MH_dev_324

Population studies of polymorphisms at loci of neuropsychiatric interest ( tryptophan hydroxylase ( P17752 ) , dopamine transporter protein ( Q01959 ) , D3 dopamine receptor ( P35462 ) , apolipoprotein E ( P02649 ) , mu opioid receptor ( P35372 ) , and ciliary neurotrophic factor ( P26441 ) ) . We determined allele frequencies for polymorphisms at several loci of interest in neuropsychiatry-tryptophan hydroxylase ( P17752 ) , dopamine transporter protein ( Q01959 ) , D3 dopamine receptor ( P35462 ) , apolipoprotein E ( P02649 ) , ciliary neurotrophic factor ( P26441 ) , and the mu opioid receptor ( P35372 ) - in samples of individuals from populations in several different parts of the world . Associations with psychiatric illness have been proposed for specific polymorphisms at P17752 ( suicide-related behaviors and impulsivity ) , P35462 ( schizophrenia and bipolar affective disorder ) , Q01959 ( susceptibility to cocaine-induced paranoia and attention-deficit disorder ) , P26441 ( psychosis ) , and P35372 ( substance dependence ) . P02649 alleles are related to risk of Alzheimer disease . We found significant allele frequency variation among populations at all six loci . These results will provide a global framework of normal variation at these loci that might have functional significance or otherwise be related to susceptibility to various disorders or behavioral phenomena . Knowledge of this variation can be important for study design and data interpretation when individuals from various population groups are research subjects and may eventually help lead to a better understanding of behavioral adaptation .

Inhibition of Q16552 as a pharmacological approach for Q9UKU7 . Several experimental approaches have been utilized , in order to critically examine the roles of Q16552 family members in intestinal inflammation . These approaches have included : ( 1 ) the use of Q16552 and Q96PD4 - deficient mice , ( 2 ) specific antibodies directed against Q16552 , ( 3 ) an Q16552 vaccine , ( 4 ) methods to block the Q16552 receptor and ( 5 ) small-molecule inhibitors of Q16552 . Previous studies found somewhat conflicting results in preclinical models of Inflammatory Bowel Disease ( Q9UKU7 ) , using specific strains of Q16552 - deficient mice . This paper will review the preclinical results using various pharmacological approaches [ specific Q16552 antibodies , an Q16552 receptor fusion protein , IL - 12 / IL - 23 p40 subunit and Q16552 vaccine approaches , as well as a small molecule inhibitor ( Vidofludimus ) ] to inhibit Q16552 in animal models of Q9UKU7 . Recent clinical results in patients with Q9UKU7 will also be discussed for DB09029 MEN ( an Q16552 antibody ) , Brodalumab ( an Q16552 receptor antibody ) and two small-molecule drugs ( Vidofludimus and DB08895 ) , which inhibit Q16552 as part of their overall pharmacological profiles . This review paper will also discuss some pharmacological lessons learned from the preclinical and clinical studies with anti - Q16552 drugs , as related to drug pharmacodynamics , Q16552 receptor subtypes and other pertinent factors . Finally , future pharmacological approaches of interest will be discussed , such as : ( 1 ) Retinoic acid receptor-related orphan nuclear receptor gamma t ( Rorγt ) antagonists , ( 2 ) P10276 ( RARα ) antagonists , ( 3 ) Pim - 1 kinase inhibitors and ( 4 ) Dual small-molecule inhibitors of NF-κB and P40763 , like synthetic triterpenoids .

