MH_dev_278

Sirtuin activators and inhibitors . Sirtuins 1-7 ( Q96EB6 - 7 ) belong to the third class of deacetylase enzymes , which are dependent on NAD ( + ) for activity . Sirtuins activity is linked to gene repression , metabolic control , apoptosis and cell survival , DNA repair , development , inflammation , neuroprotection , and healthy aging . Because sirtuins modulation could have beneficial effects on human diseases there is a growing interest in the discovery of small molecules modifying their activities . We review here those compounds known to activate or inhibit sirtuins , discussing the data that support the use of sirtuin-based therapies . Almost all sirtuin activators have been described only for Q96EB6 . DB02709 is a natural compound which activates Q96EB6 , and may help in the treatment or prevention of obesity , and in preventing tumorigenesis and the aging-related decline in heart function and neuronal loss . Due to its poor bioavailability , reformulated versions of resveratrol with improved bioavailability have been developed ( resVida , Longevinex ( ® ) , DB05073 MEN ) . Molecules that are structurally unrelated to resveratrol ( SRT 1720 , SRT 2104 , SRT 2379 , among others ) have been also developed to stimulate sirtuin activities more potently than resveratrol . Sirtuin inhibitors with a wide range of core structures have been identified for Q96EB6 , Q8IXJ6 , Q9NTG7 and Q9NXA8 ( splitomicin , sirtinol , AGK 2 , cambinol , suramin , tenovin , salermide , among others ) . Q96EB6 inhibition has been proposed in the treatment of cancer , immunodeficiency virus infections , Fragile X mental retardation syndrome and for preventing or treating parasitic diseases , whereas Q8IXJ6 inhibitors might be useful for the treatment of cancer and neurodegenerative diseases .

DB00140 MEN ( vitamin B2 ) deficiency impairs P04839 REA ( Nox 2 ) priming and defense against Listeria monocytogenes . DB00140 MEN , also known as vitamin B2 , is converted by riboflavin kinase ( Q969G6 REA ) into flavin mononucleotide ( Q68DA7 ) and flavin adenine dinucleotide ( DB03147 ) , which are essential cofactors of dehydrogenases , reductases , and oxidases including the phagocytic P04839 REA ( Nox 2 ) . DB00140 MEN deficiency is common in young adults and elderly individuals , who are at the coincidental risk for listeriosis . To address the impact of acute riboflavin deficiency on host defense against Listeria monocytogenes ( L . m . ) , we generated conditional Q969G6 REA knockout ( KO ) strains of mice . Phagocyte-specific Q969G6 REA KO impaired the capability of phagocytes to control intracellular L . m . , which corresponded to a greater susceptibility of mice to in vivo challenge with L . m . The oxidative burst of Q969G6 REA - deficient phagocytes in response to L . m . infection was significantly reduced . Mechanistically , P01375 REA - induced priming of Nox 2 , which is needed for oxidative burst , was defective in Q969G6 REA - deficient phagocytes . Lack of riboflavin in wild-type macrophages for only 6 h shut down P01375 REA - induced , Q969G6 REA - mediated de novo Q68DA7 / DB03147 generation , which was accompanied by diminished ROS production and impaired anti-listerial activity . Vice versa , ROS production by riboflavin-deprived macrophages was rapidly restored by riboflavin supplementation . Our results suggest that acute riboflavin deficiency immediately impairs priming of Nox 2 , which is of crucial relevance for an effective phagocytic immune response in vivo .

' VASPFix ' for measurement of P50552 REA phosphorylation in platelets and for monitoring effects of Q9H244 REA antagonists . P50552 REA ( P50552 REA ) is phosphorylated and dephosphorylated consequent to increases and decreases in cyclic nucleotide levels . Monitoring changes in P50552 REA phosphorylation is an established method for indirect measurement of cyclic nucleotides . Here we describe the use of an innovative cocktail , VASPFix , which allows sensitive and reproducible measurement of phosphorylated P50552 REA ( P50552 REA - P ) in a simple , single-step procedure using cytometric bead technology . Frozen VASPFix-treated samples are stable for at least six months prior to analysis . We successfully used VASPFix to measure P50552 REA - P in platelets in both platelet-rich plasma and blood in response to compounds that increase ( dibutyryl DB02527 , adenosine , iloprost , PGE 1 ) and decrease ( ADP , PGE 1 ) DB02527 , and to determine the effects of certain receptor antagonists on the results obtained . The change in P50552 REA - P brought about by adding ADP to PGE 1 - stimulated platelets is a combination of the effect of ADP at the Q9H244 REA receptor and of PGE 1 at both IP and EP3 receptors . For iloprost-stimulated platelets EP3 receptors are not involved . A procedure in which iloprost , ADP and VASPFix were used to determine effectiveness of clopidogrel and prasugrel in patients was compared with an established commercial procedure that uses PGE 1 and ADP ; the latter produced higher platelet reactivity values that were the result of PGE 1 interacting with platelet EP3 receptors . We conclude that VASPFix can be used both as a research tool and for clinical investigations and provides better specificity for Q9H244 REA receptor inhibition . The latter confers a distinct advantage over existing methods used to monitor effects of Q9H244 REA antagonists on platelet function .

Targeted agents for the treatment of advanced renal cell carcinoma . Renal cell carcinoma ( RCC ) is a highly treatment-resistant tumor type ; however , advances in elucidating the molecular pathophysiology underlying RCC has led to the identification of promising targets for therapeutic intervention . In clear-cell RCC , mutations to the von Hippel-Lindau ( P40337 REA ) gene results in the up regulation of many proteins necessary for tumor growth and survival - - such as vascular endothelial growth factor ( P15692 REA ) , basic fibroblast growth factor ( P09038 REA ) and platelet derived growth factor ( PDGF ) , which are involved in tumor-initiated angiogenesis . Q16790 REA and signaling via the epidermal growth factor receptor ( P00533 REA ) are involved in tumor cell proliferation and are also up regulated by mutation in the P40337 REA gene . The intracellular messenger pathways phosphoinositide 3 - kinase ( PI3K ) and Raf / MEK / P29323 REA act as convergence points for positive growth signaling ; the Raf / MEK / P29323 REA pathway is also implicated in apoptosis . Several agents in development target P15692 REA ( bevacizumab ) , the P15692 REA receptor ( PTK 787 , SU11248 , P15692 REA - trap , and BAY 43-9006 ) , the PDGF receptor ( SU11248 and BAY 43-9006 ) , or the P01133 REA receptor ( gefitinib , cetuximab , DB01269 , and erlotinib ) . The intracellular Raf / MEK / P29323 REA signaling cascade has been targeted at either the level of Raf ( BAY 43-9006 , ISIS 5132 ) or MEK ( CI - 1040 , PD184352 and ARRY - 142886 ) , and PI3K signaling is disrupted by CCI - 779 . DB05304 MEN targets the Q16790 REA antigen , and PS - 341 disrupts the 26S proteasome mediating the degradation of intracellular proteins . Given that multiple pathways contribute to tumor growth , anti-tumor activity may be increased by agents targeting multiple pathways , or by combining agents to allow horizontal or vertical inhibition of multiple pathways .

