MH_dev_336

Q03135 REA interacts with 5 - Q13049 REA serotonin receptors and profoundly modulates the signaling of selected Galphaq-coupled protein receptors . 5 - Hydroxytryptamine 2A ( 5 - HT ( 2A ) ) serotonin receptors are important for a variety of functions including vascular smooth muscle contraction , platelet aggregation , and the modulation of perception , cognition , and emotion . In a search for 5 - HT ( 2A ) receptor-interacting proteins , we discovered that caveolin - 1 ( Cav - 1 ) , a scaffolding protein enriched in caveolae , complexes with 5 - HT ( 2A ) receptors in a number of cell types including P13671 REA glioma cells , transfected P29320 REA - 293 cells , and rat brain synaptic membrane preparations . To address the functional significance of this interaction , we performed RNA interference-mediated knockdown of Cav - 1 in P13671 REA glioma cells , a cell type that endogenously expresses both 5 - HT ( 2A ) receptors and Cav - 1 . We discovered that the in vitro knockdown of Cav - 1 in P13671 REA glioma cells nearly abolished 5 - HT ( 2A ) receptor-mediated signal transduction as measured by calcium flux assays . RNA interference-mediated knockdown of Cav - 1 also greatly attenuated endogenous Galpha ( q ) - coupled P2Y purinergic receptor-mediated signaling without altering the signaling of P25116 REA thrombin receptors . Cav - 1 appeared to modulate 5 - HT ( 2A ) signaling by facilitating the interaction of 5 - HT ( 2A ) receptors with Galpha ( q ) . These studies provide compelling evidence for a prominent role of Cav - 1 in regulating the functional activity of not only 5 - HT ( 2A ) serotonin receptors but also selected Galpha ( q ) - coupled receptors .

Thrombin receptors and their antagonists : an update on the patent literature . IMPORTANCE OF THE FIELD : Thrombin plays a central role in cardiovascular inflammation . Most of the cellular responses to thrombin are mediated by cell surface protease-activated receptors ( PARs ) . Several preclinical studies indicate that PARs are potential targets for treating cardiovascular diseases such as thrombosis , atherosclerosis and restenosis . Among PARs , P25116 REA has emerged as an important therapeutic target . AREAS COVERED IN THIS REVIEW : This review covers recent advances in the development of thrombin receptors antagonists . It is focused on the search for P25116 REA antagonists as this is at the moment the most promising and attractive target . However , some early promising studies on PAR - 3 and - 4 antagonists are also reported . WHAT THE READER WILL GAIN : The review has been written in order to give to the reader hints and references that cover , in our opinion , the most interesting and / or promising approaches in this research field . TAKE HOME MESSAGE : Research on P25116 REA antagonists has finally led to good clinical candidates such as DB05692 MEN ( Schering-Plough ) and E - 5555 ( Eisai Co . ) . Clinical trials clearly demonstrate that development of PAR 1 antagonists is not only possible but most likely will lead to development of antiplatelet drugs as well as of drugs useful for the treatment of inflammatory , proliferative and neurodegenerative diseases .

Activation of large-conductance , Ca2 + - activated K + channels by cannabinoids . We have examined the effects of the cannabinoid anandamide ( AEA ) and its stable analog , methanandamide ( methAEA ) , on large-conductance , Ca2 + - activated K + ( BK ) channels using human embryonic kidney ( P29320 REA ) - 293 cells , in which the alpha-subunit of the Q12791 REA ( BK-alpha ) , both alpha - and beta 1 - subunits ( BK-alphabeta 1 ) , or both alpha - and beta 4 - subunits ( BK-alphabeta 4 ) were heterologously expressed . In a whole cell voltage-clamp configuration , each cannabinoid activated BK-alphabeta 1 within a similar concentration range . Because methAEA could potentiate BK-alpha , BK-alphabeta 1 , and BK-alphabeta 4 with similar efficacy , the beta-subunits may not be involved at the site of action for cannabinoids . Under cell-attached patch-clamp conditions , application of methAEA to the bathing solution increased Q12791 REA activity ; however , methAEA did not alter channel activity in the excised inside-out patch mode even when DB00171 was present on the cytoplasmic side of the membrane . Application of methAEA to P29320 REA - BK-alpha and P29320 REA - BK-alphabeta 1 did not change intracellular Ca2 + concentration . Moreover , methAEA-induced potentiation of Q12791 REA currents was not affected by pretreatment with a P21554 REA antagonist ( AM251 ) , modulators of G proteins ( cholera and pertussis toxins ) or by application of a selective CB2 agonist ( JWH 133 ) . Inhibitors of P62158 , PKG , and MAPKs ( W7 , KT5823 , and PD - 98059 ) did not affect the potentiation . Application of methAEA to mouse aortic myocytes significantly increased Q12791 REA currents . This study provides the first direct evidence that unknown factors in the cytoplasm mediate the ability of endogenous cannabinoids to activate Q12791 REA currents . Cannabinoids may be hyperpolarizing factors in cells , such as arterial myocytes , in which BK channels are highly expressed .

