MH_dev_208

Catastrophic eruptive keratoacanthomas and squamous cell cancers after treatment with an P36888 REA inhibitor quizartinib ( DB05213 MEN ) .

P04150 REA antagonism disrupts the reconsolidation of social reward-related memories in rats . Reconsolidation is the process whereby consolidated memories are destabilized upon retrieval and restabilized to persist for later use . Although the neurobiology of the reconsolidation of both appetitive and aversive memories has been intensively investigated , reconsolidation of memories of physiologically relevant social rewards has received little attention . Social play , the most characteristic social behaviour displayed by young mammals , is highly rewarding , illustrated by the fact that it can induce conditioned place preference ( CPP ) . Here , we investigated the role of signalling mechanisms implicated in memory processes , including reconsolidation , namely glucocorticoid , mineralocorticoid , DB01221 glutamatergic and P21554 REA cannabinoid receptors , in the reconsolidation of social play-induced CPP in rats . Systemic treatment with the glucocorticoid receptor antagonist mifepristone before , but not immediately after , retrieval disrupted the reconsolidation of social play-induced CPP . DB00834 SUB did not affect social play-induced CPP in the absence of memory retrieval . Treatment with the DB01221 receptor antagonist MK - 801 modestly affected the reconsolidation of social play-induced CPP . However , the reconsolidation of social play-induced CPP was not affected by treatment with the mineralocorticoid and P21554 REA cannabinoid receptor antagonists spironolactone and rimonabant , respectively . We conclude that glucocorticoid neurotransmission mediates the reconsolidation of social reward-related memories in rats . These data indicate that the neural mechanisms of the reconsolidation of social reward-related memories only partially overlap with those underlying the reconsolidation of other reward-related memories .

[ Regulation of P04271 REA expression during long term potentiation ] . In this study , contributions of intracellular regulatory cascades in the induction of P04271 REA expression in rat hippocampal P00915 REA area during long term posttetanic potentiation ( LTP ) were estimated . The activation of transcription factor p53 ( positive regulator of P04271 REA transcription ) by nutlin - 3 increased the basal content of P04271 REA mRNA up to 151 % of the control level , which was significantly lower than its content in tetanized slices ( 280 % ) . Therefore , p53 seems to be not unique transcription factor upregulating P04271 REA expression during LTP . The inhibitor of Ca2 + / calmodulin-dependent kinases ( CaMKs ) KN - 93 fully blocked the increase of P04271 REA mRNA after tetanization , while KN - 92 ( inactive analogue of KN - 93 ) was ineffective . The inhibitor of CaMKII and receptor tyrosine kinases DB02152 MEN essentially suppressed P04271 REA expression during LTP , the inhibition of MAPK p38 or P51812 REA moderately decreased , and the inhibition of Q02750 REA did not influence P04271 REA mRNA content . Thus , CaMKs play a key role in the induction of P04271 REA expression during LTP .

DB06155 inhibits proliferation , collagen secretion and induces apoptosis in hepatic stellate cells . BACKGROUND / AIMS : Liver fibrosis represents a significant health problem worldwide . Hepatic stellate cells ( HSCs ) play a critical role in the live fibrosis . DB06155 ( SR141716 ) is cannabinoid receptor type 1 ( P21554 REA ) antagonist . The pharmacological effects of rimonabant on HSCs are not well characterized in HSCs . METHODS : P21554 REA receptor was detected by immunohistochemistry in human liver fibrosis specimens . Cell proliferation was detected by MTT assay . Cell apoptosis , caspase - 3 protein expression and cell cycle were detected by TEM and flow cytometry , respectively . P42574 REA activity was measured using caspase - 3 activity assay kit . Collagen secretion was evaluated by radioimmunoassay . P21554 REA receptor and signaling molecules were evaluated by qRTPCR and Western blot . RESULTS : Immunohistochemistry showed a discrete , punctuated P21554 REA immunoreactivity in human liver fibrosis specimens . DB06155 reduced P19526 REA proliferation and increased P19526 REA apoptosis . Cell cycle analysis showed a decrease in G2 / M phase cells and an increase in G0 / P55008 phase cells in P19526 REA - Q8NHM4 cells treated with rimonabant . P42574 REA protein expression and activity were increased by rimonabant . DB06155 decreased collagen secretion in P19526 REA - Q8NHM4 cells . Moreover , rimonabant inhibited the expression of phosphorylated Q05397 REA and P29323 REA and down-regulated P21554 REA mRNA expression . CONCLUSION : The study provides new insights toward the pharmacological effect of rimonabant on HSCs in vitro . DB06155 inhibits proliferation , collagen secretion and induces apoptosis in HSCs .

P06401 REA activation of extranuclear signaling pathways in regulating p53 expression in vascular endothelial cells . We previously showed that progesterone ( P4 ) inhibited the proliferation of human umbilical vein endothelial cells ( HUVECs ) through a p53 - dependent pathway . Now we investigated further the molecular mechanism underlying the hormone activity . In cultured HUVECs , P4 increased the protein levels of phosphorylated Src ( p-Src ) , P04049 REA , and P29323 REA . The levels of p-Src and p-Src-progesterone receptor complex in HUVECs were increased by P4 treatment . These effects were blocked by pretreatment with a progesterone receptor antagonist , DB00834 SUB . The P4 - induced increase in p53 transactivity was abolished by pretreatment with Src kinase inhibitors . Moreover , administration with cSrc antisense oligonucleotide prevented the P4 - induced increases of the levels of p53 mRNA and protein . These data suggest that P4 - induced up-regulation of p53 might be mediated through activation of cSrc . Pretreatment with Src kinase inhibitors also prevented P4 - induced membrane translocation of Kras and increases of the protein levels of phosphorylated Raf and phosphorylated P29323 REA . Transfection with dominant-negative P28482 REA prevented the P4 - induced increases of protein level and promoter activity of p53 and a decrease of thymidine incorporation . P4 also increased nuclear factor-κB ( NF-κB ) nuclear translocation and NF-κB binding onto the p53 promoter . These effects were abolished by pretreatment with P29323 REA inhibitors . The P4 - induced up-regulation of the p53 promoter activity was prevented by preadministration with dominant-negative P28482 REA or NF-κB inhibitors . Taken together , our data suggest that the cSrc / Kras / P04049 REA / P28482 REA / NF-κB signaling pathway contributes to the P4 - induced up-regulation of p53 in HUVECs . These findings highlight progesterone receptor activation of extranuclear signaling pathways in regulating p53 and cell cycle progression in HUVECs .