Prasugrel : a new antiplatelet drug for the prevention and treatment of cardiovascular disease . Prasugrel , trade name DB06209 SUB , is an investigational new antiplatelet drug currently under review for clinical use by the Food and Drug Administration . It is a thienopyridine analog with a structure similar to that of clopidogrel and ticlopidine . Thienopyridine derivatives inhibit platelet aggregation induced by adenosine diphosphate by irreversibly inhibiting the binding of adenosine diphosphate to the purinergic Q9H244 REA receptor on the platelet surface . Prasugrel has been shown to be a potent antiplatelet agent with a faster , more consistent , and greater inhibition of platelet aggregation compared with clopidogrel . It is debatable , however , how effectively these pharmacologic benefits will translate to clinical benefits . The results of the large TRITON-TIMI 38 trial , which compared prasugrel and clopidogrel in patients with acute coronary syndrome who were scheduled to receive coronary stents , demonstrated a significant reduction in ischemic events , including stent thrombosis , with prasugrel , but with an increased risk of major bleeding . The exact role of prasugrel in the management of ischemic heart disease is still being defined , but the risk : benefit ratio will likely play a major role in directing the best place for therapy with this new agent .

Functional role of vasoactive intestinal polypeptide in inhibitory motor innervation in the mouse internal anal sphincter . There is evidence that vasoactive intestinal polypeptide ( P01282 REA ) participates in inhibitory neuromuscular transmission ( P30419 REA ) in the internal anal sphincter ( IAS ) . However , specific details concerning P01282 REA - ergic P30419 REA are limited , largely because of difficulties in selectively blocking other inhibitory neural pathways . The present study used the selective P47900 REA receptor antagonist MRS 2500 ( 1 μm ) and the nitric oxide synthase inhibitor N ( G ) - nitro-l-arginine ( l-NNA ; 100 μm ) to block purinergic and nitrergic P30419 REA to characterize non-purinergic , non-nitrergic ( NNNP ) inhibitory P30419 REA and the role of P01282 REA in this response . Nerves were stimulated with electrical field stimulation ( 0.1- 20 Hz , 4-60 s ) and the associated changes in contractile and electrical activity measured in non-adrenergic , non-cholinergic conditions in the IAS of wild-type and P01282 REA ( - / - ) mice . Electrical field stimulation gave rise to frequency-dependent relaxation and hyperpolarization that was blocked by tetrodotoxin . Responses during brief trains of stimuli ( 4 s ) were mediated by purinergic and nitrergic P30419 REA . During longer stimulus trains , an NNNP relaxation and hyperpolarization developed slowly and persisted for several minutes beyond the end of the stimulus train . The NNNP P30419 REA was abolished by VIP 6-28 ( 30 μm ) , absent in the P01282 REA ( - / - ) mouse and mimicked by exogenous P01282 REA ( 1-100 nm ) . Immunoreactivity for P01282 REA was co-localized with neuronal nitric oxide synthase in varicose intramuscular fibres but was not detected in the P01282 REA ( - / - ) mouse IAS . In conclusion , this study identified an ultraslow component of inhibitory P30419 REA in the IAS mediated by P01282 REA . In vivo , this pathway may be activated with larger rectal distensions , leading to a more prolonged period of anal relaxation .

DB02709 protects against peripheral deficits in a mouse model of Huntington ' s disease . Sirtuins are NAD-dependent deacetylases that regulate important biologic processes including transcription , cell survival and metabolism . Activation of Q96EB6 , a mammalian sirtuin , extends longevity and increases neuronal survival . An important substrate of Q96EB6 is peroxisome proliferator-activated receptor gamma co-activator - 1alpha ( P20142 - 1alpha ) , a principal regulator of energy metabolism , whose function is significantly impaired in Huntington ' s disease ( HD ) . We studied the effects of a pharmacological preparation of the Q96EB6 activator resveratrol ( DB05073 MEN - M ) , in the N171 - 82Q transgenic mouse model of HD . We analyzed motor performance , survival , central and peripheral pathology and levels of P20142 - 1alpha expression . Administration of DB05073 MEN - M increased expression of P20142 - 1alpha , as well as its downstream targets , nuclear respiratory factor - 1 ( Q16656 REA ) and uncoupling protein - 1 ( P25874 REA - 1 ) in brown adipose tissue ( Q14032 REA ) , but there was no effect on P20142 - 1alpha , Q16656 REA or the mitochondrial transcription factor ( Tfam ) in the striatum . DB05073 MEN - M administration also reduced Q14032 REA vacuolation and decreased elevated blood glucose levels . However , there was no significant improvement in weight loss , motor performance , survival and striatal atrophy . Activation of the P20142 - 1alpha signaling pathway via resveratrol-induced activation of Q96EB6 , therefore , is an effective therapy in Q14032 REA , but not in the central nervous system of HD transgenic mice .

DB06366 MEN ( Perjeta ) for preoperative use in P04626 REA - positive breast cancer .

The use of the VerifyNow Q9H244 REA point-of-care device to monitor platelet function across a range of Q9H244 REA inhibition levels following prasugrel and clopidogrel administration . Variability in response to antiplatelet agents has prompted the development of point-of-care ( POC ) technology . In this study , we compared the VerifyNow Q9H244 REA ( VN - Q9H244 REA ) POC device with light transmission aggregometry ( P01374 REA ) in subjects switched directly from clopidogrel to prasugrel . Healthy subjects on aspirin were administered a clopidogrel 600 mg loading dose ( LD ) followed by a 75 mg / d maintenance dose ( MD ) for 10 days . Subjects were then switched to a prasugrel 60 mg LD and then 10 mg / d MD for 10 days ( n = 16 ) , or to a prasugrel 10 mg / d MD for 11 days ( n = 19 ) . Platelet function was measured by P01374 REA and VN - Q9H244 REA at baseline and after dosing . DB00758 600 mg LD / 75 mg MD treatment led to a reduction in P2Y ( 12 ) reaction units ( PRU ) from baseline . A switch from clopidogrel MD to prasugrel 60 mg LD / 10 mg MD produced an immediate decrease in PRU , while a switch to prasugrel 10 mg MD resulted in a more gradual decline . Consistent with the reduction in PRU , device-reported percent inhibition increased during both clopidogrel and prasugrel regimens . Inhibition of platelet aggregation as measured by P01374 REA showed a very similar pattern to that found with VN - Q9H244 REA measurement , irrespective of treatment regimens . The dynamic range of VN - Q9H244 REA appeared to be narrower than that of P01374 REA . With two different thienopyridines , the VN - Q9H244 REA device , within a somewhat more limited range , reflected the overall magnitude of change in aggregation response determined by P01374 REA . The determination of the clinical utility of such POC devices will require their use in clinical outcome studies .

