interacts_with DB01016?
DB01016 -induced apoptosis is specifically enhanced by expression of the sulfonylurea receptor isoform Q09428 but not by expression of SUR2B or the mutant Q09428 (M1289T) . Q09428 ( Q09428 ) is the regulatory subunit of the pancreatic DB00171 -sensitive K+ channel ( K( DB00171 ) channel ) , which is essential for triggering insulin secretion via membrane depolarization . Sulfonylureas , such as glibenclamide and tolbutamide , act as K( DB00171 ) channel blockers and are widely used in diabetes treatment . These antidiabetic substances are known to induce apoptosis in pancreatic beta-cells or beta-cell lines under certain conditions . However , the precise molecular mechanisms of this sulfonylurea-induced apoptosis are still unidentified . To investigate the role of Q09428 in apoptosis induction , we tested the effect of glibenclamide on recombinant human embryonic kidney 293 cells expressing either Q09428 , the smooth muscular isoform SUR2B , or the mutant Q09428 (M1289T) at which a single amino acid in transmembrane helix 17 ( TM17 ) was exchanged by the corresponding amino acid of SUR2 . By analyzing cell detachment , nuclear condensation , DNA fragmentation , and caspase-3-like activity , we observed a Q09428 -specific enhancement of glibenclamide-induced apoptosis that was not seen in SUR2B , Q09428 (M1289T) , or control cells . Coexpression with the pore-forming Kir6.2 subunit did not significantly alter the apoptotic effect of glibenclamide on Q09428 cells . In conclusion , expression of Q09428 , but not of SUR2B or Q09428 (M1289T) , renders cells more susceptible to glibenclamide-induced apoptosis . Therefore , Q09428 as a pancreatic protein could be involved in specific variation of beta-cell mass and might also contribute to the regulation of insulin secretion at this level . According to our results , TM17 is essentially involved in Q09428 -mediated apoptosis . This effect does not require the presence of functional Kir6.2-containing K( DB00171 ) channels , which points to additional , so far unknown functions of Q09428 . A protective role of hydrogen sulfide against oxidative stress in rat gastric mucosal epithelium . We investigated effect of hydrogen sulfide ( H(2)S ) on oxidative stress-caused cell death in gastric mucosal epithelial cells . In rat normal gastric epithelial RGM1 cells , NaHS , a H(2)S donor , at 1.5mM strongly suppressed hydrogen peroxide ( H(2)O(2) ) -caused cell death , while it slightly augmented the H(2)O(2) toxicity at 0.5-1mM . The protective effect of NaHS was abolished by inhibitors of MEK or JNK , but not of p38 Q96HU1 kinase . NaHS at 1.5mM actually phosphorylated P29323 and JNK in RGM1 cells . DB01016 , an DB00171 -sensitive K(+) ( K( DB00171 )(+) ) channel inhibitor , did not affect the protective effect of NaHS , although mRNAs for K( DB00171 )(+) channel subunits , Kir6.1 and Q09428 , were detected in RGM1 cells . In anesthetized rats , oral administration of NaHS protected against gastric mucosal lesion caused by ischemia-reperfusion . These results suggest that NaHS/H(2)S may protect gastric mucosal epithelial cells against oxidative stress through stimulation of Q96HU1 kinase pathways , a therapeutic dose range being very narrow . Regulatory regions of growth-related genes can activate an exogenous gene of the alpha-fetoprotein promoter to a comparable degree in human hepatocellular carcinoma cells . We examined the transcriptional activation by the regulatory regions of the midkine ( MK ) , survivin ( Q09428 ) , cyclooxygenase-2 ( P35354 ) , telomerase reverse transcriptase ( O14746 ) and alpha-fetoprotein ( AFP ) genes in human hepatocellular carcinoma cells . Luciferase assays showed that the Q09428 regulatory region exhibited the greatest activity and that the MK regulatory region activated the reporter gene better than the enhancer-linked AFP promoter even in high-AFP-producing cells . The P35354 and O14746 regulatory regions also activated the reporter gene better than the AFP enhancer/promoter in intermediate-AFP-producing cells . Combination of the regulatory regions arranged in tandem modulated their transcriptional activities , depending on the arrangement of the promoters and cells examined . These data suggested that the regulatory regions of the growth-related genes could be useful to activate a therapeutic gene in hepatocellular carcinoma cells irrespective of the amounts of AFP production but combinatory use of the promoter regions could not always contribute to enhanced activity . Soluble forms of P16070 and CD54 ( P05362 ) cellular adhesion molecules are released by human prostatic cancer cell lines . We have identified that human prostatic cancer cell lines DU145 , PC3 , P03886 , ALVA31 and JCA1 released soluble P16070 molecules and DU145 , PC3 and P03886 released soluble CD54 . Both soluble and surface P16070 were not found in LNCaP , and both forms of CD54 were not expressed in LNCaP and JCA1 . CD54 was found to be highly expressed on cell surface in ALVA31 , but these cells did not release soluble CD54 . Expression of both cell surface and soluble forms were examined after treatment of cells with P01579 , TGF-beta 1 , or culturing in serum-free media . The concentration of soluble CD54 in supernatants changed to small extent after treatment with TGF-beta 1 and increased after treatment with P01579 or in serum-free media . Cell surface expression of CD54 however , changed only minimally after treatment . The levels of cell surface and soluble P16070 also changed minimally after treatment with P01579 and TGF-beta 1 but decreased in serum-free media and this was accompanied by marked elevation of soluble P16070 in supernatants . These data indicate that soluble P16070 might be released from cell surface by shedding whereas alternative splicing is the most likely mechanism of soluble CD54 release . A comparative study of the antipyretic effects of indomethacin and dipyrone in rats . OBJECTIVE : Compare the antipyretic effects of dipyrone and indomethacin . MATERIALS AND METHODS : Fever was induced in rats by i. v. LPS or i . c . v. interleukins ( IL ) , prostaglandins ( PG ) , arachidonic acid ( AA ) , pre-formed pyrogenic factor ( PFPF ) , tumour necrosis factor-alpha ( P01375 ) or corticotrophin releasing hormone ( P06850 ) . DB04817 and indomethacin were administered i.p. , arginine vasopressin V1-receptor antagonist , d(CH2)5 DB00135 (Me)AVP , into the ventral septal area . Cyclooxygenase ( P23219 /-2 ) blocking activity was assessed in transfected COS-7 cells . P06850 release from isolated hypothalami was determined by ELISA . RESULTS : Indomethacin or