Pharmacokinetics and pharmacodynamics of a bolus and infusion of cangrelor : a direct , parenteral Q9H244 REA receptor antagonist . The purpose of this study is to evaluate the safety , tolerability , pharmacokinetics , and pharmacodynamics of cangrelor administered as an intravenous bolus plus a continuous infusion in healthy volunteers . Twenty-two healthy volunteers are randomized to receive 1 of 2 intravenous cangrelor dosing regimens : a 15 - microg / kg bolus followed by a 2 - microg / kg / min infusion or a 30 - microg / kg bolus followed by a 4 - microg / kg / min infusion . The infusion is continued for 60 minutes , and serial blood samples are obtained for evaluation of pharmacokinetic and pharmacodynamic parameters . Administration of an intravenous bolus followed by a continuous infusion rapidly achieves maximum concentrations of cangrelor that are associated with extensive platelet inhibition within 2 minutes . Moreover , extensive platelet inhibition is maintained throughout the infusion period with near-full recovery of platelet function within 60 to 90 minutes of terminating the infusion . The effect of high-dose cangrelor is more consistent and demonstrates a greater level of inhibition on adenosine diphosphate-induced P16109 REA expression ; how ever , no significant differences are observed between the 2 dosing regimens with regard to platelet aggregation or time to recovery of platelet function . DB06441 MEN administered as an intravenous bolus followed by a continuous infusion in healthy volunteers offers rapid and reversible inhibition of platelet function .

P06401 REA modulator for emergency contraception : a randomized controlled trial . OBJECTIVE : Compare the efficacy and adverse effects of DB05366 MEN , a new progesterone receptor modulator , to levonorgestrel for emergency contraception . METHODS : We performed a randomized , double-blinded noninferiority trial , enrolling healthy women seeking emergency contraception within 72 hours of unprotected intercourse . Participants were randomly assigned to receive a single dose of 50 mg of DB05366 MEN , plus a placebo 12 hours later or two doses of 0.75 mg of levonorgestrel taken 12 hours apart . Follow-up was scheduled 5 to 7 days after the expected onset of the next menstrual period . Posttreatment pregnancy was established by a positive urine test at follow-up and confirmed by quantitative serum beta-hCG . Daily diaries were used from the time of emergency contraception use until next menses to record adverse effects and sexual activity . RESULTS : Product efficacy was evaluable in 775 of DB05366 MEN users and 774 of levonorgestrel users . Pregnancies occurred in 7 ( 0.9 % , 95 % confidence interval 0 . P35326 REA . 6 % ) and 13 ( 1.7 % , 95 % confidence interval 0.8- 2.6 % ) women , respectively . Based on the estimated cycle day of unprotected intercourse , 85 % and 69 % of anticipated pregnancies , respectively , were averted . Nausea was reported by a somewhat greater percentage of DB05366 MEN than levonorgestrel users ( 29 % compared with 24 % , P= . 03 ) , but the distribution of other adverse effects was similar in both groups . Women in both groups experienced considerable variation in menstrual cycle length as compared with their reported individual normal cycle lengths . CONCLUSION : DB05366 MEN is at least as effective as levonorgestrel in preventing pregnancies after unprotected intercourse and has a similar side effect profile . LEVEL OF EVIDENCE : I .

P04150 REA overexpression exerts an antisurvival effect on human small cell lung cancer cells . Small cell lung cancer ( SCLC ) is an aggressive tumour with an abysmal prognosis . These cancers are characteristically resistant to glucocorticoid ( Gc ) action , owing to impaired expression of the glucocorticoid receptor ( GR ) . We identified reduced GR expression in human SCLC cell lines , compared to a non-SCLC cell line . The SCLC cells also showed no Gc inhibition of proliferation , in contrast to non-SCLC cells . Retroviral overexpression of GR resulted in significantly increased cell death , which was partially blocked by the GR antagonist , DB00834 SUB . Indeed , in cells sorted for GR expression , there was rapid , near complete loss of live cells by 72 h , in contrast to control cells that proliferated as expected . Flow cytometry using P08758 REA revealed that cell death was by apoptosis . In addition , confocal analysis of fixed cells showed that cells overexpressing GR displayed a significant increase in fragmenting apoptotic nuclei . Microarray studies showed that transgenic GR expression upregulated the proapoptotic genes , Q92934 REA and Q07812 REA . We have , therefore , identified a profound apoptotic effect of GR in SCLC cells , which may explain the low levels of endogenous GR in SCLC cells . Understanding how GR overexpression leads to apoptotic cell death in SCLC cells may uncover new therapeutic strategies .

P06401 REA modulator DB05366 MEN down-regulates proliferative cell nuclear antigen and Bcl - 2 protein expression and up-regulates caspase - 3 and poly ( adenosine 5 ' - diphosphate-ribose ) polymerase expression in cultured human uterine leiomyoma cells . The present study was conducted to evaluate the effects of the progesterone receptor modulator DB05366 MEN on proliferative activity and apoptosis in cultured human uterine leiomyoma cells . Isolated leiomyoma cells were subcultured in phenol red-free DMEM supplemented with 10 % fetal bovine serum for 120 h and then stepped down to serum-free conditions for 12 , 24 , 48 , and 96 h in the absence or presence of graded concentrations of DB05366 MEN ( 10 ( - 9 ) , 10 (-8 ) , 10 ( - 7 ) , and 10 ( - 6 ) M ) . The number of viable cultured leiomyoma cells was determined by 3 - ( 4,5- dimethylthiazol - 2 - yl ) -2,5- diphenyltetrazodium bromide assay . P12004 REA ( P12004 REA ) expression was evaluated by immunocytochemistry and Western blot analysis . Apoptosis was examined by terminal deoxynucleotidyl transferase-mediated 2 ' - deoxyuridine 5 ' - triphosphate nick end labeling ( TUNEL ) assay . P42574 REA , cleaved poly ( ADP-ribose ) polymerase ( PARP ) , and Bcl - 2 expression were assessed by Western blot analysis . Compared with untreated control cultures , treatment with DB05366 MEN decreased the number of viable cultured leiomyoma cells and the P12004 REA - positive rate in those cells and increased the TUNEL-positive rate in cultured leiomyoma cells in a dose-dependent manner . Western blot analysis revealed that treatment with DB05366 MEN significantly decreased the expression of P12004 REA and Bcl - 2 protein and increased the expression of cleaved caspase - 3 and cleaved PARP in a dose-dependent manner compared with untreated control cultures . These results suggest that DB05366 MEN inhibits the proliferation of cultured leiomyoma cells by down-regulating P12004 REA expression and induces apoptosis by up-regulating cleaved caspase - 3 and PARP expression and down-regulating Bcl - 2 protein expression in those cells .