Consequences of the Y139F Vkorc 1 mutation on resistance to AVKs : in-vivo investigation in a 7th generation of congenic Y139F strain of rats . OBJECTIVES : In humans , warfarin is used as an anticoagulant to reduce the risk of thromboembolic clinical events . DB00682 SUB derivatives are also used as rodenticides in pest control . The gene encoding the protein targeted by anticoagulants is the Vitamin K -2,3- epoxide reductase subunit 1 ( Q9BQB6 ) . Since its discovery in 2004 , various amino acid and transcription-regulatory altering Q9BQB6 mutations have been identified in patients who required extreme antivitamin K dosages , or wild populations of rodents that were difficult to control with anticoagulant rodenticides . One unresolved question concerns the dependency of the Q9BQB6 on the genetic background in humans and rodents that respond weakly or not at all to anticoagulants . Moreover , an important question requiring further analyses concerns the role of the Vkorc 1 gene in mediating resistance to more recently developed warfarin derivatives ( superwarfarins ) . METHODS : In this study , we bred a quasicongenic rat strain by using a wild-caught anticoagulant resistant rat as a donor to introduce the Y > F amino acid change at position 139 in the Vkorc 1 into the genetic background of an anticoagulant susceptible Spraque-Dawley recipient strain . RESULTS AND CONCLUSION : In this manuscript we report the prothrombin times measured in the P08709 generation after exposure to chlorophacinone , bromadiolone , difenacoum and difethialone . We observed that the mutation Y139F mediates resistance in an otherwise susceptible genetic background when exposed to chlorophacinone and bromadiolone . However , the physiological response to the super-warfarins , difenacoum and difethialone , may be strongly dependent on other genes located outside the congenic interval ( 28.3 cM ) bracketing the Vkorc 1 in our P08709 generation congenic strain .

P12004 - dependent kinase 5 is associated with risk for Alzheimer ' s disease in a Dutch population-based study . Although the role of the Cdk 5 protein in Alzheimer ' s disease ( AD ) is well recognized , there have been relatively few studies investigating genetic variants in the Q00535 gene in AD . In this study , we assessed the association between five previously described single nucleotide polymorphisms ( SNPs ) in the Q00535 gene and late onset AD by means of logistic regression and haplotype association analyses . Including all prevalent and incident AD cases , we found a significantly increased risk of AD for carriers of the GG genotype of SNP rs2069442 ( OR = 1.79 , 95 % CI 1.16- 2.79 , p = 0.001 ) in those without P02649 * 4 . When limiting the analysis to incident cases without P02649 * 4 , carriers of the GG genotype showed a 1.9- fold increased risk of AD ( 95 % CI 1.16- 3.10 , p = 0.003 ) . Variations in the Q00535 gene can be described in 5 haplotype blocks . In our analysis , the haplotype tagged by the G allele of SNP rs2069442 was significantly associated with AD ( p = 0.05 ) . In conclusion , our study suggests that Q00535 may be associated with AD .

Polymorphisms of the HTR 1a allele are linked to frontal brain electrical asymmetry . Polymorphic variations in genes related to serotonin synthesis , transport , recognition , or degradation may convey subtle changes in serotonin system architecture that may place an individual at risk for psychopathology when faced with life stressors . The relationship between three key serotonin alleles and frontal brain electrical asymmetry , a putative endophenotype of depression , was examined . Risk alleles were hypothesized to predict relatively greater right frontal brain activity regardless of current clinical state . A sample of 313 college-age individuals , spanning a range of depressive severity from no symptomotology to clinically meaningful levels , participated . Resting encephalographic ( EEG ) activity was recorded from 64 scalp sites on four occasions separated by at least 24h ( two 8 - min recording sessions occurring at each occasion ) . Alpha power asymmetry scores between homologous sites were calculated for each session and then averaged to form a trait metric of asymmetry for each pair . PCR based genotyping was conducted for the HTR 1a , HTR 2a , and HTTLPR genes . Variations in the HTR 1a gene were related to trait EEG asymmetry , regardless of any history of depression . Compared to subjects with at least one non-risk allele , subjects with homozygous P08908 risk alleles had significantly greater relative right frontal activity at sites P08709 / P00451 , P12259 / F6 , and F1 / F2 . In conclusion , variation in HTR 1a can influence trait level brain activity , which may ultimately be indicative of risk for psychopathology .

