interacts_with DB00946?
A new algorithm for weekly phenprocoumon dose variation in a southern Brazilian population : role for P11712 , P08684 /5 and Q9BQB6 genes polymorphisms . DB00946 is widely used in prophylaxis and treatment of thromboembolic disorders . However , its pharmacokinetics and pharmacodynamics vary according to several genetic and non-genetic factors . DB00946 metabolism is mediated by P11712 and CYP3A enzymes . Moreover , Q9BQB6 is phenprocoumon target of action . Therefore , the aim of this study was to evaluate the association of single nucleotide polymorphisms ( SNPs ) in Q9BQB6 , P11712 , P08684 and P20815 genes with the variance of weekly phenprocoumon dose as well as to develop an algorithm for dose prediction based on genetic and environmental factors . A total of 198 patients with stable phenprocoumon dose , 81 % of European ancestry , were investigated . Genotypes were determined by allelic discrimination with TaqMan assays . Polymorphisms -1639G > A and 1173C > T in Q9BQB6 and the presence of P11712 *2 and/or P11712 *3 are associated with lower doses . On the other hand , 3730G > A in Q9BQB6 gene is associated with higher doses . No association was found between P08684 *1B , P20815 *3 and P20815 *6 polymorphisms . Among non-genetic factors , gender , height , age and use of captopril , omeprazole , simvastatin and β-blockers are associated with dose . Two algorithms were derived : one for the whole sample explained 42 % of dose variation and one for patients of European ancestry only which explained 46 % of phenprocoumon dose . The mean absolute difference between observed and predicted dose was low in both models ( 3.92 mg/week and 3.54 mg/week , for models 1 and 2 , respectively ) . However , more studies with other genes and environmental factors are needed to test and to improve the algorithm . DB00142 decarboxylase ( Q99259 ) antibodies in epilepsy : diagnostic yield and therapeutic implications . PURPOSE : The aetiology of adult onset epilepsy remains unascertained in a significant proportion of patients . Antibodies directed against neuronal antigens have been suggested to have a potential pathogenic role in some cases of epilepsy . We describe a series of patients with adult onset epilepsy in whom antibodies to glutamic acid decarboxylase ( Q99259 Abs ) have been identified . METHODS : All patients attending a regional epilepsy service with unexplained adult onset epilepsy ' were tested for the presence of Q99259 Abs . Those with high serum titres underwent P04141 analysis , and were offered additional treatment with immunotherapy . Those who underwent immunotherapy were monitored by monthly review . Clinical details and response to treatment was collated by review of notes . RESULTS : Of 112 patients tested , high serum titres were found in 6 ( 5.4 % ) patients . These patients had clinical and electroencephalographic evidence of focal epilepsy . P04141 analysis revealed oligoclonal bands and intrathecal Q99259 Abs in all patients . Five patients received immunotherapy . No improvement in seizures was observed in any . One patient with equivocal Q9BWK5 evidence of hippocampal sclerosis and concordant video EEG and PET scan , achieved 12 months seizure freedom following temporal lobectomy . CONCLUSIONS : The relevance of Q99259 Abs to epilepsy remains uncertain . Our experience does not support the routine use of immunotherapy in patients with epilepsy and Q99259 Abs . Larger studies enrolling greater numbers of patients are required to identify sufficient numbers of patients for controlled treatment trials . Interaction between P20292 and P20815 gene variants significantly increases the risk for cerebral infarctions in Chinese . In this study , we investigated associations between susceptibility genes and cerebral infarctions in a Chinese population , and whether gene-gene interactions increase the risk of cerebral infarctions . Overall , 292 patients with cerebral infarctions and 259 healthy control individuals were included . Eight variants in five candidate genes were examined for the risk of stroke , including the SG13S32 ( rs9551963 ) , SG13S42 ( rs4769060 ) , SG13S89 ( rs4769874 ) , and SG13S114 ( rs10507391 ) variants of the P09917 activating protein ( P20292 ) gene , the G860A ( rs751141 ) variant of the soluble epoxide hydrolase ( P34913 ) gene , the A1075C ( rs1057910 ) variant of the P11712 *2 gene , the C430T ( rs1799853 ) variant of the P11712 *3 gene , and the A6986G ( rs776746 ) variant of the P20815 gene . Gene-gene interactions were explored using generalized multifactor