P04150 REA and histone deacetylase - 2 mediate dexamethasone-induced repression of P98088 REA gene expression . Airway occlusion in obstructive airway diseases is caused in part by the overproduction of secretory mucin glycoproteins through the up-regulation of mucin ( MUC ) genes by inflammatory mediators . Some pharmacological agents , including the glucocorticoid dexamethasone ( DB00514 ) , repress mucin concentrations in lung epithelial cancer cells . Here , we show that DB00514 reduces the expression of P98088 REA , a major airway mucin gene , in primary differentiated normal human bronchial epithelial ( NHBE ) cells in a dose-dependent and time-dependent manner , and that the DB00514 - induced repression is mediated by the glucocorticoid receptor ( GR ) and two glucocorticoid response elements ( GREs ) in the P98088 REA promoter . The pre-exposure of cells to DB00834 SUB , a GR antagonist , and mutations in either the GRE 3 or GRE 5 cis-sites abolished the DB00514 - induced repression . Chromatin immunoprecipitation ( ChIP ) assays showed a rapid temporal recruitment of GR to the GRE 3 and GRE 5 cis-elements in the P98088 REA promoter in NHBE and in A549 cells . Immunofluorescence showed nuclear colocalization of GR and histone deacetylase - 2 ( Q92769 REA ) in P98088 REA - expressing NHBE cells . ChIP also showed a rapid temporal recruitment of Q92769 REA to the GRE 3 and GRE 5 cis-elements in the P98088 REA promoter in both cell types . The knockdown of Q92769 REA by Q92769 REA - specific short interfering RNA prevented the DB00514 - induced repression of P98088 REA in NHBE and A549 cells . These data demonstrate that GR and Q92769 REA are recruited to the GRE 3 and GRE 5 cis-sites in the P98088 REA promoter and mediate the DB00514 - induced cis repression of P98088 REA gene expression . A better understanding of the mechanisms whereby glucocorticoids repress P98088 REA gene expression may be useful in formulating therapeutic interventions in chronic lung diseases .

Association of a polymorphism of the apolipoprotein E gene with chronic kidney disease in Japanese individuals with metabolic syndrome . The purpose of the present study was to identify genetic variants that confer susceptibility to chronic kidney disease ( CKD ) in Japanese individuals with metabolic syndrome . The study population comprised 2150 Japanese individuals with metabolic syndrome , including 411 subjects with CKD [ estimated glomerular filtration rate ( eGFR ) < 50 mL / min / 1.73 m ( 2 ) ] and 1739 controls ( eGFR > /= 60 mL / min / 1.73 m ( 2 ) ) . The genotypes for 100 polymorphisms of 80 candidate genes were determined . The chi-square test , multivariable logistic regression analysis with adjustment for covariates , as well as a stepwise forward selection procedure revealed that nine polymorphisms of P02649 REA , O95477 REA , P23219 REA , P01375 REA , Q96IY4 , P30556 REA , Q8NGZ3 , and P16520 REA were associated ( P < 0.05 ) with the prevalence of CKD . Among these polymorphisms , the - 219G --> T polymorphism of P02649 REA ( rs405509 ) was most significantly associated with CKD in Japanese individuals with metabolic syndrome .

Q9UBC3 interacts with O60264 REA chromatin remodeling enzyme , HDACs 1 and 2 , and components of the histone methylation system . The non-random pattern of genome-wide DNA methylation in mammalian cells is established and maintained by DNA methyltransferases P26358 REA , 3A , and 3B . De novo DNA methyltransferase Q9UBC3 is critical for embryonic development and is mutated in ICF syndrome . Despite its importance in normal cellular functioning , little is known about how Q9UBC3 operates in the context of chromatin . Here we demonstrate that Q9UBC3 associates with four chromatin-associated enzymatic activities common to transcriptionally repressed , heterochromatic regions of the genome : DNA methyltransferase , histone deacetylase , ATPase , and histone methylase activities . By immunoprecipitation and Q86UG4 pull-down , we show that Q9UBC3 interacts with Q13547 REA , Q92769 REA , P59665 REA proteins , Suv 39h1 , and the DB00171 - dependent chromatin remodeling enzyme O60264 REA . Endogenous O60264 REA is also associated with DNA methyltransferase activity . These proteins co-localize extensively with Q9UBC3 in heterochromatic regions . Our results therefore link Q9UBC3 to three other components of the epigenetic machinery and provide important insights into how DNA methylation patterns may be established within the chromatin environment .

P29323 REA signalling pathway is not involved in PSA - P13591 REA - dependent alterations of hippocampal plasticity evoked by P21554 REA receptor activation . The present study investigated the potential role of the extracellular signal-regulated kinase ( P29323 REA ) pathway in the alternation of polysialylated neural cell adhesion molecule ( PSA - P13591 REA ) expression and proliferation rates in the dentate gyrus ( DG ) evoked by activation of the P21554 REA receptor . When given at a dose of 0.1 mg / kg , the P21554 REA receptor agonist , 3 - ( 1,1- dimethylheptyl ) - 11 - hydroxy-Delta (8 ) - tetrahydrocannabinol ( HU - 210 ) , increased the levels of the phosphorylated forms of P29323 REA ( pERK 1 and pERK 2 ) in the hippocampus when measured 30 min after injection . This HU - 210 - induced effect was inhibited by alpha - { amino [ ( 4 - aminophenyl ) thio ] methylene } - 2 - ( trifluoromethyl ) benzeneacetonitrile ( SL327 , 30 mg / kg ) - an inhibitor of mitogen-activated protein kinase kinase ( Q02750 REA / 2 ) , the upstream kinase of P29323 REA - given 1 h before HU - 210 administration . Additionally , SL327 alone significantly attenuated the basal level of both pERK 1 and pERK 2 . HU - 210 ( 0.1 mg / kg ) decreased the number of PSA - P13591 REA - immunoreactive ( IR ) cells but did not affect the rate of proliferation , which was analyzed as the number of Ki - 67 - IR cells measured in the DG 2 days after HU - 210 administration . The data indicated that SL327 ( 30 mg / kg ) alone decreased the number of PSA - P13591 REA - IR cells 2 days after treatment . Joint administration of SL327 and HU - 210 decreased the number of PSA - P13591 REA cells more robustly than did the administration of either alone . In addition , SL327 did not decrease the number of Ki - 67 - IR cells , while pretreatment with SL327 1 h before HU - 210 administration did . These results suggest that stimulation of the P29323 REA cascade caused by P21554 REA receptor activation is not involved in hippocampal plasticity governed by PSA - P13591 REA expression .

P36888 REA inhibition as therapy in acute myeloid leukemia : a record of trials and tribulations . Acute myeloid leukemia ( AML ) is a hematologic malignancy with a poor prognosis . Approximately one quarter of the patients with AML also carry an internal tandem duplication ( ITD ) mutation in the gene encoding P07333 REA - like tyrosine kinase 3 ( P36888 REA ) , which has a significantly deleterious impact on prognosis . The ITD mutation renders P36888 REA constitutively active and leads to uncontrolled proliferation of the leukemic blast . Over the course of the last decade , a variety of compounds have been developed in preclinical and clinical studies as potent inhibitors of P36888 REA . Many of the earlier agents under investigation , such as lestaurtinib , midostaurin , and sunitinib , were initially developed as inhibitors of other tyrosine kinases and as targeted therapies in a variety of malignancies . These compounds have been demonstrated to have some efficacy in clinical trials of AML , mainly manifesting as transient decreases in circulating blasts correlating with effective in vivo suppression of the P36888 REA target . Nevertheless , the cumbersome pharmacokinetics of some compounds and the suboptimal specificity and potency of others have limited their therapeutic efficacy . In the last few years , newer , more potent and specific agents have been under investigation , with the leading example being DB05213 MEN . This agent has shown significant promise in early phases of clinical investigation , and is currently in more advanced clinical trials . Hope remains that P36888 REA inhibition will be become an effective therapeutic adjunct to our current treatment approach to AML .

