interacts_with DB00163?
Alpha-tocopherol decreases tumor necrosis factor-alpha mRNA and protein from activated human monocytes by inhibition of P09917 . Cardiovascular disease is the leading cause of morbidity in Westernized populations . Low levels of DB00163 ( AT ) are associated with increased incidence of atherosclerosis and increased intakes appear to be protective . AT supplementation decreases interleukin 1 and 6 release from human monocytes . Thus , the aim of this study was to examine the effect of AT on an important proinflammatory cytokine , tumor necrosis factor-alpha ( P01375 ) release from human monocytes . AT supplementation ( 1200 IU/day for 3 months ) significantly decreased P01375 release from activated human monocytes . Mechanisms that were examined included its effect as a general antioxidant , its inhibitory effect on protein kinase C ( PKC ) , and the cycloxygenase-lipoxygenase pathway . While AT decreased P01375 release from activated monocytes , other antioxidants had no effect on P01375 release . Specific PKC inhibitors had no effect on P01375 release from activated monocytes . The inhibition of P01375 release by AT in activated monocytes was reversed by leukotriene B(4) ( Q06643 (4) ) , a major product of the P09917 ( P09917 ) pathway . Similar observations were seen with inhibitors of P09917 . Indomethacin , a P36551 inhibitor , in the presence and absence of AT failed to affect P01375 activity . These findings suggest that AT decreases P01375 release from activated human monocytes via inhibition of P09917 . Also , AT as well as a P09917 inhibitor significantly decreased P01375 mRNA . Furthermore , AT and the P09917 inhibitor decreased NFkappab-binding activity . Thus , in activated human monocytes , AT appears to inhibit P01375 mRNA and protein by inhibition of P09917 . Arachidonate cascade , apoptosis , and vitamin E in peripheral blood mononuclear cells from hemodialysis patients . BACKGROUND : Lipid peroxidation and oxidative stress are enhanced in peripheral blood mononuclear cells ( PBMCs ) from hemodialysis ( HD ) patients because of upregulation of the P09917 pathway of the arachidonate cascade . 5-Lipoxygenase activity is specifically inhibited by vitamin E both in vitro and in vivo regardless of its administration route . METHODS : The effect of arachidonate cascade enzymes and vitamin E on oxidative stress and apoptosis was investigated in PBMCs from 16 maintenance HD patients treated for at least 6 months with cuprammonium rayon membranes in a two-step crossover study : after a 4-week treatment with vitamin E-coated cuprammonium rayon membranes and again after a 4-week treatment with oral vitamin E. Control PBMCs were obtained from 16 healthy volunteers . RESULTS : Membrane lipoperoxidation , cellular luminescence , membrane fluidity , and leukotriene B(4) content were significantly greater in PBMCs from HD patients ; lipoxygenase was upregulated , but prostaglandin H synthase ( P61457 ) was not affected . Regardless of administration route , vitamin E partially controlled lipid peroxidation and oxidative stress through direct inhibition of P09917 . Cultured PBMCs from HD patients showed a significant increase in apoptotic cells compared with controls . DB00163 markedly reduced cell luminescence , membrane fluidity , and apoptosis , whereas the P61457 inhibitor indomethacin was ineffective . Similar results were obtained with control PBMCs induced to apoptosis by hydrogen peroxide . CONCLUSION : Reported data suggest that the P09917 branch of the arachidonate cascade is only responsible for membrane peroxidation , oxidative stress , and apoptosis of PBMCs of HD patients , and administration of vitamin E may be helpful in the control of oxidative stress-related disease in these subjects . Roles of protein kinase C and actin-binding protein 280 in the regulation of intracellular trafficking of dopamine D3 receptor . P35462 ( D(3)R ) is expressed mainly in parts of the brain that control the emotional behaviors . It is believed that the improper regulation of D(3)R is involved