiponectin . Thus , we explored the possibility and mechanism that fibrates enhance adiponectin in humans , mice , and cells . METHODS AND RESULTS : Significant increase of serum adiponectin was observed in bezafibrate-treated subjects compared with placebo group in patients enrolled in The DB01393 Infarction Prevention study . Higher baseline adiponectin levels were strongly associated with reduced risk of new diabetes . Fibrates , bezafibrate and fenofibrate , significantly elevated adiponectin levels in wild-type mice and 3T3- Q9NUQ9 adipocytes . Such an effect was not observed in PPARalpha-deficient mice and adipocytes . Fibrates activated adiponectin promoter but failed to enhance its activity when the point mutation occurred in peroxisome proliferators response element site and the endogenous PPARalpha was knocked down by PPARalpha-RNAi . CONCLUSIONS : Our results suggest that fibrates enhance adiponectin partly through adipose PPARalpha and measurement of adiponectin might be a useful tool for searching subjects at high risk for diabetes . Cytoplasmic and nuclear estrogen binding capacity in the rat uterus during treatment with danazol and testosterone . DB01406 , testosterone and dihydrotestosterone ( DB02901 ) were tested as competitors for estrogen receptors on immature rat uterus cytosol . No competitive binding could be demonstrated for any of these steroids . After that , prepubertal Wistar rats were exposed to danazol , testosterone or propylene glycol ( control ) for 3 days or 17 days . After the appropriate exposure to medication , the animals were killed . Both danazol and testosterone appeared to be uterotropic after 3 days of treatment , although the increase in the uterine weight was significant only in the danazol-treated group ( p less than 0.05 ) . This effect was lost after 17 days of treatment . P03372 binding assays were done on the cytosolic and nuclear fractions of the homogenized uterine tissue of each group . The estrogen binding capacity of cytosols was increased in both the danazol ( p less than 0.05 ) and the testosterone ( p less than 0.01 ) groups after 3 days of treatment . A parallel increase was found in the nuclear fraction of both groups . After 17 days of treatment , the comparison between the 3 groups showed no differences in the cytosolic or nuclear estrogen binding capacity . The information provided by this study suggests that some effects of danazol may be due to an androgenic action and that may be associated to increases in the free fraction of testosterone . DB00278 -coupled Affi-Gel matrix for the purification of thrombin from plasma . Sometimes it is necessary to obtain thrombin from limited amounts of human plasma for laboratory assay . None of the available purification methods easily deals with this subject . The procedure described in the present paper uses a readily available pharmaceutical agent , argatroban , to construct an affinity matrix . DB00278 has a high affinity for thrombin and its thrombin binding is reversible . P00734 derived from a Ba(2+) precipitate of human plasma is used as the starting material . The crude prothrombin can be bulk activated to thrombin using taipan-snake ( Oxyuranus scutellatus ) venom and bound to the argatroban-coupled matrix without further processing steps . The thrombin product eluted from the argatroban matrix is very pure as judged by high specific activity and by electrophoresis . This purification scheme is rapid , yielding purified thrombin within 2 days . A novel 5-HT1-like receptor subtype mediates DB02527 synthesis in porcine pial vein . The 5-hydroxytryptamine ( 5-HT ) receptor subtype mediating 5-HT inhibition of spontaneous rhythmic contractions ( P12931 ) in the porcine pial vein was characterized . Results from pharmacological studies using in vitro tissue bath techniques indicated that the inhibitory effects of 5-HT on P12931 were qualitatively and quantitatively mimicked by 5-HT1-like agonists 5-methoxytryptamine ( 5-MT ) and 5-carboxamidotryptamine ( 5-CT ) . 5-HT- , 5-MT- , and 5-CT-induced inhibitions of P12931 were attenuated in a concentration-dependent manner by methysergide , which yielded similar pA2 values against these three agonists , suggesting that 5-HT , 5-MT , and 5-CT act on the same 5-HT1-like receptors . 5-MT inhibition of P12931 was not affected by blocking 5-HT2 ( with ketanserin and spiperone ) , 5- Q9H205 ( with MDL-72222 and ICS-205-930 ) , or Q13639 ( with ICS-205-930 ) receptors . Neither was 5-MT inhibition of P12931 affected by blocking P08908 ( with propranolol and spiperone ) , P28222 ( with propranolol ) , or P28335 ( with ketanserin ) receptors . Furthermore , 5-HT and 5-MT inhibitions of P12931 were enhanced by cilostazol [ a selective adenosine 3',5'-cyclic monophosphate ( DB02527 ) phosphodiesterase inhibitor ] and were diminished by KT-5720 ( a DB02527 -dependent protein kinase inhibitor ) but were not affected by M & B-22948 [ a selective guanosine 3',5'-cyclic monophosphate ( cGMP ) phosphodiesterase inhibitor ] or KT-5823 ( a cGMP-dependent protein kinase inhibitor ) . Biochemical studies further demonstrated that 5-HT inhibition of P12931 in porcine pial veins was accompanied by an increase in DB02527 , but not cGMP , synthesis. ( ABSTRACT TRUNCATED AT 250 WORDS ) The potential role of PD0332991 ( DB09073 ) in the treatment of multiple myeloma . INTRODUCTION : Multiple myeloma ( MM ) remains an incurable malignancy indicating a need for continued investigation of novel therapies . Recent studies have highlighted the role of cyclin-dependent kinases ( CDK ) in the pathogenesis of MM . PD0332991 ( DB09073 ) is an orally bioavailable , highly selective inhibitor of the P11802 /6-cyclin complex and downstream retinoblastoma protein ( Rb ) activation pathway that induces cell cycle arrest in the P55008 phase . AREAS COVERED : In this review , the authors summarize the role of the P11802 /6 signaling pathway in MM . They also summarize the development of PD0332991 as a specific inhibitor of P11802 /6 , and the reported preclinical and clinical data supporting the potential role of PD0332991 in MM . EXPERT OPINION : While PD0332991 is essentially cytostatic , inducing prolonged P55008 arrest , it enhances the cytotoxic effect of other agents effective in MM , including bortezomib and lenalidomide , as confirmed in early phase clinical trials . However , with a plethora of other drugs of different classes being tested in MM , further development of PD0332991 will depend on defining the most efficacious combination with least toxicity . An unexplored opportunity remains the potential protective effect of PD0332991 against lytic bone lesions of MM . The next few years are likely to better define the place of PD0332991 in the treatment of MM .