The cooperation between hMena overexpression and P04626 REA signalling in breast cancer . hMena and the epithelial specific isoform hMena ( 11a ) are actin cytoskeleton regulatory proteins belonging to the Ena / P50552 REA family . P01133 REA treatment of breast cancer cell lines upregulates hMena / hMena ( 11a ) expression and phosphorylates hMena ( 11a ) , suggesting cross-talk between the ErbB receptor family and hMena / hMena ( 11a ) in breast cancer . The aim of this study was to determine whether the hMena / hMena ( 11a ) overexpression cooperates with HER - 2 signalling , thereby affecting the P04626 REA mitogenic activity in breast cancer . In a cohort of breast cancer tissue samples a significant correlation among hMena , P04626 REA overexpression , the proliferation index ( high Ki67 ) , and phosphorylated MAPK and AKT was found and among the molecular subtypes the highest frequency of hMena overexpressing tumors was found in the P04626 REA subtype . From a clinical viewpoint , concomitant overexpression of P04626 REA and hMena identifies a subgroup of breast cancer patients showing the worst prognosis , indicating that hMena overexpression adds prognostic information to P04626 REA overexpressing tumors . To identify a functional link between P04626 REA and hMena , we show here that P04626 REA transfection in MCF 7 cells increased hMena / hMena ( 11a ) expression and hMena ( 11a ) phosphorylation . On the other hand , hMena / hMena ( 11a ) knock-down reduced P21860 REA , AKT and Q8TCB0 / 42 MAPK phosphorylation and inhibited the P01133 REA and Q02297 REA - dependent P04626 REA phosphorylation and cell proliferation . Of functional significance , hMena / hMena ( 11a ) knock-down reduced the mitogenic activity of P01133 REA and Q02297 REA . Collectively these data provide new insights into the relevance of hMena and hMena ( 11a ) as downstream effectors of the ErbB receptor family which may represent a novel prognostic indicator in breast cancer progression , helping to stratify patients .

Key residues at the riboflavin kinase catalytic site of the bifunctional riboflavin kinase / Q8NFF5 from Corynebacterium ammoniagenes . Many known prokaryotic organisms depend on a single bifunctional enzyme , encoded by the RibC of RibF gene and named DB03147 synthetase ( FADS ) , to convert DB00140 MEN ( RF ) , first into Q68DA7 and then into DB03147 . The reaction occurs through the sequential action of two activities present on a single polypeptide chain where the N-terminus is responsible for the DB00171 : Q8NFF5 ( FMNAT ) activity and the C-terminus for the DB00171 : riboflavin kinase ( Q969G6 REA ) activity . Sequence and structural analysis suggest that T208 , N210 and E268 at the C-terminus Q969G6 REA module of Corynebacterium ammoniagenes FADS ( CaFADS ) might be key during RF phosphorylation . The effect of site-directed mutagenesis on the Q969G6 REA activity , as well as on substrates and products binding , indicates that T208 and N210 provide the Q969G6 REA active-site geometry for binding and catalysis , while E268 might be involved in the catalytic step as catalytic base . These data additionally suggest concerted conformational changes at the Q969G6 REA module of CaFADS during its activity . Mutations at the Q969G6 REA site also modulate the binding parameters at the FMNAT active site of CaFADS , altering the catalytic efficiency in the transformation of Q68DA7 into DB03147 . This observation supports the hypothesis that the hexameric assembly previously revealed by the crystal structure of CaFADS might play a functional role during catalysis .

P30968 REA and peritoneal plasmin activity . Most surgical procedures performed by obstetrician-gynecologists are associated with pelvic adhesions that cause subsequent serious sequelae , including small bowel obstruction , infertility , chronic pelvic pain , and difficulty in postoperative treatment , including complexity during subsequent surgical procedures . This study was conducted to determine if gonadotropin-releasing hormone analogues ( GnRHa ) affect the expressing tissue-type plasminogen activator ( t-PA ) and its inhibitor - 1 ( P05121 REA ) in peritoneal cells in culture . Human peritoneal Met 5A cells were used to examine the effects of GnRHa leuprolide , buserelin and goserelin on the levels of t-PA and PA - 1 . Antigen concentrations were measured in conditioned media and cell lysates by real-time PCR and ELISA . P30968 REA ( GnRHR ) mRNA was determined by RT-PCR . GnRHR mRNA was detected in Met 5A cells . Exposure of Met 5A cells to GnRHa induced a rapid decrease of P05121 REA level in cultured medium but not in cell lysate ( protein and mRNA ) . These effects of GnRHa on P05121 REA were not associated with any changes in t-PA level . These results suggest that GnRHa may be an effective stimulator of local peritoneal fibrinolytic activity , as it decreases P05121 REA secretion in peritoneal Met 5A cells by a mechanism linked to GnRHR .

The role of heat shock proteins in Amyotrophic Lateral Sclerosis : The therapeutic potential of DB05025 MEN . DB05025 MEN is a hydroxylamine derivative , a group of compounds which have unique properties as co-inducers of heat shock protein expression , but only under conditions of cellular stress . DB05025 MEN has been found to be neuroprotective in a number of neurodegenerative disease models , including Amyotrophic Lateral Sclerosis ( P35858 REA ) , and in mutant Superoxide Dismutase 1 ( P00441 REA ) mice that model P35858 REA , DB05025 MEN rescues motor neurons , improves neuromuscular function and extends lifespan . The therapeutic potential of DB05025 MEN is currently under investigation in a Phase II clinical trial for P35858 REA patients with P00441 REA mutations . In this review we summarize the evidence for the neuroprotective effects of enhanced heat shock protein expression by DB05025 MEN and other inducers of the Heat Shock Response . P35858 REA is a complex , multifactorial disease affecting a number of cell types and intracellular pathways . Cells and pathways affected by P35858 REA pathology and which may be targeted by a heat shock protein-based therapy are also discussed in this review . For example , protein aggregation is a characteristic pathological feature of neurodegenerative diseases including P35858 REA . Enhanced heat shock protein expression not only affects protein aggregation directly , but can also lead to more effective clearance of protein aggregates via the unfolded protein response , the proteasome-ubiquitin system or by autophagy . However , compounds such as DB05025 MEN have effects beyond targeting protein mis-handling and can also affect additional pathological mechanisms such as oxidative stress . Therefore , by targeting multiple pathological mechanisms , compounds such as DB05025 MEN may be particularly effective in the development of a disease-modifying therapy for P35858 REA and other neurodegenerative disorders .

Structure of the human Q9H244 REA receptor in complex with an antithrombotic drug . P2Y receptors ( P2YRs ) , a family of purinergic G-protein-coupled receptors ( GPCRs ) , are activated by extracellular nucleotides . There are a total of eight distinct functional P2YRs expressed in human , which are subdivided into P47900 REA - like receptors and Q9H244 REA - like receptors . Their ligands are generally charged molecules with relatively low bioavailability and stability in vivo , which limits our understanding of this receptor family . P2Y12R regulates platelet activation and thrombus formation , and several antithrombotic drugs targeting P2Y12R - - including the prodrugs clopidogrel ( Plavix ) and prasugrel ( DB06209 SUB ) that are metabolized and bind covalently , and the nucleoside analogue ticagrelor ( DB08816 ) that acts directly on the receptor - - have been approved for the prevention of stroke and myocardial infarction . However , limitations of these drugs ( for example , a very long half-life of clopidogrel action and a characteristic adverse effect profile of ticagrelor ) suggest that there is an unfulfilled medical need for developing a new generation of P2Y12R inhibitors . Here we report the 2.6 Å resolution crystal structure of human P2Y12R in complex with a non-nucleotide reversible antagonist , AZD 1283 . The structure reveals a distinct straight conformation of helix V , which sets P2Y12R apart from all other known class A GPCR structures . With AZD 1283 bound , the highly conserved disulphide bridge in GPCRs between helix III and extracellular loop 2 is not observed and appears to be dynamic . Along with the details of the AZD 1283 - binding site , analysis of the extracellular interface reveals an adjacent ligand-binding region and suggests that both pockets could be required for dinucleotide binding . The structure provides essential insights for the development of improved P2Y12R ligands and allosteric modulators as drug candidates .