in the etiology of schizophrenia . Desensitization of D(3)R is weakly associated with G protein-coupled receptor kinase ( GRK ) /beta-arrestin-directed internalization . This suggests that there might be an alternative pathway that regulates D(3)R signaling . This report shows that D(3)R undergoes robust protein kinase C ( PKC ) -dependent sequestration that is accompanied by receptor phosphorylation and the desensitization of signaling . PKC-dependent D(3)R sequestration , which was enhanced by P05771 or -delta , was dynamin dependent but independent of GRK , beta-arrestin , or caveolin 1 . Site-directed mutagenesis of all possible phosphorylation sites within the intracellular loops of D(3)R identified serine residues at positions 229 and 257 as the critical amino acids responsible for phorbol-12-myristate-13-acetate ( PMA ) -induced D(3)R phosphorylation , sequestration , and desensitization . In addition , the LxxY endocytosis motif , which is located between residues 252 and 255 , was found to play accommodating roles for PMA-induced D(3)R sequestration . A continuous interaction with the actin-binding protein 280 ( filamin A ) , which was previously known to interact with D(3)R , is required for PMA-induced D(3)R sequestration . In conclusion , the PKC-dependent but GRK-/beta-arrestin-independent phosphorylation of D(3)R is the main pathway responsible for the sequestration and desensitization of D(3)R . Filamin A is essential for both the efficient signaling and sequestration of D(3)R . Antisense oligonucleotide to PKC-epsilon alters DB02527 -dependent stimulation of P13569 in Calu-3 cells . Protein kinase C ( PKC ) regulates cystic fibrosis transmembrane conductance regulator ( P13569 ) channel activity but the PKC signaling mechanism is not yet known . The goal of these studies was to identify PKC isotype(s) required for control of P13569 function . P13569 activity was measured as 36Cl efflux in a Chinese hamster ovary cell line stably expressing wild-type P13569 ( CHO-wtCFTR ) and in a Calu-3 cell line . Chelerythrine , a PKC inhibitor , delayed increased P13569 activity induced with phorbol 12-myristate 13-acetate or with the DB02527 -generating agents (-)-epinephrine or forskolin plus 8-(4-chlorophenylthio)adenosine 3',5'- cyclic monophosphate . Immunoblot analysis of Calu-3 cells revealed that P17252 , -betaII , -delta , -epsilon , and -zeta were expressed in confluent cell cultures . Pretreatment of cell monolayers with Lipofectin plus antisense oligonucleotide to PKC-epsilon for 48 h prevented stimulation of P13569 with (-)-epinephrine , reduced PKC-epsilon activity in unstimulated cells by 52.1 % , and decreased PKC-epsilon mass by 76.1 % but did not affect hormone-activated protein kinase A activity . Sense oligonucleotide to PKC-epsilon and antisense oligonucleotide to PKC-delta and -zeta did not alter (-)-epinephrine-stimulated P13569 activity . These results demonstrate the selective regulation of P13569 function by constitutively active PKC-epsilon . Lack of association between Q9HAW7 , O60656 , ARP , P00995 and P13569 gene polymorphisms and pancreatic cancer in Italian patients . AIM : To investigate simultaneously Q9HAW7 , O60656 , ARP , SPINK and P13569 genes to verify whether genetic polymorphisms predispose to the development of pancreatic cancer ( PC ) . METHODS : Genomic DNA of 61 pancreatic cancer patients and 105 healthy controls ( HC ) were analyzed . Q9HAW7 genotyping was determined by PCR-RFLP analysis . Specific PCR and sequencing were used to analyze genetic variants of O60656 , ARP , P00995 and P13569 genes . RESULTS : Four different alleles ( *1 : WT ; *2 : N129K and R131K ; *3 : N129K , R131K , and W208R ; and *4 : W208R ) in Q9HAW7 and three different alleles ( *1 : WT ; *4 : Y242X ; and *5 : D256N ) in O60656 were detected . All P22309 polymorphisms were observed at similar frequency in PC patients and HC . Seven different alleles in ARP were found in PC patients and HC at similar frequency . The P00995 mutations N34S and P55S occurred in five PC patients with a prevalence ( 4.1 % ) not significantly different from that observed ( 2.0 % ) in HC . The only P13569 DeltaF508 mutation was recognized in three PC patients with a prevalence ( 4.9 % ) similar to HC . CONCLUSION : Q9HAW7 , O60656 , ARP , P00995 and P13569 gene polymorphisms are not associated with PC in Italian patients . DB06212 , a selective oral vasopressin V2 receptor antagonist , ameliorates podocyte injury in puromycin aminonucleoside nephrotic rats . BACKGROUND : Proteinuria caused by glomerular disease is characterized by podocyte injury . P30518 antagonists are effective in reducing albuminuria , although their actions on glomerular podocytes have not been explored . The objective of this study was to evaluate the effects of tolvaptan , a selective oral V2 receptor antagonist , on podocytes in a puromycin aminonucleoside ( PAN ) -induced nephrosis rat model . METHODS : Rats were allocated to a control , PAN nephrosis , or tolvaptan-treated PAN nephrosis group ( n = 9 per group ) . Urinary protein excretion and serum levels of total protein , albumin , creatinine , and total cholesterol were measured on day 10 . The influence of tolvaptan on podocytes was examined in renal tissues by immunofluorescence and electron microscopy . RESULTS : PAN induced massive proteinuria and serum creatinine elevation on day 10 , both of which were significantly ameliorated by tolvaptan . Immunofluorescence studies of the podocyte-associated proteins nephrin and podocin revealed granular staining patterns in PAN nephrosis rats . In tolvaptan-treated rats , nephrin and podocin expressions retained their normal linear pattern . Electron microscopy showed foot process effacement was ameliorated in tolvaptan-treated rats . CONCLUSIONS : DB06212 is protective against podocyte damage and proteinuria in PAN nephrosis . This study indicates that tolvaptan exerts a renoprotective effect by affecting podocyte morphology and probably function in PAN nephrosis . DB06212 is a promising pharmacological tool in the treatment of renal edema . DB00640 regulation of cystic fibrosis transmembrane conductance regulator through prostenoids in airway epithelia . Cystic fibrosis is caused by dysfunction of the cystic fibrosis transmembrane conductance regulator ( P13569 ) protein , leading to altered ion transport , chronic infection , and excessive inflammation . Here we investigated regulation of P13569 in airway cell monolayers by adenosine , adenosine receptors , and arachidonic acid . Our studies demonstrate that the A2B adenosine receptor is expressed at high levels relative to the other adenosine receptor subtypes , with a characteristic low-affinity profile for adenosine-stimulated P13569 Cl- currents in both Calu-3 cells and CFBE41o- airway cell monolayers stably transduced with wild-type P13569 . The levels of adenosine found in sputum from patients with cystic fibrosis with moderate to severe lung disease stimulated apical prostaglandin release in Calu-3 and CFBE41o- cells , implicating adenosine regulation of phospholipase A2 ( P04054 ) activity . A2B adenosine receptor and arachidonic acid stimulation produced P13569 -dependent currents in airway monolayers and increased DB02527 levels that were sensitive to cyclooxygenase inhibition . Arachidonic acid demonstrated dual regulation of P13569 , stimulating P13569 and Cl- currents in intact airway monolayers , and potently inhibiting PKA-activated Cl- currents in excised membrane patches . Cl- currents produced by arachidonic acid were sensitive to inhibition of PKA , cyclooxygenase , and P09917 . Together , the results provide a converging mechanism to link regulation of P13569 and airway cell inflammation through adenosine and adenosine receptors . Involvement of P05771 in PTH , P01375 , and P01584 effects on P05231 promoter in osteoblastic cells and on PTH-stimulated bone resorption . Protein kinase C ( PKC ) has been shown to be activated by parathyroid hormone ( PTH ) in osteoblasts . Prior evidence suggests that this activation mediates responses leading to bone resorption , including