Novel pyrrolyllactone and pyrrolyllactam indolinones as potent cyclin-dependent kinase 2 inhibitors . P12004 - dependent kinases ( CDKs ) are essential in the control of cell cycle progression . Inhibition of CDKs represents a new approach for pharmacological intervention in the treatment of a variety of proliferative diseases , especially cancer . Based on the crystal structure of P24941 in complex with an imidazole indolinone compound 1 ( DB03428 MEN ) , lead optimization through modeling , synthesis , and SAR studies has led to the discovery of a novel series of pyrrolyllactone and pyrrolyllactam indolinones as potent P24941 inhibitors .

Interleukin 23 regulates proliferation of lung cancer cells in a concentration-dependent way in association with the interleukin - 23 receptor . A proinflammatory cytokine , interleukin 23 ( IL - 23 ) , plays a role in tumor progression by inducing inflammation in the tumor microenvironment , although there is debate about its role in carcinogenesis . Direct effects of IL - 23 on tumor cells have been reported rarely , and contradictory effects have been observed . Here , we studied such effects of IL - 23 in lung cancer cells in vitro and in vivo and explored the underlying mechanism . We found Q5VWK5 expression in tissues from lung adenocarcinoma and small cell carcinoma but not in lung squamous cell carcinoma tissue . Interestingly , different concentrations of IL - 23 had opposite effects in the same types of cells . We confirmed that the different effects could be explained by differences in binding to the Q5VWK5 ( subunits IL - 23r and IL - 12Rβ1 ) . Low concentrations of IL - 23 promoted the proliferation of Q5VWK5 - positive A549 and P08709 - 1 lung cancer cells by binding to IL - 23r , whereas high concentrations of IL - 23 inhibited proliferation of these cells by binding to both IL - 23r and IL - 12Rβ1 . In contrast , IL - 23 had no effect on Q5VWK5 - negative SK-MES - 1 cells . IL - 23 regulated the growth of human lung cancer cells through its effects on P40763 expression and phosphorylation in a concentration-dependent way ; the Ki - 67 gene was involved in these processes . Our findings demonstrate for the first time that IL - 23 affects the proliferation of Q5VWK5 - positive lung cancer cells and that this effect is dependent on the IL - 23 concentration . This can explain at least part of the inconsistent reports on the role of IL - 23 in the progression of carcinogenesis .

Effects of lesopitron on the central nervous system arising from its interaction with P08908 receptors . DB04970 MEN acts as a ligand for central serotonin P08908 receptors . Ki obtained from [ 3H ]8 - OH-DPAT competition studies was 104.8 + / - 10.6 nmol / l . As lesopitron did not affect the binding of [ 3H ] paroxetine , involvement of the serotonin reuptake system in the effects of lesopitron is rejected . DB04970 MEN inhibits haloperidol-induced catalepsy that is the consequence of its action on P08908 autoreceptors . The ability of lesopitron to induce 5 - HT syndrome reflects post-synaptic P08908 receptor activation and the reversion of 8 - OHDPAT-induced 5 - HT syndrome by lesopitron suggests a partial agonist effect on this receptor-type . DB04970 MEN induced a hypothermic effect due to the enhanced activation of post-synaptic P08908 receptors . The agonist effect of lesopitron on P08908 receptors and its marked hypothermic effect is an added value for this drug and a stimulus to the study of its possible neuroprotective action .

Q9BQB6 pharmacogenetics and pharmacoproteomics in patients on warfarin anticoagulant therapy : transthyretin precursor as a potential biomarker . BACKGROUND : Recognizing specific protein changes in response to drug administration in humans has the potential for the development of personalized medicine . Such changes can be identified by pharmacoproteomics approach based on proteomic technologies . It can also be helpful in matching a particular target-based therapy to a particular marker in a subgroup of patients , in addition to the profile of genetic polymorphism . DB00682 SUB is a commonly prescribed oral anticoagulant in patients with prosthetic valve disease , venous thromboembolism and stroke . METHODS AND FINDING : We used a combined pharmacogenetics and iTRAQ-coupled LC-MS / MS pharmacoproteomics approach to analyze plasma protein profiles of 53 patients , and identified significantly upregulated level of transthyretin precursor in patients receiving low dose of warfarin but not in those on high dose of warfarin . In addition , real-time RT-PCR , western blotting , human P05231 ELISA assay were done for the results validation . CONCLUSION : This combined pharmacogenomics and pharmacoproteomics approach may be applied for other target-based therapies , in matching a particular marker in a subgroup of patients , in addition to the profile of genetic polymorphism .

