MH_dev_328

Genetically rescued tetrahydrobiopterin-depleted mice survive with hyperphenylalaninemia and region-specific monoaminergic abnormalities . One of the possibly mutated genes in DOPA-responsive dystonia ( DRD , Segawa ' s disease ) is the gene encoding P30793 REA , which is the rate-limiting enzyme for tetrahydrobiopterin ( BH4 ) biosynthesis . Based on our findings on 6 - pyruvoyltetrahydropterin synthase ( Q03393 REA ) gene-disrupted ( Pts ( - / - ) ) mice , we suggested that the amount of tyrosine hydroxylase ( TH ) protein in dopaminergic nerve terminals is regulated by the intracellular concentration of BH4 . In this present work , we rescued Pts ( - / - ) mice by transgenic introduction of human Q03393 REA cDNA under the control of the dopamine beta-hydroxylase promoter to examine regional differences in the sensitivity of dopaminergic neurons to BH4 - insufficiency . The DPS-rescued ( Pts ( - / - ) , DPS ) mice showed severe hyperphenylalaninemia . Human Q03393 REA was efficiently expressed in noradrenergic regions but only in a small number of dopaminergic neurons . DB03886 MEN and dopamine contents , and TH activity in the striatum were poorly restored compared with those in the midbrain . TH-immunoreactivity in the lateral region of the striatum was far weaker than that in the medial region or in the nucleus accumbens . We concluded that dopaminergic nerve terminals projecting to the lateral region of the striatum are the most sensitive to BH4 - insufficiency . Biochemical and pathological changes in DPS-rescued mice were similar to those in human malignant hyperphenylalaninemia and DRD .

DB00115 MEN is a strong determinant of low methionine synthase activity and DNA hypomethylation in gastrectomized rats . BACKGROUND / AIMS : The respective influence of folate and vitamin B12 deficiency on Q99707 REA activity and transcription , and on DNA methylation is not clearly established . The aim of this study was to assess the respective influence of folate and vitamin B12 deficiency on Q99707 REA transcription and activity , and on DNA methylation . METHODS : Sixty-one rats were administered normal diet or diet deficient in choline , methionine , folic acid and vitamin B12 . Forty-seven of them underwent total gastrectomy or ileal resection . RESULTS : Low vitamin B12 was observed only in gastrectomized rats . Low folate was observed in rats under deficient diet . Total Q99707 REA activity ( holo - + apoenzyme ) was lowered only with vitamin B12 level < 200 pmol / l ( p= 0.0002 ) , while the ratios of total vs . holo - Q99707 REA activity and of transcripts Q99707 REA vs . P04406 REA ( RT-PCR ) were unchanged . DB00115 MEN was the single determinant of low Q99707 REA ( lower quartile , odds ratio = 15.75 , p= 0.0017 ) . Low Q99707 REA and low vitamin B12 were the two determinants of DNA hypomethylation ( lower quartile ) ( odds ratio = 17.07 , p= 0.0006 , and odds ratio = 7.31 , p= 0.006 , respectively ) . CONCLUSION : DB00115 MEN affects Q99707 REA expression by a non-transcriptional mechanism different from a protective effect on Q99707 REA proteolysis . It is also a strong determinant of DNA hypomethylation .

Bioassay-guided isolation of an alkaloid with antiangiogenic and antitumor activities from the extract of Fissistigma cavaleriei root . Fissistigma cavaleriei ( Levl ) Rehd ( Annonaceae ) is used as a folklore medicine for treatment of inflammation , arthritis , and tuberculosis by Miao people in China . In the present study , the antiangiogenic activity of F . cavaleriei was investigated . The chorioallantoic membrane of the fertilized hen ' s egg ( P62158 assay ) was used to determine antiangiogenic activity of the plant extract . Compound ( 1 ) , a compound with antiangiogenic activity , was isolated by bioassay-guided fractionation from F . cavaleriei for the first time . The structure of compound ( 1 ) was elucidated on the basis of spectroscopic methods . Colorimetric P36551 REA ( ovine ) inhibitor screening assay was used to determine its inhibitory effect on P23219 REA and P35354 REA . MTT and Sulforhodamine B assays were used to investigate its cytotoxic effects on tumor cell lines . As a result , compound ( 1 ) showed a selectively inhibiting effect on P35354 REA and could inhibit the growth of tumor cells in vitro . The antitumor activity of compound ( 1 ) was further confirmed by the observation that compound ( 1 ) administration significantly inhibited the growth of S - 180 cells in mice . Moreover , compound ( 1 ) was able to enhance the antitumor activity of doxorubicin in the mice bearing with S - 180 cells while combined with doxorubicin . In conclusion , compound ( 1 ) is a multi-target molecule and further experimental investigations are needed to determine whether it can be used as a lead molecule for tumor treatment .