Deciphering the molecular and biologic processes that mediate histone deacetylase inhibitor-induced thrombocytopenia . Histone deacetylase inhibitor ( HDACI ) - induced thrombocytopenia ( DB01520 ) is a major dose-limiting toxicity of this new class of drugs . Using preclinical models to study the molecular and biologic events that underpin this effect of HDACI , we found that C57BL / 6 mice treated with both the Q13547 REA / 2 - selective HDACI romidepsin and the pan-HDACI DB06603 MEN developed significant DB01520 . HDACI-induced DB01520 was not due to myelosuppression or reduced platelet lifespan , but to decreased platelet release from megakaryocytes . Cultured primary murine megakaryocytes showed reductions in proplatelet extensions after HDACI exposure and a dose-dependent increase in the phosphorylation of myosin light chain 2 ( MLC 2 ) . Phosphorylation of MLC to phospho-MLC ( pMLC ) and subsequent proplatelet formation in megakaryocytes is regulated by the Rho-GTPase proteins Rac 1 , P60953 REA , and RhoA . Primary mouse megakaryocytes and the human megakaryoblastic cell line Meg - 01 showed reductions in Rac 1 , P60953 REA , and RhoA protein levels after treatment with HDACIs . We were able to overcome HDACI-induced DB01520 by administering the mouse-specific thrombopoietin ( P07202 REA ) mimetic AMP - 4 , which improved platelet numbers to levels similar to untreated controls . Our report provides the first detailed account of the molecular and biologic processes involved in HDACI-mediated DB01520 . Moreover , our preclinical studies provide evidence that dose-limiting DB01520 induced by HDACIs may be circumvented using a P07202 REA mimetic .

Improving development of cloned goat embryos by supplementing α-lipoic acid to oocyte in vitro maturation medium . α-Lipoic acid ( LA ) is a powerful antioxidant for clinical therapy of some metabolic diseases , but there are few reports about the effect of LA on animal occyte in vitro maturation ( IVM ) . The objective of this study is to investigate the effect of supplementing LA to IVM medium on subsequently developmental competence of goat cloning embryos after somatic cell nucleus transfer ( SCNT ) . Twenty-five micromolars LA significantly increased 12 % oocyte maturation rate from control 57.8 % to treated group 69.8 % ( P < 0.05 ) . The reconstructed rate of cloning embryos in LA supplement group ( 67.3 % ) was significantly higher than control ( 56.5 % , P < 0.05 ) . Although the SCNT embryo cleavage rates did not have significant difference between the two groups ( 42.0 % vs . 47.9 % , P > 0.05 ) , LA supplement group had significantly higher blastocyst formation rate and hatched rate than control ( 24.0 % vs . 18.4 % and 37.0 % vs . 30.9 % , respectively , P < 0.05 ) . In addition , supplementing LA significantly reduced the cellular apoptosis rate of nucleus transfer blastocysts by inhibiting the expression of apoptotic activators , such as Bax , Bad , P42574 REA , and CytC genes and promoting cumulus-oocyte complexes to synthesize glutathione ( DB00143 MEN ) and express antioxidant enzymes such as P36969 REA and SOD genes . In conclusion , supplement of LA to oocyte IVM medium could improve the maturation rate and antioxidant ability of oocytes and increase the developmental competence of oocytes after SCNT .

Treatment with DB06603 MEN induces glucose-regulated protein 78 acetylation and endoplasmic reticulum stress in breast cancer cells . Increased levels of misfolded polypeptides in the endoplasmic reticulum ( ER ) triggers the dissociation of glucose-regulated protein 78 ( P11021 REA ) from the three transmembrane ER-stress mediators , i . e . , protein kinase RNA-like ER kinase ( Q9NZJ5 ) , activating transcription factor - 6 ( P18850 REA ) , and inositol-requiring enzyme 1alpha , which results in the adaptive unfolded protein response ( UPR ) . In the present studies , we determined that histone deacetylase - 6 ( Q9UBN7 ) binds and deacetylates P11021 REA . Following treatment with the pan-histone deacetylase inhibitor DB06603 MEN ( Novartis Pharmaceuticals ) , or knockdown of Q9UBN7 by short hairpin RNA , P11021 REA is acetylated in 11 lysine residues , which dissociates P11021 REA from Q9NZJ5 . This is associated with the activation of a lethal UPR in human breast cancer cells . Coimmunoprecipitation studies showed that binding of Q9UBN7 to P11021 REA requires the second catalytic and COOH-terminal BUZ domains of Q9UBN7 . Treatment with DB06603 MEN increased the levels of phosphorylated-eukaryotic translation initiation factor ( p-eIF 2alpha ) , P18848 REA , and CAAT / enhancer binding protein homologous protein ( P35638 REA ) . DB06603 MENMAX DB06603 MEN treatment also increased the proapoptotic Q13323 , O43521 REA , Q07812 REA , and Q16611 REA levels , as well as increased the activity of caspase - 7 . Knockdown of P11021 REA sensitized MCF - 7 cells to bortezomib and DB06603 MEN - induced UPR and cell death . These findings indicate that enforced acetylation and decreased binding of P11021 REA to Q9NZJ5 is mechanistically linked to DB06603 MEN - induced UPR and cell death of breast cancer cells . Mol Cancer Ther ; 9 ( 4 ) ; 942-52 . ( c ) 2010 AACR .