First report of warfarin dose requirements in patients possessing the P11712 * 12 allele . BACKGROUND : DB00682 SUB is the most frequently prescribed anticoagulant in North America and Europe . It is administered as a racemate , but S-warfarin is principally responsible for its anticoagulant activity . Cytochrome P450 ( CYP ) 2C9 is the enzyme primarily responsible for the metabolism of S-warfarin . Numerous variant alleles of P11712 have been identified . The P11712 * 12 ( rs9332239 ) allele harbors a P489S substitution in P11712 which has been shown to result in a 40 % decline in catalytic activity in vitro . CASES : Four Caucasian patients with a low mean weekly warfarin dose ( MWWD ) were genotyped for P11712 , Q9BQB6 and P02649 variant alleles . None of the four patients carried the common P11712 variant alleles ( * 2 , * 3 , * 5 , * 6 , * 7 , * 8 , * 9 , * 11 , * 13 ) despite a relatively low MWWD ( 23.4 ± 7.94 mg ) compared to 208 patients carrying the CYP 29C9 * 1 genotype ( 32.2 ± 12.65 mg ) . Given that P11712 * 12 confers decreased in vitro activity to the enzyme , we investigated whether these patients carried this allele . All four patients were P11712 * 12 CT heterozygotes . Individual comparisons with patients possessing the same Q9BQB6 and P02649 genotypes also demonstrated lower dose requirements in the patients that possessed P11712 * 12 allele . CONCLUSIONS : There are no reports of the clinical impact of rs9332239 on P11712 substrates . This is the first report of patients with the rare P11712 * 12 genotype and lower warfarin dose requirements .

DB00133 MEN palmitoyltransferase , a key enzyme for de novo synthesis of sphingolipids , is essential for male gametophyte development in Arabidopsis . Sphingolipids are important signaling molecules involved in various cellular activities . De novo sphingolipid synthesis is initiated by a rate-limiting enzyme , serine palmitoyltransferase ( P21549 ) , a heterodimer consisting of LONG-CHAIN BASE 1 ( O15269 ) and O15270 subunits . A mutation in the Arabidopsis thaliana O15269 gene , lcb 1-1 , was found to cause embryo lethality . However , the underpinning molecular and cellular mechanisms remain largely unclear . Here , we report the identification of the fumonisin B ( 1 ) resistant 11-2 ( fbr 11-2 ) mutant , an allele of lcb 1-1 . The fbr 11-2 mutation , most likely an allele stronger than lcb 1-1 , was transmitted only through female gametophytes and caused the formation of abortive microspores . During the second pollen mitosis , fbr 11-2 initiated apoptotic cell death in binucleated microspores characteristic of nuclear DNA fragmentation , followed by cytoplasm shrinkage and organelle degeneration at the trinucleated stage . In addition , a double mutant with T-DNA insertions in two homologous O15270 genes showed a phenotype similar to fbr 11-2 . Consistent with these observations , the FBR 11 / O15269 expression was confined in microspores during microgametogenesis . These results suggest that P21549 - modulated programmed cell death plays an important role in the regulation of male gametophyte development .