Involvement of sphingosine kinase in P01375 REA - stimulated tetrahydrobiopterin biosynthesis in P13671 REA glioma cells . In P13671 REA glioma cells , the sphingolipid second messenger ceramide potentiates expression of inducible nitric-oxide synthase ( P35228 REA ) induced by tumor necrosis factor alpha ( P01375 REA ) without affecting P30793 REA ( GTPCH ) , the rate-limiting enzyme in the biosynthesis of 6 ( R ) - DB00360 ( BH ( 4 ) ) , a cofactor required for P35228 REA activity . P01375 REA also stimulates sphingosine kinase , the enzyme that phosphorylates sphingosine to form sphingosine - 1 - phosphate ( Q8TCT9 ) , a further metabolite of ceramide . Several clones of P13671 REA cells , expressing widely varying levels of sphingosine kinase , were used to examine the role of Q8TCT9 in regulation of GTPCH and BH ( 4 ) biosynthesis . Overexpression of sphingosine kinase , with concomitant increased endogenous Q8TCT9 levels , potentiated the effect of P01375 REA on GTPCH expression and activity and BH ( 4 ) biosynthesis . In contrast , enforced expression of sphingosine kinase had no effect on P35228 REA expression or NO formation . Furthermore , N , N-dimethylsphingosine , a potent sphingosine kinase inhibitor , completely eliminated the increased GTPCH activity and expression induced by P01375 REA . Surprisingly , we found that , although P13671 REA cells can secrete Q8TCT9 , which is enhanced by P01375 REA , treatment of P13671 REA cells with exogenous Q8TCT9 or dihydro - Q8TCT9 had no affect on BH ( 4 ) biosynthesis . However , both Q8TCT9 and dihydro - Q8TCT9 markedly stimulated P29323 REA 1/2 in P13671 REA cells , which express cell surface Q8TCT9 receptors . Interestingly , although this P29323 REA activation was blocked by PD98059 , which also reduced cellular proliferation induced by enforced expression of sphingosine kinase , PD98059 had no effect on GTPCH activity . Collectively , these results suggest that only intracellularly generated Q8TCT9 plays a role in regulation of GTPCH and BH ( 4 ) levels .

P10275 REA inducing bladder cancer progression by promoting an epithelial-mesenchymal transition . The study investigated the role of androgen receptor ( AR ) as a potential target for the treatment of bladder cancer in regulating epithelial-mesenchymal transition or transformation ( EMT ) . Cell proliferation , and migration capacity were determined in bladder cancer T24 cells treated with small interfering RNA directed against AR , and expression levels of P12830 REA , β-catenin and N - cadherin were assessed using quantitative reverse transcription PCR ( qRT-PCR ) . Tumour cell growth was evaluated in vivo in T24 tumour-bearing nude mice receiving electroporation-assisted administration of anti-AR small interfering RNA . It was found that low AR expression decreased proliferation and migration of bladder cancer cells . In vivo experiments showed that silencing AR expression significantly suppressed AR-positive bladder tumour growth with decreased cell proliferation . Low AR level of T24 bladder cancer cells treated with DB01541 MEN ( DB02901 ) decreased expression of P12830 REA , β-catenin and P19022 REA expression , indicating a strong sensitivity to the EMT and In cells with low AR content , TGF-β induced down-regulation of P12830 REA and β-catenin . It is concluded that suppression of AR expression decreased the production of TGF-β , inhibiting EMT and bladder cancer cell growth in vitro and in vivo , implying that its use might be a potential therapeutic target for the treatment of bladder cancer .