production of the osteoclastogenic cytokine interleukin-6 ( P05231 ) . However , the importance of specific PKC isozymes in this process has not been investigated . A selective antagonist of P05771 , LY379196 , was used to determine the role of the P05771 isozyme in the expression of P05231 in UMR-106 rat osteoblastic cells and in bone resorption in fetal rat limb bone organ cultures . PTH , tumor necrosis factor-alpha ( P01375 ) , and interleukin-1 beta ( P01584 ) induced translocation of P17252 and -beta(I) to the plasma membrane in UMR-106 cells within 5 min . The stimulation of P05771 (I) translocation by PTH , P01375 or P01584 was inhibited by LY379196 . In contrast , LY379196 did not affect PTH , P01375 - , or P01584 -stimulated translocation of P17252 . PTH , P01375 , and P01584 increased luciferase expression in UMR-106 cells transiently transfected with a -224/+11 bp P05231 promoter-driven reporter construct . The P05231 responses were also attenuated by treatment with LY379196 . Furthermore , LY379196 inhibited bone resorption elicited by PTH in fetal rat bone organ cultures . These results indicate that P05771 (I) is a component of the signaling pathway that mediates PTH- , P01375 - , and P01584 -stimulated P05231 expression and PTH-stimulated bone resorption . Oral keratinocytes support non-replicative infection and transfer of harbored HIV-1 to permissive cells . BACKGROUND : Oral keratinocytes on the mucosal surface are frequently exposed to HIV-1 through contact with infected sexual partners or nursing mothers . To determine the plausibility that oral keratinocytes are primary targets of HIV-1 , we tested the hypothesis that HIV-1 infects oral keratinocytes in a restricted manner . RESULTS : To study the fate of HIV-1 , immortalized oral keratinocytes ( OKF6/ O14746 -2 ; O14746 -2 cells ) were characterized for the fate of HIV-specific RNA and DNA . At 6 h post inoculation with X4 or R5-tropic HIV-1 , HIV-1gag RNA was detected maximally within O14746 -2 cells . Reverse transcriptase activity in O14746 -2 cells was confirmed by VSV-G-mediated infection with HIV-NL4-3Deltaenv-EGFP . DB00495 inhibited EGFP expression in a dose-dependent manner , suggesting that viral replication can be supported if receptors are bypassed . Within 3 h post inoculation , integrated HIV-1 DNA was detected in O14746 -2 cell nuclei and persisted after subculture . Multiply spliced and unspliced HIV-1 mRNAs were not detectable up to 72 h post inoculation , suggesting that HIV replication may abort and that infection is non-productive . Within 48 h post inoculation , however , virus harbored by P01730 negative O14746 -2 cells trans infected co-cultured peripheral blood mononuclear cells ( PBMCs ) or MOLT4 cells ( P01730 + P51681 + ) by direct cell-to-cell transfer or by releasing low levels of infectious virions . Primary tonsil epithelial cells also trans infected HIV-1 to permissive cells in a donor-specific manner . CONCLUSION : Oral keratinocytes appear , therefore , to support stable non-replicative integration , while harboring and transmitting infectious X4- or R5-tropic HIV-1 to permissive cells for up to 48 h . Tocotrienols activate the steroid and xenobiotic receptor , O75469 , and selectively regulate expression of its target genes . DB00163 is an essential nutrient with antioxidant activity . DB00163 is comprised of eight members , alpha- , beta- , gamma- , and delta-tocopherols and alpha- , beta- , gamma- , and delta-tocotrienols . All forms of vitamin E are initially metabolized by omega-oxidation , which is catalyzed by cytochrome P450 enzymes . The steroid and xenobiotic receptor ( O75469 ) is a nuclear receptor that regulates drug clearance in the liver and intestine via induction of genes involved in drug and xenobiotic metabolism . We show here that all four tocotrienols specifically bind to and activate O75469 , whereas tocopherols neither bind nor activate . Surprisingly , tocotrienols show tissue-specific induction of O75469 target genes , particularly P08684 . Tocotrienols up-regulate expression of