interacts_with DB08918?
Fetzima ( levomilnacipran ) , a drug for major depressive disorder as a dual inhibitor for human serotonin transporters and beta-site amyloid precursor protein cleaving enzyme-1 . Pharmacological management of Major Depressive Disorder includes the use of serotonin reuptake inhibitors which targets serotonin transporters ( P31645 ) to increase the synaptic concentrations of serotonin . Beta-site amyloid precursor protein cleaving enzyme-1 ( P56817 -1 ) is responsible for amyloid β plaque formation . Hence it is an interesting target for Alzheimer 's disease ( AD ) therapy . This study describes molecular interactions of a new Food and Drug Administration approved antidepressant drug named ' Fetzima ' with P56817 -1 and P31645 . Fetzima is chemically known as levomilnacipran . The study has explored a possible link between the treatment of Depression and AD . ' Autodock 4.2 ' was used for docking study . The free energy of binding ( ΔG ) values for ' levomilnacipran- P31645 ' interaction and ' levomilnacipran- P56817 ' interaction were found to be -7.47 and -8.25 kcal/mol , respectively . DB08918 was found to interact with S438 , known to be the most important amino acid residue of serotonin binding site of P31645 during ' levomilnacipran- P31645 ' interaction . In the case of ' levomilnacipran- P56817 ' interaction , levomilnacipran interacted with two very crucial aspartic acid residues of P56817 -1 , namely , D32 and D228 . These residues are accountable for the cleavage of amyloid precursor protein and the subsequent formation of amyloid β plaques in AD brain . Hence , Fetzima ( levomilnacipran ) might act as a potent dual inhibitor of P31645 and P56817 -1 and expected to form the basis of a future dual therapy against depression and AD . It is an established fact that development of AD is associated with Major Depressive Disorder . Therefore , the design of new P56817 -1 inhibitors based on antidepressant drug scaffolds would be particularly beneficial . Synthesis , biological activity and HPLC validation of 1,2,3,4-tetrahydroacridine derivatives as acetylcholinesterase inhibitors . The synthesis and biochemical evaluation of new hybrids of tacrine ( DB00382 ) and 4-fluorobenzoic acid ( 4-FBA ) possessing activity towards acetylcholinesterase ( P22303 ) and butyrylcholinesterase ( BuChE ) inhibition are presented . The compounds of interest were obtained from the reaction of activated 4-FBA and diamino derivatives of 1,2,3,4-tetrahydroacridine . The compounds P13671 -2KW/HCl , P13671 -4KW/HCl and P13671 -3KW/HCl have four-fold higher antiacetylcholinesterase activity than DB00382 . All of the acquired compounds present higher selectivity towards P22303 than DB00382 and lower selectivity towards BuChE . In addition , a rapid , selective and stability-indicating HPLC method was developed and validated for the determination of P13671 -2KW/HCl , P13671 -3KW/HCl and P13671 -4KW/HCl . DB00382 and 4-FBA were found to be the main impurities . Chromatographic separation was achieved isocratically on a Waters Symmetry C18 150 × 3.9 mm , 4 μm column with a mobile phase of acetonitrile/buffer ( 17 mM sodium dodecyl sulphate and 8.3 mM sodium dihydrogen phosphate , 50:50 v/v ) ( overall pH 4 ) . A 1.5 ml/min flow rate and a 247 nm wavelength were chosen for this method . P13671 -2KW/HCl , P13671 -3KW/HCl and P13671 -4KW/HCl were subjected to acidic and basic hydrolysis , chemical oxidation , thermal exposition at 60 °C and intense UV light . The limits of detection ( LOD ) and quantification ( LOQ ) were less than 2 μg/ml and 6 μg/ml for P13671 -2KW/HCl , P13671 -3KW/HCl and P13671 -4KW/HCl , 0.04 μg/ml and 0.12 μg/ml for DB00382 , 0.42 μg/ml and 1.41 μg/ml for 4-FBA , respectively . Human epidermal Langerhans ' cells are targets for the immunosuppressive macrolide tacrolimus ( FK506 ) . BACKGROUND : The immunosuppressive macrolide tacrolimus ( FK506 ) has been shown to inhibit allergic contact dermatitis in animal models as well as in human beings . More recently , successful treatment of atopic dermatitis with an ointment containing tacrolimus has been reported . OBJECTIVES : We explored the effects of this compound on epidermal Langerhans ' cells ( LCs ) , which are known to play an important pathophysiologic role in inflammatory skin diseases . METHODS : The expression of the intracellular FK506 binding protein ( P62942 ) was monitored on freshly isolated and cultured epidermal LCs . Phenotyping and functional exploration of LCs treated with different concentrations of tacrolimus and beta-methasone valerate ( betaMv ) were performed . RESULTS : P62942 is