The ' allosteric modulator ' P35240 REA - 202676 disrupts G protein-coupled receptor function via sulphydryl-sensitive mechanisms . 1 . Previous studies suggest that the thiadiazole compound P35240 REA - 202676 ( N - ( 2,3- diphenyl -1,2 , 4 - thiadiazol - 5 - ( 2H ) - ylidene ) methanamine ) acts as an allosteric modulator of a variety of structurally distinct G protein-coupled receptors ( GPCRs ) . It was postulated that P35240 REA - 202676 would directly bind a structural motif in the receptor molecule common to divergent members of the GPCR family . The molecular mechanisms of such a promiscuous action , however , remain obscure . 2 . To clarify the mechanism of P35240 REA - 202676 action , we used the functional approach of [ 35S ] GTPgammaS autoradiography with rat brain cryostat sections together with classical membrane [ 35S ] GTPgammaS binding assays to evaluate how the thiadiazole affects G protein activity mediated by various receptors linked to the Gi-family of G proteins . 3 . We found that in the absence of dithiotreitol ( DTT ) , P35240 REA - 202676 ( 10 ( - 7 ) - 10 ( - 5 ) M ) elicits nonspecific effects in the [ 35S ] GTPgammaS-based G protein activation assays , thereby severely compromising interpretations on the compounds ability to allosterically inhibit receptor-mediated G protein activity . Such a nonspecific behaviour was fully reversed upon addition of DTT ( 1 mM ) , revealing thiol-based mechanism of action . 4 . In routine incubations containing DTT , P35240 REA - 202676 had no effect on receptor-driven G protein activity , as assessed for adenosine A1 , alpha 2 - adrenergic , cannabinoid P21554 REA , lysophosphatidic acid Q92633 REA , muscarinic M2 / M4 , purinergic Q9H244 REA or sphingosine 1 - phosphate receptors , suggesting that the thiadiazole does not act as an allosteric modulator of GPCR function . 5 . 1H NMR analysis indicated that P35240 REA - 202676 underwent structural changes after incubation with the reducing agent DTT or with brain tissue . 6 . We conclude that P35240 REA - 202676 modulates GPCRs via thiol modification rather than via true allosteric mechanisms .

Emerging Q9H244 REA receptor antagonists : role in coronary artery disease . The use of oral antiplatelet therapy in reducing vascular events has been extensively studied . Currently available oral antiplatelet agents include aspirin and the thienopyridine Q9H244 REA receptor antagonists . These classes are combined frequently in the setting of acute coronary syndrome and percutaneous coronary intervention ( P05154 REA ) . Resistance to either or both of these agents is a major concern , as antiplatelet resistance has been linked to an increase in thrombotic events and worse clinical outcomes . As a result , there is a need for newer , more effective antiplatelet agents to address the limitations of currently available therapy . Prasugrel , a third generation thienopyridine , has been approved by both the FDA and European Commission . Two additional Q9H244 REA agents , ticagrelor and cangrelor are in advanced stages of development . The possible advantages of prasugrel over clopidogrel include a faster onset of action , reduced inter-patient variability and more potent platelet inhibition . DB08816 is an oral reversible Q9H244 REA antagonist with greater platelet inhibition compared with clopidogrel . DB06441 MEN is being developed as an intravenous Q9H244 REA antagonist with a very fast onset and offset , which may offer advantages particularly in the setting of coronary intervention . These emerging antiplatelet agents may offer advantages such as faster onset of action , greater potency and reversibility of platelet inhibition . This article summarizes the available clinical data on the upcoming Q9H244 REA antiplatelet agents in the treatment of coronary artery disease .

Effect of vitamin E on monosodium glutamate induced hepatotoxicity and oxidative stress in rats . Monosodium glutamate ( MSG ) , administered to rats ( by gavage ) at a dose of 0.6 mg / g body weight for 10 days , significantly ( P < 0.05 ) induced lipid peroxidation ( P22079 REA ) , decreased reduced glutathione ( DB00143 MEN ) level and increased the activities of glutathione-s-transferase ( Q86UG4 ) , catalase and superoxide dismutase ( SOD ) in the liver of the animals ; these were observed 24 hr after 10 days of administration . The activities of alanine aminotransferase ( ALT ) , aspartate aminotransferase ( Q9NRA2 ) and gamma glutamyl transferase ( P19440 REA ) were also significantly increased in the serum , on MSG administration . DB00163 ( 0.2 mg / g body wt ) co-administered with MSG , significantly reduced the P22079 REA , increased the DB00143 MEN level and decreased the hepatic activities of Q86UG4 , catalase and SOD . The activities of ALT , Q9NRA2 and P19440 REA in the serum were also significantly reduced . The results showed that MSG at a dose of 0.6 mg / g body wt induced the oxidative stress and hepatotoxicity in rats and vitamin E ameliorated MSG-induced oxidative stress and hepatotoxicity .

P21554 REA gene is associated with alcohol dependence . BACKGROUND : DB00898 dependence ( AD ) vulnerability is determined by a complex array of genetic factors . Given the potential role of endocannabinoid system in AD , polymorphisms within cannabinoid receptor 1 gene ( P21554 REA ) have been potentially associated with susceptibility to this disease . We thus aimed to examine the relationship between 3 allelic variants of P21554 REA ( rs6454674 , rs1049353 , and rs806368 ) and AD . METHODS : Genotyping of the aforementioned polymorphisms was carried out by PCR in 298 male alcoholics ( 187 of them with AD ) and 155 healthy controls . Single-marker , haplotype , and interaction analysis were performed to analyze the influence of P21554 REA gene on AD susceptibility . RESULTS : We found an association between P21554 REA gene and AD after haplotype analysis . Alcoholic patients with TGT haplotype ( corresponding to rs6454674 - rs1049353 - rs806368 polymorphisms in this order ) were less prone to have AD ( p = 0.017 ) . Besides , alcoholics with a G / T substitution of the first marker ( P19440 REA haplotype ) or a C / T substitution of the third marker ( P21980 haplotype ) were more likely to develop AD ( p = 0.006 and 0.004 , respectively ) and an interaction was found between the G allele of rs6454674 single nucleotide polymorphism ( SNP ) and the C allele of rs806368 SNP ( p = 0.009 ) . CONCLUSIONS : Our findings support previously reported associations of P21554 REA with dependence to alcohol and other substances and emphasizes the relevance of endocannabinoid system in AD .

P06401 REA - mediated up-regulation of transthyretin in preimplantation mouse uterus . P02766 REA ( P02766 REA ) , a carrier for thyroxine and retinol , has its messenger RNA ( mRNA ) expressed in the glandular endometrial epithelium and its protein detected in the glandular endometrial epithelium and the uterine lumen . P02766 REA mRNA is dramatically up-regulated in the preimplantation mouse uterus as well as the P-treated ovariectomized mouse uterus , and in both situations the up-regulation of P02766 REA is blocked by treatment with the P receptor antagonist DB00834 SUB .

Serum-free differentiation of murine embryonic stem cells into alveolar type II epithelial cells . Alveolar type II ( P50052 REA ) epithelial cells have important functions including the production of surfactant and regeneration of lost alveolar type I epithelial cells . The ability of in vitro production of P50052 REA cells would offer new therapeutic options in treating pulmonary injuries and disorders including genetically based surfactant deficiencies . Aiming at the generation of P50052 REA - like cells , the differentiation of murine embryonic stem cells ( mESCs ) toward mesendodermal progenitors ( MEPs ) was optimized using a " Brachyury-eGFP-knock in " mESC line . eGFP expression demonstrated generation of up to 65 % MEPs at day 4 after formation of embryoid bodies ( EBs ) under serum-free conditions . Plated EBs were further differentiated into P50052 REA - like cells for a total of 25 days in serum-free media resulting in the expression of endodermal marker genes ( FoxA 2 , Sox 17 , P02766 REA , Q15669 REA - 1 ) and of markers for distal lung epithelium ( surfactant proteins ( SP - ) A , B , C , and D , P11684 , aquaporin 5 ) . Notably , expression of P11686 REA as the only known P50052 REA cell specific marker could be detected after serum-induction as well as under serum-free conditions . Cytoplasmic localization of P11686 REA was demonstrated by confocal microscopy . The presence of P50052 REA - like cells was confirmed by electron microscopy providing evidence for polarized cells with apical microvilli and lamellar body-like structures . Our results demonstrate the differentiation of P50052 REA - like cells from mESCs after serum-induction and under serum-free conditions . The established serum-free differentiation protocol will facilitate the identification of key differentiation factors leading to a more specific and effective generation of P50052 REA - like cells from ESCs .