P08684 but not P22309 ( P22309 ) or multidrug resistance protein-1 ( P08183 ) in primary hepatocytes . In contrast , tocotrienols induce P08183 and P22309 but not P08684 expression in intestinal LS180 cells . We found that nuclear receptor corepressor ( NCoR ) is expressed at relatively high levels in intestinal LS180 cells compared with primary hepatocytes . The unliganded O75469 interacts with NCoR , and this interaction is only partially disrupted by tocotrienols . Expression of a dominant-negative NCoR enhanced the ability of tocotrienols to induce P08684 in LS180 cells , suggesting that NCoR plays an important role in tissue-specific gene regulation by O75469 . Our findings provide a molecular mechanism explaining how vitamin supplements affect the absorption and effectiveness of drugs . Knowledge of drug-nutrient interactions may help reduce the incidence of decreased drug efficacy . Release of cytokines by blood monocytes during strenuous exercise . During strenuous exercise in endurance athletes , monocytes are activated and there is an acute inflammation and hypoxemia possibly due to lesional pulmonary edema . P05231 and P01375 released by monocytes may be implicated in the acute phase of lesional pulmonary edema . A study was carried out to determine whether P01375 and P05231 are released during strenuous exercise , and , if adrenalin released during exercise alters their generation . Ten young and six master athletes underwent an incremental exercise test . Arterial blood was drawn at rest , at the end of the exercise , and 20 minutes afterwards . Monocytes were isolated and incubated for 18 hours in the presence or absence of adrenalin . Il-6 and P01375 were measured in monocyte supernatants . The spontaneous release of P05231 or P01375 was increased in young athletes when compared to older subjects . The spontaneous release of P01375 was increased , but not significantly , by exercise and there was no correlation between the release of P05231 and P01375 and lung function measured during hypoxemia . DB00668 inhibited the release of P05231 or P01375 . Correlations were observed between the in vitro release of P05231 or P01375 and age , VO2max , maximal ventilation and maximal power output of the subjects . Inhibitors of arachidonic acid metabolism reduce DNA and nuclear fragmentation induced by P01375 plus cycloheximide in U937 cells . U937 human myeloid leukemia cells are induced to apoptosis by tumour necrosis factor ( P01375 ) plus cycloheximide ( CHX ) . We have analysed the effect of various inhibitors of the arachidonic acid ( AA ) metabolism on several features of this process . The formation of high molecular weight and oligonucleosomal DNA fragments as well as nuclear fragmentation were reduced by inhibitors of P09917 ( BWA4C and BWB70C ) , P09917 activating protein ( MK-886 ) , and cytosolic P04054 ( AACOCF3 ) . None of these agents blocked the morphological changes detected by microscopy or flow cytometry , phosphatidylserine exposure on the cell surface or Caspase 3-like activation . AA also induced nuclear fragmentation at a concentration of 1-20 microM . However , the mechanisms by which these inhibitors act , remain unexplained since there was no P09917 expression in the U937 cells and no AA release followed their stimulation with P01375 plus CHX . Hypoxia-mediated expression of P09917 -activating protein involves HIF-1alpha and NF-kappaB and microRNAs 135a and 199a-5p . Hypoxia occurs in a number of pathological states , such as pulmonary , hematological , and cardiovascular disorders . In this study , we examined the molecular mechanism by which hypoxia contributes to increased leukotriene formation . Our studies showed hypoxia augmented the expression of P09917 activating protein ( P20292 ) , a key enzyme in leukotriene formation , in both human pulmonary microvascular endothelial cells and a transformed human brain endothelial cell line . Hypoxia-induced P20292 mRNA expression involved activation of NADPH-oxidase , P19957 kinase , mitogen-activated protein kinase , NF-kappaB , and