dimensionality reduction methods . There were no statistically significant differences in the frequencies of the genotypes of the eight candidate genes . The generalized multifactor dimensionality reduction analysis showed a significant gene-gene interaction between SG13S114 and A6986G , with scores of 10 for cross-validation consistency and 9 for the sign test ( P=0.0107 ) . These gene-gene interactions predicted a significantly higher risk of cerebral infarction ( adjusted for age , hypertension , and diabetes mellitus ; odds ratio=1.80495 % , confidence interval : 1.180-2.759 , P=0.006 ) . A two-loci gene interaction confers a significantly higher risk for cerebral infarction . The combinational analysis used in this study may be helpful in the elucidation of genetic risk factors for common and complex diseases . Dual ligands targeting dopamine D2 and serotonin P08908 receptors as new antipsychotical or anti-Parkinsonian agents . Psychiatric disorders like schizophrenia and neurodegenerative diseases like Parkinson 's disease are associated with poly-factorial pathogenic mechanisms , with several neurotransmitter systems closely involved . In addition to the cerebral dopaminergic ( DA ) system , the serotoninergic ( 5-HT ) system also plays a crucial role in regulating psychoemotional , cognitive and motor functions in the central nervous system ( CNS ) . Among the large 5-HT receptor family , accumulating data have revealed new insights into the therapeutic benefit of the P08908 receptor in treating various CNS disorders , especially schizophrenia and Parkinson 's disease . The present review discusses the advance of dual agents with mixed actions at the dopamine D2 and serotonin P08908 receptors in the treatment of these diseases . Aripiprazole was the only marketed drug with dual D2 and P08908 profile . It is a partial D2 and P08908 receptor agonist and has been prescribed as an atypical antipsychotical drug . Two other drugs DB06016 and Pardoprunox are being investigated in clinic . Most of the other candidate compounds , including DB04888 , Sarizotan , Mazapertine succinate , PF-217830 , and Adoprazine were discontinued due to either non-optimal pharmacokinetic properties or insufficient therapeutical efficacy . Although much effort has been done to highlight the advantages of the P08908 and D2 dual approach , it has to be pointed out that many of these drugs showed poly-pharmacological profile by targeting many other receptors and/or transporters besides the D2 and P08908 receptors . In this regard , ' pure ' compounds exclusively acting on the D2 and P08908 receptors are highly needed to further validate this approach . Meanwhile , safety concerns and in vivo pharmacokinetic alerts should also be implanted to the drug design art early . Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis/metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long-term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 *4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P=0.003 and P=0.007 ) and were 2.2- and 2.5-fold more likely to develop P42126 and CND ( P=0.039 and P=0.041 ) , respectively . P34913 55Arg , P51589 *7 , P10632 *1B , and P10632 g.36785A allele carriers had lower EET and DHET P04141 levels . P10632 g.25369T and P10632 g.36755A allele carriers had higher EET levels . Patients with P10632 *2C and P34913 404del variants had worse long-term outcomes while those with P34913 287Gln , P51589 *7 , and P11712 g.816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3-month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis/metabolic pathway and the pathophysiology of aSAH . Mechanism of oral absorbent DB05269 in lipid abnormalities in experimental uremic rats . BACKGROUND : We have reported that oral sorbent DB05269 ( Q9NRA2 ) is effective in delaying the induction of dialysis in patients with chronic renal failure ( CRF ) because of its effect on lipid metabolism . To clarify the precise mechanism of Q9NRA2 in lipid abnormalities in CRF , we examined the effect of Q9NRA2 on plasma lipid profile , total bile acids ( TBA ) , and lipoprotein lipase ( P06858 ) activity in experimental uremic rats . METHODS : Uremic rats were prepared using male Wistar rats by ligating 5/6 of the renal artery . Uremic rats were randomly divided into two groups as follows : a control group in which rats were maintained on the standard diet and an Q9NRA2 group in which rats were maintained on a diet containing 5 g of Q9NRA2 per 100 g of standard diet for 10 weeks . Plasma P06858 activity was measured as free fatty acid ( FFA ) generation after