Structural basis for P01133 REA receptor inhibition by the therapeutic antibody DB05774 MEN . Therapeutic anticancer strategies that target and inactivate the epidermal growth factor receptor ( P00533 REA ) are under intense study in the clinic . Here we describe the mechanism of P00533 REA inhibition by an antibody drug DB05774 MEN . DB05774 MEN is a fully human antibody that has similar antitumor potency as the chimeric cetuximab / Erbitux and might represent a safer therapeutic alternative . We report the X-ray crystal structure of the Fab fragment of DB05774 MEN ( Fab 11F8 ) in complex with the entire extracellular region and with isolated domain III of P00533 REA . We compare this to our previous study of the cetuximab / P00533 REA interaction . Fab 11F8 interacts with a remarkably similar epitope , but through a completely different set of interactions . Both the similarities and differences in binding of these two antibodies have important implications for the development of inhibitors that could exploit this same mechanism of P00533 REA inhibition .

Anandamide drives cell cycle progression through P21554 REA receptors in a rat model of synchronized liver regeneration . The endocannabinoid system , through cannabinoid receptor signaling by endocannabinoids , is involved in a wide range of functions and physiopathological conditions . To date , very little is known concerning the role of the endocannabinoids in the control and regulation of cell proliferation . An anti-proliferative action of P21554 REA signaling blockade in neurogenesis and angiogenesis argues in favor of proliferation-promoting functions of endocannabinoids through P21554 REA receptors when pro-growth signals are present . Furthermore , liver regeneration , a useful in vivo model of synchronized cell proliferation , is characterized by a peak of anandamide that elicits through P21554 REA receptor , the expression of critical mitosis genes . The aim of this study was to focus on the timing of endocannabinoid signaling changes during the different phases of the cell cycle , exploiting the rat liver regeneration model following partial hepatectomy , the most useful to study synchronized cell cycle in vivo . Hepatic regeneration led to increased levels of anandamide and endocannabinoid-like molecules oleoylethanolamide ( OEA ) and palmitoylethanolamide ( PEA ) in the P55008 phase of the cell cycle , with a concomitant increase in P21554 REA mRNA levels , whose protein expression peaked later during the S phase . Blocking of P21554 REA receptor with a low dose of the selective antagonist / inverse agonist SR141716 ( 0.7 mg / kg / dose ) affected cell cycle progression reducing the expression of P12004 REA , and through the inhibition of pERK and pSTAT 3 pathways . These results support the notion that the signaling mediated by anandamide through P21554 REA receptor may be important for the entry and progression of cells into the cell cycle and hence for their proliferation under mitogenic signals .

Biodistribution of 131I - , 186Re - , 177Lu - , and 88Y - labeled hLL 2 ( DB04958 MEN ) in nude mice with P20273 REA - positive lymphoma . Radioimmunotherapy ( Q92963 REA ) is a new and effective treatment modality in patients with non-Hodgkin ' s lymphoma . The monoclonal antibody ( mAb ) hLL 2 ( epratuzumab ) , a humanized mAb directed against the P20273 REA antigen , and which internalizes , can be labeled with various radionuclides . The biodistribution of hLL 2 labeled with ( 131 ) I , ( 186 ) Re , ( 177 ) Lu , and (8 8) Y was studied in nude mice with subcutaneous human lymphoma xenografts in order to determine the most suitable of these four radionuclides for Q92963 REA with hLL 2 . METHODS : Human Ramos lymphoma xenografts were transplanted in cyclophosphamide-pretreated athymic BALB / c mice . Four groups of mice were injected intravenously with ( 131 ) I - , ( 186 ) Re - , (8 8) Y - , or ( 177 ) Lu-labeled hLL 2 , respectively . To determine the nonspecific tumor uptake , two groups of mice received (8 8) Y-labeled or ( 131 ) I-labeled control antibody , cG250 . The biodistribution of the radiolabel was determined 1 , 3 , and 7 days postinjection ( p . i . ) . RESULTS : Radiolabeled hLL 2 had a higher tumor uptake than the nonspecific mAb at all time-points , irrespective of the radiolabel used . Tumor accretion of (8 8) Y - and ( 177 ) Lu-hLL 2 was higher than tumor uptake of ( 131 ) I - and ( 186 ) Re-hLL 2 . Activity in the bone , represented by the femur without bone marrow , was higher for ( 177 ) Lu - and (8 8) Y-hLL 2 than for ( 131 ) I - and ( 186 ) Re-hLL 2 on day 7 p . i . CONCLUSION : The use of the residualizing radiolabels (8 8) Y and ( 177 ) Lu in combination with a mAb directed against an internalizing antigen resulted in higher uptake and better retention of the radiolabel in the tumor .

P04150 REA regulates DB00171 - binding cassette transporter-A 1 expression and apolipoprotein-mediated cholesterol efflux from macrophages . OBJECTIVE : The DB00171 - binding cassette transporter-A 1 ( O95477 REA ) regulates cholesterol efflux from cells and is involved in high-density lipoprotein metabolism and atherogenesis . The objective of this study was to investigate the effect of dexamethasone ( DB00514 ) and other glucocorticoid receptor ( GR ) ligands on apolipoprotein AI-mediated cholesterol efflux from macrophages and O95477 REA expression in them . METHODS AND RESULTS : DB00514 , a GR agonist , decreased O95477 REA mRNA levels in a dose - and time-dependent fashion , and DB00834 SUB , a GR antagonist , reversed the inhibitory effect of DB00514 . The effects of DB00514 and DB00834 SUB on O95477 REA protein levels and apolipoprotein AI-mediated cholesterol efflux from the macrophages were consistent with these changes in mRNA levels . Transfected RAW 264.7 , together with a human O95477 REA promoter-luciferase construct , inhibited transcriptional activity by DB00514 and overexpression of human GR . Transrepression by GR was not mediated by liver X receptor ( LXR ) , because there were no differences in the effects of the GR ligands on promoter activity between a reporter construct with mutations at the LXR binding site and one without the mutations , and no changes were brought about in P45844 REA and Q9H172 REA expression by GR ligands . CONCLUSIONS : Our results showed that GR ligands affected O95477 REA expression and cholesterol efflux from macrophages , which are regulated by GR through a LXR-independent mechanism .