hypoxia-inducible factor ( HIF ) -1alpha . Hypoxia-induced P20292 promoter activity was attenuated on mutation of hypoxia-response elements ( HREs ) and NF-kappaB binding motif in the P20292 promoter . Hypoxia also augmented binding of HIF-1alpha to HREs in P20292 promoter as demonstrated by EMSA with nuclear extracts . Furthermore , chromain immunoprecipitation analysis showed HIF-1alpha bound to HREs in native chromatin obtained from hypoxia-treated cells . Next , we examined the role of HIF-1alpha regulated microRNAs on P20292 expression . Our studies showed decreased expression of miR-135a and miR-199a-5p in response to hypoxia . However , overexpression of anti-miR-135a and anti-miR-199a-5p oligonucleotides led to a several fold increased P20292 mRNA and protein expression . These studies demonstrate for the first time that hypoxia-mediated P20292 expression is regulated by HREs and NF-kappaB site in its promoter , and negatively regulated by miR-135a and miR-199a-5p , which target the 3'-UTR of P20292 mRNA . An understanding of these regulatory pathways provides new avenues to ameliorate leukotriene formation and hence reactive airway disease , and inflammation in individuals who have sickle cell disease . The effect of DB00163 on monocyte proatherogenic activity . Atherosclerosis is the leading cause of morbidity and mortality in Westernized populations . The monocyte is a crucial cell in the genesis of the atherosclerotic lesion and is present during all stages of atherosclerosis . alpha-Tocopherol ( AT ) is the most active component of the vitamin E family and is the principal and most potent lipid-soluble antioxidant in plasma and LDL . With regard to monocyte function , AT supplementation ( 1200 IU/d ) has been shown to decrease release of reactive oxygen species , lipid oxidation , release of cytokines such as interleukin-1ss ( IL-1ss ) and tumor necrosis factor-alpha ( P01375 ) and decrease adhesion of monocytes to human endothelium . The mechanism of inhibition of superoxide and lipid oxidation by monocytes appears to be via inhibition of protein kinase C ( PKC ) , the decrease in IL-1ss and P01375 release by inhibition of P09917 and the inhibition of monocyte-endothelial cell adhesion via decrease in adhesion molecules on monocytes , CD11b and VLA-4 and by decreasing DNA-binding activity of nuclear transcription factor kappaB . Thus , in addition to the decrease in oxidative stress resulting from AT supplementation , as evidenced by decreased F(2)-isoprostanes and LDL oxidizability , AT is anti-inflammatory and exerts beneficial antiatherogenic effects on cells crucial in atherogenesis such as monocytes . Specific cellular responses to DB00163 . In the last 10 years precise cellular functions of DB00163 , some of which are independent of its antioxidant/radical-scavenging ability , have been revealed . Absorption of DB00163 from the gut is a selective process . Other tocopherols are not absorbed or are absorbed to a lesser extent . At the post-translational level , DB00163 inhibits protein kinase C and P09917 and activates protein phosphatase 2A and diacylglycerol kinase . Some genes [ platelet glycoprotein IV/thrombospondin receptor/class B scavenger receptor ( P16671 ) , DB00163 transfer protein ( alpha-TTP ) , alpha-tropomyosin , connective tissue growth factor and collagenase ] are affected by DB00163 at the transcriptional level . alpha-Tocopherol also inhibits cell proliferation , platelet aggregation , monocyte adhesion and the oxygen burst in neutrophils . Other antioxidants , such as beta-tocopherol and probucol , do not mimic these effects , suggesting a nonantioxidant , DB00163 -specific molecular mechanism . The influence of metabolic gene polymorphisms on urinary 1-hydroxypyrene concentrations in Chinese coke oven workers . Urinary 1-hydroxypyrene ( 1-OHP ) , a biomarker of polycyclic aromatic hydrocarbons ( PAHs ) exposure , may be influenced by metabolic gene polymorphisms . Such knowledge could benefit us in understanding the inter-individual difference in the mechanism of PAHs-induced