[ Optimalisation of treatment with vitamin K antagonists - - the role of gene polymorphisms ] . The magnitude of a maintenance vitamin K antagonist ( VKA ) dose during anticoagulant therapy depends not only on clinical , environmental , and demographic factors , but also on genetic factors . Known genetic polymorphisms explain 40-50 % of the variance in VKA dosing . Polymorphisms of two genes encoding enzymes involved in vitamin K and / or VKA metabolism such as vitamin K epoxide reductase complex subunit 1 ( Q9BQB6 ) and cytochrome P450 2C9 isoform ( P11712 REA ) play a key role in this variance . Polymorphisms of cytochrome P450 4F2 isoform ( P78329 REA ) , apolipoprotein E ( P02649 REA ) and gamma-glutamyl carboxylase ( P38435 REA ) are of minor or negligible importance . In European populations , 3 haplotypes of Q9BQB6 , Q9BQB6 * 2 , Q9BQB6 * 3 and Q9BQB6 * 4 - - have been identified and they determined 99 % of genetic variability of this enzyme . The presence of - 1639G > A Q9BQB6 polymorphism is associated with increased VKA dose requirements . Allelic variants of P11712 REA * 2 and P11712 REA * 3 ( found in 8-12 % and 3-8 % of individuals , respectively ) increase the risk of haemorrhage due to slow VKA metabolism , especially at the therapy initiation . Pharmacogenetic algorithms incorporating Q9BQB6 and P11712 REA genotypes help to predict the VKA dosage , particularly if the dose requirements are low or moderate . However , there is no compelling evidence showing reduced risk for clinical adverse events during VKA therapy following the identification of the patient ' s genetic profile .

Proposal of pharmacogenetics-based warfarin dosing algorithm in Korean patients . DB00682 MENMAX DB00682 MEN is a commonly prescribed anticoagulant drug for the prevention of thromboembolic disorders . We investigated the contribution of genetic variations of four genes and clinical factors to warfarin dose requirement and provided a warfarin-dosing algorithm based on genetic and clinical variables in Korean patients . We recruited 564 Korean patients on stable anticoagulation . Single nucleotide polymorphisms ( SNPs ) for the Q9BQB6 , P11712 REA , P78329 REA and P38435 REA were analyzed . Using multiple regression analysis , we developed a model to predict the warfarin requirement . The SNPs of Q9BQB6 , P11712 REA , P78329 REA and P38435 REA showed significant correlation with warfarin dose . Patients with the 3730AA genotype received significantly higher doses of warfarin than those with the 3730GG ( P= 0.0001 ) . For P11712 REA , the highest maintenance dose was observed in the patients with wild-type genotype compared with the variant allele carriers ( P < 0.0001 ) . The multiple regression model including age , gender , body surface area ( BSA ) , international normalized ratio ( INR ) and four genetic polymorphisms accounted for 35 % of total variations in warfarin dose ( R ( 2 )= 0.3499 ; P < 0.0001 ) . This study shows that age , gender , BSA , INR and Q9BQB6 , P11712 REA and P78329 REA polymorphism affect warfarin dose requirements in Koreans . Translation of this knowledge into clinical guidelines for warfarin prescription may contribute to improve the efficacy and safety of warfarin treatment for Korean patients .

Extracellular control of O76095 localization during asymmetric cell division in the C . elegans embryo . The axis of asymmetric cell division is controlled to determine the future position of differentiated cells during animal development . The asymmetric localization of PAR proteins in the Drosophila neuroblast and C . elegans embryo are aligned with the axes of the embryo . However , whether extracellular or intracellular signals determine the orientation of the localization of PAR proteins remains controversial . In C . elegans , the P0 zygote and germline cells ( P1 , P2 , and P09131 ) undergo a series of asymmetric cell divisions . Interestingly , the axis of the P0 and P1 divisions is opposite to that of the P2 and P09131 divisions . P55085 REA , a ring-finger protein , and P25116 REA , a kinase , relocalize to the anterior side of the P2 and P09131 germline precursors at the site of contact with endodermal precursors . Using an in vitro method , we have found that the P55085 REA protein is distributed asymmetrically in the absence of extracellular signals , but the orientation of the protein localization in the P2 and P09131 cells is determined by contact with endodermal precursor cells . Our mutant analyses suggest that mes - 1 and src - 1 , which respectively encode a transmembrane protein and a tyrosine kinase , were not required to establish the asymmetric distribution of P55085 REA , but were required to determine its orientation at the site of contact with the endodermal precursors . The P55085 REA localization during the asymmetric P2 and P09131 divisions is controlled by extracellular signals via MES - 1 / Q15788 REA signaling . Our findings suggest that Src functions as an evolutionarily conserved molecular link that coordinates extrinsic cues with O76095 localization .

Identification of Fyn as the binding partner for the WASP N-terminal domain in T cells . P42768 REA ( WASP ) plays important roles in TCR signaling . In transgenic ( Tg ) mice , over-expression of the WASP N-terminal region ( exons 1-5 ) including the enabled / vasodilator-stimulated phosphoprotein ( Ena / P50552 REA ) homology 1 ( EVH 1 ) domain and anti-WASP-EVH 1 single-chain variable fragment ( scFv ) intracellular expressed antibodies ( intrabodies ) impairs P60568 REA production in activated T cells . However , it largely remains unknown that how this domain transduces TCR signaling . Here , we demonstrate for the first time that the WASP N-terminal domain specifically associates with the Fyn SH3 domain ; the interaction was uncovered by screening a λgt 11 cDNA expression library obtained from the mouse T-cell line KKF . The interaction between Fyn and WASP was inhibited by over-expression of the WASP N-terminal domain and anti-WASP-EVH 1 scFv intrabodies in gene-transfected NIH 3T3 cells and T cells derived from these Tg mice . O43516 REA binding to the EVH 1 domain of WASP was also inhibited in these Tg mice T cells . Furthermore , tyrosine phosphorylation of WASP and nuclear translocation of nuclear factor of activated T cells following TCR stimulation was severely inhibited by over-expression of the WASP N-terminal domain . These observations strongly suggest that the WASP N-terminal domain plays a pivotal role in the TCR signaling cascade by binding to Fyn .

Reduced toll-like receptor 4 and DB05875 gene expression is associated with airway bacterial colonization in children . Neuro-immune interactions are increasingly relevant to human health and disease . The neuropeptide Substance P also has antibacterial activity and bears similarities to the innate immune antibacterial defensins . This suggests possible co-regulation of neuropeptide and innate immune mediators . In this study , non-bronchoscopic bronchoalveolar lavage ( BAL ) was performed on 69 children . BAL was examined for cellular profile , microbiology ( bacteria , virus ) and gene expression for TLRs 2 , 3 , 4 ; chemokine receptors ( P51677 REA , P51681 REA , P25024 REA ) ; neurotrophins and neurokinin genes ( P20366 REA , Q9UHF0 , P8 0511 , P01138 REA ) . In children with bacterial colonization ( n = 10 ) there was an airway inflammatory response with increased BAL neutrophils , P10145 REA protein , and P25024 REA expression . Substance P ( P20366 REA ) and O00206 REA RNA expression were reduced in children with bacterial colonization . O15455 REA mRNA was increased in 7.2 % ( n = 5 ) children with rhinovirus , and there was a non-significant trend to increased O60603 REA . There is evidence for co-regulation of neurokinin ( P20366 REA ) and O00206 REA gene expression in airway cells from children with airway bacterial colonization and their reduced expression may be associated with an impaired bacterial clearance .