dipyrone reduced LPS , IL-1beta , P05231 or P01375 induced fever and P06850 release from rat hypothalamus . Only dipyrone inhibited P10145 , PFPF or PGF2alpha fever . Only indomethacin inhibited fever induced by AA or IL-1beta , plus AA . Neither antipyretic affected fever caused by DB00917 or P06850 . d(CH2)5Tyr(Me)AVP only blocked antipyresis induced by indomethacin . DB04817 at a very high concentration ( 10 mM ) inhibited only P23219 , while indomethacin ( 0.1 microM ) blocked P23219 and P35354 in COS-7 cells . CONCLUSION : The antipyretic effect of dipyrone differs from that of indomethacin in that it does not depend on AVP release or inhibition of PG synthesis . Platelet Q9H244 receptor inhibition by thienopyridines : status and future . Thienopyridines have a well-established role in the treatment of coronary artery disease , especially in the setting of acute coronary syndromes and percutaneous coronary interventions . DB00208 , the first FDA-approved thienopyridine , was shown to be effective in reducing coronary events in high risk patients , but the original enthusiasm was hampered by concerns about its serious bone marrow toxicity . DB00758 a second generation thienopyridine with lesser side effects , is not only at least as effective as ticlopidine , but in combination with a low dose of aspirin , has been demonstrated to reduce the risk of major cardiovascular events in acute coronary syndrome patients in large-scale , randomised trials . Recent studies have highlighted major flaws in clopidogrel pharmacokinetics due to its delayed onset of action , and much attention has been devoted to the phenomenon of clopidogrel ' resistance ' . Among the novel , third generation thienopyridines , prasugrel as compared to clopidogrel has demonstrated lower inter-patient response variability and a reduced incidence of ischaemic events , but at an increased risk of major bleeding . Currently , several studies are continuing to test new direct Q9H244 receptor antagonists , such as cangrelor and AZD6140 , characterised by a faster reversal of platelet inhibition . Whole genome SNP genotyping and exome sequencing reveal novel genetic variants and putative causative genes in congenital hyperinsulinism . Congenital hyperinsulinism of infancy ( CHI ) is a rare disorder characterized by severe hypoglycemia due to inappropriate insulin secretion . The genetic causes of CHI have been found in genes regulating insulin secretion from pancreatic β-cells ; recessive inactivating mutations in the Q09428 and Q14654 genes represent the most common events . Despite the advances in understanding the molecular pathogenesis of CHI , specific genetic determinants in about 50 % of the CHI patients remain unknown , suggesting additional locus heterogeneity . In order to search for novel loci contributing to the pathogenesis of CHI , we combined a family-based association study , using the transmission disequilibrium test on 17 CHI patients lacking mutations in Q09428 / Q14654 , with a whole-exome sequencing analysis performed on 10 probands . This strategy allowed the identification of the potential causative mutations in genes implicated in the regulation of insulin secretion such as transmembrane proteins ( O00555 , Q9H252 , P78508 , Q04721 , Q15413 , Q9UQD0 , Q8NET8 , Q9UL62 ) , cytosolic ( O00763 , Q13557 , Q5VV42 , GNAS , NOS2 , Q08493 , Q92569 ) and mitochondrial enzymes ( PC , Q6J4K2 ) , and in four genes ( Q96PZ7 , Q8NCC5 , Q8IWU6 , O43897 ) suggested by P04053 family-based association study . Moreover , the exome-sequencing approach resulted to be an efficient diagnostic tool for CHI , allowing the identification of mutations in three causative CHI genes ( Q09428 , P00367 , and P20823 ) in four out of 10 patients . Overall , the present study should be considered as a starting point to design further investigations : our results might indeed contribute to meta-analysis studies , aimed at the identification/confirmation of novel causative or modifier genes . Echicetin coated polystyrene beads : a novel tool to investigate GPIb-specific platelet activation and aggregation. P04275 /ristocetin ( P04275 /R ) induces GPIb-dependent platelet agglutination and activation of αIIbβ3 integrin , which also binds P04275 . These conditions make it difficult to investigate GPIb-specific signaling pathways in washed platelets . Here , we investigated the specific mechanisms of GPIb signaling using echicetin-coated polystyrene beads , which specifically activate GPIb . We compared platelet activation induced by echicetin beads to P04275 /R . Human platelets were stimulated with polystyrene beads coated with increasing amounts of echicetin and platelet activation by echicetin beads was then investigated to reveal GPIb specific signaling . Echicetin beads induced αIIbβ3-dependent aggregation of washed platelets , while under the same conditions P04275 /R treatment led only to αIIbβ3-independent platelet agglutination . The average distance between the echicetin molecules on the polystyrene beads must be less than 7 nm for full platelet activation , while the total amount of echicetin used for activation is not critical . Echicetin beads induced strong phosphorylation of several proteins including p38 , P29323 and P31749 . Synergistic signaling via Q9H244 and thromboxane receptor through secreted ADP and TxA2 , respectively , were important for echicetin bead triggered platelet activation . Activation of PKG by the NO/sGC/cGMP pathway inhibited echicetin bead-induced platelet aggregation . Echicetin-coated beads are powerful and reliable tools to study signaling in human platelets activated solely via GPIb and GPIb-triggered pathways . A hierarchical approach employing metabolic and gene expression profiles to identify the pathways that confer cytotoxicity in HepG2 cells . BACKGROUND : Free fatty acids ( FFA ) and tumor necrosis factor alpha ( P01375 ) have been implicated in the pathogenesis of many obesity-related metabolic disorders . When human hepatoblastoma cells ( HepG2 ) were exposed to different types of FFA and P01375 , saturated fatty acid was found to be cytotoxic and its toxicity was exacerbated by P01375 . In order to identify the processes associated with the toxicity of saturated FFA and P01375 , the metabolic and gene expression profiles were measured to characterize the cellular states . A computational model was developed to integrate these disparate data to reveal the underlying pathways and mechanisms involved in saturated fatty acid toxicity . RESULTS : A hierarchical framework consisting of three stages was developed to identify the processes and genes that