carcinogenesis . We investigated the influence of gene polymorphisms on urinary 1-OHP concentrations in 447 coke oven workers from two coking plants in south China . After adjustment for age , plant , level of occupational exposure , body mass index , level of education , alcohol consumption , cigarette smoking and respirator usage , P35869 R554K ( rs2066853 ) , P22309 -3263T > G ( rs4124874 ) and P09211 I105V ( rs1695 ) were associated with urinary 1-OHP excretion with the p-value of 0.053 , 0.006 and 0.021 , respectively . The concentrations of urinary 1-OHP ( Geometric mean , micromol/mol creatinine ) in the homozygous major variant carriers and homozygous minor variant carriers for P35869 R554K , P22309 -3263T > G and P09211 I105V were listed as follows : 4.20 and 5.12 , 5.11 and 3.92 , 4.93 and 2.91 , respectively . P30711 present carriers had a significantly higher urinary 1-OHP level than that in null carriers in the case with P35869 R554K GA/AA carriers ( 5.17 vs. 3.64 micromol/mol creatinine , p=0.038 ) , as well as in the case with P22309 -3263T > G TG/GG carriers ( 5.67 vs. 3.38 micromol/mol creatinine , p=0.001 ) . These results showed that P35869 , P22309 , P09211 and P30711 polymorphisms were associated with urinary 1-OHP concentrations in Chinese coke oven workers . No influence was found in the association between urinary 1-OHP and other genetic polymorphisms such as P04798 , P05177 , Q16678 , P05181 , P07099 , P34913 in this population . DB00163 and drug metabolism . Tocopherols and tocotrienols are metabolized by side chain degradation initiated by cytochrome P450 ( CYP ) -catalyzed omega-hydroxylation followed by beta-oxidation . Whereas DB00163 is only poorly metabolized , high amounts of the final products , carboxyethyl hydroxychroman ( CEHC ) , are found from other tocols in HepG2 cells and in human urine . P08684 and P78329 were suggested to be involved in tocopherol degradation . P08684 metabolizes most of the drugs and is induced by many of its substrates via the activation of the pregnane X receptor ( O75469 ) . Also tocopherols and in particular tocotrienols induce the expression of a O75469 -driven reporter gene and the expression of endogenous P08684 and P20815 which is supported by sporadic publications spread over the last 30 years . The potential interference of vitamin E with drug metabolism is discussed in the light of related complications evoked by herbal remedies . A case study of acenocoumarol sensitivity and genotype-phenotype discordancy explained by combinations of polymorphisms in Q9BQB6 and P11712 . To determine the cause of a genotype-phenotype discordancy for acenocoumarol sensitivity . Methods A patient , highly sensitive to acenocoumarol , and previously determined to carry only a single P11712 *3 allele , was genotyped for additional functionally defective alleles in the P11712 and Q9BQB6 genes . Family members were also analyzed to trace the pedigree . Results The acenocoumarol-sensitive patient was found to possess , in addition to P11712 *3 allele , a P11712 *11 allele and the Q9BQB6 AA diplotype which were all traced back through the parental lines . Conclusions DB01418 sensitivity in this subject is the consequence of inheritance of multiple functionally defective alleles in both the P11712 and Q9BQB6 genes . The study provides additional data in support of diminished P11712 activity due to the presence of the rare *11 allele . Design , synthesis , and biological evaluation of conformationally constrained aci-reductone mimics of arachidonic acid . An efficient and convergent synthesis has been developed for the production of 3,4-dihydroxy-5- [ 4- ( 2- ( ( 2Z ) -hexenyl ) phenyl ) -3-(1Z)-but enyl ] -2 ( 5H ) -furanone ( 12d ) . This hydrophobic antioxidant is a stable conformationally constrained mimic of arachidonic acid ( AA ) ( 1 ) and its respective aci-reductone analogue ( 2 ) . Pd(0)-catalyzed cross-coupling of 5-(3-butynyl)-3,4-dihydroxy-2(5H)-furanone ( 7 ) with 2- ( ( 2Z ) -hexenyl ) iodobenzene ( 8d ) followed by Lindlar catalyzed hydrogenation