interacts_with DB00784?
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 , which is the rate-limiting enzyme for tetrahydrobiopterin ( BH4 ) biosynthesis . Based on our findings on 6-pyruvoyltetrahydropterin synthase ( Q03393 ) 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 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 was efficiently expressed in noradrenergic regions but only in a small number of dopaminergic neurons . DB03886 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 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 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 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 activity ( holo- + apoenzyme ) was lowered only with vitamin B12 level < 200 pmol/l ( p=0.0002 ) , while the ratios of total vs. holo- Q99707 activity and of transcripts Q99707 vs. P04406 ( RT-PCR ) were unchanged . DB00115 was the single determinant of low Q99707 ( lower quartile , odds ratio=15.75 , p=0.0017 ) . Low Q99707 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 affects Q99707 expression by a non-transcriptional mechanism different from a protective effect on Q99707 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 ( ovine ) inhibitor screening assay was used to determine its inhibitory effect on P23219 and P35354 . 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 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 -stimulated tetrahydrobiopterin biosynthesis in P13671 glioma cells . In P13671 glioma cells , the sphingolipid second messenger ceramide potentiates expression of inducible nitric-oxide synthase ( P35228 ) induced by tumor necrosis factor alpha ( P01375 ) without affecting P30793 ( GTPCH ) , the rate-limiting enzyme in the biosynthesis of 6(R)- DB00360 ( BH(4) ) , a cofactor required for P35228 activity . P01375 also stimulates sphingosine kinase , the enzyme that phosphorylates sphingosine to form sphingosine-1-phosphate ( Q8TCT9 ) , a further metabolite of ceramide . Several clones of P13671 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 on GTPCH expression and activity and BH(4) biosynthesis . In contrast , enforced expression of sphingosine kinase had no effect on P35228 expression or NO formation . Furthermore , N,N-dimethylsphingosine , a potent sphingosine kinase inhibitor , completely eliminated the increased GTPCH activity and expression induced by P01375 . Surprisingly , we found that , although P13671 cells can secrete Q8TCT9 , which is enhanced by P01375 , treatment of P13671 cells with exogenous Q8TCT9 or dihydro- Q8TCT9 had no affect on BH(4) biosynthesis . However , both Q8TCT9 and dihydro- Q8TCT9 markedly stimulated P29323 1/2 in P13671 cells , which express cell surface Q8TCT9 receptors . Interestingly , although this P29323 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 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 , 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 ( DB02901 ) decreased expression of P12830 , β-catenin and P19022 expression , indicating a strong sensitivity to the EMT and In cells with low AR content , TGF-β induced down-regulation of P12830 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 ( Q16739 ) 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 ) 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 -hydroxyl of the deoxynojirimycin core is important for Q16739 inhibition . Here we show that P13671 -OH appears of less important , which may set guidelines for the development of Q16739 inhibitors that have less affinity ( in comparison with DB00419 ) 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 ) targets and eicosanoid products in tumor cell growth . Sulindac sulfide , a P36551 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 . Both sulindac sulfide and ciglitazone , a defined peroxisome proliferator-activated receptor-gamma ( PPARgamma ) agonist , stimulated a promoter construct containing a Q07869 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 , 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 , or P35354 , 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 -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 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 and P35354 ) , prostaglandin-E(2) production and caspase-independent cell death . Cell death was inhibited by S-ketoprofen , but not by the much weaker P36551 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 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 antagonist GW9662 showed no affect on the cell death . These results indicated that protection by S-ketoprofen was P36551 -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 and P35354 activities ( approximately equal 1microM ) . Further design of S-ketoprofen derivatives devoid of P36551 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 receptor expression . Following spinal cord injury ( SCI ) , neuropathic , chronic pain is a major cause of disability . Recently , glial Q99571 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 + hypertrophic neurites correlated with proximity to the lesion . Further , P2X4R+ cells coexpressed the intracellular regulators of signalling cascades , P23219 ( > 20 % ) , P35354 ( > 5 % ) , RhoA ( > 60 % ) and RhoB ( > 10 % ) . Topical glucocorticoids downregulate P23219 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 ) are key enzymes in the synthesis of both pro- ( P23219 , P35354 ) and anti-inflammatory prostanoids ( P35354 ) , we investigated the role of