regulate the toxicity . First , discriminant analysis identified that fatty acid oxidation and intracellular triglyceride accumulation were the most relevant in differentiating the cytotoxic phenotype . Second , gene set enrichment analysis ( GSEA ) was applied to the cDNA microarray data to identify the transcriptionally altered pathways and processes . Finally , the genes and gene sets that regulate the metabolic responses identified in step 1 were identified by integrating the expression of the enriched gene sets and the metabolic profiles with a multi-block partial least squares ( MBPLS ) regression model . CONCLUSION : The hierarchical approach suggested potential mechanisms involved in mediating the cytotoxic and cytoprotective pathways , as well as identified novel targets , such as DB00157 dehydrogenases , aldehyde dehydrogenases 1A1 ( P00352 ) and endothelial membrane protein 3 ( P54852 ) as modulator of the toxic phenotypes . These predictions , as well as , some specific targets that were suggested by the analysis were experimentally validated . Inhibitors of DB00171 -binding cassette transporters suppress interleukin-12 p40 production and major histocompatibility complex II up-regulation in macrophages . DB00171 -binding cassette ( DB01048 ) transporters are a large family of proteins whose role is to translocate various substances across biological membranes . They include the Tangier disease protein ABC1 , sulfonylurea receptors ( Q09428 ) , multidrug resistance protein ( MDR ) , and cystic fibrosis transmembrane regulator ( P13569 ) . In the current study , we investigated the involvement of ABC transporters in the regulation of lipopolysaccharide ( LPS ) and/or interferon ( IFN ) -gamma-induced interleukin ( IL ) -12 p40 and tumor necrosis factor ( P01375 ) -alpha production , nitric oxide formation , as well as major histocompatibility complex II up-regulation in macrophages . The general ABC transporter inhibitor glibenclamide suppressed both IL-12 p40 and nitric oxide production . However , glibenclamide failed to affect the production of P01375 . The selective ABC1 inhibitors 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid and sulfobromophthalein mimicked the suppressive effect of glibenclamide on IL-12 p40 production . On the other hand , both the MDR inhibitor verapamil and P13569 blocker 2,2'-iminodibenzoic acid failed to suppress the production of IL-12 p40 . Furthermore , selective inhibitors and activators of SURs were without effect . In agreement with the pharmacological data , macrophages expressed mRNA for ABC1 , but not SURs or P13569 . Intracellular levels of IL-12 p40 were decreased by glibenclamide , suggesting that glibenclamide does not affect IL-12 p40 secretion . The effect of glibenclamide did not involve an interference with the activation of the p38 and Q8NFH3 /44 mitogen-activated protein kinases or c-Jun kinase . DB01016 also suppressed P01579 -induced up-regulation of major histocompatibility complex II . Taken together , our results indicate that ABC proteins regulate LPS and/or P01579 -induced macrophage activation . (-)- DB03823 -3-gallate ameliorates learning and memory deficits by adjusting the balance of TrkA/p75NTR signaling in P05067 / P49768 transgenic mice . Alzheimer 's disease ( AD ) is pathologically characterized by deposition of β-amyloid ( Aβ ) peptides , which closely correlates with the balance of nerve growth factor ( P01138 ) -related TrkA/p75NTR signaling . (-)- DB03823 -3-gallate ( EGCG ) is used for prevention and treatment of many neurodegenerative diseases , including AD . However , whether the neuroprotective effects of EGCG treatment were via modulating the balance of TrkA/p75NTR signaling was still unknown . In this study , we found that EGCG treatment ( 2 mg·kg(-1)·day(-1) ) dramatically ameliorated the cognitive impairments , reduced the overexpressions of Aβ(1-40) and amyloid precursor protein ( P05067 ) , and inhibited the neuronal apoptosis in the P05067 / P49768 mice . Interestingly , the EGCG treatment enhanced the relative expression level of P01138 by increasing the P01138 /proNGF ratio in the P05067 / P49768 mice . Moreover , after EGCG treatment , TrkA signaling was activated by increasing the phosphorylation of TrkA following the increased phosphorylation of c-Raf , P27361 /2 , and DB02527 response element-binding protein ( CREB ) , simultaneously the p75NTR signaling was significantly inhibited by decreasing the p75ICD expression , P45984 phosphorylation , and cleaved-caspase 3 expression , so that the Aβ deposits and neuronal apoptosis in the hippocampus were inhibited . Administration of adenosine diphosphate-ribosyl transferase antagonist allows in vivo control of anti-dinitrophenyl response . DB03073 ( 3MB ) is one of a series of chemical inhibitors of the nuclear enzyme adenosine diphosphate ( ADP ) -ribosyl transferase ( P09874 ) , 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 ) numbers to less than 10 % of those of control animals . The period for maximum P27918 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 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 showed a lower average affinity than P27918 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 . DB01268 : a P15692 and PDGF receptor protein kinase and angiogenesis inhibitor . DB01268 ( SU-11248 , Sutent ) inhibits at least eight receptor protein-tyrosine kinases including vascular endothelial growth factor receptors 1-3 ( P17948 - P35916 ) , platelet-derived growth factor receptors ( PDGFRalpha and PDGFRbeta ) , stem cell factor receptor ( Kit ) , Flt-3 , and colony-stimulating factor-1 receptor ( P07333 ) . P17948 and P35968 play key roles in vasculogenesis and angiogenesis . PDGFRbeta , which is found in pericytes that surround capillary endothelial cells , plays a pivotal role in stabilizing the vascular endothelium . DB01268 inhibits angiogenesis by diminishing signaling through P17948 , P35968 , and PDGFRbeta . Renal cell cancers that have metastasized , or spread from the primary tumor , exhibit extensive vascularity , and sunitinib is approved for the treatment of these neoplasms . Activating Kit mutations occur in about 85 % of gastrointestinal stromal tumors and activating PDGFRalpha mutations occur in about 5 % of these tumors . DB01268 is approved for the treatment of those tumors that are resistant to imatinib ( STI-571 , Gleevec ) , another Kit and PDGFRalpha protein-tyrosine kinase inhibitor . Both sunitinib and imatinib bind reversibly to the DB00171 binding site of their target kinases and thereby inhibit their catalytic activity . The secondary P36888 -ITD F691L mutation induces resistance to DB05213 in P36888 -ITD+ AML but retains in vitro sensitivity to PKC412 and DB01268 . Engineering human T cells for resistance to methotrexate and mycophenolate mofetil as an in vivo cell selection strategy . Gene transfer and drug selection systems that enforce ongoing transgene expression in vitro and in vivo which are compatible with human pharmaceutical drugs are currently underdeveloped . Here , we report on the utility of incorporating human enzyme muteins that confer resistance to the lymphotoxic/immunosuppressive drugs methotrexate ( MTX ) and mycophenolate mofetil ( DB00688 ) in a multicistronic lentiviral vector for in vivo T lymphocyte selection . We found that co-expression of human dihydrofolate reductase ( P00374 (FS) ; L22F , F31S ) and inosine monophosphate dehydrogenase II ( P12268 (IY) ; T333I , S351Y ) conferred T cell resistance to the cytocidal and anti-proliferative effects of these drugs at concentrations that can be achieved clinically ( up to 0.1 µM MTX and 1.0 µM DB00603 ) . Furthermore , using a immunodeficient mouse model that supports the engraftment of central memory derived human T cells , in vivo selection studies demonstrate that huEGFRt(+) P00374 (FS+) P12268 (IY+) T cells could be enriched following adoptive transfer either by systemic administration of MTX alone ( 4.4 -fold ) , DB00688 alone ( 2.9-fold ) , or combined MTX and DB00688 ( 4.9-fold ) . These findings demonstrate the utility of both P00374 (FS)/MTX and P12268 (IY)/ DB00688 for in vivo selection of lentivirally transduced human T cells . Vectors incorporating these muteins in combination with other therapeutic transgenes may facilitate the selective engraftment of therapeutically active cells in recipients . [ Thienopyridines in the treatment and prevention of cardiovascular diseases. Part I. DB00208 ] . In a series of articles the authors consider clinical pharmacology and experience of clinical application of blockers of platelet Q9H244 receptors , most well known representatives of which ticlopidine and clopidogrel according to chemical structure belong to thienopyridine derivatives . In the first communication pharmacodynamics and pharmacokinetics of the first thienopyridine ticlopidine are described in detail . Results of randomized studies in which cerebro and cardioprotective efficacy and safety of ticlopidine was studied in patients with cerebrovascular , peripheral artery diseases , and acute coronary syndromes are discussed . It has been established that ticlopidine is more effective and safe in patients having undergone coronary and femoral bypass surgery . Results of meta analyses have shown which evidence that ticlopidine is not less and may be more effective than clopidogrel in patients after coronary bypass surgery . Most frequent and most severe side effects of ticlopidine and measures of their prevention are also considered . Anti-inflammatory activities of mogrosides from Momordica grosvenori in murine macrophages and a murine ear edema model . Momordica grosvenori ( Luo Han DB02857 ) , grown primarily in Guangxi province in China , has been traditionally used for thousands of years by the Chinese to make hot drinks for the treatment of sore throat and the removal of phlegm . The natural noncaloric sweetening triterpenoid glycosides ( mogrosides ) contained in the M. grosvenori fruits are also antioxidative , anticarcinogenic , and helpful in preventing diabetic complications . The aim of this study was to assess the anti-inflammatory properties of mogrosides in both murine macrophage RAW 264.7 cells and a murine ear edema model . The results indicate that mogrosides can inhibit inflammation induced by lipopolysaccharides ( LPS ) in RAW 264.7 cells by down-regulating the expression of key inflammatory genes P35228 , P35354 , and P05231 and up-regulating some inflammation protective genes such as P09874 , BCL2l1 , TRP53 , and P45984 . Similarly , in the murine ear edema model , 12-O-tetradecanoylphorbol-13-acetate-induced inflammation was inhibited by mogrosides by down-regulating P35354 and P05231 and up-regulating P09874 , BCL2l1 , TRP53 , P45984 , and PPARδ gene expression . This study shows that the anticancer and antidiabetic effects of M. grosvenori may result in part from its anti-inflammatory activity . DB00674 ameliorates the impairment of recognition memory in mice repeatedly treated with methamphetamine : involvement of allosteric potentiation of nicotinic acetylcholine receptors and dopaminergic- P27361 /2 systems . DB00674 , a drug used to treat Alzheimer 's disease , inhibits acetylcholinesterase ( P22303 ) and allosterically modulates nicotinic acetylcholine receptors ( nAChRs ) resulting in stimulation of catecholamine neurotransmission . In this study , we investigated whether galantamine exerts cognitive-improving effects through the allosteric modulation of nAChRs in an animal model of methamphetamine ( Meth ) psychosis . The mice treated with Meth ( 1 mg/kg.d ) for 7 d showed memory impairment in a novel object recognition test . DB00674 ( 3 mg/kg ) ameliorated the memory impairment , and it increased the extracellular dopamine release in the prefrontal cortex ( P27918 ) of Meth-treated mice . Donepezil , an P22303 inhibitor ( 1 mg/kg ) increased the extracellular ACh release in the P27918 , whereas it had no effect on the memory impairment in Meth-treated mice . The nAChR antagonist , mecamylamine , and dopamine D1 receptor antagonist , P35240 23390 , blocked the ameliorating effect of galantamine on Meth-induced memory impairment , whereas the muscarinic AChR antagonist , scopolamine , had no effect . The effects of galantamine on extracellular dopamine release were also antagonized by mecamylamine . DB00674 attenuated the defect of the novelty-induced activation of extracellular signal-regulated kinase 1/2 ( P27361 /2 ) . The ameliorating effect of galantamine on recognition memory in Meth-treated mice was negated by microinjection of an P29323 inhibitor , PD98059 , into the P27918 . These results suggest that the ameliorating effect of galantamine on Meth-induced memory impairment is associated with indirect activation of dopamine D1 receptor- P27361 /2 following augmentation with dopaminergic neurotransmission in the P27918 through the allosteric activation of nAChRs . DB00674 could be a useful therapeutic agent for treating cognitive deficits in schizophrenia/Meth psychosis , as well as Alzheimer 's disease . Functional network reconstruction reveals somatic stemness genetic maps and dedifferentiation-like transcriptome reprogramming induced by P23769 . Somatic stem