Role of cyclooxygenase - 2 in the prolonged regulation of renal function . The role of cyclooxygenase - 2 ( P35354 REA ) in the prolonged regulation of renal function was evaluated during changes in sodium intake and reduction of NO synthesis . It was evaluated in conscious dogs by administering a selective inhibitor ( nimesulide ) during 8 consecutive days . DB04743 MEN administration to dogs with normal or high sodium load did not modify glomerular filtration rate but reduced renal blood flow ( 16 % ; P < 0.05 ) . The vasoconstriction elicited by P35354 REA inhibition was greater when NO production was inhibited because glomerular filtration rate decreased by > 25 % when nimesulide was administered to dogs with a reduced NO synthesis . During low sodium intake , P35354 REA inhibition elicited a decrease ( P < 0.05 ) of both glomerular filtration rate ( 34 % ) and renal blood flow ( 31 % ) . Sodium excretion only decreased ( P < 0.05 ) during the first day of P35354 REA inhibition in dogs with normal or high sodium load . The increase in plasma potassium levels elicited by P35354 REA inhibition was greater in dogs with low sodium intake and was enhanced when NO production was inhibited . This change in potassium was not secondary to a decrease in plasma aldosterone levels . The results of this study suggest that P35354 REA - derived metabolites ( 1 ) play a more important role in the long-term regulation of renal hemodynamic when sodium intake is low , ( 2 ) protect the renal vasculature from the vasoconstriction secondary to a reduction in NO , ( 3 ) are only acutely involved in regulating urinary sodium excretion , and ( 4 ) play a more important role in regulating plasma potassium concentration when NO synthesis is reduced .

Skinned coronary smooth muscle : calmodulin , calcium antagonists , and DB02527 influence contractility . The effects of Ca2 + , calmodulin , DB02527 , the catalytic subunit of DB02527 - dependent protein kinase ( CSU ) and some Ca2 + antagonists were studied in chemically ( Triton X - 100 ) skinned coronary smooth muscle . P62158 increased the Ca2 + responsiveness of the muscle fiber as indicated by the reduction in the threshold as well as the half-maximal activating Ca2 + concentration . DB00831 MENMAX DB00831 MEN , a calmodulin antagonist , inhibited Ca2 + - calmodulin-induced contraction . Both DB02527 and CSU were effective inhibitors of contraction induced at an intermediate Ca2 + concentration . DB08980 , a Ca2 + - antagonist , at 2 x 10 ( - 4 ) M produced a significant inhibitory effect , which was reduced by increasing the Ca2 + concentration . From other Ca2 + antagonists tested , W - 7 , but not D600 and verapamil , produced some inhibitory effect . The data indicate that the response of skinned coronary smooth muscle to Ca2 + , calmodulin and DB02527 are similar to those obtained with other skinned smooth muscles . Furthermore , skinned fiber preparation can serve as a useful tool to investigate possible direct effects of drugs on the activating and regulatory systems in smooth muscle .