Genome-wide association study identifies genetic determinants of warfarin responsiveness for Japanese . DB00682 SUB is a commonly used anticoagulant , whose dose needs to be determined for each individual patient owing to large inter-individual variability in its therapeutic dose . Although several clinical and genetic variables influencing warfarin dose have been identified , uncovering additional factors are critically important for safer use of warfarin . Through a genome-wide association study , we identified single-nucleotide polymorphism ( SNP ) rs2108622 [ cytochrome P450 , family 4 , subfamily F , polypeptide 2 ( P78329 ) ] as a genetic determinant of warfarin responsiveness for Japanese . Stratifying subjects who have been pre-classified according to the genotypes of SNP rs10509680 [ cytochrome P450 , family 2 , subfamily C , polypeptide 9 ( P11712 ) ] and SNP rs9923231 [ vitamin K epoxide reductase complex subunit 1 ( Q9BQB6 ) ] , based on their genotypes of rs2108622 allowed identification of subjects who require higher dose of warfarin . Incorporating genotypes of rs2108622 into a warfarin dosing algorithm that considers age , body surface area , status of amiodarone co-administration and genotypes of SNPs in the P11712 and Q9BQB6 genes improved the model ' s predictability to 43.4 % . In this study , the association of P78329 with warfarin dose of the Japanese has been established for the first time . Besides , a warfarin dosing algorithm that incorporates genotypes of rs2108622 and amiodarone co-administration status was suggested for the Japanese . Our study also implied that common SNPs other than those in the P11712 , Q9BQB6 and P78329 genes that show strong effect on the therapeutic warfarin dose might not exist .

A new cell culture-based assay quantifies vitamin K 2,3- epoxide reductase complex subunit 1 function and reveals warfarin resistance phenotypes not shown by the dithiothreitol-driven Q9BQB6 assay . BACKGROUND : DB00682 SUB directly inhibits the vitamin K 2,3- epoxide reductase complex subunit 1 ( Q9BQB6 ) enzyme to effect anticoagulation . Q9BQB6 function has historically been assessed in vitro using a dithiothreitol ( DTT ) - driven vitamin K 2,3- epoxide reductase ( Q9BQB6 ) assay . DB00682 SUB inhibits wild-type Q9BQB6 function by the DTT - Q9BQB6 assay . However , Q9BQB6 variants with warfarin resistance-associated missense mutations often show low Q9BQB6 activities and warfarin sensitivity instead of resistance . OBJECTIVES : A cell culture-based , indirect Q9BQB6 assay was developed and characterized that accurately reports warfarin sensitivity or resistance for wild-type and variant Q9BQB6 proteins . METHODS : Human coagulation factor ( F ) IX and Q9BQB6 variants were coexpressed in P29320 293T cells under standardized conditions at various warfarin concentrations . Secreted FIX activity served as surrogate marker to report wild-type and variant Q9BQB6 inhibition by warfarin . RESULTS AND CONCLUSIONS : DB00682 SUB dose-response curves fit to the secreted FIX activity data for coexpressed hVKORC 1 wild-type , Val 29Leu , Val 45Ala and Leu 128Arg variants . The corresponding calculated IC50 values were 24.7 , 136.4 , 152.0 and 1226.4 nm , respectively . Basal activities in the absence of warfarin for all Q9BQB6 variants were similar to that of wild-type Q9BQB6 . Ranked IC50 values from the cell culture-based assay accurately reflect elevated warfarin dosages for patients with Q9BQB6 missense mutation-associated warfarin resistance .

In vitro effects and in vivo efficacy of a novel cyclooxygenase - 2 inhibitor in cats with lipopolysaccharide-induced pyrexia . OBJECTIVE : To determine cyclooxygenase ( P36551 ) - 2 selectivity , pharmacokinetic properties , and in vivo efficacy of firocoxib ( Q9NTI2 , 785,713 ) in cats . ANIMALS : 5 healthy male and 14 healthy female domestic shorthair cats . PROCEDURE : Selectivity of firocoxib for inhibiting P35354 was determined by comparing the potency for inhibiting P23219 with that of P35354 in feline blood . Pharmacokinetic properties were determined after i . v . ( 2 mg / kg ) and oral ( 3 mg / kg ) administration in male cats . In vivo efficacy was evaluated in female cats with lipopolysaccharide ( LPS ) - induced pyrexia with administration of firocoxib 1 or 14 hours before LPS challenge . RESULTS : Blood concentrations resulting in 50 % inhibition of P23219 and P35354 activity in vitro were 75 + / - 2 microM and 0.13 + / - 0.03 microM , respectively , and selectivity for inhibiting P35354 relative to P23219 was 58 . DB09217 MEN had moderate to high oral bioavailability ( 54 % to 70 % ) , low plasma clearance ( 4.7 to 5.8 mL / min / kg ) , and an elimination half-life of 8.7 to 12.2 hours . DB09217 MEN at doses from 0.75 to 3 mg / kg was efficacious in attenuating fever when administered to cats 1 or 14 hours before LPS challenge . CONCLUSIONS AND CLINICAL RELEVANCE : DB09217 MEN is a potent P35354 inhibitor and is the only selective P35354 inhibitor described for use in cats to date . It is effective in attenuating febrile responses in cats when administered 14 hours before LPS challenge , suggesting it would be suitable for once-a-day dosing . Because selective P35354 inhibitors have an improved therapeutic index relative to nonselective nonsteroidal anti-inflammatory drugs in humans , firocoxib has the potential to be a safe , effective anti-inflammatory agent for cats .