cell transplantation holds great promise in regenerative medicine . The best-characterized adult stem cells are DB05914 ( MSCs ) , neural stem cells ( NSCs ) , and CD133(+) hematopoietic stem cells ( HSCs ) . The applications of HSCs are hampered since these cells are difficult to maintain in an undifferentiated state in vitro . Understanding genes responsible for stem cell properties and their interactions will help on this issue . The construction of stem cell genetic networks will also help to develop rational strategies to revert somatic cells back to a stem-like state . We performed a systemic study on human CD133(+) HSCs , NSCs , MSCs , and embryonic stem cells and two different progenies of CD133(+) HSCs , microvascular endothelial cells ( MVECs ) and peripheral blood mononuclear cells . Genes abundant in each or in all three somatic stem cells were identified . We also observed complex genetic networks functioning in postnatal stem cells , in which several genes , such as Q06124 and P00374 , acted as hubs to maintain the stability and connectivity of the whole genetic network . Eighty-seven P19526 genes , including Q15389 and P23769 , were independently identified by comparing P28906 (+) P20138 (-) P28907 (-) hematopoietic stem cells with P28906 (+) precursors and various matured progenies . Introducing P23769 into MVECs resulted in dedifferentiation-like transcriptome reprogramming , with P19526 genes ( such as Q15389 ) being up and endothelial genes ( such as P29323 ) being down . This study provides a foundation for a more detailed understanding of human somatic stem cells . Expressing the newly discovered stem cell genes in matured cells might lead to a global reversion of somatic transcriptome to a stem-like status . An overview of phenserine tartrate , a novel acetylcholinesterase inhibitor for the treatment of Alzheimer 's disease . Existing cholinesterase ( ChE ) inhibitor therapies for Alzheimer 's disease ( AD ) , while effective in improving cognitive , behavioral and functional impairments , do not alter disease progression . Novel drug design studies have focused on the classical ChE inhibitor , (-)-physostigmine , producing alterations in chemical composition and three-dimensional structure , which may offer an improved therapeutic index . The phenylcarbamate derivative , DB04892 , is a selective , non-competitive inhibitor of acetylcholinesterase ( P22303 ) . In vivo , DB04892 produces rapid , potent , and long-lasting P22303 inhibition . As a possible result of its preferential brain selectivity , DB04892 is significantly less toxic than (-)-physostigmine . In studies using the Stone maze paradigm , DB04892 has been shown to improve cognitive performance in both young learning-impaired and elderly rats . In addition to reducing inactivation of acetylcholine in the brain , DB04892 appears to have a second mode of action . Reduced secretion of beta-amyloid ( Abeta ) has been observed in cell lines exposed to DB04892 , occurring through translational regulation of beta-amyloid precursor protein ( beta- P05067 ) mRNA via a non-cholinergic mechanism . These in vitro findings appear to translate in vivo into animal models and humans . In a small study of patients with AD , DB04892 treatment tended to reduce beta- P05067 and Abeta levels in plasma samples . Clinical studies also reveal that DB04892 ( 5-10 mg b.i.d. ) had a favorable safety and pharmacological profile , produced significant improvements in cognitive function and was well tolerated in patients with AD treated for 12 weeks . Further randomized , double-blind , placebo-controlled Phase III studies assessing the efficacy , safety/tolerability and potential disease-modifying effects of DB04892 in patients with AD are currently ongoing . Domain organization of the DB00171 -sensitive potassium channel complex examined by fluorescence resonance energy transfer . K( DB00171 ) channels link cell metabolism to excitability in many cells . They are formed as tetramers of Kir6.2 subunits , each associated with a Q09428 subunit . We used mutant GFP-based FRET to assess domain organization in channel complexes . Q8N1N2 -length Kir6.2 subunits were linked to YFP or cyan fluorescent protein ( P27918 ) at N or C termini , and all such constructs , including double-tagged YFP-Kir6.2- P27918 ( Y6.2C ) , formed functional K( DB00171 ) channels . In intact COSm6 cells , background emission of YFP excited by 430-nm light was ∼6 % , but the Y6.2C construct expressed alone exhibited an apparent FRET efficiency of ∼25 % , confirmed by trypsin digestion , with or without Q09428 co-expression . Similar FRET efficiency was detected in mixtures of P27918 - and YFP-tagged full-length Kir6.2 subunits and transmembrane domain only constructs , when tagged at the C termini but not at the N termini . The FRET-reported Kir6.2 tetramer domain organization was qualitatively consistent with Kir channel crystal structures : C termini and M2 domains are centrally located relative to N termini and M1 domains , respectively . Additional FRET analyses were performed on cells in which tagged full-length Kir6.2 and tagged Q09428 constructs were co-expressed . These analyses further revealed that 1 ) NBD1 of Q09428 is closer to the C terminus of Kir6.2 than to the N terminus ; 2 ) the Kir6.2 cytoplasmic domain is not essential for complexation with Q09428 ; and 3 ) the N-terminal half of Q09428 can complex with itself in the absence of either the C-terminal half or Kir6.2 . Ligand-induced transrepression by P11473 through association of Q9UIG0 with acetylated histones . We have previously shown that the novel DB00171 -dependent chromatin-remodeling complex WINAC is required for the ligand-bound vitamin D receptor ( P11473 ) -mediated transrepression of the DB00146 1alpha-hydroxylase ( 1alpha(OH)ase ) gene . However , the molecular basis for P11473 promoter association , which does not involve its binding to specific DNA sequences , remains unclear . To address this issue , we investigated the function of Q9UIG0 in terms of the association between WINAC and chromatin for ligand-induced transrepression by P11473 . Results of in vitro experiments using chromatin templates showed that the association of unliganded P11473 with the promoter required physical interactions between Q9UIG0 and both P11473 and acetylated histones prior to P11473 association with chromatin . The acetylated histone-interacting region of Q9UIG0 was mapped to the bromodomain , and a Q9UIG0 mutant lacking the bromodomain served as a dominant-negative mutant in terms of ligand-induced transrepression of the 1alpha(OH)ase gene . Thus , our