Molecular components and functions of the endocannabinoid system in mouse prefrontal cortex . BACKGROUND : Cannabinoids have deleterious effects on prefrontal cortex ( P27918 REA ) - mediated functions and multiple evidences link the endogenous cannabinoid ( endocannabinoid ) system , cannabis use and schizophrenia , a disease in which P27918 REA functions are altered . Nonetheless , the molecular composition and the physiological functions of the endocannabinoid system in the P27918 REA are unknown . METHODOLOGY / PRINCIPAL FINDINGS : Here , using electron microscopy we found that key proteins involved in endocannabinoid signaling are expressed in layers v / vi of the mouse prelimbic area of the P27918 REA : presynaptic cannabinoid P21554 REA receptors ( CB1R ) faced postsynaptic P41594 REA while diacylglycerol lipase alpha ( Q9Y4D2 REA ) , the enzyme generating the endocannabinoid 2 - arachidonoyl-glycerol ( 2 - AG ) was expressed in the same dendritic processes as P41594 REA . Activation of presynaptic CB1R strongly inhibited evoked excitatory post-synaptic currents . Prolonged synaptic stimulation at 10Hz induced a profound long-term depression ( LTD ) of layers V / VI excitatory inputs . The endocannabinoid - LTD was presynaptically expressed and depended on the activation of postsynaptic P41594 REA , phospholipase C and a rise in postsynaptic Ca ( 2 + ) as predicted from the localization of the different components of the endocannabinoid system . Blocking the degradation of 2 - AG ( with Q76M96 602 ) but not of anandamide ( with Q76M96 597 ) converted subthreshold tetanus to LTD-inducing ones . Moreover , inhibiting the synthesis of 2 - AG with DB01083 , blocked endocannabinoid-mediated LTD . All together , our data show that 2 - AG mediates LTD at these synapses . CONCLUSIONS / SIGNIFICANCE : Our data show that the endocannabinoid - retrograde signaling plays a prominent role in long-term synaptic plasticity at the excitatory synapses of the P27918 REA . Alterations of endocannabinoid - mediated synaptic plasticity may participate to the etiology of P27918 REA - related pathologies .

Inactivation of caspase - 1 in rodent brain : a novel anticonvulsive strategy . PURPOSE : Cytokines and related inflammatory mediators are rapidly synthesized in the brain during seizures . We previously found that intracerebral administration of interleukin - 1 ( IL - 1 ) - beta has proconvulsant effects , whereas its endogenous receptor antagonist ( IL - 1Ra ) mediates potent anticonvulsant actions in various models of limbic seizures . In this study , we investigated whether seizures can be effectively inhibited by blocking the brain production of IL - 1beta , by using selective inhibitors of interleukin-converting enzyme ( ICE / caspase - 1 ) or through caspase - 1 gene deletion . METHODS : P29466 REA was selectively blocked by using pralnacasan or DB05507 MEN . IL - 1beta release was induced in mouse organotypic hippocampal slice cultures by proinflammatory stimuli [ lipopolysaccharide ( LPS ) + adenosine triphosphate ( DB00171 ) ] and measured with enzyme-linked immunosorbent assay ( ELISA ) . IL - 1beta production during seizures was measured in the rat hippocampus by Western blot . Seizures were induced in freely moving mice and rats by intrahippocampal injection of kainic acid and recorded by EEG analysis . RESULTS : P29466 REA inhibition reduced the release of IL - 1beta in organotypic slices exposed to LPS + DB00171 . Administration of pralnacasan ( intracerebroventricular , 50 microg ) or DB05507 MEN ( intraperitoneal , 25-200 mg / kg ) to rats blocked seizure-induced production of IL - 1beta in the hippocampus , and resulted in a twofold delay in seizure onset and 50 % reduction in seizure duration . Mice with caspase - 1 gene deletion showed a 70 % reduction in seizures and an approximate fourfold delay in their onset . CONCLUSIONS : Inhibition of caspase - 1 represents an effective and novel anticonvulsive strategy , which acts by selectively reducing the brain availability of IL - 1beta .