Aflatoxin B1 induces Src phosphorylation and stimulates lung cancer cell migration . AflatoxinB 1 ( AFB 1 ) is well known as a potent carcinogen . Epidemiological studies have shown an association between AFB 1 exposure and lung cancer in humans . AFB 1 can induce the mutations of genes such as tumor suppressor p53 through its metabolite AFB 1-8 , 9 - exo-epoxide , which acts as a mutagen to react with DNA . In addition , recent study demonstrates AFB 1 positively regulates type I insulin-like growth factor receptor ( IGF-IR ) signaling in hepatoma cells . The current study aims to determine the effects of AFB 1 on Src kinase and insulin receptor substrate ( P41252 ) in lung cancer cells and the effects of AFB 1 on lung cancer cell migration . To this end , the effects of AFB 1 on P41252 expression , Src , Akt , and P29323 phosphorylation were measured by Western blot analysis . The migration of lung cancer cells was detected by wound-healing assay . AFB 1 downregulates P35568 but paradoxically upregulates Q9Y4H2 through positive regulation of the stability of Q9Y4H2 and the proteasomal degradation of P35568 in lung cancer cell lines A549 and P08709 - 1 . In addition , AFB 1 induces Src , Akt , and P27361 / 2 phosphorylation . Treatment of lung cancer cells with Src inhibitor saracatinib abrogates AFB 1 - induced Q9Y4H2 accumulation . Moreover , AFB 1 stimulates lung cancer cell migration , which can be inhibited by saracatinib . We conclude that AFB 1 may upregulate Q9Y4H2 and stimulate lung cancer cell migration through Src .

[ A novel function of anti-fibrinolytic factor , P05121 , in the central nervous system : a possible role as the neurotrophic factor ] . P00747 activator inhibitor - 1 ( P05121 ) is a serpin that suppresses fibrinolysis by inhibiting the activity of plasminogen activator ( PA ) . Together with PA , P05121 is expressed in the central nervous system and may play a role in the regulation of PA activity . Our present study has demonstrated that , in cultures of PC - 12 neurons , depletion of P05121 from the culture medium induces disappearance of the cell ' s neurites and the cell death . DB06692 MEN and antipain , the inhibitors of PA , were not counterparts of P05121 in the protection of neurite disappearance . We also found that P05121 had the abilities to promote release of the survival factors of neurons , P05231 and P15692 and activation of a survival serine / threonine kinase Akt . These results suggest that P05121 has physiological functions other than its role as PA inhibitor for the survival of neurons .