Assessment of partially deoxygenated deoxynojirimycin derivatives as glucosylceramide synthase inhibitors . Q16739 REA ( Q16739 REA ) is an approved drug target for the treatment of Gaucher disease and is considered as a valid target for combating other human pathologies , including type 2 diabetes . The clinical drug N-butyldeoxynojirimycin ( DB00419 MEN ) is thought to inhibit through mimicry of its substrate , ceramide . In this work we demonstrate that , in contrast to what is proposed in this model , the P06681 REA - hydroxyl of the deoxynojirimycin core is important for Q16739 REA inhibition . Here we show that P13671 REA - OH appears of less important , which may set guidelines for the development of Q16739 REA inhibitors that have less affinity ( in comparison with DB00419 MEN ) for other glycoprocessing enzymes , in particular those hydrolases that act on glucosylceramide .

Peroxisome proliferator-activated receptor-gamma is a target of nonsteroidal anti-inflammatory drugs mediating cyclooxygenase-independent inhibition of lung cancer cell growth . Nonsteroidal anti-inflammatory drugs ( NSAIDs ) inhibit the growth of different cancer cell types , suggesting a broad role for their cyclooxygenase ( P36551 REA ) targets and eicosanoid products in tumor cell growth . Sulindac sulfide , a P36551 REA inhibitor , inhibited the growth of non-small-cell lung cancers ( NSCLC ) both in soft agar and as xenografts in nude mice . Importantly , the concentration of sulindac sulfide required to inhibit NSCLC cell growth greatly exceeded the concentration required to inhibit prostaglandin ( PG ) E ( 2 ) synthesis in NSCLC cells , suggesting that NSAID inhibition of cell growth is mediated by additional targets distinct from P36551 REA . Both sulindac sulfide and ciglitazone , a defined peroxisome proliferator-activated receptor-gamma ( PPARgamma ) agonist , stimulated a promoter construct containing a Q07869 REA response element linked to luciferase and potently inhibited NSCLC cell growth at similar concentrations , indicating a role for PPARgamma as a target of NSAID action in these cells . Overexpression of PPARgamma in NSCLC cells strongly inhibited the transformed growth properties of the cells , providing a molecular confirmation of the results obtained with the PPARgamma agonists . Increased expression of PPARgamma , as well as ciglitazone and sulindac sulfide induced expression of P12830 REA , which has been linked to increased differentiation of NSCLC . Despite the fact that SCLC cell lines expressed little or no cytosolic phospholipase A ( 2 ) , P23219 REA , or P35354 REA , sulindac sulfide and PPARgamma agonists also inhibited the transformed growth of these lung cancer cells . We propose that PPARgamma serves as a target for NSAIDs that accounts for P36551 REA - independent inhibition of lung cancer cell growth .

P62158 - mediated effects of loperamide on chloride transport by brush border membrane vesicles from human ileum . We investigated whether the synthetic opiate loperamide-HCl is able to regulate specific transport systems for sodium and chloride in brush border membrane vesicles ( BBMVs ) from human ileum and whether such activities are mediated by calcium / calmodulin . In BBMVs we studied Na + / H + antiport , Cl + / OH - antiport , Na + / Cl - cotransport , and the Cl - conductive pathway . Brush border membrane vesicles were incubated with 10 microM loperamide over 4 h at 5 degrees C before the uptake experiments . In ileal BBMVs , loperamide stimulated intravesicular accumulation of Na + in the presence of Cl - and vice versa . After 1 min of incubation , the stimulatory effect was 35 % + / - 5 % ( p less than 0.005 ) of the control without loperamide . DB00836 MEN also stimulated Cl - / OH - antiport by 30 % + / - 5 % ( p less than 0.005 ) in BBMVs of ileum . In addition , we studied the role of Ca2 + / calmodulin in the action of loperamide on chloride transport by human BBMVs . In loperamide-pretreated BBMVs , calmodulin activity was significantly decreased ( 12 + / - 2 vs . 38 + / - 4 pmol / mg protein ) . When loperamide-pretreated vesicles were incubated with 2 microM calcium ( free concentration ) plus 5 microM calmodulin for 1 h at 5 degrees C , complete inhibition of the stimulatory effect of loperamide on Cl - / OH - antiport and Na + / Cl - cotransport was observed . Increasing the Ca2 + / calmodulin activity of loperamide-pretreated BBMVs with 2 microM calcium plus 5 microM calmodulin led to a significant inhibition of Cl - / OH - antiport and Na + / Cl - cotransport by 40 % + / - 5 % ( p less than 0.005 ) .