expressed in freshly isolated LCs but is lost while they are maturating into mature dendritic cells . DB00864 inhibited the expression of IL-2R ( CD25 ) and of the costimulatory molecules P33681 ( P33681 .1 ) and P25942 . Expression of MHC class I and II was also affected , whereas P42081 ( P33681 .2 ) expression was not altered . In contrast , betaMv strongly increased the expression of CD25 . Paradoxically , while decreasing P25942 and MHC class I expression , betaMv significantly increased the expression of MHC class II , P33681 , and P42081 on cultured LCs but impaired their allostimulatory activity . DB00864 was about 100 times more potent than betaMv at inhibiting LC stimulatory function . CONCLUSION : DB00864 can exert immunopharmacologic alterations on LCs , which may account , at least in part , for the therapeutic effect of this compound in eczematous skin diseases . β-Secretase ( P56817 ) inhibition causes retinal pathology by vascular dysregulation and accumulation of age pigment . β-Secretase ( P56817 ) is a major drug target for combating Alzheimer 's disease ( AD ) . Here we show that P56817 (-/-) mice develop significant retinal pathology including retinal thinning , apoptosis , reduced retinal vascular density and an increase in the age pigment , lipofuscin . P56817 expression is highest in the neural retina while Q9Y5Z0 was greatest in the retinal pigment epithelium ( Q96AT9 ) /choroid . Pigment epithelial-derived factor , a known regulator of γ-secretase , inhibits vascular endothelial growth factor ( P15692 ) -induced in vitro and in vivo angiogenesis and this is abolished by P56817 inhibition . Moreover , intravitreal administration of P56817 inhibitor or P56817 small interfering RNA ( siRNA ) increases choroidal neovascularization in mice . P56817 induces ectodomain shedding of vascular endothelial growth factor receptor 1 ( P17948 ) which is a prerequisite for γ-secretase release of a 100 kDa intracellular domain . The increase in lipofuscin following P56817 inhibition and RNAI knockdown is associated with lysosomal perturbations . Taken together , our data show that P56817 plays a critical role in retinal homeostasis and that the use of P56817 inhibitors for AD should be viewed with extreme caution as they could lead to retinal pathology and exacerbate conditions such as age-related macular degeneration . Ca2+-calmodulin and janus kinase 2 are required for activation of sodium-proton exchange by the Gi-coupled 5-hydroxytryptamine 1a receptor . The type 1 sodium-proton exchanger ( P19634 ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 remain incompletely defined . In this work , we present evidence that stimulation of the 5-hydroxytryptamine 1A ( P08908 ) receptor results in the formation of a signaling complex that includes activated O60674 ( Jak2 ) , Ca2+/calmodulin ( P62158 ) , and P19634 , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist-induced association of P62158 and P19634 as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 is activated through this pathway : P08908 receptor --> G(i2)alpha and/or G(i3)alpha --> Jak2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 --> induction of a conformational change in P19634 that unmasks an obscured proton-sensing and/or proton-transporting region of P19634 --> activation of P19634 . The G(i/o)-coupled P08908 receptor now joins a handful of Gq-coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2+ . We have also shown for the first time that the association of P62158 with P19634 in living cells is a dynamic process . Ceramide stabilizes beta-site amyloid precursor protein-cleaving enzyme 1 and promotes amyloid beta-peptide biogenesis . The lipid second messenger ceramide regulates several biochemical events that occur during aging . In addition , its level is highly elevated in the amyloid-burdened brains of Alzheimer 's disease patients . Here , we analyzed the impact of aberrant ceramide levels on amyloid beta-peptide ( Abeta ) generation by using a cell-permeable analog of ceramide , P13671 -ceramide , and several biochemical inhibitors of the sphingomyelin/glycosphingolipid biosynthetic pathway . We found that P13671 -ceramide increased the biogenesis of Abeta by affecting beta-but not gamma-cleavage of the amyloid precursor protein . Similarly to P13671 -ceramide , increased levels of endogenous ceramide induced by neutral sphingomyelinase treatment also promoted the biogenesis of Abeta . Conversely , fumonisin B1 , which inhibits the biosynthesis of endogenous ceramide , reduced Abeta production . Exogenous P13671 -ceramide restored both intracellular ceramide levels and Abeta