topical GC on P23219 , P35354 and inflammatory markers in nasal polyps ( NP ) . METHODS : Immunohistochemical analysis of inflammatory markers ( P34810 , CD117 , MBP , elastase , IgE , BB-1 , P05112 , P05113 and P05231 ) , P23219 and P35354 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 + cells and IgE+ cells and decreased numbers of mastcells are striking features of NP inflammation ( P < 0.05 ) . In addition , increased numbers of P23219 + cells are observed in NP epithelium compared to NM ( P < 0.05 ) . CONCLUSION : Topical GC significantly reduce the number of P23219 + NP cells ( P < 0.05 ) , but have no significant effect on P35354 + NP cells . No significant reduction in the number of eosinophils is observed for GC treated NP . The number of P05113 + 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 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 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 and an inducible form termed P35354 . We report here fluorescence resonance energy transfer analysis of isoform-selective inhibitors interacting with P23219 and P35354 . 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 with the P23219 inhibitor and an R0 of 21 A for P35354 with the P35354 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 and 18 A in P35354 . 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 ) , 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 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 or P35354 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 ) has been implicated in regulating breast cancer cell differentiation and apoptosis , the effects of beta-carotene on the P37231 -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 mRNA and protein levels in time-dependent manner . In addition , beta-carotene increased the cyclin-dependent kinase inhibitor P38936 ( P38936 /CIP1) expression and decreased the prostanoid synthesis rate-limiting enzyme cyclooxygenase-2 expression . DB07863 ( GW9662 ) , an irreversible P37231 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 expression and ROS production may account for beta-carotene-mediated anticancer activities . DB01411 , a leukotriene receptor antagonist , inhibits interleukin-5 production via a mechanism distinct from leukotriene receptor antagonism . BACKGROUND : DB01411 , a cysteinyl leukotriene receptor 1 ( Q9Y271 ) 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 ) 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 protein level in the culture medium was measured , and in situ hybridization of P05113 and Q9Y271 mRNA was performed using lung tissues . RESULTS : Pretreatment of lung tissues with pranlukast alone significantly decreased the amount of P05113 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 mRNA in eosinophils , lymphocytes , and mast cells in sensitized and allergen-stimulated lung tissues . Q9Y271 mRNA was detected in macrophages , smooth muscle cells , eosinophils , and mast cells , but was less expressed in lymphocytes . DB01411 -induced inhibition of P05113 mRNA expression was noted in various cells , irrespective of their Q9Y271 mRNA expression status . In addition , cysteinyl leukotrienes per se failed to upregulate the P05113 production . CONCLUSION : Our results indicate that pranlukast inhibits P05113 synthesis via a mechanism distinct from Q9Y271 antagonism . DB00945 and NSAID sensitivity . DB00945 and the older nonsteroidal anti-inflammatory drugs ( NSAIDs ) that block cyclo-oxygenase-1 ( P23219 ) induce asthma attacks in patients with aspirin-exacerbated respiratory disease and urticaria in patients with chronic idiopathic urticaria . Weak inhibitors of P23219 , such as acetaminophen and salsalate , crossreact also but only with high doses of the drugs . Partial inhibitors of both P23219 and P35354 , such as nimesulide and meloxicam , also cross-react but only at high drug doses . P35354 inhibitors do not cross-react ; however , all NSAIDs , including the selective P35354 inhibitors , can sensitize patients and induce urticaria or anaphylaxis on next exposure to the drug . 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 . Genotype frequencies of 50 polymorphisms for 241 Japanese non-cancer patients . This paper lists the genotype frequencies of 50 polymorphisms of 37 genes ( P05091 , P07550 , P13945 , P21964 , P16671 , P25025 , P24385 , P35354 , P11509 , P05093 , P11511 , IGF1 , IL-1A , IL-1B , IL-1RN , IL-1R1 , P05231 , P10145 , P22301 , P41159 , Le , L-myc , P05164 , Q99707 , P42898 , P21397 , P15559 , O15527 , p53 , p73 , Se , P31213 , TGF-B , P01375 -A , P01375 -B , P18074 , and P18887 ) 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 A52C , P25025 C785T , P24385 G870A , IGF1 C/T at intron 2 and G2502T , IL-1A 46-bp VNTR , IL-1R1 C-116T , P05231 Ins/Del 17C , P10145 A-278T and C74T , IL- 10 T-819C , P41159 A-2548G , P31213 2-bp VNTR , P18074 Lys751Gln , and P18887 Arg399Gln ) 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 -A G-308A and P01375 -B A252G , P31213 Val89Leu and 2-bp VNTR , and P18887 Arg399Gln and P18074 Lys751Gln ) 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 and P31645 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 ) and the 5-HT transporter ( P31645 ) in the pre-frontal area . Enhanced expression of 5HT(2A) and P23219 in the pre-frontal area was observed in all stressed animals . In turn , indoleamine-2,3-dioxygenase ( P14902 ) 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 -targeted therapy for major depression .