findings indicate that WINAC associates with chromatin through a physical interaction between the Q9UIG0 bromodomain and acetylated his tones , which appears to be indispensable for P11473 /promoter association for ligand-induced transrepression of 1alpha(OH)ase gene expression . Comparative kinome analysis to identify putative colon tumor biomarkers . Kinase domains are the type of protein domain most commonly found in genes associated with tumorigenesis . Because of this , the human kinome ( the protein kinase component of the genome ) represents a promising source of cancer biomarkers and potential targets for novel anti-cancer therapies . Alterations in the human colon kinome during the progression from normal colon ( NC ) through adenoma ( AD ) to adenocarcinoma ( AC ) were investigated using integrated transcriptomic and proteomic datasets . Two hundred thirty kinase genes and 42 kinase proteins showed differential expression patterns ( fold change ≥ 1.5 ) in at least one tissue pair-wise comparison ( AD vs. NC , AC vs. NC , and/or AC vs. AD ) . Kinases that exhibited similar trends in expression at both the mRNA and protein levels were further analyzed in individual samples of NC ( n = 20 ) , AD ( n = 39 ) , and AC ( n = 24 ) by quantitative reverse transcriptase PCR . Individual samples of NC and tumor tissue were distinguishable based on the mRNA levels of a set of 20 kinases . Altered expression of several of these kinases , including chaperone activity of bc1 complex-like ( Q8NI60 ) kinase , bromodomain adjacent to zinc finger domain protein 1B ( Q9UIG0 ) kinase , calcium/calmodulin-dependent protein kinase type II subunit delta ( Q13557 ) , serine/threonine-protein kinase 24 ( Q9Y6E0 ) , vaccinia-related kinase 3 ( Q8IV63 ) , and DB01361 kinase 3 ( Q9H2K8 ) , has not been previously reported in tumor tissue . These findings may have diagnostic potential and may lead to the development of novel targeted therapeutic interventions for colorectal cancer . The efficacy of combination antiretroviral therapy in HIV type 1-infected patients treated in Curaçao compared with Antillean , Surinam , and Dutch HIV type 1-infected patients treated in The Netherlands . We compared the efficacy of combination antiretroviral therapy ( cART ) of Antillean HIV-1-infected patients treated on the Caribbean island of Curaçao ( CUR-AN ) with Antillean ( NL-AN ) , Surinam ( NL- Q09428 ) , and Dutch ( NL-NL ) patients treated in The Netherlands . In total 2118 therapy-naive patients who started cART between January 2005 and August 2008 were included in the comparison . The CUR-AN patients initiated cART at a median P01730 cell count of 141 cells/mm(3) and 63 % had counts below 200 cells/mm(3) . Within 12 months of the start of cART 76 % of the CUR-AN patients achieved viral suppression , defined as HIV-1 RNA plasma levels below 80 copies/ml . The percentage achieving viral suppression was higher in patients treated in The Netherlands ( NL-AN = 87 % , NL- Q09428 = 93 % , and NL-NL = 96 % ) . Lost to follow-up after 30 months of cART was 10 % among CUR-AN patients and was higher than observed among patients treated in The Netherlands ( NL-AN = 8 % , NL- Q09428 = 3 % , and NL-NL = 2 % ) . A similar pattern was found for progression to AIDS and death ( 10 % of CUR-AN vs. 5 % , 6 % , and 7 % of NL-AN , NL- Q09428 , and NL-NL patients , respectively ) . Late start of cART and limited viral suppression after the start of cART determine the higher rate of disease progression to AIDS and death among Antillean patients treated in Curaçao . The high percentage of lost to follow-up may result in an underestimation of AIDS and AIDS-related death among HIV-1-infected Antilleans treated in Curaçao . Expression of P20839 is regulated in response to mycophenolate concentration . DB04335 5'-monophosphate dehydrogenase ( IMPDH ) catalyzes de novo guanine nucleotide synthesis . DB01024 ( DB00603 ) exerts immunosuppressive effects by inhibiting IMPDH . The aim of this study was to investigate gene expressions of two IMPDH isoforms , during in vivo exposure to DB00603 . Healthy volunteers ( n=5 ) were given single doses of 100 , 250 , 500 and 1000 mg mycophenolate mofetil ( DB00688 ) . Blood was sampled pre-dose and at 1 , 2 , 4 , 6 , 8 , 12 , and 24 h post-dose . The expressions of P20839 and 2 were quantified in P01730 + cells and whole blood by real-time reverse transcription-PCR . Following DB00688 doses of 500 mg , the expression of P20839 and 2 in P01730 + cells was reduced 39 % ( P=0.043 ) and 10 % ( P=0.043 ) , respectively . Smaller reductions ( ns ) were observed after 1000 mg DB00688 . Similar trends were demonstrated for whole blood . The largest reductions of P20839 occurred at DB00603 AUC ( 0-12 h ) of 20 mg h/L . Below this , increasing DB00603 exposure correlated with larger reductions of P20839 expression ( P01730 + cells : r=-0.82 , P < 0.001 , and whole blood : r=-0.50 , P=0.04 , n=17 ) , while higher DB00603 exposure seemed to be associated with smaller reductions of expression ( P01730 + cells : r=0.42 , ns , and whole blood : r=0.77 , P=0.039 , n=8 ) . The concentration-dependent modulation of P20839 and 2 expressions by DB00603 might impact IMPDH activity . Knowledge of the regulation of the two IMPDH isoenzymes in vivo by DB00603 is of importance considering pharmacodynamic monitoring and optimization of DB00603 treatment . Expression of vitamin D receptor ( P11473 ) , cyclooxygenase-2 ( P35354 ) and 15-hydroxyprostaglandin dehydrogenase ( P15428 ) in benign and malignant ovarian tissue and DB00146 ( 25(OH2)D3 ) and prostaglandin E2 ( DB00917 ) serum level in ovarian cancer patients . Ovarian carcinomas are associated with increased inflammation which is based upon an up-regulation of inducible cyclooxygenase-2 ( P35354 ) . Moreover , based on our previous published data , the extra-renal vitamin D metabolism seems to be dysregulated in comparison to healthy tissue . In order to gain further insight into the prostaglandin ( PG ) - and vitamin D-metabolism in ovarian carcinomas , the study aimed to evaluate the expression of the PG metabolising enzymes P35354 and 15-hydroxyprostaglandin dehydrogenase ( P15428 ) compared to the vitamin D receptor ( P11473 ) in benign and malignant ovarian tissues . Additionally , we determined the DB00146 ( 25(OH2)D3 ) serum levels . Expression of P11473 , P35354 and P15428 was determined by Western blot analysis . Serum levels of 25(OH2)D3 and DB00917 were measured by chemiluminescence-based and colorimetric immunoassay . We detected significantly higher expressions of the PG metabolising enzymes P15428 and P35354 in malignant