Cyclooxygenase-independent inhibition of H2O2 - induced cell death by S-ketoprofen in renal cells . The stress response of the distal tubule to oxidative attack may be relevant to recovery from acute renal failure . In distal tubular Madin-Darby cells ( MDCK ) , H ( 2 ) O ( 2 ) induced up-regulation of cyclooxygenases ( P23219 REA and P35354 REA ) , prostaglandin-E ( 2 ) production and caspase-independent cell death . Cell death was inhibited by S-ketoprofen , but not by the much weaker P36551 REA inhibitor R-ketoprofen . Interestingly , we identified 15 - deoxy-Delta ( 12,14 ) - prostaglandin-J ( 2 ) ( 15d - PGJ ( 2 ) ) , a peroxisome-proliferator activated receptor-gamma agonist , as a lethal prostaglandin whose effect was reproduced by the P37231 REA agonist ciglitazone . Nevertheless , H ( 2 ) O ( 2 ) - induced cell death was unaffected by other non-steroidal anti-inflammatory drugs ( NSAIDs ) or all-trans-retinoic acid . Moreover , c-Jun-N-terminal kinase inhibitor SP600125 prevented 15 - deoxy-Delta ( 12,14 ) - PGJ ( 2 ) - induced cell death , but not H ( 2 ) O ( 2 ) - induced cell death . P37231 REA antagonist GW9662 showed no affect on the cell death . These results indicated that protection by S-ketoprofen was P36551 REA - independent and PPARgamma independent . Moreover , the IC ( 50 ) value of the action of S-ketoprofen for the inhibition of H ( 2 ) O ( 2 ) - induced MDCK cell death ( approximately equal 140microM ) was much higher than the IC ( 50 ) value for the inhibition of P23219 REA and P35354 REA activities ( approximately equal 1microM ) . Further design of S-ketoprofen derivatives devoid of P36551 REA inhibitory activity will give opportunity to protect the kidney against oxidative attack while avoiding unwanted effects of NSAID .

Spinal cord injury induces early and persistent lesional Q99571 REA receptor expression . Following spinal cord injury ( SCI ) , neuropathic , chronic pain is a major cause of disability . Recently , glial Q99571 REA receptor ( P2X4R ) has been identified as a major contributor to the development of neuropathic pain after peripheral nerve injury . Here we report analysis of P2X4R expression following rat SCI . Significant lesional accumulation of P2X4R + cells was detected as early as 24 h after SCI , reaching maximum cell numbers on Day 7 . Thereafter cell numbers declined but persisted at significantly elevated , sub-maximal levels ( > 70 % ) until 1 month post injury . Double-immunolabeling identified the majority of lesional P2X4R + cells as activated microglia / macrophages and surviving neurons / neurites . Increase of P2X4R + , beta - P05067 REA + hypertrophic neurites correlated with proximity to the lesion . Further , P2X4R + cells coexpressed the intracellular regulators of signalling cascades , P23219 REA ( > 20 % ) , P35354 REA ( > 5 % ) , RhoA ( > 60 % ) and RhoB ( > 10 % ) .

Topical glucocorticoids downregulate P23219 REA positive cells in nasal polyps . BACKGROUND : Influx of inflammatory cells is one of the hallmarks of nasal polyposis . As glucocorticoids ( GC ) are known to exhibit strong anti-inflammatory effects , these drugs are frequently used in the treatment of the disease . Part of the anti-inflammatory effects of GC is attributed to their interference with prostanoid synthesis . As cyclooxygenases ( P36551 REA ) are key enzymes in the synthesis of both pro - ( P23219 REA , P35354 REA ) and anti-inflammatory prostanoids ( P35354 REA ) , we investigated the role of topical GC on P23219 REA , P35354 REA and inflammatory markers in nasal polyps ( NP ) . METHODS : Immunohistochemical analysis of inflammatory markers ( P34810 REA , CD117 , MBP , elastase , IgE , BB - 1 , P05112 REA , P05113 REA and P05231 REA ) , P23219 REA and P35354 REA was performed on normal nasal mucosa ( NM ) ( n = 18 ) , non-GC treated NP ( n = 27 ) and topical GC treated NP ( n = 12 ) . NP groups were matched for allergy , asthma and ASA intolerance . RESULTS : Increased numbers of eosinophils , P05113 REA + cells and IgE + cells and decreased numbers of mastcells are striking features of NP inflammation ( P < 0.05 ) . In addition , increased numbers of P23219 REA + cells are observed in NP epithelium compared to NM ( P < 0.05 ) . CONCLUSION : Topical GC significantly reduce the number of P23219 REA + NP cells ( P < 0.05 ) , but have no significant effect on P35354 REA + NP cells . No significant reduction in the number of eosinophils is observed for GC treated NP . The number of P05113 REA + cells is however increased significantly upon GC treatment ( P < 0.05 ) .