generation in fumonisin B1-treated cells . These events were specific for amyloid precursor protein and were not associated with apoptotic cell death . Pulse-chase and time-course degradation experiments showed that ceramide post-translationally stabilizes the beta-secretase P56817 . Taken together , these data indicate that the lipid second messenger ceramide , which is elevated in the brains of Alzheimer 's disease patients , increases the half-life of P56817 and thereby promotes Abeta biogenesis . Aripiprazole : a novel atypical antipsychotic drug with a uniquely robust pharmacology . Aripiprazole ( DB01238 ) is an atypical antipsychotic drug that has been recently introduced for clinical use in the treatment of schizophrenia . Aripiprazole has a unique pharmacologic profile that includes partial agonism at several G-protein coupled receptors ( GPCRs ) [ especially dopamine ( D2 ) and P08908 ] and antagonistic action at others ( especially 5- Q13049 ) . Clinical trials indicate that aripiprazole is effective in treating the positive and negative symptoms of schizophrenia . In short-term studies rapid onset of action ( within one week ) has been demonstrated . Preliminary data indicate that aripiprazole may also be effective in the treatment of manic symptoms of bipolar disorder . At recommended doses , aripiprazole appears to be safe and well tolerated in most adult patients with schizophrenia and schizoaffective disorder . There is only limited information available on the use of aripiprazole in children and adolescents , and pilot data suggest that a revised dosing strategy , based on weight , is indicated in this population . In the long-term studies , the use of aripiprazole was associated with continued efficacy , good compliance and increased time-to-relapse . Aripiprazole represents the first functionally selective atypical antipsychotic drug . P01579 -induced P56817 expression is mediated by activation of O60674 and P27361 /2 signaling pathways and direct binding of P42224 to P56817 promoter in astrocytes . P56817 ( P56817 ) is an essential enzyme for the production of beta amyloid . Since we found that injection of interferon-gamma ( P01579 ) into young mouse brains increased P56817 expression in astrocytes , we investigated molecular mechanisms underlying this process by cloning a putative P56817 promoter . P56817 promoter activity was differentially regulated by P01579 in a region specific manner and down-regulated by an inhibitor of O60674 ( O60674 ) . A dominant negative mutant of signal transducer and activator of transcription 1 ( P42224 ) expression suppressed P56817 promoter activity , and this was rescued by transfecting wild type P42224 . Electrophoretic mobility shift assay and promoter activity assays indicated that P42224 binds directly to the putative P42224 binding sequence of P56817 promoter . Because P01579 treatment induced P42224 phosphorylation , we examined whether the expression of a suppressor of cytokine signaling ( Q9NSE2 ) , negative regulator of O60674 , suppresses P56817 promoter activity . The results show that O15524 or O14543 expression suppressed P56817 promoter by blocking phosphorylation of Tyr701 residue in P42224 . Also , because P01579 treatment specifically potentiated extracellular signal regulated Q96HU1 kinase ( P29323 ) 1/2 activation , pretreatment of mitogen-activated or extracellular signal-regulated protein kinase ( MEK ) inhibitor , PD98059 , significantly attenuated P01579 -induced P56817 promoter activity and protein expression through blocking phosphorylation of Ser727 residue in P42224 , suggesting that P27361 /2 is associated with P01579 -induced P42224 signaling cascade . Taken together , our results suggest that P01579 activates O60674 and P27361 /2 and then phosphorylated P42224 binds to the putative P42224 binding sequences in P56817 promoter region to modulate P56817 protein expression in astrocytes . Novel systemic markers for patients with Alzheimer disease ? - a pilot study . Almost 2 % of the population of western industrialized countries are affected by Alzheimer 's disease ( AD ) . Nevertheless the pathogenetic process leading to this neurodegenerative disease is widely unknown . Thus , we focus on novel pathophysiological aspects of AD . We hypothesize that AD patients reveal increased levels of peripheral blood mononuclear cells ( PBMCs ) expressing proinflammatory ( P35354 , P01375 , P25942 ) , proapoptotic ( P09874 ) , adhesion-relevant ( P28907 ) or AD associated ( C99 , P56817 , P49768 ) proteins as well as elevated proinflammatory biochemical plasma parameters . Therefore , PBMCs of AD patients