Differential recruitment of coregulator proteins steroid receptor coactivator - 1 and silencing mediator for retinoid and thyroid receptors to the estrogen receptor-estrogen response element by beta-estradiol and 4 - hydroxytamoxifen in human breast cancer . P03372 REA ( ER ) - alpha and Q92731 REA function as transcription factors , and both interact with nuclear regulatory proteins to enhance or inhibit transcription . We hypothesized that coregulators are expressed in breast cancer and may be differentially recruited by ERs in the presence of estrogen and tamoxifen . Q92731 REA was found to be expressed more frequently in node-negative patients ( P < 0.05 ) . Expression of steroid receptor coactivator - 1 ( Q15788 REA ) was associated with nodal positivity ( P < 0.05 ) and resistance to endocrine treatment ( P < 0.001 ) . The spatial coexpression of P03372 REA , Q92731 REA , and the coregulatory proteins was established using immunofluorescence . In both cell lines ( MCF - 7 and T47D ) and in primary breast cancer cell cultures , beta-estradiol up-regulated Q92731 REA and coregulator protein expression and increased P03372 REA / Q92731 REA interaction with the estrogen response element ( ERE ) . 4 - Hydroxy-tamoxifen ( DB04468 MEN ) increased P03372 REA and silencing mediator for retinoid and thyroid receptors ( Q9Y618 REA ) expression and increased ER-ERE binding . Q15788 REA and Q9Y618 REA were identified at the ER-ERE complex , and interactions between ER isoforms and coregulatory proteins were determined using immunoprecipitation . Both P03372 REA and Q92731 REA preferentially bound Q15788 REA in the presence of beta-estradiol . Conversely , in cells treated with DB04468 MEN , P03372 REA and Q92731 REA bound Q9Y618 REA . Differential recruitment of Q15788 REA and Q9Y618 REA by P03372 REA and Q92731 REA in the presence of beta-estradiol and DB04468 MEN may be central to the response of the tumor to endocrine treatment .

Treatment with arimoclomol , a coinducer of heat shock proteins , delays disease progression in P35858 REA mice . Amyotrophic lateral sclerosis ( P35858 REA ) is a fatal neurodegenerative condition in which motoneurons of the spinal cord and motor cortex die , resulting in progressive paralysis . This condition has no cure and results in eventual death , usually within 1-5 years of diagnosis . Although the specific etiology of P35858 REA is unknown , 20 % of familial cases of the disease carry mutations in the gene encoding Cu / Zn superoxide dismutase - 1 ( P00441 REA ) . Transgenic mice overexpressing human mutant P00441 REA have a phenotype and pathology that are very similar to that seen in human P35858 REA patients . Here we show that treatment with arimoclomol , a coinducer of heat shock proteins ( HSPs ) , significantly delays disease progression in mice expressing a P00441 REA mutant in which glycine is substituted with alanine at position 93 ( P00441 REA ( G93A ) ) . DB05025 MEN - treated P00441 REA ( G93A ) mice show marked improvement in hind limb muscle function and motoneuron survival in the later stages of the disease , resulting in a 22 % increase in lifespan . Pharmacological activation of the heat shock response may therefore be a successful therapeutic approach to treating P35858 REA , and possibly other neurodegenerative diseases .

Glycoprotein IIb / IIIa and Q9H244 REA receptor antagonists yield additive inhibition of platelet aggregation , granule secretion , soluble P29965 REA release and procoagulant responses . Glycoprotein IIb / IIIa ( P08514 REA / IIIa ) antagonists , including abciximab and tirofiban , are administered concurrently with clopidogrel , a Q9H244 REA antagonist , and aspirin in some patients undergoing percutaneous coronary intervention . We studied the effects of , and interactions between , abciximab , tirofiban , aspirin and the Q9H244 REA antagonist cangrelor on platelet aggregation , alpha and dense granule secretion and procoagulant responses in vitro . Blood was obtained from healthy volunteers . Platelet aggregation , dense granule secretion , alpha granule secretion ( P05121 REA and soluble P29965 REA levels ) and procoagulant responses ( annexin-V and microparticle formation ) were assessed using collagen and thrombin receptor activating peptide ( TRAP ) as agonists . All the antagonists used singularly inhibited collagen-induced responses . Combinations of abciximab or tirofiban with aspirin and / or cangrelor gave additive inhibition with the greatest effect seen when abciximab or tirofiban was combined with both aspirin and cangrelor . DB06441 inhibited TRAP-induced responses and , again , there was additive inhibition of these parameters when abciximab or tirofiban were combined with cangrelor . The P08514 REA / IIIa receptor plays an important role in amplification of platelet activation such that there are important interactions between P08514 REA / IIIa antagonists and inhibitors of both Q9H244 REA receptor activation and , to a lesser extent , thromboxane A2 generation . These interactions are likely to have important influences on the safety and efficacy of combination anti-platelet therapies .

[ P08473 REA activity in the guinea pig model of asthma ] . P08473 REA exists in airway epithelial cells , smooth muscle , and submucosa near glands , and cleaves tachykinins to inactive metabolites , thereby reducing there effects . To study the role of enkephalinase in asthmatic response , we measured its activity in guinea pig model of asthma . When compared with the control values , the enkephalinase activity was reduced during in immediate asthmatic response ( Q92932 REA ) and late asthmatic response ( P10586 REA ) . Compared with the control values ( 100 % ) , each value was 79.7 % , 73.4 % in the trachea and 74.3 % , 55.7 % in the lung respectively . Tracheal muscle preparation taken from the control , Q92932 REA , and P10586 REA groups were made and mounted in oxygenated modified Krebs-Ringer solution . The response was monitored by isometric transducer . Concentration response curves to P20366 REA with or without phosphoramidon were obtained . The contractile responses of the P10586 REA groups were enhanced in potency and efficiency . DB02557 MEN potentiated the P20366 REA induced contraction of control and the Q92932 REA groups but was less potent in enhancing the contractile response in the P10586 REA group , showing less enkephalinase activity in the P10586 REA . These results suggest that the enkephalinase plays an important role in P10586 REA . In P10586 REA , the enkephalinase activity may be inhibited and the responsiveness of the smooth muscle to some bronchoconstrictor , such as tachykinins , may be increased .

First report of warfarin dose requirements in patients possessing the P11712 REA * 12 allele . BACKGROUND : DB00682 MEN is the most frequently prescribed anticoagulant in North America and Europe . It is administered as a racemate , but S-warfarin is principally responsible for its anticoagulant activity . Cytochrome P450 ( CYP ) 2C9 is the enzyme primarily responsible for the metabolism of S-warfarin . Numerous variant alleles of P11712 REA have been identified . The P11712 REA * 12 ( rs9332239 ) allele harbors a P489S substitution in P11712 REA which has been shown to result in a 40 % decline in catalytic activity in vitro . CASES : Four Caucasian patients with a low mean weekly warfarin dose ( MWWD ) were genotyped for P11712 REA , Q9BQB6 and P02649 REA variant alleles . None of the four patients carried the common P11712 REA variant alleles ( * 2 , * 3 , * 5 , * 6 , * 7 , * 8 , * 9 , * 11 , * 13 ) despite a relatively low MWWD ( 23.4 ± 7.94 mg ) compared to 208 patients carrying the CYP 29C9 * 1 genotype ( 32.2 ± 12.65 mg ) . Given that P11712 REA * 12 confers decreased in vitro activity to the enzyme , we investigated whether these patients carried this allele . All four patients were P11712 REA * 12 CT heterozygotes . Individual comparisons with patients possessing the same Q9BQB6 and P02649 REA genotypes also demonstrated lower dose requirements in the patients that possessed P11712 REA * 12 allele . CONCLUSIONS : There are no reports of the clinical impact of rs9332239 on P11712 REA substrates . This is the first report of patients with the rare P11712 REA * 12 genotype and lower warfarin dose requirements .