Acute renal failure from hemoglobinuric and interstitial nephritis secondary to iodine and mefenamic acid . DB00784 SUB ingestion , usually in excess and over prolonged period is known to produce interstitial nephritis , or less commonly papillary necrosis , with acute renal failure . However , it is not dose-dependent for the induction of tubulointerstitial damage . Excess iodine ingestion is known to produce toxicity and possible death , but acute renal failure is rare . There is evidence from clinical and experimental data that iodine has toxic effect on tubular epithelial cells . Iodine has not been documented to produce red cell hemolysis and hemoglobinuria . We present a unique case of acute renal failure from hemoglobinuric and acute interstitial nephritis secondary to suicidal ingestion of potassium iodide solution and also ingestion of a few mefenamic acid tablets . These agents led to potentiation of the renal injury from hemoglobinuric tubulopathy , probably from the iodine , and renal dysfunction from alteration of renal perfusion by selective P23219 REA inhibition of prostaglandin production , and induction of acute interstitial nephritis from mefenamic acid , leading to acute renal failure which was reversible by hemodialysis and supportive therapy .

Investigation of the binding of isoform-selective inhibitors to prostaglandin endoperoxide synthases using fluorescence spectroscopy . Prostaglandin endoperoxide synthase ( PGHS ) is a heme protein that catalyzes the committed step in prostaglandin and thromboxane biosynthesis . Two isoforms of PGHS exist , a constitutive form termed P23219 REA and an inducible form termed P35354 REA . We report here fluorescence resonance energy transfer analysis of isoform-selective inhibitors interacting with P23219 REA and P35354 REA . By measuring fluorescence quenching due to the energy transfer of the inhibitor fluorescence to the heme prosthetic group of PGHS , we determined these inhibitors bind in the arachidonic acid substrate access channel with an R0 of 35 A for P23219 REA with the P23219 REA inhibitor and an R0 of 21 A for P35354 REA with the P35354 REA inhibitor . The observed fluorescence quenching is completely dynamic and dominated by quenching by the heme . Time-resolved results combined with molecular modeling determine the distance from the inhibitor to the heme moiety to be 20 A in P23219 REA and 18 A in P35354 REA . Preliminary stopped-flow kinetic studies reveal that the rate of quenching is limited by a first-order protein transition , which is slow , and that bound inhibitor undergoes rapid exchange .

Perinuclear localization of cytosolic phospholipase A ( 2 ) alpha is important but not obligatory for coupling with cyclooxygenases . In response to Ca ( 2 + ) signaling , cytosolic phospholipase A ( 2 ) alpha ( cPLA ( 2 ) alpha ) translocates from the cytosol to the perinuclear membrane , where downstream eicosanoid-synthetic enzymes , such as cyclooxygenase ( P36551 REA ) , are localized . Although the spatiotemporal perinuclear colocalization of cPLA ( 2 ) alpha and COXs has been proposed to be critical for their functional coupling leading to prostanoid production , definitive evidence for this paradigm has remained elusive . To circumstantiate this issue , we took advantage of a chimeric cPLA ( 2 ) alpha mutant harboring the P06681 REA domain of protein kinase Calpha , which translocates to the plasma membrane following cell activation . Transfection analyses of the native or chimeric cPLA ( 2 ) alpha in combination with P23219 REA or P35354 REA revealed that , even though the arachidonate-releasing capacities of native and mutant cPLA ( 2 ) alpha were comparable , prostaglandin production by mutant cPLA ( 2 ) alpha was markedly impaired as compared with that by native cPLA ( 2 ) alpha . We thus conclude that the perinuclear localization of cPLA ( 2 ) alpha is preferential , even if not obligatory , for efficient coupling with COXs .