and age-matched control subjects were studied by two color fluorescence-activated cell sorter ( FACS ) analysis . Furthermore , concentration of plasma oxidized low-density lipoprotein ( oxLDL ) and P01375 were measured by enzyme-linked immunosorbent assay ( ELISA ) . We found a significantly increased percentage of P01375 , P35354 , P09874 , P28907 , C99 or presenilin-1 positive PBMCs in AD patients compared with healthy subjects . FACS analyses revealed that the percentage of C99 or presenilin-1 positive PBMCs , which also express P01375 , P35354 , P09874 or P28907 is also increased in AD patients . Additionally , AD patients had significantly increased plasma oxLDL and P01375 levels . Furthermore , we found positive correlations between plasma oxLDL or P01375 concentrations and the percentage of TNFalpha+ , P35354 + or P09874 + , as well as P49768 + , C99+ or P56817 + PBMCs . Our findings suggest that immunocytological investigations , based on immunophenotyping of AD relevant proteins combined with measurement of proinflammatory , proapoptotic and adhesion-relevant proteins in PBMCs may provide more insight into the pathophysiology of AD . [ Cell cycle analysis of endometrial cancer cells in vitro treated with growth factor and steroid hormone ] . The aim of this study was to overtake the mechanism of the control system in endometrial cancer cell line in vitro . Ishikawa cell ( IK cell ) and O14777 -1 cell ( O14777 cell ) derived from endometrial cancers were cultured with serum free medium ( SFM-101 ) . IK cell possessed P03372 ( ER ) , P06401 ( PR ) , Epidermal growth factor ( P01133 ) and its receptor ( P00533 ) . O14777 cell had PR , P01133 , and P00533 , however O14777 cell did not keep ER . P01133 stimulated the growth of IK cell , but the growth of O14777 cell was not stimulated by P01133 . S phase cells were increased by P01133 in IK cell , but were not increased by P01133 in O14777 cell . The growth of IK cell was stimulated significantly by P01133 and Estradiol-17 beta ( E2 ) + P01133 than control . However , E2+ P01133 did not stimulate the growth of IK cell than P01133 significantly . DB01406 ( D ) and D+ P01133 inhibited the growth of IK cell significantly than control . S phase cells were decreased by the treatment of D and D+ P01133 . From our results , P01133 stimulated the growth of ER positive endometrial cancer cell , but P01133 did not stimulate ER negative endometrial cancer cell . E2+ P01133 and P01133 stimulated the growth of IK cell as a same . However , D inhibited the growth of IK cell that was stimulated by P01133 . Signalling pathways involved in retinal endothelial cell proliferation induced by advanced glycation end products : inhibitory effect of gliclazide . AIM : We have previously demonstrated that advanced glycation end products ( AGEs ) stimulate bovine retinal endothelial cell ( BREC ) proliferation through induction of vascular endothelial growth factor ( P15692 ) production by these cells . We have also shown that gliclazide , a sulfonylurea which decreases oxidative stress , inhibits this effect . The aim of the present study was to characterize the signalling pathways involved in P51606 -induced BREC proliferation and P15692 production and mediating the inhibitory effect of gliclazide on these biological events . METHODS : BRECs were treated or not treated with AGEs in the presence or absence of gliclazide , antioxidants , protein kinase C ( PKC ) , mitogen-activated protein kinase ( MAPK ) or nuclear factor-kappaB ( NF-kappaB ) inhibitors . BREC proliferation was assessed by measuring [ 3H ] -thymidine incorporation into DNA . Activation of PKC , MAPK and NF-kappaB signal transduction pathways and determination of P15692 expression were assessed by Western blot analysis using specific antibodies . MAPK activity was also determined by an in vitro kinase assay . RESULTS : Treatment of BRECs with AGEs significantly increased cell proliferation and P15692 expression . AGEs induced P05771 translocation , extracellular signal-regulated protein kinase 1/2 and NF-kappaB activation in these cells . Pharmacological inhibition of these signalling pathways abolished P51606 effects on cell proliferation and P15692 expression . Exposure of BRECs to gliclazide or antioxidants such as vitamin E or N-acetyl-l-cysteine resulted in a significant decrease in P51606 -induced activation of PKC- , MAPK- and NF-kappaB-signalling pathways . CONCLUSIONS : Our results demonstrate the involvement of PKC , MAPK and NF-kappaB in P51606 -induced BREC proliferation and P15692 expression . DB01120 inhibits BREC proliferation by interfering with these intracellular