P21554 REA inhibition improves cardiac function and remodelling after myocardial infarction and in experimental metabolic syndrome . The cannabinoid receptors , P21554 REA and CB2 , are expressed in the heart , but their role under pathological conditions remains controversial . This study examined the effect of P21554 REA receptor blockade on cardiovascular functions after experimental MI and in experimental metabolic syndrome . MI was induced in Wistar rats by permanent ligation of the left coronary artery . Treatment with the P21554 REA receptor antagonist rimonabant ( 10 mg / kg i . p . daily ) started 7 days before or 6 h after MI and continued for 6 weeks . Haemodynamic parameters were measured via echocardiography and intracardiac Samba catheter . P21554 REA blockade improved systolic and diastolic heart function , decreased cardiac collagen and hydroxyproline content and down-regulated TGF-β 1 . Additionally , rimonabant decreased arterial stiffness , normalised QRS complex duration and reduced brain natriuretic peptide levels in serum . In primary cardiac fibroblasts , rimonabant decreased P14780 REA activity and TGF-β 1 expression . Furthermore , rimonabant improved depressed systolic function of spontaneously hypertensive obese rats and reduced weight gain . Blocking of P21554 REA receptor with rimonabant improves cardiac functions in the early and late stages after MI , decreases arterial stiffness and reduces cardiac remodelling . DB06155 also has cardioprotective actions in rats characterised by the metabolic syndrome . Inhibition of proteolysis and TGF-β 1 expression and reduced collagen content by rimonabant may attenuate destruction of the extracellular matrix and decrease fibrosis after MI .

Administration of adenosine diphosphate-ribosyl transferase antagonist allows in vivo control of anti-dinitrophenyl response . DB03073 MEN ( 3MB ) is one of a series of chemical inhibitors of the nuclear enzyme adenosine diphosphate ( ADP ) - ribosyl transferase ( P09874 REA ) , which has been shown to inhibit cell differentiation in vitro , but has no effect on differentiation independent proliferation . Treatment of mice with an optimal concentration of 3MB ( 20 mg / kg body weight ) at or 1 day after dinitrophenyl-keyhole limpet haemocyanin ( DNP-KLH ) immunisation reduced anti-DNP plaque-forming cell ( P27918 REA ) numbers to less than 10 % of those of control animals . The period for maximum P27918 REA suppression showed a narrow time window relative to immunisation , suggesting that in vivo , as in vitro , 3 MB was acting only on those lymphocytes differentiating in response to antigen . Experimental findings showed that it was possible to select for P27918 REA derived from different populations of DNP-responsive lymphocytes by adjusting the time of 3MB treatment relative to immunisation . When 3MB was used with antigen priming , the residual P27918 REA showed a lower average affinity than P27918 REA in mice treated with 3MB 3 days after priming , suggesting a differential selection of those lymphocytes responding either ' early ' or ' late ' in the primary immune response .

DB05387 MEN ( AEterna ) . AEterna is developing DB05387 MEN , an angiogenesis inhibitor derived from the ultrafiltration of liquid shark cartilage , with matrix metalloprotease ( MMP ) - 2 , P14780 REA and vascular endothelial growth factor inhibitory properties , for the potential treatment of non-small-cell lung cancer .

P29466 REA and caspase - 8 cleave and inactivate cellular parkin . Lesions in the parkin gene cause early onset Parkinson ' s disease by a loss of dopaminergic neurons , thus demonstrating a vital role for parkin in the survival of these neurons . O60260 REA is inactivated by caspase cleavage , and the major cleavage site is after Asp 126 . Caspases responsible for parkin cleavage were identified by several experimental paradigms . Transient coexpression of caspases and wild type parkin in P29320 REA - 293 cells identified caspase - 1 , - 3 , and - 8 as efficient inducers of parkin cleavage whereas caspase - 2 , - 7 , - 9 , and - 11 did not induce cleavage . A D126A parkin mutation abrogates cleavage induced by caspase - 1 and - 8 , but not by caspase - 3 . In anti-Fas-treated Jurkat T cells , parkin cleavage was inhibited by caspase inhibitors hFlip and CrmA ( but not by X-linked inhibitor of apoptosis ( P98170 REA ) ) , indicating that caspase - 8 ( but not caspase - 3 ) is responsible for the parkin cleavage in this model . Moreover , induction of apoptosis in caspase - 3 - deficient MCF 7 cells , either by caspase - 1 or - 8 overexpression or by tumor necrosis factor-alpha treatment , led to parkin cleavage . These results demonstrate that caspase - 1 and - 8 can directly cleave parkin and suggest that death receptor activation and inflammatory stress can cause loss of the ubiquitin ligase activity of parkin , thus causing accumulation of toxic parkin substrates and triggering dopaminergic cell death .