beta-Carotene induces apoptosis and up-regulates peroxisome proliferator-activated receptor gamma expression and reactive oxygen species production in MCF - 7 cancer cells . Although the pharmacological role of beta-carotene in the prevention and treatment of many cancer cells has received increasing attention , the molecular mechanisms underlying such chemopreventive activity are not clear . Since peroxisome proliferator-activated receptor gamma ( P37231 REA ) has been implicated in regulating breast cancer cell differentiation and apoptosis , the effects of beta-carotene on the P37231 REA - mediated pathway and its association with reactive oxygen species production in MCF - 7 cells were investigated in the present study . The results demonstrated that beta-carotene significantly increased P37231 REA mRNA and protein levels in time-dependent manner . In addition , beta-carotene increased the cyclin-dependent kinase inhibitor P38936 REA ( P38936 REA / CIP 1 ) expression and decreased the prostanoid synthesis rate-limiting enzyme cyclooxygenase - 2 expression . DB07863 MEN ( GW9662 ) , an irreversible P37231 REA antagonist , partly attenuated the cell death caused by beta-carotene . Further , reactive oxygen species ( ROS ) production was induced by beta-carotene , resulting in mitochondrial dysfunction and cytochrome C release . DB00143 ( DB00143 ) treatment decreases the intracellular ROS and prevents cytochrome C release and cell apoptosis induced by beta-carotene . In total , these observations suggest that the synergistic effect of P37231 REA expression and ROS production may account for beta-carotene-mediated anticancer activities .

DB01411 MEN , a leukotriene receptor antagonist , inhibits interleukin - 5 production via a mechanism distinct from leukotriene receptor antagonism . BACKGROUND : DB01411 MEN , a cysteinyl leukotriene receptor 1 ( Q9Y271 REA ) antagonist , inhibits not only airway smooth muscle contraction , but also allergic inflammation . The aim of this study was to determine the mechanism of pranlukast-induced interleukin - 5 ( P05113 REA ) inhibition in allergic inflammation . METHODS : Surgically resected human lung tissue was passively sensitized in vitro with mite-allergen-sensitized sera , followed by stimulation with mite allergen after pretreatment of the tissue with pranlukast , dexamethasone , or both . The P05113 REA protein level in the culture medium was measured , and in situ hybridization of P05113 REA and Q9Y271 REA mRNA was performed using lung tissues . RESULTS : Pretreatment of lung tissues with pranlukast alone significantly decreased the amount of P05113 REA protein in the culture medium by 40 % . The combination of pranlukast and dexamethasone synergistically enhanced this effect . Quantitative in situ hybridization with image analysis revealed abundant expression of P05113 REA mRNA in eosinophils , lymphocytes , and mast cells in sensitized and allergen-stimulated lung tissues . Q9Y271 REA mRNA was detected in macrophages , smooth muscle cells , eosinophils , and mast cells , but was less expressed in lymphocytes . DB01411 MEN - induced inhibition of P05113 REA mRNA expression was noted in various cells , irrespective of their Q9Y271 REA mRNA expression status . In addition , cysteinyl leukotrienes per se failed to upregulate the P05113 REA production . CONCLUSION : Our results indicate that pranlukast inhibits P05113 REA synthesis via a mechanism distinct from Q9Y271 REA antagonism .

DB00945 MEN and NSAID sensitivity . DB00945 MENMAX DB00945 MEN and the older nonsteroidal anti-inflammatory drugs ( NSAIDs ) that block cyclo-oxygenase - 1 ( P23219 REA ) induce asthma attacks in patients with aspirin-exacerbated respiratory disease and urticaria in patients with chronic idiopathic urticaria . Weak inhibitors of P23219 REA , such as acetaminophen and salsalate , crossreact also but only with high doses of the drugs . Partial inhibitors of both P23219 REA and P35354 REA , such as nimesulide and meloxicam , also cross-react but only at high drug doses . P35354 REA inhibitors do not cross-react ; however , all NSAIDs , including the selective P35354 REA inhibitors , can sensitize patients and induce urticaria or anaphylaxis on next exposure to the drug .