signal transduction pathways . DB01016 exerts an antitumor activity through reactive oxygen species-c-jun NH2-terminal kinase pathway in human gastric cancer cell line MGC-803 . DB01016 , a blocker of DB00171 -sensitive potassium ( K( DB00171 ) ) channels , can suppress progression of many cancers , but the involved mechanism is unclear . Herein we reported that MGC-803 cells expressed the K( DB00171 ) channels composed of Kir6.2 and Q09428 subunits . DB01016 induced cellular viability decline , coupled with cell apoptosis and reactive oxygen species ( ROS ) generation in MGC-803 cells . Meanwhile , glibenclamide increased NADPH oxidase catalytic subunit gp91(phox) expression and superoxide anion ( O2- ) generation , and caused mitochondrial respiration dysfunction in MGC-803 cells , suggesting that glibenclamide induced an increase of ROS derived from NADPH oxidase and mitochondria . DB01016 could also lead to loss of mitochondrial membrane potential , release of cytochrome c and apoptosis-inducing factor ( O95831 ) , and activation of c-jun NH2-terminal kinase ( JNK ) in MGC-803 cells . Pretreatment with antioxidant N-acetyl-l-cysteine ( Q9C000 ) prevented glibenclamide-induced JNK activation , apoptosis and cellular viability decline . Furthermore , glibenclamide greatly decreased the cellular viability , induced apoptosis and inhibited Akt activation in wild-type mouse embryonic fibroblast ( MEF ) cells but not in P45983 -/- or P45984 -/- MEF cells . Taken together , our study reveals that glibenclamide exerts an antitumor activity in MGC-803 cells by activating ROS-dependent , JNK-driven cell apoptosis . These findings provide insights into the use of glibenclamide in the treatment of human gastric cancer . Effects of early maternal separation on biobehavioral and neuropathological markers of Alzheimer 's disease in adult male rats . Stress has been described as a risk factor for the development of Alzheimer´s disease ( AD ) . In the present work we aim to study the validity of an experimental model of neonatal chronic stress in order to recapitulate the main hallmarks of AD . Male Wistar rats that were separated daily from the dam during the first 3 weeks of life ( maternal separation , MS ) showed in adulthood cognitive deficits novel object recognition test . In the hippocampus of MS rats , increases in both Aβ40 and Aβ42 levels , the principal constituent of amyloid plaques observed in AD , were accompanied by increased expression of the cleaving enzyme P56817 . Hyperphosphorylation of Tau associated to increased activation of the tau kinase P45983 was also found . Decreased cell number in the hippocampus was observed in stressed rats , as a consequence of both decreased cell proliferation and increased apoptotic death . Decreases in P23560 and in the synaptic markers synaptophysin and P78352 were also found in MS rats . All these effects could be related to an Q9Y251 axis hyperactivity , as reflected in significant increases in corticosterone levels and decreases in glucocorticoid receptor expression . Further , SHSY5Y neuroblastoma cells treated with corticosterone showed increased P56817 , pTau and pJNK1 expression . In addition , venlafaxine , an antidepressant able to modulate Q9Y251 axis activity , reversed all the above cited deleterious effects of chronic stress , both in vivo and in vitro . It is proposed that the MS model can be considered as an appropriate experimental model for the study of sporadic AD . Structural bioinformatics-based identification of P00533 inhibitor gefitinib as a putative lead compound for P56817 . β-secretase ( P56817 -1 ) is a potential target for the treatment of Alzheimer 's disease ( AD ) . Despite its potential , only few compounds targeting P56817 have entered the clinical trials . Herein , we describe the identification of Gefitinib as a potential lead compound for P56817 through an integrated approach of structural bioinformatics analysis , experimental assessment and computational analysis . In particular , we performed ELISA and western analysis to assess the effect of Gefitinib using N2a human APP695 cells . In addition , we investigated the binding mechanism of Gefitinib with P56817 through molecular docking coupled with molecular dynamics simulations . The computational analyses revealed that hydrophobic contact is a major contributing factor to the binding of Gefitinib with P56817 . The results obtained in the study have rendered Gefitinib as a putative lead compound for P56817 . Further optimization studies are warranted to improve its potency and pharmacological properties against P56817 for potential AD treatment .