DB08901 MEN is active against imatinib-resistant mutants of Q6UN15 - P16234 REA and P10721 REA , and against P11362 REA - derived fusion kinases .

Role of phospholipase D2 in the agonist-induced and constitutive endocytosis of G-protein coupled receptors . We have recently shown that the mu-opioid receptor [ P35372 REA , also termed mu-opioid peptide ( MOP ) receptor ] is associated with the phospholipase D2 ( O14939 REA ) , a phospholipid-specific phosphodiesterase located in the plasma membrane . We further demonstrated that , in human embryonic kidney ( P29320 REA ) 293 cells co-expressing P35372 REA and O14939 REA , treatment with ( D-Ala 2 , Me Phe 4 , Glyol 5 ) enkephalin ( DAMGO ) led to an increase in O14939 REA activity and an induction of receptor endocytosis , whereas morphine , which does not induce opioid receptor endocytosis , failed to activate O14939 REA . In contrast , a C-terminal splice variant of the mu-opioid receptor ( MOR 1D , also termed MOP ( 1D ) ) exhibited robust endocytosis in response to both DAMGO and morphine treatment . We report here that MOR 1D also mediates an agonist-independent ( constitutive ) O14939 REA - activation facilitating agonist-induced and constitutive receptor endocytosis . Inhibition of O14939 REA activity by over-expression of a dominant negative O14939 REA ( nPLD 2 ) blocked the constitutive O14939 REA activation and impaired the endocytosis of MOR 1D receptors . Moreover , we provide evidence that the endocytotic trafficking of the delta-opioid receptor [ Q8IXH6 , also termed delta-opioid peptide ( DOP ) receptor ] and cannabinoid receptor isoform 1 ( P21554 REA ) is also mediated by a O14939 REA - dependent pathway . These data indicate the generally important role for O14939 REA in the regulation of agonist-dependent and agonist-independent G protein-coupled receptor ( GPCR ) endocytosis .

AM2389 , a high-affinity , in vivo potent P21554 REA - receptor-selective cannabinergic ligand as evidenced by drug discrimination in rats and hypothermia testing in mice . RATIONALE : The endocannabinoid signaling system ( ECS ) has been targeted for developing novel therapeutics since ECS dysfunction has been implicated in various pathologies . Current focus is on chemical modifications of the hexahydrocannabinol ( HHC ) nabilone ( DB00486 SUB ( ® ) ) . OBJECTIVE : To characterize the novel , high-affinity cannabinoid receptor 1 ( CB ( 1 ) R ) HHC-ligand AM2389 [ 9β - hydroxy - 3 - ( 1 - hexyl-cyclobut - 1 - yl ) - hexahydrocannabinol in two rodent pre-clinical assays . MATERIALS AND METHODS : CB ( 1 ) R mediation of AM2389 - induced hypothermia in mice was evaluated with AM251 , a CB ( 1 ) R-selective antagonist / inverse agonist . Additionally , two groups of rats discriminated the full cannabinergic aminoalkylindole AM5983 ( 0.18 and 0.56 mg / kg ) from vehicle 20 min post-injection in a two-choice operant conditioning task motivated by 0.1 % saccharin / water . Generalization / substitution tests were conducted with AM2389 , AM5983 , and Δ ( 9 ) - tetrahydrocannabinol ( Δ ( 9 ) - THC ) . RESULTS : Δ ( 9 ) - THC ( 30 mg / kg ) - induced hypothermia exhibited a faster onset and shorter duration of action compared with AM2389 ( 0.1 and 0.3 mg / kg ) . AM251 ( 3 and 10 mg / kg ) attenuated / blocked hypothermia induced by 0.3 mg / kg AM2389 . In drug discrimination , the order of potency was AM2389 > AM5983 > Δ ( 9 ) - THC with ED ( 50 ) values of 0.0025 , 0.0571 , and 0.2635 mg / kg , respectively , in the low-dose condition . The corresponding ED ( 50 ) values in the high-dose condition were 0.0069 , 0.1246 , and 0.8438 mg / kg , respectively . Onset of the effects of AM2389 was slow with a protracted time-course ; the functional , perceptual in vivo half-life was approximately 17 h . CONCLUSIONS : This potent cannabinergic HHC exhibited a slow onset of action with a protracted time-course . The AM2389 chemotype appears well suited for further drug development , and AM2389 currently is used to probe behavioral consequences of sustained ECS activation .