Regional selective neuronal degeneration after protein phosphatase inhibition in hippocampal slice cultures : evidence for a Q96HU1 kinase-dependent mechanism . The regional selectivity and mechanisms underlying the toxicity of the serine / threonine protein phosphatase inhibitor okadaic acid ( OA ) were investigated in hippocampal slice cultures . Image analysis of propidium iodide-labeled cultures revealed that okadaic acid caused a dose - and time-dependent injury to hippocampal neurons . Pyramidal cells in the P07451 REA region and granule cells in the dentate gyrus were much more sensitive to okadaic acid than the pyramidal cells in the P00915 REA region . Electron microscopy revealed ultrastructural changes in the pyramidal cells that were not consistent with an apoptotic process . Treatment with okadaic acid led to a rapid and sustained tyrosine phosphorylation of the mitogen-activated protein kinases P27361 REA and P28482 REA ( Q8TCB0 / 42 ( mapk ) ) . The phosphorylation was markedly reduced after treatment of the cultures with the microbial alkaloid DB02152 MEN ( a nonselective protein kinase inhibitor ) or the Q96HU1 kinase kinase ( Q02750 REA / 2 ) inhibitor PD98059 . DB02152 MEN and PD98059 also ameliorated the okadaic acid-induced cell death . Inhibitors of protein kinase C , Ca2 + / calmodulin-dependent protein kinase II , or tyrosine kinase were ineffective . These results indicate that sustained activation of the Q96HU1 kinase pathway , as seen after e . g . , ischemia , may selectively harm specific subsets of neurons . The susceptibility to Q96HU1 kinase activation of the P07451 REA pyramidal cells and dentate granule cells may provide insight into the observed relationship between cerebral ischemia and dementia in Alzheimer ' s disease .

P06401 REA - induced gene expression in primary mouse granulosa cell cultures . The progesterone receptor ( P06401 REA ) is induced by luteinizing hormone ( LH ) in granulosa cells of preovulatory follicles , and the P06401 REA - A isoform is essential for ovulation based on the phenotypes of Pgr isoform-specific knockout mice . Although several genes regulated by P06401 REA - A in vivo have been identified , whether these genes are primary targets of P06401 REA - A or if their expression also depends on other signaling molecules that are induced by the LH surge has not been resolved . Therefore , to identify genes that are either induced or repressed by P06401 REA in the absence of LH-mediated signaling cascades , we infected primary cultures of mouse granulosa cells with either P06401 REA - A or P06401 REA - B adenoviral vectors without or with R - 5020 as a P06401 REA ligand . Total RNA was extracted from infected cells at 16 h and analyzed by Affymetrix Mouse 430 2.0 microarrays . P06401 REA - A in the presence or absence of ligand significantly induced approximately 50 genes 2 - fold or more ( local pooled error test at P < or = 0.01 ) . Fewer and different genes were induced by P06401 REA - B in the absence of ligand . Edn 1 , Apoa 1 , and Cited 1 were primarily regulated by P06401 REA - A as verified by additional RT-PCR analyses , suppression by the P06401 REA antagonist DB00834 SUB , and the lack of induction by protein kinase A , protein kinase C , or epidermal growth factor ( P01133 REA ) - like factors pathways . P06401 REA regulation of these genes was confirmed further by gene expression analyses in hormonally primed Pgr mutant mouse ovaries . Because Edn 1 , Apoa 1 , and Cited 1 are known to regulate angiogenesis , P06401 REA may affect the neovascularization of follicles that is initiated with ovulation .

Acute myeloid leukemia subgroups identified by pathway-restricted gene expression signatures . Acute myeloid leukemia ( AML ) is a heterogeneous group of disorders characterized by abnormal proliferation of myeloid precursors and a maturation block . Underlying genetic lesions determine an altered expression program ( transcriptosome ) that can be studied in depth by massive technologies . Alternatively , we selected a pathway profiling strategy based on the current knowledge in order to stratify de novo AML patients and identify those cases which would potentially benefit from the use of new chemotherapeutic agents . One hundred and thirty-two RNA samples obtained from de novo adult AML patients were tested for P36888 REA , P36888 REA - LG , P52848 REA , Q92769 REA , P46100 REA , P01100 REA , P26358 REA , Q9Y6K1 REA , Q9UBC3 , NBS 1 , Q92878 REA , P49959 REA , Meis 1 and Meis 2 expression using quantitative PCR ( qPCR ) assays . Clinical and biologic findings were correlated with expression results . Cluster analysis was also performed . P36888 REA expression defined three subgroups of patients . The best outcome was found in the group with the lowest P36888 REA expression . Intermediate levels of P36888 REA were associated with the worst outcome . Patients with low levels of P46100 REA more frequently presented an adverse karyotype whereas cases with preserved P46100 REA levels showed an excellent outcome . In accordance with previous results , Meis 1 downregulation is a useful surrogate marker indicating a good prognosis in AML patients . Simple qPCR platforms may help to identify different biologic subgroups in AML .

A fully human recombinant IgG-like bispecific antibody to both the epidermal growth factor receptor and the insulin-like growth factor receptor for enhanced antitumor activity . Both the epidermal growth factor receptor ( P00533 REA ) and the insulin-like growth factor receptor ( IGFR ) have been implicated in the tumorigenesis of a variety of cancers . Here we propose that simultaneous targeting of both receptors with a bispecific antibody would lead to enhanced antitumor activity . To this end , we produced a recombinant human IgG-like bispecific antibody , a Di-diabody , using the variable regions from two antagonistic antibodies : DB05774 MEN to P00533 REA and DB05759 to IGFR . The Di-diabody binds to both P00533 REA and IGFR and effectively blocked both P01133 REA - and IGF-stimulated receptor activation and tumor cell proliferation . The Di-diabody also inherited the biological properties from both of its parent antibodies ; it triggers rapid and significant IGFR internalization and degradation and mediates effective antibody-dependent cellular cytotoxicity in a variety of tumor cells . Finally , the Di-diabody strongly inhibited the growth of two different human tumor xenografts in vivo . Our results underscore the benefits of simultaneous targeting of two tumor targets with bispecific antibodies .

Translocation ( 3 ; 5 ) ( Q9Y3Q3 REA ; q13 ) in a patient with chronic T-cell lymphoproliferative disorder . A 67 - year-old patient with large granular lymphocyte ( LGL ) leukemia is described . At fluorescence-activated cell sorting ( FACS ) analysis of the peripheral blood , the lymphocytes were positive for CD3 , P01730 REA , P06127 , CD29 , CD45RA , CD57 , and TCR alpha / beta and negative for P09564 , CD8 , CD16 , CD56 , P15391 REA , P20273 REA , and TCR gamma / delta . Bone marrow histology and immunohistochemistry did not reveal any lymphocyte infiltration . Cytogenetic examination of peripheral blood cultures showed a clone with the karyotype 46 , XY , t ( 3 ; 5 ) ( Q9Y3Q3 REA ; q13 ) . Molecular analysis revealed rearrangement of the gamma-T-cell-receptor chain . The region 3p25 - 3p26 which harbors the von Hippel-Lindau tumor suppressor gene and the P04049 REA oncogene has been rearranged in a few cases of T-cell leukemia . The translocation in this case has not yet been described and may reflect an alternative mechanism in the pathogenesis of these disorders .