P21453 as a useful target for treatment of multiple sclerosis . DB03203 1 - phosphate ( Q14703 ) , a lysophospholipid mediator , is generated from sphingosine by sphingosine kinases and binds five known cell surface receptors . P21453 ( P21453 ) plays an essential role in lymphocyte egress from secondary lymphoid organs ( Q12791 ) , as evinced by the inability of lymphocytes to exit from the Q12791 in mice lacking lymphocytic P21453 . DB08868 MEN hydrochloride ( FTY 720 ) is a first-in-class , orally active , Q14703 receptor modulator with a structure closely related to sphingosine . FTY 720 was first synthesized by chemical modification of a natural product , myriocin . FTY 720 is effectively converted to an active metabolite , FTY 720 phosphate ( FTY 720 - P ) by sphingosine kinases . FTY 720 - P shows high affinity to 4 of the Q14703 receptors ( P21453 , Q99500 , O95977 , and Q9H228 ) . In particular , FTY 720 - P strongly induces internalization and degradation of P21453 , inhibits Q14703 responsiveness of lymphocytes in the Q12791 , and acts as a functional antagonist at lymphocytic P21453 . Consequently , FTY 720 inhibits P21453 - dependent lymphocyte egress from the Q12791 to decrease circulation of lymphocytes including autoreactive Th17 cells and is highly effective in experimental autoimmune encephalomyelitis ( EAE ) , an animal model of multiple sclerosis ( MS ) . Because FTY 720 shows a superior efficacy in relapsing remitting MS patients compared to intramuscular interferon-β - 1a ( Avonex ® ) , P21453 is presumed to be a useful target for the therapy of MS .

Evaluation of commercial antibodies against human sphingosine - 1 - phosphate receptor 1 . DB03203 - 1 - phosphate receptor 1 ( P21453 ) , also called endothelial differentiation gene 1 , plays an important role in migration , proliferation , and survival of several types of cells including endothelial cells and lymphocytes and is involved in multiple sclerosis . Two commercial rabbit anti - P21453 antibodies ( polyclonal and monoclonal ) were tested on CHO cells expressing P21453 receptors fused to the green fluorescent protein at the C-terminal end and on Pichia pastoris and P29320 cells expressing cmyc-tagged P21453 . Polyclonal antibodies did not give any signal by Western blot , immunofluorescence , and flow cytofluorometry . Monoclonal antibodies were able to reveal an unspecific band by Western blot performed on various cell types . Consequently , in our hands and using our protocols , we show that these antibodies did not specifically detect P21453 receptors .

Oral L-serine supplementation reduces production of neurotoxic deoxysphingolipids in mice and humans with hereditary sensory autonomic neuropathy type 1 . Hereditary sensory and autonomic neuropathy type 1 ( HSAN 1 ) causes sensory loss that predominantly affects the lower limbs , often preceded by hyperpathia and spontaneous shooting or lancinating pain . It is caused by several missense mutations in the genes encoding 2 of the 3 subunits of the enzyme serine palmitoyltransferase ( P21549 ) . The mutant forms of the enzyme show a shift from their canonical substrate L-serine to the alternative substrate L-alanine . This shift leads to increased formation of neurotoxic deoxysphingolipids ( dSLs ) . Our initial analysis showed that in P29320 cells transfected with O15269 mutants , dSL generation was modulated in vitro in the presence of various amino acids . We therefore examined whether in vivo specific amino acid substrate supplementation influenced dSL levels and disease severity in HSAN 1 . In mice bearing a transgene expressing the C133W O15269 mutant linked to HSAN 1 , a 10 % L-serine – enriched diet reduced dSL levels . L-serine supplementation also improved measures of motor and sensory performance as well as measures of male fertility . In contrast , a 10 % L-alanine – enriched diet increased dSL levels and led to severe peripheral neuropathy . In a pilot study with 14 HSAN 1 patients , L-serine supplementation similarly reduced dSL levels . These observations support the hypothesis that an altered substrate selectivity of the mutant P21549 is key to the pathophysiology of HSAN 1 and raise the prospect of l-serine supplementation as a first treatment option for this disorder .