intravenous administration of heparin . RESULTS : Plasma creatinine at 1.5 +/- 0.1 mg/dl was lower in the Q9NRA2 group than the 1.9 +/- 0.5 mg/ml level in the control group . Q9NRA2 significantly decreased plasma total cholesterol from 192 +/- 29 to 142 +/- 25 mg/dl , triglycerides from 198 +/- 71 to 99 +/- 38 mg/dl , and TBA from 19.6 +/- 2.6 mumol/liter to 8.8 +/- 3.5 mumol/ml . Plasma P06858 activity at 0.22 +/- 0.01 mumol FFA/min/hr was significantly higher in the Q9NRA2 group than 0.15 +/- 0.03 mumol FFA/min/hr in the control group . CONCLUSIONS : These results suggest that Q9NRA2 may improve plasma lipid abnormalities by binding to bile acids in the intestinal lumen and preventing their reabsorption and inhibiting the reduction of P06858 activity in experimental uremic rats . The effect of cytokine profiles on the viral response to re-treatment in antiviral-experienced patients with chronic hepatitis C virus infection . BACKGROUND : There have been few studies on the potential immunological factors associated with viral controls in antiviral-experienced patients on a second round of combination therapy . In this study , we evaluated the level of systemic cytokines and potential impact on combination therapy in both antiviral-naïve and -experienced patients chronically infected with hepatitis C virus . METHODS : Longitudinal analysis of 27 cytokines and chemokines was performed using the multiplex Biorad 27 plex assay in 37 antiviral-naïve and 24 experienced chronically HCV-1b-infected patients during combination therapy with peginterferon-alfa and ribavirin . A group of healthy donors was included as the control ( n=11 ) . RESULTS : Fifty percent of antiviral-experienced chronically HCV-patients could achieve a delayed and slow virologic response after 48 weeks combination therapy , comparing with an early and fast virologic response in antiviral-naïve patients . A distinction of immune mediators profiling before and during antiviral therapy between antiviral-naïve and -experienced patients was identified , P05112 , IFN-γ and DB00833 -3 ( MIP-1a ) were significantly higher in naïve patients than those in experienced patients ( P=0.005 , 0.047 and 0.017 , respectively ) while G- P04141 in naïve was lower than in experienced patients ( P < 0.05 ) . Notably , higher Th1 type cytokine IFN-γ and lower Th2 type cytokine P05112 at baseline and week 4 were associated with HCV clearance in naïve patients , and a similar trend appeared at week 12 in experienced patients . CONCLUSIONS : We found a successful second round therapy in antiviral-experienced patients appears to be associated with the host immune response . Dominant Th1-polar cytokines , especially IFN-γ , is a potential predictor of viral responsiveness . Structure-function studies of linear and cyclized peptide antagonists of the P30968 . Structurally new analogs of the peptidic P30968 antagonist DB00050 as well as conformationally constrained cyclized deca- or pentapeptides were synthesized and selected peptides evaluated comprehensively . To understand how structural variations of the antagonistic peptide effect pharmacodynamic properties , binding affinities and antagonistic potencies toward the human and rat P30968 were determined . Whereas large substituents in position 6 of linear peptides are compatible with high binding affinity ( K(D) < 0.5 nM ) , all cyclized peptides except the cyclo[3-10] analog D-52391 depicted low binding affinity ( K(D) > 10 nM ) . Binding affinity and antagonistic potency in vitro correlated for all peptides and surprisingly no discrimination between human and rat receptor proteins was observed . Since receptor residues W(101) and N(102) are involved in agonist and antagonist binding , equally potent but structurally different antagonists were tested for binding to the respective W(101)A and N(102)A mutants . In contrast to linear decapeptides , residues N(102) and W(101) are not involved in binding of D-23938 and W(101) is the critical residue for D-52391 binding . We conclude that although equally potent , peptidic P30968 antagonists do have distinct interactions within the ligand binding pocket . Finally , selected antagonists were tested for testosterone suppression in male rats . The duration of testosterone suppression below castration levels differed largely from 1 day for DB06785 to 27 days for D-23487 . Systemic availability became evident as the most important parameter for in vivo efficacy . Combined adenine phosphoribosyltransferase and P34059 deficiency . We describe a Czech patient with combined adenine phosphoribosyltransferase ( P07741 ) deficiency ( 2,8-dihydroxyadenine urolithiasis ) and P34059 ( P34059 ) deficiency ( mucopolysaccharidosis Type IVA , Morquio disease A ) . DB00173 and its extremely insoluble derivative , 2,8-dihydroxyadenine , were identified in the urine , and P07741 deficiency was confirmed in erythrocytes . There was excessive excretion of keratan sulfate in the urine , and P34059 deficiency was confirmed in leukocytes . P34059 and P07741 are both located on chromosome 16q24.3 , suggesting that the patient had a deletion involving both genes . PCR amplification of genomic DNA indicated that a novel junction was created by the fusion of sequences distal to P34059 exon 2 and proximal to P07741 exon 3 , and that the size of the deleted region was approximately 100 kb . The deletion breakpoints were localized within P34059 intron 2 and P07741 intron 2 . Several other genes , including the alpha subunit of cytochrome B ( P13498 ) , which is deleted or mutated in the autosomal form of chronic granulomatous disease , are located in the 16q24.3 region , but PCR amplification showed that this gene was present in the proband . A patient with hemizygosity for P34059 deficiency and P07741 deficiency has been reported from Japan recently . These findings indicate that : ( i ) P07741 is located telomeric to P34059 ; ( ii ) P34059 and P07741 are transcribed in the same orientation ( centromeric to telomeric ) ; and ( iii ) combined P07741 / P34059 deficiency may be more common than hitherto realized . P06858 ( P06858 ) is associated with neurite pathology and its levels are markedly reduced in the dentate gyrus of Alzheimer 's disease brains . P06858 ( P06858 ) is involved in regulation of fatty acid metabolism , and facilitates cellular uptake of lipoproteins , lipids and lipid-soluble vitamins . We evaluated P06858 distribution in healthy and Alzheimer 's disease ( AD ) brain tissue and its relative levels in cerebrospinal fluid . P06858 immunostaining is widely present in different neuronal subgroups , microglia , astrocytes and oligodendroglia throughout cerebrum , cerebellum and spinal cord . P06858 immunoreactivity is also present in leptomeninges , small blood vessels , choroid plexus and ependymal cells , Schwann cells associated with cranial nerves , and in anterior and posterior pituitary . In vitro studies have shown presence of secreted P06858 in conditioned media of human cortical neuronal cell line ( Q9UL51 ) and neuroblastoma cells ( SK-N-SH ) , but not in media of cultured primary human astrocytes . P06858 was present in cytoplasmic and nuclear fractions of neuronal cells and astrocytes in vitro . P06858 immunoreactivity strongly associates with AD-related pathology , staining diffuse plaques , dystrophic and swollen neurites , possible Hirano bodies and activated glial cells . We observed no staining associated with neurofibrillary tangles or granulovacuolar degeneration . Granule cells of the dentate gyrus and the associated synaptic network showed significantly reduced staining in AD compared to control tissue . P06858 was also reduced in AD P04141 samples relative to those in controls . Lack of endothelial nitric oxide synthase aggravates murine pneumococcal meningitis . DB00435 ( NO ) plays a central role in the pathogenesis of bacterial meningitis . However , the role of NO produced by endothelial NO synthase ( P29474 ) in meningitis is still unclear . We investigated the influence of P29474 depletion on the inflammatory host response , intracranial complications , and outcome in experimental pneumococcal meningitis . Leukocyte accumulation in the cerebrospinal fluid was more pronounced in infected P29474 -deficient mice than in infected wild type mice . This effect could be attributed to an increased expression of P16109 , macrophage inflammatory protein-2 , keratinocyte-derived cytokine , and interleukin ( IL ) -1beta in the brain of infected P29474 -deficient mice . However , no differences in the cerebral expression of intercellular adhesion molecule-1 , tumor necrosis factor-alpha , and P05231 as well as of neuronal NOS and inducible NOS could be detected between infected wild type and mutant mice . In addition to enhanced leukocyte infiltration into the P04141 , meningitis-associated intracranial complications including blood-brain barrier disruption and the rise in intracranial pressure were significantly augmented in infected P29474 -deficient mice . The aggravation of intracranial complications was paralleled by a worsening of the disease , as evidenced by a more pronounced hypothermia , an enhanced weight reduction , and an increased death rate . The current data indicate that P29474 deficiency is detrimental in bacterial meningitis . This effect seems to be related to an increased expression of ( certain ) cytokines/chemokines and adhesion molecules ; thus leading to increased meningeal inflammation and , subsequently , to aggravated intracranial complications . Fetzima ( levomilnacipran ) , a drug for major depressive disorder as a dual inhibitor for human serotonin transporters and beta-site amyloid precursor protein cleaving enzyme-1 . Pharmacological management of Major Depressive Disorder includes the use of serotonin reuptake inhibitors which targets serotonin transporters ( P31645 ) to increase the synaptic concentrations of serotonin . Beta-site amyloid precursor protein cleaving enzyme-1 ( P56817 -1 ) is responsible for amyloid β plaque formation . Hence it is an interesting target for Alzheimer 's disease ( AD ) therapy . This study describes molecular interactions of a new Food and Drug Administration approved antidepressant drug named ' Fetzima ' with P56817 -1 and P31645 . Fetzima is chemically known as levomilnacipran . The study has explored a possible link between the treatment of Depression and AD . ' Autodock 4.2 ' was used for docking study . The free energy of binding ( ΔG ) values for ' levomilnacipran- P31645 ' interaction and ' levomilnacipran- P56817 ' interaction were found to be -7.47 and -8.25 kcal/mol , respectively . DB08918 was found to interact with S438 , known to be the most important amino acid residue of serotonin binding site of P31645 during ' levomilnacipran- P31645 ' interaction . In the case of ' levomilnacipran- P56817 ' interaction , levomilnacipran interacted with two very crucial aspartic acid residues of P56817 -1 , namely , D32 and D228 . These residues are accountable for the cleavage of amyloid precursor protein and the subsequent formation of amyloid β plaques in AD brain . Hence , Fetzima ( levomilnacipran ) might act as a potent dual inhibitor of P31645 and P56817 -1 and expected to form the basis of a future dual therapy against depression and AD . It is an established fact that development of AD is associated with Major Depressive Disorder . Therefore , the design of new P56817 -1 inhibitors based on antidepressant drug scaffolds would be particularly beneficial . Taurine biosynthesis in rat brain : a new specific and sensitive microassay of cysteine sulfinate decarboxylase ( CSDI ) activity through selective immunotrapping and its use for distribution studies . DB00151 sulfinate decarboxylase ( Q9Y600 ) , the putative biosynthetic enzyme for taurine , has been shown to exist in two forms in rat brain , respectively CSDI and CSDII , one of which ( CSDII ) is considered to be in fact glutamate decarboxylase ( Q99259 ) . CSDI assay after immunotrapping was made possible by using an anti- Q9Y600 antiserum raised in sheep immunized with a partially purified Q9Y600 fraction from liver . This antiserum immunoprecipitated both liver Q9Y600 and brain CSDI activities with the same affinity but did not inhibit their enzymatic activities . The immunotrapping of CSDI was selective without any contamination by Q99259 /CSDII activity . The immunotrapped Q9Y600 activity , which corresponded exactly to the amount of Q9Y600 not precipitated by a Q99259 /CSDII antiserum , was not inhibited by a specific irreversible Q99259 inhibitor . A quantitative , selective and sensitive assay was thus developed by measuring Q9Y600 activity on the solid phase after immunotrapping . Kinetic parameters of the immunotrapped enzyme remained unchanged . CSDI activity represented only a fraction , around 20 % with saturating concentration of substrate , of the total Q9Y600 activity in rat brain homogenate . This indicates that most studies on total Q9Y600 activity dealt essentially with CSDII activity that is indeed Q99259 . Regional and subcellular distributions of CSDI have been determined . CSDI activity was about threefold higher in the richest ( cerebellum ) compared to the poorest ( striatum ) region without any correlation with Q99259 /CSDII distribution . Subcellular distribution showed a fourfold enrichment of CSDI activity in the synaptosomal fraction . The precise role of CSDI and CSDII in the biosynthesis of taurine in vivo remains to be elucidated . Reduced expression of flavocytochrome b558 , a component of the NADPH oxidase complex , in neutrophils from patients with myelodysplasia . OBJECTIVE : Patients with myelodysplasia ( P43034 ) show a disturbed production of ROS in response to