tissue and DB00917 serum levels were 2-fold higher in tumour patients . Furthermore , we found an inverse correlation to the P11473 -expression which was 62.1 % lower in malignant tissues compared to that in benign tissues . Surprisingly , we could not detect any differences between the 25(OH2)D3 serum levels in either group ( n=20 ) . These data suggest a correlation between PG- and vitamin D-metabolism in ovarian carcinomas . DB04892 . DB04892 , a derivative of physostigmine , was first described as an inhibitor of acetylcholinesterase ( P22303 ) and was shown to improve cognition in various experimental paradigms in rodents and dogs . It was clinically tested for Alzheimer 's disease , with moderate success in initial Phase II studies . DB04892 deserves attention for an additional quality of action : in addition to inhibiting P22303 , it modulates the amount of beta-amyloid precursor protein ( P05067 ) in neuronal cell culture by reducing P05067 translation . This effect probably involves interaction of phenserine with a regulatory element in the 5'-untranslated region of the P05067 gene that controls P05067 expression . DB04892 apparently reduces translational efficiency of P05067 mRNA into protein , a process that may involve an interaction with iron and/or an iron-responsive element . As a consequence , phenserine reduces beta-amyloid peptide ( Abeta ) formation in vitro and in vivo . DB04892 is also unique because of differing actions of its enantiomers : DB04892 is the active enantiomer for inhibition of P22303 , whereas (+)-phenserine ( ' posiphen ' ) has weak activity as an P22303 inhibitor and can be dosed much higher . Both enantiomers are equipotent in downregulating P05067 expression . (+)-Posiphen may be a promising drug , either alone or in combination with DB04892 , to attenuate the progression of Alzheimer 's disease . Analysis of the differentially expressed genes in Microsporum canis in inducing smooth skin and scalp tissue conditions . Microsporum canis is a common zoophilic dermatophyte , which causes a range of infections . To explore the pathogenic mechanism of tinea capitis , we used the suppression subtractive hybridization ( SSH ) technique to investigate the differences in gene expression between different cultures of Microsporum canis incubated on three different types of mineral media containing child glabrous skin , child scalp tissue and adult scalp tissue . Using dot-blot hybridization and real-time PCR technique , we successfully screened and identified a pair of genes that had expression levels 44.6 and 117 times higher in culture 1 ( M. canis cultured in mineral medium with child scalp tissue ) than in culture 2 ( M. canis cultured in mineral medium with glabrous skin tissue ) , and another pair of genes with expression levels 78.2 and 9.8 times higher in culture 1 than in culture 3 ( M. canis cultured in mineral medium with adult scalp tissue ) . These four genes were found to have 41 % , 53 % , 40 % and 94 % homology to those encoding a hypothetical protein [ family of serine hydrolases 1 ; ( FSH1 ) ] , PQ loop repeat protein ( PQ- Q14764 ) , a predicted protein [ porphyrin galactose 4 ; ( P-GAL4 ) ] and DB00157 dehydrogenase subunit ( DB00157 )1 , respectively . The upregulation of the FSH1 , PQ- Q14764 , P-GAL4 and P03886 genes in cultures of child scalp tissue indicates that they are essential in the pathogenesis of tinea capitis caused by M. canis . A guide to picking the most selective kinase inhibitor tool compounds for pharmacological validation of drug targets . To establish the druggability of a target , genetic validation needs to be supplemented with pharmacological validation . Pharmacological studies , especially in the kinase field , are hampered by the fact that many reference inhibitors are not fully selective for one target . Fortunately , the initial trickle of selective inhibitors released in the public domain has steadily swelled into a stream . However , rationally picking the most selective tool compound out of the increasing amounts of available inhibitors has become progressively difficult due to the lack of accurate quantitative descriptors of drug selectivity . A recently published approach , termed ' selectivity entropy ' , is an improved way of expressing selectivity as a single-value parameter and enables rank ordering of inhibitors . We provide a guide to select the best tool compounds for pharmacological validation experiments of candidate drug targets using selectivity entropy . In addition , we recommend which inhibitors to use for studying the biology of the 20 most investigated kinases that are clinically relevant : Abl ( P00519 ) , P31749 , Q9UM73 , Aurora A/B , CDKs , MET , P07333 ( P07333 ) , P00533 , P36888 , P04626 ( P04626 ) , O14920 ( O14920 ) , O60674 /3 , P45983 /2/3 ( P45983 /9/10 ) , Q02750 /2 , P53350 , PI3Ks , p38α ( Q16539 ) , P15056 , P12931 and P35968 ( P35968 ) . P01308 secretory defects and impaired islet architecture in pancreatic beta-cell-specific P40763 knockout mice . Normal islet formation and function depends on the action of various growth factors operating in pre- and postnatal development ; however , the specific physiological function of each factor is largely unknown . Loss-of-function analyses in mice have provided little information so far , perhaps due to functional redundancies of the growth factors acting on the pancreas . The present study focuses on the role of the transcription factor P40763 in insulin-producing cells . P40763 is one of the potential downstream mediators for multiple growth factors acting on the pancreatic beta-cells , including betacellulin , hepatocyte growth factor , growth hormone , and heparin-binding P01133 -like growth factor . To elucidate its role in the beta-cells , the P40763 gene was disrupted in insulin-producing cells in mice ( P40763 -insKO ) , using a cre-mediated gene recombination approach . Unexpectedly , P40763 -insKO mice exhibited an increase in appetite and obesity at 8 weeks of age or older . The mice showed partial leptin resistance , suggesting that expression of the RIP ( rat insulin promoter ) -cre transgene in hypothalamus partially inhibited the appetite-regulating system . Intraperitoneal glucose tolerance tests , performed in non-obese 5-week-old mice , showed that the P40763 -insKO mice were glucose intolerant . Islet perifusion experiments further revealed a deficiency in early-phase insulin secretion . Whereas islet insulin content or islet mass was not affected , expression levels of P11168 , Q09428 , and P15692 were significantly reduced in P40763 -insKO islets . Interestingly , P40763 -insKO mice displayed impaired islet morphology : alpha-cells were frequently seen in central regions of islets . Our present observations demonstrate a unique role of P40763 in maintaining glucose-mediated early-phase insulin secretion and normal islet morphology . 