DB04958 MEN - SN - 38 : a new antibody-drug conjugate for the therapy of hematologic malignancies . We previously found that slowly internalizing antibodies conjugated with SN - 38 could be used successfully when prepared with a linker that allows approximately 50 % of the IgG-bound SN - 38 to dissociate in serum every 24 hours . In this study , the efficacy of SN - 38 conjugates prepared with epratuzumab ( rapidly internalizing ) and veltuzumab ( slowly internalizing ) , humanized anti - P20273 REA and anti - P11836 IgG , respectively , was examined for the treatment of B-cell malignancies . Both antibody-drug conjugates had similar nanomolar activity against a variety of human lymphoma / leukemia cell lines , but slow release of SN - 38 compromised potency discrimination in vitro even against an irrelevant conjugate . When SN - 38 was stably linked to the anti - P20273 REA conjugate , its potency was reduced 40 - to 55 - fold . Therefore , further studies were conducted only with the less stable , slowly dissociating linker . In vivo , similar antitumor activity was found between P20273 REA and P11836 antibody-drug conjugate in mice-bearing Ramos xenografts , even though Ramos expressed 15 - fold more P11836 than P20273 REA , suggesting that the internalization of the epratuzumab-SN - 38 conjugate ( Emab-SN - 38 ) enhanced its activity . Emab-SN - 38 was more efficacious than a nonbinding , irrelevant IgG-SN - 38 conjugate in vivo , eliminating a majority of well-established Ramos xenografts at nontoxic doses . In vitro and in vivo studies showed that Emab-SN - 38 could be combined with unconjugated veltuzumab for a more effective treatment . Thus , Emab-SN - 38 is active in lymphoma and leukemia at doses well below toxic levels and therefore represents a new promising agent with therapeutic potential alone or combined with anti - P11836 antibody therapy .

Expression of renin-angiotensin system components in the early bovine embryo . The renin-angiotensin system ( DB01367 ) , mainly associated with the regulation of blood pressure , has been recently investigated in female reproductive organs and the developing foetus . Angiotensin II ( Ang II ) influences oviductal gamete movements and foetal development , but there is no information about DB01367 in the early embryo . The aim of this study was to determine whether DB01367 components are present in the pre-implantation embryo , to determine how early they are expressed and to investigate their putative role at this stage of development . Bovine embryos produced in vitro were used for analysis of DB01367 transcripts ( RT-PCR ) and localisation of the receptors P30556 REA and P50052 REA ( immunofluorescent labelling ) . We also investigated the effects of Ang II , DB00275 MEN ( P30556 REA antagonist ) and PD123319 ( P50052 REA antagonist ) on oocyte cleavage , embryo expansion and hatching . Pre-implanted embryos possessed P30556 REA and P50052 REA but not the other DB01367 components . Both receptors were present in the trophectoderm and in the inner cell mass of the blastocyst . P30556 REA was mainly localised in granular-like structures in the cytoplasm , suggesting its internalisation into clathrin-coated vesicles , and P50052 REA was found mainly in the nuclear membrane and in the mitotic spindle of dividing trophoblastic cells . Treating embryos with PD123319 increased the proportion of hatched embryos compared with the control . These results , the first on DB01367 in the early embryo , suggest that the pre-implanted embryo responds to Ang II from the mother rather than from the embryo itself . This may be a route by which the maternal DB01367 influences blastocyst hatching and early embryonic development .

The cannabinoid agonist WIN 55,212- 2 suppresses opioid-induced emesis in ferrets . BACKGROUND : Cannabinoid receptor agonists reverse nausea and vomiting produced by chemotherapy and radiation therapy in animals and humans but have not been tested against opioid-induced emesis . This study tests the hypothesis that cannabinoid receptor agonists will prevent opioid-induced vomiting . METHODS : Twelve male ferrets were used . They weighed 1 . P35326 REA . 6 kg at the beginning and 1.8- 2.3 kg at the end of the experiments . All drugs were injected subcutaneously . WIN 55,212- 2 , a mixed P21554 REA - CB2 cannabinoid receptor agonist , was administered 25 min before morphine . Retches and vomits were counted at 5 - min intervals for 30 min after morphine injection . RESULTS : Retching and vomiting responses increased with increasing morphine doses up to 1.0 mg / kg , above which the responses decreased . Previous administration of naloxone prevented morphine-induced retching and vomiting . WIN 55,212- 2 dose-dependently reduced retching and vomiting . The ED50 was 0.05 mg / kg for retches and 0.03 mg / kg for vomits . At 0.13 mg / kg , retching decreased by 76 % and vomiting by 92 % . AM251 , a P21554 REA receptor-selective antagonist , blocked the antiemetic actions of WIN 55,212- 2 , but AM630 , a CB2 receptor-selective antagonist , did not . CONCLUSIONS : These results demonstrate that WIN 55,212- 2 prevents opioid-induced vomiting and suggest that the antiemetic activity of WIN 55,212- 2 occurs at P21554 REA receptors . This is consistent with findings that P21554 REA receptors are the predominant cannabinoid receptors in the central nervous system and that antiemetic effects of cannabinoids appear to be centrally mediated .

Comparison of effects of olmesartan and telmisartan on blood pressure and metabolic parameters in Japanese early-stage type - 2 diabetics with hypertension . P30556 REA blockers ( ARBs ) are regarded as first-line treatments for type - 2 diabetes with hypertension . Despite the availability of various types of ARBs , there are no comparative studies of their effects on patients with diabetes . In this open-label prospective crossover study , we compared the effects of olmesartan ( 20 mg / day ) and telmisartan ( 40 mg / day ) . Twenty Japanese early-stage type - 2 diabetes patients with hypertension treated with valsartan ( 80 mg / day ) for at least 8 weeks were recruited to this study . At study entry , valsartan was changed to olmesartan ( 20 mg / day ) or telmisartan ( 40 mg / day ) and administered for 8 weeks . The drugs were then switched and treatment was continued for another 8 weeks . We analyzed the blood pressure lowering effects of each drug by 24 - h ambulatory blood pressure monitoring at 0 , 8 , and 16 weeks . Simultaneously , we measured metabolic parameters and inflammation markers . DB00275 MEN lowered mean systolic and diastolic blood pressure more significantly than did telmisartan . While there were no differences between the groups in metabolic parameters , including HbA 1c and adiponectin , the decreases in serum interleukin - 6 and highly sensitive P02741 REA were more significant by olmesartan treatment . Our results indicate that olmesartan has more potent arterial blood pressure lowering and anti-inflammatory effects than telmisartan .