N-formyl-L-methionyl-L-leucyl-L-phenylalanine ( fMLP ) in granulocyte-macrophage colony-stimulating factor ( GM- P04141 ) -primed neutrophils . Because generation of ROS is mediated by the NADPH oxidase complex , a component of which is flavocytochrome b558 , we investigated whether the expression of flavocytochrome b558 in neutrophils from P43034 patients is affected . MATERIAL AND METHODS : Neutrophils were stimulated with fMLP and GM- P04141 , and plasma membrane expression of flavocytochrome b558 and specific granule markers were assessed by fluorescence-activated cell sorting analysis . Protein levels of the flavocytochrome b558 subunits gp91phox and P13498 in whole neutrophil lysates were detected by Western blotting . RESULTS : Stimulation of neutrophils with GM- P04141 and fMLP increased the flavocytochrome b558 plasma membrane expression . The fMLP-induced translocation of flavocytochrome b558 was reduced in neutrophils from P43034 patients ( 140 % +/-9 % vs 180 % +/-13 % , p < 0.05 ) . Analysis of cell surface expression of markers of flavocytochrome b558 containing granules ( CD35 and CD66b ) indicated that exocytosis of these granules in response to fMLP stimulation was not affected in P43034 patients . Western blot analysis demonstrated a decreased protein expression level of the flavocytochrome b558 subunits gp91phox and P13498 in neutrophils from P43034 patients . CONCLUSION : Our results indicate both a lower basal protein level and a disturbed fMLP-induced increase in plasma membrane expression of flavocytochrome b558 in neutrophils from P43034 patients , which together might play a role in decreased ROS production . Gene therapy-mediated delivery of targeted cytotoxins for glioma therapeutics . Restricting the cytotoxicity of anticancer agents by targeting receptors exclusively expressed on tumor cells is critical when treating infiltrative brain tumors such as glioblastoma multiforme ( GBM ) . GBMs express an P35225 receptor ( IL13Rα2 ) that differs from the physiological P24394 /IL13R receptor . We developed a regulatable adenoviral vector ( Ad.mhIL-4.TRE.mhIL-13-PE ) encoding a mutated human P35225 fused to Pseudomonas exotoxin ( mhIL-13-PE ) that specifically binds to IL13Rα2 to provide sustained expression , effective anti-GBM cytotoxicity , and minimal neurotoxicity . The therapeutic Ad also encodes mutated human P05112 that binds to the physiological P24394 /IL13R without interacting with IL13Rα2 , thus inhibiting potential binding of mhIL-13-PE to normal brain cells . Using intracranial GBM xenografts and syngeneic mouse models , we tested the Ad.mhIL-4.TRE.mhIL-13-PE and two protein formulations , hIL-13-PE used in clinical trials ( DB05305 ) and a second-generation mhIL-13-PE . DB05305 doubled median survival without eliciting long-term survival and caused severe neurotoxicity ; mhIL-13-PE led to ∼40 % long-term survival , eliciting severe neurological toxicity at the high dose tested . In contrast , Ad-mediated delivery of mhIL-13-PE led to tumor regression and long-term survival in over 70 % of the animals , without causing apparent neurotoxicity . Although DB05305 was originally developed to target GBM , when tested in a phase III trial it failed to achieve clinical endpoints and revealed neurotoxicity . Limitations of DB05305 include its short half-life , which demanded frequent or continued administration , and binding to P24394 /IL13R , present in normal brain cells . These shortcomings were overcome by our therapeutic Ad , thus representing a significant advance in the development of targeted therapeutics for GBM . Inhibition of human steroid 5beta-reductase ( P51857 ) by finasteride and structure of the enzyme-inhibitor complex . The Delta(4)-3-ketosteroid functionality is present in nearly all steroid hormones apart from estrogens . The first step in functionalization of the A-ring is mediated in humans by steroid 5alpha- or 5beta-reductase . DB01216 is a mechanism-based inactivator of 5alpha-reductase type 2 with subnanomolar affinity and is widely used as a therapeutic for the treatment of benign prostatic hyperplasia . It is also used for androgen deprivation in hormone-dependent prostate carcinoma , and it has been examined as a chemopreventive agent in prostate cancer . The effect of finasteride on steroid 5beta-reductase ( P51857 ) has not been previously reported . We show that finasteride competitively inhibits P51857 with low micromolar affinity but does not act as a mechanism-based inactivator . The structure of the P51857 .NADP(+)*finasteride complex determined at 1.7 A resolution shows that it is not