Effects of neuropeptides on human lung fibroblast proliferation and chemotaxis . An increase in subepithelial mesenchymal cells and associated connective tissue is a feature of bronchial asthma . We determined whether neuropeptides could modulate fibroblast activity , particularly with respect to proliferation and chemotaxis . Human lung fibroblasts were cultured with neurokinin A ( P20366 REA ) , DB05875 ( SP ) , vasoactive intestinal peptide ( P01282 REA ) , and calcitonin-gene-related peptide ( P8 0511 ) . After 48 h , fibroblast proliferation was measured by a colorimetric assay based on the uptake and subsequent release of methylene blue . The chemotactic response to neuropeptides was determined with the use of a modified Boyden chamber . Both P20366 REA and SP ( 10 ( - 7 ) - 10 ( - 4 ) M ) stimulated human lung fibroblast proliferation in Q03591 REA and IMR - 90 fibroblasts . P01282 REA and P8 0511 had no effect on fibroblast proliferation . P20366 REA alone stimulated fibroblast chemotaxis maximally at 10 ( - 10 ) M . P08473 REA ( NEP ) activity of 0.52 and 5.2 pmol / 10 ( 6 ) cells was assayed in IMR - 90 and Hs68 fibroblasts , respectively . DB02557 MEN ( 5 x 10 ( - 6 ) - 10 ( - 5 ) M ) , an NEP inhibitor , enhanced fibroblast proliferation in a dose-dependent manner . Thus neuropeptides have the potential to cause activation of mesenchymal cells , and neuropeptide release may contribute to the structural abnormalities observed in asthmatic airways .

DB06366 MEN monotherapy after trastuzumab-based treatment and subsequent reintroduction of trastuzumab : activity and tolerability in patients with advanced human epidermal growth factor receptor 2 - positive breast cancer . PURPOSE : The combination of pertuzumab and trastuzumab resulted in a clinical benefit rate ( P16152 REA ) of 50 % in patients with human epidermal growth factor receptor 2 ( P04626 REA ) - positive breast cancer whose disease progressed during prior trastuzumab-based therapy . To define whether this previously observed encouraging activity was a result of the combination of pertuzumab and trastuzumab or of pertuzumab alone , we recruited a third cohort of patients who received pertuzumab without trastuzumab . We then investigated the impact of reintroducing trastuzumab to patients whose disease progressed on pertuzumab monotherapy . PATIENTS AND METHODS : Twenty-nine patients with P04626 REA - positive breast cancer whose disease progressed during prior trastuzumab-based therapy received pertuzumab ( 840 mg loading dose , then 420 mg every 3 weeks ) until progressive disease or unacceptable toxicity . Seventeen patients with disease progression continued to receive pertuzumab ( at the same dose ) , with the addition of trastuzumab ( 4 mg / kg loading dose and then 2 mg / kg weekly or 8 mg / kg loading dose and then 6 mg / kg every 3 weeks ) . RESULTS : All 29 patients enrolled for pertuzumab monotherapy experienced disease progression . The objective response rate ( ORR ) and P16152 REA were 3.4 % and 10.3 % , respectively , during pertuzumab monotherapy . With the addition of trastuzumab , the ORR and P16152 REA were 17.6 % and 41.2 % , respectively . Progression-free survival was longer with combination therapy than pertuzumab monotherapy ( 17.4 v 7.1 weeks , respectively ) . Treatment was well tolerated with minimal cardiac dysfunction . CONCLUSION : Although pertuzumab has some activity in patients with P04626 REA - positive breast cancer that progressed during therapy with trastuzumab , the combination of pertuzumab and trastuzumab seems to be more active than monotherapy .

Death receptors 4 and 5 activate Nox 1 NADPH oxidase through riboflavin kinase to induce reactive oxygen species-mediated apoptotic cell death . Stimulation of the proapoptotic tumor necrosis factor ( P01375 REA ) - related apoptosis-inducing ligand ( P50591 REA ) receptors , death receptors 4 ( DR4 ) and 5 ( DR5 ) , conventionally induces caspase-dependent apoptosis in tumor cells . Here we report that stimulation of DR4 and / or DR5 by the agonistic protein KD548 - Fc , an Fc-fused DR4 / DR5 dual-specific Kringle domain variant , activates plasma membrane-associated Nox 1 NADPH oxidase to generate superoxide anion and subsequently accumulates intracellular reactive oxygen species ( ROS ) , leading to sustained c-Jun N-terminal kinase activation and eventual apoptotic cell death in human HeLa and Jurkat tumor cells . KD548 - Fc treatment induces the formation of a DR4 / DR5 signaling complex containing riboflavin kinase ( Q969G6 REA ) , Nox 1 , the Nox 1 subunits ( Rac 1 , Noxo 1 , and Noxa 1 ) , P01375 REA receptor-associated death domain ( Q15628 REA ) , and Q12933 REA ( TRAF 2 ) . Depletion of Q969G6 REA , but not the Nox 1 subunits , Q15628 REA and TRAF 2 , failed to recruit Nox 1 and Rac 1 to DR4 and DR5 , demonstrating that Q969G6 REA plays an essential role in linking DR4 / DR5 with Nox 1 . Knockdown studies also reveal that Q969G6 REA , Q15628 REA , and TRAF 2 play critical , intermediate , and negligible roles , respectively , in the KD548 - Fc-mediated ROS accumulation and downstream signaling . Binding assays using recombinantly expressed proteins suggest that DR4 / DR5 directly interact with cytosolic Q969G6 REA through Q969G6 REA - binding regions within the intracellular death domains , and Q15628 REA stabilizes the DR4 / DR5 - Q969G6 REA complex . Our results suggest that DR4 and DR5 have a capability to activate Nox 1 by recruiting Q969G6 REA , resulting in ROS-mediated apoptotic cell death in tumor cells .

P25116 REA genotype influences platelet aggregation and procoagulant responses in patients with coronary artery disease prior to and during clopidogrel therapy . Genetic variations of the protease-activated receptor - 1 ( P25116 REA ) have been associated with platelet receptor density and linked to thrombin receptor-activating peptide ( TRAP ) - induced phenotypes of platelet aggregation and P16109 REA expression . We investigated whether the P25116 REA intervening sequence - 14 A > T dimorphism influences platelet procoagulant activity . We also determined whether the Q9H244 REA antagonist clopidogrel could offset any observed functional polymorphism of the P25116 REA receptor by inhibiting Q9H244 REA - mediated amplification of TRAP-induced responses . We studied 54 patients listed for elective percutaneous coronary intervention assessing TRAP-induced platelet aggregation and markers of procoagulant activity . Platelet responses were measured at baseline , 4 h post clopidogrel 300 mg , and 10 and 28 days following clopidogrel 75 mg daily . Each patient was genotyped for the P25116 REA intervening sequence - 14 A / T dimorphism . Increased platelet aggregation and procoagulant responses were observed with P25116 REA A allele homozygotes . DB00758 significantly inhibited these platelet responses regardless of P25116 REA genotype , but did not offset the hyper-reactivity associated with the A / A homozygotes . We conclude that a common sequence variation within the P25116 REA gene influences TRAP-induced platelet procoagulant activity as well as aggregation . Higher platelet reactivity associated with P25116 REA IVSn - 14 A allele homozygotes persists despite clopidogrel therapy . These individuals may be at higher risk of thromboembolic events and may require additional anti-platelet medication .