Safety profile of maraviroc in patients coinfected with HIV - 1 and hepatitis B or C included in the maraviroc expanded access program . OBJECTIVE : To evaluate the safety of maraviroc with other antiretrovirals in patients with HIV - 1 coinfected with hepatitis B virus ( HBV ) or hepatitis C virus ( HCV ) . METHODS : This was a multicenter , noncomparative , open-label , expanded access program ( EAP ) initiated in February 2007 . Patients with P51681 REA - tropic HIV - 1 and HIV - 1 RNA ≥ 1000 copies / mL on their current treatment received maraviroc 300 mg ( 150 mg with protease inhibitors ) twice daily with optimized background therapy ( OBT ) , which could include the newer agents raltegravir , etravirine , and darunavir . The adverse event ( AE ) profile was compared with the active and placebo arms of the maraviroc phase III clinical trials MOTIVATE 1 and 2 , where the OBT did not include these agents . RESULTS : A total of 1,032 patients were enrolled : 51 HIV / HBV coinfected ; 149 HIV / HCV coinfected , 9 HIV / HBV / HCV coinfected , and 823 HIV - 1 monoinfected . Most ( 76 % ) received at least 1 newer agent . Overall AE frequency was comparable across coinfection groups ( 63 % - 72 % ) . Hepatobiliary events were more common in HIV / HCV coinfection than in HIV monoinfection or HIV / HBV coinfection ( 10.0 , 4.8 , and 3.1 per 100 patient-years , respectively ) . Across all coinfection groups , there was a trend toward lower exposure-adjusted rates of serious and hepatobiliary AEs in the EAP than in the MOTIVATE studies . Grade 3/4 transaminase elevations in patients receiving maraviroc in the EAP and MOTIVATE were comparable with those seen in the MOTIVATE placebo arm . CONCLUSION : DB04835 MEN plus an OBT did not increase the incidence of AEs or severe laboratory liver abnormalities in HIV - 1 - infected patients coinfected with HBV or HCV .

Cannabinoid 1 receptor-dependent transactivation of fibroblast growth factor receptor 1 emanates from lipid rafts and amplifies extracellular signal-regulated kinase 1/2 activation in embryonic cortical neurons . G-protein coupled receptors may mediate their effects on neuronal growth and differentiation through activation of extracellular signal-regulated kinases 1/2 ( P27361 REA / 2 ) , often elicited by transactivation of growth factor receptor tyrosine kinases . This elaborate signaling process includes inducible formation and trafficking of multiprotein signaling complexes and is facilitated by pre-ordained membrane microdomains , in particular lipid rafts . In this study , we have uncovered novel signaling interactions of cannabinoid receptors with fibroblast growth factor receptors , which depended on lipid rafts and led to P27361 REA / 2 activation in primary neurons derived from chick embryo telencephalon . More specifically , the cannabinoid 1 receptor ( CB1R ) agonist methanandamide induced tyrosine phosphorylation and transactivation of fibroblast growth factor receptor ( FGFR ) 1 via Src and Fyn , which drove an amplification wave in P27361 REA / 2 activation . Transactivation of P11362 REA was accompanied by the formation of a protein kinase C ε-dependent multiprotein complex that included CB1R , Fyn , Src , and P11362 REA . Recruitment of molecules increased with time of exposure to methanandamide , suggesting that in addition to signaling it also served trafficking of receptors . Upon agonist stimulation we also detected a rapid incorporation of CB1R , as well as activated Src and Fyn , and P11362 REA in lipid rafts . Most importantly , lipid raft integrity was a pre-requisite for CB1R - dependent complex formation . Our data provide evidence that lipid rafts may organize P21554 REA receptor proximal signaling events , namely activation of Src and Fyn , and transactivation of P11362 REA towards activation of P27361 REA / 2 and induction of neuronal differentiation .