possible for NADPH to reduce the Delta(1-2)-ene of finasteride because the cofactor and steroid are not proximal to each other . The P01024 -ketone of finasteride accepts hydrogen bonds from the catalytic residues DB00135 -58 and DB00142 -120 in the active site of P51857 , providing an explanation for the competitive inhibition observed . This is the first reported structure of finasteride bound to an enzyme involved in steroid hormone metabolism . Prime-boost immunization of rabbits with HIV-1 gp120 elicits potent neutralization activity against a primary viral isolate . Development of a vaccine for HIV-1 requires a detailed understanding of the neutralizing antibody responses that can be experimentally elicited to difficult-to-neutralize primary isolates . Rabbits were immunized with the gp120 subunit of HIV-1 JR- P04141 envelope ( Env ) using a DNA-prime protein-boost regimen . We analyzed five sera that showed potent autologous neutralizing activity ( IC50s at ∼10(3) to 10(4) serum dilution ) against pseudoviruses containing Env from the primary isolate JR- P04141 but not from the related isolate JR-FL . Pseudoviruses were created by exchanging each variable and constant domain of JR- P04141 gp120 with that of JR-FL or with mutations in putative N-glycosylation sites . The sera contained different neutralizing activities dependent on P01024 and V5 , P01024 and V4 , or V4 regions located on the glycan-rich outer domain of gp120 . All sera showed enhanced neutralizing activity toward an Env variant that lacked a glycosylation site in V4 . The JR- P04141 gp120 epitopes recognized by the sera are generally distinct from those of several well characterized mAbs ( targeting conserved sites on Env ) or other type-specific responses ( targeting V1 , V2 , or V3 variable regions ) . The activity of one serum requires specific glycans that are also important for 2G12 neutralization and this serum blocked the binding of 2G12 to gp120 . Our findings show that different fine specificities can achieve potent neutralization of HIV-1 , yet this strong activity does not result in improved breadth . Combined treatment with a P56817 inhibitor and anti-Aβ antibody gantenerumab enhances amyloid reduction in APPLondon mice . Therapeutic approaches for prevention or reduction of amyloidosis are currently a main objective in basic and clinical research on Alzheimer 's disease . Among the agents explored in clinical trials are anti-Aβ peptide antibodies and secretase inhibitors . Most anti-Aβ antibodies are considered to act via inhibition of amyloidosis and enhanced clearance of existing amyloid , although secretase inhibitors reduce the de novo production of Aβ . Limited information is currently available on the efficacy and potential advantages of combinatorial antiamyloid treatment . We performed a chronic study in APPLondon transgenic mice that received treatment with anti-Aβ antibody gantenerumab and P56817 inhibitor RO5508887 , either as mono- or combination treatment . Treatment aimed to evaluate efficacy on amyloid progression , similar to preexisting amyloidosis as present in Alzheimer 's disease patients . Mono-treatments with either compound caused a dose-dependent reduction of total brain Aβ and amyloid burden . Combination treatment with both compounds significantly enhanced the antiamyloid effect . The observed combination effect was most pronounced for lowering of amyloid plaque load and plaque number , which suggests effective inhibition of de novo plaque formation . Moreover , significantly enhanced clearance of pre-existing amyloid plaques was observed when gantenerumab was coadministered with RO5508887 . P56817 inhibition led to a significant time- and dose-dependent decrease in P04141 Aβ , which was not observed for gantenerumab treatment . Our results demonstrate that combining these two antiamyloid agents enhances overall efficacy and suggests that combination treatments may be of clinical relevance . Clinical pharmacology of serotonin-altering medications for decreasing alcohol consumption . Variations in serotonin neurotransmission influence alcohol consumption ( AC ) . Levels of 5-HT and metabolites are low in some brain regions of alcohol preferring rats and in P04141 of alcoholics . Pharmacological treatments which enhance serotonergic neurotransmission ( uptake inhibitors , releasers , agonists ) consistently reduce AC in rats . Serotonin uptake inhibitors ( SUI ; e.g. , citalopram , fluoxetine ) have been studied extensively in humans . In several double-blind randomized , placebo-controlled clinical trials , SUI have