P2Y ( 12 ) receptor on the verge of a neuroinflammatory breakdown . In the CNS , neuroinflammation occurring during pathologies as amyotrophic lateral sclerosis ( P35858 REA ) and multiple sclerosis ( MS ) is the consequence of an intricate interplay orchestrated by various cell phenotypes . Among the molecular cues having a role in this process , extracellular nucleotides are responsible for intercellular communication and propagation of inflammatory stimuli . This occurs by binding to several receptor subtypes , defined P2X / P2Y , which are widespread in different tissues and simultaneously localized on multiple cells . For instance , the metabotropic Q9H244 REA subtype is found in the CNS on microglia , affecting activation and chemotaxis , on oligodendrocytes , possessing a hypothesized role in myelination , and on astrocytes . By comparative analysis , we have established here that Q9H244 REA receptor immunolabelled by antibodies against C-terminus or second intracellular loop , is , respectively , distributed and modulated under neuroinflammatory conditions on ramified microglia or myelinated fibers , in primary organotypic cerebellar cultures , tissue slices from rat striatum and cerebellum , spinal cord sections from symptomatic / end stage P00441 REA - G93A P35858 REA mice , and finally autoptic cortical tissue from progressive MS donors . We suggest that modulation of Q9H244 REA expression might play a dual role as analytic marker of branched / surveillant microglia and demyelinating lesions , thus potentially acquiring a predictive value under neuroinflammatory conditions as those found in P35858 REA and MS .

P03372 REA - alpha 36 mediates mitogenic antiestrogen signaling in ER-negative breast cancer cells . It is prevailingly thought that the antiestrogens tamoxifen and ICI 182 , 780 are competitive antagonists of the estrogen-binding site of the estrogen receptor-alpha ( ER-α ) . However , a plethora of evidence demonstrated both antiestrogens exhibit agonist activities in different systems such as activation of the membrane-initiated signaling pathways . The mechanisms by which antiestrogens mediate estrogen-like activities have not been fully established . Previously , a variant of ER-α , EP-α 36 , has been cloned and showed to mediate membrane-initiated estrogen and antiestrogen signaling in cells only expressing ER-α 36 . Here , we investigated the molecular mechanisms underlying the antiestrogen signaling in ER-negative breast cancer MDA-MB - 231 and MDA-MB - 436 cells that express high levels of endogenous ER-α 36 . We found that the effects of both 4 - hydoxytamoxifen ( DB04468 MEN ) and ICI 182 , 780 ( ICI ) exhibited a non-monotonic , or biphasic dose response curve ; antiestrogens at low concentrations , elicited a mitogenic signaling pathway to stimulate cell proliferation while at high concentrations , antiestrogens inhibited cell growth . Antiestrogens at l nM induced the phosphorylation of the Src-Y 416 residue , an event to activate Src , while at 5 µM induced Src-Y 527 phosphorylation that inactivates Src . Antiestrogens at 1 nM also induced phosphorylation of the MAPK / P29323 REA and activated the P12004 REA D1 promoter activity through the Src / P00533 REA / P42229 REA pathways but not at 5 µM . Knock-down of ER-α 36 abrogated the biphasic antiestrogen signaling in these cells . Our results thus indicated that ER-α 36 mediates biphasic antiestrogen signaling in the ER-negative breast cancer cells and Src functions as a switch of antiestrogen signaling dependent on concentrations of antiestrogens through the P00533 REA / P42229 REA pathway .

Roles of purinergic receptor P2Y , G protein-coupled 12 in the development of atherosclerosis in apolipoprotein E-deficient mice . OBJECTIVE : The aim of the study was to evaluate the role of purinergic receptor P2Y , G protein-coupled 12 ( Q9H244 REA ) , an ADP receptor , in the development of atherosclerotic lesions . METHODS AND RESULTS : P02649 REA - null mice were crossed with P2y12 ( - / - ) mice to generate double knockout mice . The double knockout mice and the control apolipoprotein E-null mice were fed a high-fat diet for 20 weeks . Assessment of the atherosclerotic lesions in the control and double knockout mice demonstrated that Q9H244 REA deficiency caused a diminished lesion area , an increased fibrous content at the plaque site , and decreased monocyte / macrophage infiltration of the lesions . Polymerase chain reaction studies revealed that white blood cells do not express significant levels of Q9H244 REA . Bone marrow transplantation experiments confirmed that Q9H244 REA expressed on platelets is a key factor responsible for atherosclerosis , but do not exclude a role of smooth muscle cell Q9H244 REA . Supernatant fluid from activated P2y12 ( + / + ) but not P2y12 ( - / - ) platelets was capable of causing monocyte migration . In vitro studies showed that platelet Q9H244 REA deficiency suppressed platelet factor 4 secretion and P16109 REA expression . Further work demonstrated that platelet Q9H244 REA , through inhibition of the DB02527 / protein kinase A pathway , critically regulates the release of platelet factor 4 , and thereby affects monocyte recruitment and infiltration . CONCLUSIONS : These results demonstrate that Q9H244 REA modulates atherogenesis , at least in part by augmenting inflammatory cell recruitment via regulation of platelet α-granule release .

Development of DB00644 antagonists for prostate cancer : new approaches to treatment . Prostate cancer has become the most common cancer among American men and is second only to lung cancer as a cause of male cancer-related death . Several treatment options exist for different stages of prostate cancer including observation , prostatectomy , radiation therapy , chemotherapy , and hormone therapy . Hormone therapy has evolved from the use of estrogens to gonadotropin-releasing hormone ( DB00644 ) agonists and recently , investigational DB00644 antagonists . P30968 REA agonists such as leuprolide , bruserelin and goserelin have been used for the treatment of prostate cancer . These agonists eventually cause the inhibition of lutenizing hormone production , which in turn causes a suppression of testosterone and dihydrotestosterone , on which continued growth of prostate cancer cells depend . Several comparative studies of leuprorelin administered as daily injections or monthly depot injections have been reported . Disease progression was prevented in more than 72 % of men administered daily leuprorelin , and in 82 % to 89 % of those receiving monthly depots . Another synthetic DB00644 analog , goserelin , has been studied in a similar population of men with daily injections producing partial responses in 60 % to 80 % of men with previously untreated prostate cancer . DB00106 MEN , a peptide antagonist of P30968 REA , is also being studied for the treatment of prostate cancer . The discovery and development of DB00644 antagonists may provide an important advance for patients with prostate cancer . Clearly the studies described herein , as well as many others , outline an exciting era of research to define the optimal use of hormonal therapy in prostate cancer .