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 . Sulfonylureas inhibit cytokine-induced eosinophil survival and activation . Eosinophils play a key role in the pathogenesis of asthma and other allergic inflammatory diseases . We have previously shown that treatment of eosinophils with lidocaine preferentially inhibits P05113 -induced survival . This inhibition can not be overcome by increasing concentrations of P05113 and is not due to the blocking of Na+ channels by lidocaine . Here we report that one class of K+ channel blockers , the sulfonylureas , inhibits eosinophil survival in a manner similar to lidocaine . The sulfonylurea glyburide inhibits eosinophil survival even at high concentrations of P05113 . In contrast , increasing concentrations of P08700 or granulocyte-macrophage P04141 overcome glyburide inhibition . Glyburide also blocks cytokine-induced eosinophil superoxide production . Similar results were seen with the sulfonylureas tolbutamide and glipizide . Interestingly , the effects of glyburide are not antagonized by the DB00171 -sensitive K+ channel openers cromakalim , pinacidil , or diazoxide . Although Scatchard analysis of [3H]glyburide binding to eosinophil membranes indicated that the high affinity sulfonylurea receptor ( Q09428 ) is not present on eosinophils , human eosinophils do express mRNA homologous to the sulfonylurea receptor family , in keeping with the presence of a sulfonylurea receptor . Finally , coculture of eosinophils with combinations of glyburide , lidocaine , and dexamethasone resulted in synergistic inhibition of cytokine-mediated eosinophil survival and superoxide production . These results have intriguing clinical implications for the treatment of eosinophil-associated diseases . Evaluation of the endogenous cannabinoid system in mediating the behavioral effects of dipyrone ( metamizol ) in mice . DB04817 is a common nonopioid analgesic and antipyretic , which , in many countries , is available over the counter and is more widely used than paracetamol or aspirin . However , the exact mechanisms by which dipyrone acts remain inconclusive . Two novel arachidonoyl-conjugated metabolites are formed in mice following the administration of dipyrone that are dependent on the activity of fatty acid amide hydrolase ( FAAH ) , which also represents the major catabolic enzyme of the endogenous cannabinoid ligand anandamide . These arachidonoyl metabolites not only inhibit cyclooxygenase ( P23219 / P35354 ) but also bind to cannabinoid receptors at low micromolar concentrations . The relative contributions of cannabinoid receptors and FAAH in the overall behavioral response to dipyrone remain untested . Accordingly , the two primary objectives of the present study were to determine whether the behavioral effects of dipyrone would ( a ) be blocked by cannabinoid receptor antagonists and ( b ) occur in FAAH mice . Here , we report that thermal antinociceptive , hypothermic , and locomotor suppressive actions of dipyrone are mediated by a noncannabinoid receptor mechanism of action and occurred after acute or repeated administration irrespective of FAAH . These findings indicate that FAAH-dependent arachidonoyl metabolites and cannabinoid receptors are not requisites by which dipyrone exerts these pharmacological effects under noninflammatory conditions . Leishmania mexicana amazonensis : ADP-ribosyltransferase antagonists specifically inhibit amastigote to promastigote differentiation . Leishmania mexicana amazonensis amastigotes were induced to differentiate by incubation at 27 C . Morphological transformation was studied both in untreated cultures and in cultures where DNA synthesis , and consequently the final stage in the production of promastigotes , was inhibited by hydroxyurea . DB03073 and other antagonists of ADP-ribosyltransferase ( P09874 ) specifically inhibited differentiation at a very early stage in both experimental systems . Cell proliferation ( in the absence of hydroxyurea ) was not inhibited by P09874 antagonists -- indeed greater multiplication of undifferentiated parasites was observed in the presence of these compounds . This indicated that the parasites were being diverted from differentiation to proliferation . Preincubation of the amastigotes with the P09874 antagonists was required to produce this effect , providing further evidence that ADP-ribosylation of proteins is required for the initiation of differentiation in Leishmania . Different cholinesterase inhibitor effects on P04141 cholinesterases in Alzheimer patients . BACKGROUND : The current study aimed to compare the effects of different cholinesterase inhibitors on acetylcholinesterase ( P22303 ) and butyrylcholinesterase ( BuChE ) activities and protein levels , in the cerebrospinal fluid ( P04141 ) of Alzheimer disease ( AD ) patients . METHODS AND FINDINGS : AD patients aged 50-85 years were randomized to open-label treatment with oral rivastigmine , donepezil or galantamine for 13 weeks . P22303 and BuChE activities were assayed by Ellman 's colorimetric method . Protein levels were assessed by enzyme-linked immunosorbent assay ( ELISA ) . Primary analyses were based on the Completer population ( randomized patients who completed Week 13 assessments ) . 63 patients were randomized to treatment . DB00989 was associated with decreased P22303 activity by 42.6 % and decreased P22303 protein levels by 9.3 % , and decreased BuChE activity by 45.6 % and decreased BuChE protein levels by 21.8 % . DB00674 decreased P22303 activity by 2.1 % and BuChE activity by 0.5 % , but increased P22303 protein levels by 51.2 % and BuChE protein levels by 10.5 % . Donepezil increased P22303 and BuChE activities by 11.8 % and 2.8 % , respectively . Donepezil caused a 215.2 % increase in P22303 and 0.4 % increase in BuChE protein levels . Changes in mean P22303 -Readthrough/Synaptic ratios , which might reflect underlying neurodegenerative processes , were 1.4 , 0.6 , and 0.4 for rivastigmine , donepezil and galantamine , respectively . CONCLUSION : The findings suggest pharmacologically-induced differences between rivastigmine , donepezil and galantamine . DB00989 provides sustained inhibition of P22303 and BuChE , while donepezil and galantamine do not inhibit BuChE and are associated with increases in P04141 P22303 protein levels . The clinical implications require evaluation .