consistently decreased AC by averages of 15 % to 20 % in nondepressed mildly/moderately dependent alcoholics who received no other treatment . Effects were dose-dependent and not related to side effects ( few and mild ) or changes in anxiety or depression ( not observed ) . SUI also decreased desire to drink and liking for alcohol , thus suggesting a mechanism for effects . Other drugs acting on the 5-HT system have been tested in humans , but results are difficult to interpret . For example , buspirone , a P08908 receptor partial agonist , reduced anxiety and alcohol craving , but not AC ; a 5-HT partial agonist , m-CPP , increased alcohol craving in abstinent alcoholics ; modest reductions in AC were observed with a 5- Q9H205 antagonist , ondansetron ( 0.5 mg/day , but not 4 mg/day ) . The therapeutic potentials of these medications are being studied . For example , SUI effects on AC were enhanced by a brief psychosocial intervention . Since SUI decrease urge to drink , they may be suitable pharmacological adjuncts in relapse prevention strategies . SUI and other serotonin-altering medications are promising new neuropharmacological treatments for reducing AC . Production of leukotrienes in gonadotropin-releasing hormone-stimulated pituitary cells : potential role in luteinizing hormone release . DB00644 ( DB00644 ) stimulated the formation of two major metabolites of the P09917 pathway , leukotriene ( LT ) B4 and LTC4 , as well as luteinizing hormone ( LH ) release in primary cultures of rat anterior pituitary cells . Several lines of evidence suggested the presence of a DB00644 -dependent pituitary endocrine system in which LTs act as second messengers for LH release : ( i ) DB00644 -dependent LT formation was observed within 1 min and immediately preceded DB00644 -induced LH release , whereas exogenous LTs stimulated LH release at low concentrations ; ( ii ) the dose responses of DB00644 -induced LT production and LH release were similar and both effects required the presence of extracellular Ca2+ ions ; ( iii ) DB00644 -induced LH release was blocked by up to 45 % following the administration of several LT receptor antagonists ; ( iv ) LTE4 action on LH secretion was entirely abolished by LT receptor antagonists ; and ( v ) an activator of protein kinase C acted synergistically with LTE4 to induce LH release . The major source of LT formation in the pituitary cell cultures appeared to be the gonadotrophs , as shown by P30968 desensitization experiments . The results demonstrate the presence of a DB00644 -activatable P09917 pathway in anterior pituitary cells and provide strong support for the hypothesis that LTs play a role in LH release in the DB00644 signaling pathway . DB01686 ( DB01686 ) induces vascular endothelium impairment and aggravates post-ischemic ventricular dysfunction in rats . DB01686 ( DB01686 ) is an endogenous nitric oxide ( NO ) inhibitor recognized as an independent risk factor for endothelial dysfunction and coronary heart diseases . This study investigated whether DB01686 ( 10 mg/kg day for 14 days ) affected endothelial function and aggravated post-ischemic ventricular dysfunction in the perfused rat heart . Systolic blood pressure and heart rate , plasma levels of DB01686 and nitrite/nitrate were measured in vehicle- and DB01686 -treated rats . Perfused hearts were submitted to global ischemia-reperfusion and vascular endothelial dysfunction was examined with angiotensin II in coronary vessels and aortic rings . Endothelial NO synthase ( P29474 ) and angiotensin-converting enzyme ( P12821 ) mRNA expression in aortic and cardiac tissues were measured . DB01686 -treated rats had higher systolic blood pressure ( 1.3-fold , P < 0.01 ) and slower heart rate ( 16 % , P < 0.05 ) than controls . Plasma DB01686 rose ( 1.9-fold , P < 0.01 ) and nitrite/nitrate concentration decreased 59 % ( P < 0.001 ) . Ventricular contraction ( stiffness ) increased significantly , with worsening of post-ischemic ventricular dysfunction . In preparations from DB01686 -treated rats the coronary vasculature 's response to angiotensin II was almost doubled ( P < 0.01 ) and the maximal vasorelaxant effect of acetylcholine in aortic rings was significantly lower than in preparations from vehicle-treated rats . In cardiac and aortic tissues P29474 mRNA and P12821 mRNA levels were similar in controls and DB01686 -treated rats . The increased plasma levels of DB01686 presumably cause endothelial dysfunction because of a deficiency in NO production , which also appears involved in the aggravation of myocardial ischemia-reperfusion injury .