DB00173 nucleotides inhibit cytokine generation by human mast cells through a Gs-coupled receptor . DB00171 and ADP activate functionally distinct G protein-coupled purinergic ( P2Y ) receptors . We determined the expression and function of adenine nucleotide-specific P2Y receptors on cord blood-derived human mast cells ( hMCs ) . Human MCs expressed mRNA encoding the ADP-specific P47900 REA , Q9H244 REA , and Q9BPV8 receptors ; the DB00171 / UTP-specific P41231 REA receptor ; and the DB00171 - selective Q96G91 REA receptor . ADP ( 0.05- 50 muM ) induced calcium flux that was completely blocked by a P47900 REA receptor-selective antagonist and was not cross-desensitized by DB00171 . Low doses of ADP induced strong phosphorylation of P29323 REA and p38 MAPKs ; higher doses stimulated eicosanoid production and exocytosis . Although MAPK phosphorylation was blocked by a combination of P47900 REA - and Q9H244 REA - selective antagonists , neither interfered with secretion responses . Unexpectedly , both ADP and DB00171 inhibited the generation of P01375 REA in response to the O60603 REA ligand , peptidoglycan , and blocked the production of P01375 REA , P10145 REA , and MIP - 1beta in response to leukotriene D ( 4 ) . These effects were mimicked by two DB00171 analogues , adenosine 5 ' - O - ( 3 - thiotriphosphate ) and 2 ' , 3 ' - O - ( 4 - benzoyl-benzoyl ) adenosine 5 ' - triphosphate ( BzATP ) , but not by adenosine . ADP , DB00171 , adenosine 5 ' - O - ( 3 - thiotriphosphate ) , and 2 ' , 3 ' - O - ( 4 - benzoyl-benzoyl ) adenosine 5 ' - triphosphate each induced DB02527 accumulation , stimulated the phosphorylation of CREB , and up-regulated the expression of inducible DB02527 early repressor , a CREB-dependent inhibitor of cytokine transcription . Human MCs thus express several ADP-selective P2Y receptors and at least one G ( s ) - coupled ADP / DB00171 receptor . Nucleotides could therefore contribute to MC-dependent microvascular leakage in atherosclerosis , tissue injury , and innate immunity while simultaneously limiting the extent of subsequent inflammation by attenuating the generation of inducible cytokines by MCs .

DB00106 MEN and other gonadotrophin-releasing hormone antagonists in prostate cancer . Hormonal therapy is the main recommended treatment for locally advanced and metastatic prostate cancer . DB00044 - releasing hormone ( P01148 REA ) agonists , such as buserelin , goserelin , leuprorelin and triptorelin , stimulate the pituitary ' s gonadotrophin-releasing hormone ( DB00644 ) receptor , ultimately leading to its de-sensitization and subsequent reduction of LH and testosterone levels . However , this reduction is accompanied by a well described increase or ' surge ' in LH and testosterone levels , necessitating the concomitant administration of an antiandrogen to combat the potential effects of transient acceleration in cancer activity . Two pure DB00644 antagonists have been developed , abarelix and degarelix , that are devoid of any agonist effect on the P30968 REA and consequently do not result in testosterone flare . DB00106 MEN was the first DB00644 antagonist to be developed and was approved by the USA Food and Drug Administration in 2004 for the initiation of hormonal castration in advanced or metastasizing hormone-dependent prostate carcinoma , when rapid androgen suppression is necessary . Clinical data on both abarelix and degarelix show that they can produce rapid and sustained decreases in testosterone to castrate levels without the need for co-administration of an antiandrogen , and with a very low complication rate in the short term .

A clinical trial with chimeric monoclonal antibody DB05304 MEN and low dose interleukin - 2 pulsing scheme for advanced renal cell carcinoma . PURPOSE : DB05304 MEN is a chimeric monoclonal antibody that binds to carbonic anhydrase IX ( Q16790 REA / MN ) , which is present on greater than 95 % of RCCs of the clear cell subtype . The suggested working mechanism of DB05304 MEN is by ADCC . Because the number of activated ADCC effector cells can be increased by a low dose interleukin - 2 pulsing schedule , a multicenter study was initiated to investigate whether DB05304 MEN combined with LD - P60568 REA could lead to an improved clinical outcome in patients with progressive RCC . MATERIALS AND METHODS : A total of 35 patients with progressive clear cell RCC received weekly infusions of DB05304 MEN for 11 weeks combined with a daily LD - P60568 REA regimen . Patients were monitored longitudinally for ADCC capacity . Radiological assessment of metastatic lesions was performed at week 16 and regularly until disease progression . RESULTS : A durable clinical benefit was achieved in 8 of 35 patients ( 23 % ) , including 3 with a partial response and 5 with stabilization at 24 weeks or greater . Mean survival was 22 months . In general treatment was well tolerated with little toxicity . The number of effector cells increased during treatment but lytic capacity per cell did not increase . ADCC and clinical outcome did not appear to correlate . CONCLUSIONS : DB05304 MEN combined with LD - P60568 REA in patients with metastatic RCC is safe and well tolerated . With a substantial clinical benefit and a median survival of 22 months in patients with metastatic RCC who have progressive disease at study entry combination therapy showed increased overall survival compared to DB05304 MEN monotherapy . Survival was at least similar to that of currently used cytokine regimens but with a favorable toxicity profile .

DB02709 attenuates the release of inflammatory cytokines from human bronchial smooth muscle cells exposed to lipoteichoic acid in chronic obstructive pulmonary disease . During bacterial infections , pathogen-associated molecular patterns ( PAMPs ) induce cytokine / chemokine release in immunoactive cells . This increases corticosteroid-resistant airway inflammation in chronic obstructive pulmonary disease ( P48444 REA ) and leads to exacerbations . Anti-inflammatory therapies other than corticosteroids are required and resveratrol is currently under discussion . DB02709 is an activator of sirtuins , which are class III histone deacetylases ( HDACs ) . We suggested that human airway smooth muscle cells ( HASMCs ) release P48444 REA - associated cytokines / chemokines in response to lipoteichoic acid ( P01374 REA ) , a major Q96TA2 of gram-positive bacteria and that resveratrol is superior to the corticosteroid dexamethasone in suppressing these cytokines / chemokines . Cultivated HASMCs of patients with P48444 REA were pre-incubated with resveratrol or dexamethasone before stimulation with P01374 REA . P13500 REA , GM - P04141 REA , P05231 REA and P10145 REA were analysed in culture supernatants by enzyme-linked immunosorbent assay . Drug effects were investigated in the absence and presence of trichostatin A ( P32119 REA ) , an inhibitor of class I / II HDACs , and EX527 , an inhibitor of the sirtuin Q96EB6 . P01374 REA induced robust cytokine / chemokine release . DB02709 was superior to dexamethasone in reducing DB00833 - 2 , P05231 REA and P10145 REA in P01374 REA - exposed HASMCs of patients with P48444 REA . Both drugs were equally effective in reducing GM - P04141 REA . DB02709 effects were partially reversed by EX527 but not by P32119 REA . Dexamethasone effects were partially reversed by P32119 REA but not by EX527 . We conclude that HASMCs contribute to the increase in airway inflammation in P48444 REA exacerbations caused by gram-positive bacterial infections . Our data suggest resveratrol as an alternative anti-inflammatory therapy in infection-induced P48444 REA exacerbations . DB02709 and corticosteroids suppress cytokine / chemokine expression through activation of Q96EB6 or interaction with class I / II HDACs , respectively , in HASMCs .