Cytochromes P450 are differently expressed in normal and varicose human saphenous veins : linkage with varicosis . The expression of cytochrome P450 ( CYP ) enzymes and cyclo-oxygenases ( P36551 ) was investigated in human saphenous veins by reverse transcription-polymerase chain reaction analysis . Non-varicose veins were obtained from patients undergoing aortocoronary bypass grafting , whereas varicose veins were obtained from patients undergoing stripping removal of varicose saphenous veins . In non-varicose veins , Q16678 , CYP 2C , P05181 and Q02928 were detected , whereas P51589 , P20815 , P23219 and P35354 were detected almost exclusively in varicose veins . P78329 was not detectable . Except for Q02928 , the levels of individual CYP mRNA were higher in varicose veins than in control veins . Smooth muscle cell volume , determined by a colour image-analysis system , was increased approximately 1.5- fold in varicose veins . Because CYPs and COXs produce various vasoactive compounds , increased expression of these enzymes could be involved in the impairment of vascular tone and may contribute to varicose pathology . Then , CYP or P36551 modulators may be potentially active in the treatment of chronic venous insufficiency .

P35372 - dependent and independent components in effects of tramadol . DB00193 MEN is thought to induce analgesia via both opioid and non-opioid pathways , although the precise mechanisms remain to be elucidated . In this study , we investigated the roles of the mu-opioid receptor ( MOP ) in analgesic and rewarding effects of tramadol by using MOP knockout ( KO ) mice . DB00193 MENMAX DB00193 MEN - induced antinociception , assessed by hot-plate and tail-flick tests , was significantly reduced in heterozygous and homozygous MOP-KO mice when compared with that in wild-type mice . Interestingly , however , tramadol retained its ability to induce significant antinociception in homozygous MOP-KO mice . The tramadol-induced antinociception remaining in homozygous MOP-KO mice was not significantly affected by methysergide , a serotonin receptor antagonist , but was partially blocked by yohimbine , an adrenaline alpha 2 receptor antagonist , and both naloxone , a non-selective opioid receptor antagonist , and yohimbine . In addition , antinociceptive effects of an active tramadol metabolite M1 were abolished or remarkably reduced in MOP-KO mice . On the other hand , neither wild-type nor homozygous MOP-KO mice showed significant place preference for tramadol in a conditioned place preference test , although there were slight tendencies toward preference in wild-type mice and avoidance in homozygous MOP-KO mice . These results strongly support the idea suggested in the previous pharmacological studies that MOP and the adrenaline alpha 2 receptor mediate most of the analgesic properties of tramadol .

An acetylcholinesterase inhibitor , eserine , induces long-term depression at P07451 - P00915 synapses in the hippocampus of adult rats . Studies in humans and rodents support a role for muscarinic ACh receptor ( mAChR ) and nicotinic AChR in learning and memory , and both regulate hippocampal synaptic plasticity using complex and often times opposing mechanisms . P22303 ( P22303 ) inhibitors are commonly prescribed to enhance cholinergic signaling in Alzheimer ' s disease in hopes of rescuing cognitive function , caused , in part , by degeneration of cholinergic innervation to the hippocampus and cortex . Unfortunately , therapeutic efficacy is moderate and inconsistent , perhaps due to unanticipated mechanisms . M1 mAChRs bidirectionally control synaptic strength at P07451 - P00915 synapses ; weak pharmacological activation using carbachol ( CCh ) facilitates potentiation , whereas strong agonism induces muscarinic long-term depression ( mLTD ) via an P29323 - dependent mechanism . Here , we tested the prediction that accumulation of extracellular ACh via inhibition of P22303 is sufficient to induce LTD at P07451 - P00915 synapses in hippocampal slices from adult rats . Although P22303 inhibition with eserine induces LTD , it unexpectedly does not share properties with mLTD induced by CCh , as reported previously . DB00981 MEN - LTD was prevented by the M3 mAChR-preferring antagonist 1,1- dimethyl - 4 - diphenylacetoxypiperidinium iodide ( 4 - DAMP ) , and pharmacological inhibition of MEK was completely ineffective . Additionally , pharmacological inhibition of p38 MAPK prevents mLTD but has no effect on eserine-LTD . Finally , long-term expression of eserine-LTD is partially dependent on a decrease in presynaptic release probability , likely caused by tonic activation of mAChRs by the sustained increase in extracellular ACh . Thus these findings extend current literature by showing that pharmacological P22303 inhibition causes a prolonged decrease in presynaptic glutamate release at P07451 - P00915 synapses , in addition to inducing a likely postsynaptic form of LTD .