DB04892 MEN . DB04892 MEN , a derivative of physostigmine , was first described as an inhibitor of acetylcholinesterase ( P22303 REA ) 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 MEN deserves attention for an additional quality of action : in addition to inhibiting P22303 REA , it modulates the amount of beta-amyloid precursor protein ( P05067 REA ) in neuronal cell culture by reducing P05067 REA translation . This effect probably involves interaction of phenserine with a regulatory element in the 5 ' - untranslated region of the P05067 REA gene that controls P05067 REA expression . DB04892 MEN apparently reduces translational efficiency of P05067 REA 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 MEN is also unique because of differing actions of its enantiomers : DB04892 MEN is the active enantiomer for inhibition of P22303 REA , whereas ( + ) - phenserine ( ' posiphen ' ) has weak activity as an P22303 REA inhibitor and can be dosed much higher . Both enantiomers are equipotent in downregulating P05067 REA expression . ( + ) - Posiphen may be a promising drug , either alone or in combination with DB04892 MEN , to attenuate the progression of Alzheimer ' s disease .

Genotype frequencies of 50 polymorphisms for 241 Japanese non-cancer patients . This paper lists the genotype frequencies of 50 polymorphisms of 37 genes ( P05091 REA , P07550 REA , P13945 REA , P21964 REA , P16671 REA , P25025 REA , P24385 REA , P35354 REA , P11509 REA , P05093 REA , P11511 REA , IGF 1 , IL - 1A , IL - 1B , IL - 1RN , IL - 1R1 , P05231 REA , P10145 REA , P22301 REA , P41159 REA , Le , L-myc , P05164 REA , Q99707 REA , P42898 REA , P21397 REA , P15559 REA , O15527 REA , p53 , p73 , Se , P31213 REA , TGF-B , P01375 REA - A , P01375 REA - B , P18074 REA , and P18887 REA ) and 6 sets of combined genotype frequencies for 241 non-cancer Japanese outpatients . Though the genotype frequencies of 25 polymorphisms have already been reported in our previous papers , 15 polymorphisms ( P16671 REA A52C , P25025 REA C785T , P24385 REA G870A , IGF 1 C / T at intron 2 and G2502T , IL - 1A 46 - bp VNTR , IL - 1R1 C - 116T , P05231 REA Ins / Del 17C , P10145 REA A - 278T and C74T , IL - 10 T - 819C , P41159 REA A - 2548G , P31213 REA 2 - bp VNTR , P18074 REA Lys 751Gln , and P18887 REA Arg 399Gln ) and six sets of combined genotype frequencies ( IL - 1B C - 31T and IL - 1A C - 889T , IL - 1B C - 31T and IL - 1RN 86 - bp VNTR , IL - 1B C - 31T and IL - 1R1 C - 116T , P01375 REA - A G - 308A and P01375 REA - B A252G , P31213 REA Val 89Leu and 2 - bp VNTR , and P18887 REA Arg 399Gln and P18074 REA Lys 751Gln ) were reported in this paper for the first time for Japanese . Although microarray technology will produce this kind of information in near future , this is the first document that reports the genotype / allele frequencies among Japanese for an archival purpose .

Microglial activation , increased P01375 REA and P31645 REA expression in the prefrontal cortex define stress-altered behaviour in mice susceptible to anhedonia . A chronic stress paradigm comprising exposure to predation , tail suspension and restraint induces a depressive syndrome in C57BL / 6J mice that occurs in some , but not all , animals . Here , we sought to extend our behavioural studies to investigate how susceptibility ( sucrose preference < 65 % ) or resilience ( sucrose preference > 65 % ) to stress-induced anhedonia affects the 5HT system and the expression of inflammation-related genes . All chronically stressed animals , displayed increased level of anxiety , but susceptible mice exhibited an increased propensity to float in the forced swim test and demonstrate hyperactivity under stressful lighting conditions . These changes were not present in resilient or acutely stressed animals . Compared to resilient animals , susceptible mice showed elevated expression of tumour necrosis factor alpha ( P01375 REA ) and the 5 - HT transporter ( P31645 REA ) in the pre-frontal area . Enhanced expression of 5HT ( 2A ) and P23219 REA in the pre-frontal area was observed in all stressed animals . In turn , indoleamine -2,3- dioxygenase ( P14902 REA ) was significantly unregulated in the raphe of susceptible animals . At the cellular level , increased numbers of Iba - 1 - positive microglial cells were also present in the prefrontal area of susceptible animals compared to resilient animals . Consequently , the susceptible animals display a unique molecular profile when compared to resilient , but anxious , animals . Unexpectedly , this altered profile provides a rationale for exploring anti-inflammatory , and possibly , P01375 REA - targeted therapy for major depression .