Synthesis and biological evaluation of novel oxindole-based RTK inhibitors as anti-cancer agents . Given that receptor tyrosine kinases ( RTKs ) have emerged as key regulators of all aspects of cancer development , including proliferation , invasion , angiogenesis and metastasis , the RTK family represents an important therapeutic target for anti-cancer drug development . Oxindole structure has been used in RTK inhibitors such as DB02058 MEN and intedanib . In this study , two series of new heterocyclic compounds containing oxindole scaffold have been designed and synthesized , and their inhibitory activity against the proliferation of nine cancer cell lines has been evaluated . Among them , compounds 9a and 9b displayed the strongest anti-proliferative activity with the IC50s below 10μM . Flow cytometric analysis showed that the compounds 9a and 9b dose-dependently arrested the cell cycle at G0 / P55008 phase . Although the leading compounds DB02058 MEN and intedanib targets P11362 REA , the kinase activity test revealed that these compounds only showed slight inhibitory activity on P11362 REA kinase . Further enzymatic test aided by molecular docking simulation in the DB00171 - binding site demonstrated that 9a and 9b are potent inhibitors of c-Kit kinase . These compounds are worthy of further evaluation as anticancer agents .

Inhibition of cyclooxygenase - 2 elicits a P21554 REA - mediated decrease of excitatory transmission in rat P00915 REA hippocampus . Cannabinoid receptor ( P21554 REA ) ligands decrease excitatory and inhibitory transmission in the hippocampus , but the influence of endogenously formed cannabinoids ( eCBs ) on basal excitatory transmission remains uncertain . Here , we investigated the influence of eCBs on synaptic transmission in P00915 REA hippocampus using the slice preparation . Blockade of P21554 REA with the selective receptor antagonists SR141716 ( rimonabant ) or AM251 augmented synaptic responses evoked upon stimulation of the Schaffer collaterals . This effect persisted in the presence of bicuculline or CGP 55845 to block GABA ( A ) or GABA ( B ) receptors , revealing a tonic eCB influence on excitatory transmission . Selective inhibition of cyclooxygenase - 2 ( P35354 REA ) with meloxicam or NS - 398 decreased excitatory responses partly in a P21554 REA - dependent manner , independently of GABA ( A ) transmission . Paired-pulse paradigms suggested a presynaptic P21554 REA mechanism to decrease glutamate release . Inhibition of P23219 REA or other routes of eCB degradation did not affect synaptic transmission . We conclude that P35354 REA regulates the formation of P21554 REA ligands that decrease hippocampal excitatory transmission .

Δ ( 9 ) - DB00470 treatment during human monocyte differentiation reduces macrophage susceptibility to HIV - 1 infection . The major psychoactive component of marijuana , Δ ( 9 ) - tetrahydrocannabinol ( THC ) , also acts to suppress inflammatory responses . Receptors for THC , P21554 REA , CB2 , and Q9Y2T6 REA , are differentially expressed on multiple cell types including monocytes and macrophages , which are important modulators of inflammation in vivo and target cells for HIV - 1 infection . Use of recreational and medicinal marijuana is increasing , but the consequences of marijuana exposure on HIV - 1 infection are unclear . Ex vivo studies were designed to investigate effects on HIV - 1 infection in macrophages exposed to THC during or following differentiation . THC treatment of primary human monocytes during differentiation reduced HIV - 1 infection of subsequent macrophages by replication competent or single cycle P51681 REA using viruses . In contrast , treatment of macrophages with THC immediately prior to or continuously following HIV - 1 exposure failed to alter infection . Specific receptor agonists indicated that the THC effect during monocyte differentiation was mediated primarily through CB2 . THC reduced the number of p24 positive cells with little to no effect on virus production per infected cell , while quantitation of intracellular viral gag pinpointed the THC effect to an early event in the viral life cycle . Cells treated during differentiation with THC displayed reduced expression of P08571 REA , CD16 , and Q86VB7 and donor dependent increases in mRNA expression of selected viral restriction factors , suggesting a fundamental alteration in phenotype . Ultimately , the mechanism of THC suppression of HIV - 1 infection was traced to a reduction in cell surface HIV receptor ( P01730 REA , P51681 REA and P61073 REA ) expression that diminished entry efficiency .