produces 12d . Butynyl intermediate 7 is prepared from 2-(benzyloxy)-5-deoxyascorbic acid ( 15 ) by iodination ( I2 , PPh3 , Imd ) , iodo substitution with lithium acetylide ethylenediamine complex ( LiAEDA , HMPA , -5 degrees C ) , and benzyl group cleavage ( Ac2O , Pyr , BCl3 ) . The utility of this synthetic method was demonstrated by the synthesis of analogues 10e-k . Biological testing revealed that certain of these antioxidants inhibit both cyclooxygenase ( P36551 ) and P09917 ( P09917 ) with comparable efficacy as reported for aspirin and zileuton , respectively . The antioxidant activity of these aci-reductones , measured as a function of their inhibitory effect on CCl4-induced lipid peroxidation of hepatic microsomes , exceeds that produced by DB00163 . Synthetic routes and initial structure-activity relationships ( SAR ) for these novel mixed functioning antioxidants are presented . Correlation between tumor volume response to radiotherapy and expression of biological markers in patients with cervical squamous cell carcinoma . OBJECTIVE : To determine the factors associated with tumor volume response to radiotherapy ( RT ) in cervical cancer patients , and the relationship between the tumor volume response and alteration of the expression of biological markers during RT . METHODS : Twenty consecutive patients with cervical squamous cell carcinoma who received definitive RT were enrolled . Tumor volumes were calculated by Q9BWK5 examinations performed at the start of RT ( pre-RT ) , at the fourth week of RT ( mid-RT ) , and 1 month after RT completion ( post-RT ) . Two serial punch biopsies were performed at pre- and mid-RT , and immunohistochemical staining was performed for cyclooxygenase ( P36551 ) -2 and epidermal growth factor receptor ( P00533 ) . RESULTS : For the pre-RT evaluation , fourteen ( 70 % ) and eleven ( 55 % ) patients showed positive immunoreactivity for P35354 and P00533 , respectively . Among the seven patients whose median percentage residual tumor at mid-RT ( P30518 ) was greater than 0.5 , seven ( 100 % , p=0.0515 ) and five ( 71.4 % , p=0.3742 ) patients showed positive immunoreactivity for P35354 and P00533 , respectively . The logistic regression analysis showed that positive immunoreactivity for both P35354 and P00533 at pre-RT were associated with P30518 ( p=0.0782 ) . For the mid-RT evaluation , eight cases showed an interval increase in the distribution of immunoreactivity for P35354 , and six out of the eight patients had a P30518 greater than 0.5 ( p=0.2222 ) . CONCLUSION : The poor mid-RT tumor response was associated with the coexpression of P35354 and P00533 . Activation of PKC but not of P29323 is required for vitamin E-succinate-induced apoptosis of HL-60 cells . DB00163 -succinate ( VES ) induced HL-60 human leukemia cells to undergo apoptosis . Treatment with VES induced membrane translocation of Fas ; cleavages of caspase-3 , PARP , and lamin B ; hypophosphorylation of retinoblastoma protein ; and increase of P38936 ( P38936 ) protein level . During the induction of apoptosis , activity of PKC was gradually increased with downregulation of VES-induced P29323 activity and accompanied by activation of caspase-3 . Inhibition of PKC by GF109203X blocked VES-mediated membrane translocation of P17252 and cleavage of caspase-3 cascade , resulting in prevention of VES-induced apoptosis . On the contrary , PKC activation by cotreatment with Q16549 or thapsigargin and VES synergistically increased VES-mediated apoptosis . However , inhibition of P29323 activity by PD98059 showed no significant effect on VES-induced PKC activity and apoptosis . Taken together , our data suggest that VES induces activation of PKC and PKC-dependent hypophosphorylation of retinoblastoma protein , which results in induction of apoptosis , and that VES-induced early activation of P29323 and P29323 -dependent induction of P38936 ( P38936 ) are not required for apoptosis . Acute effects of sarpogrelate , a 5- Q13049 receptor antagonist on cytokine production in endotoxin shock model of rats . Serotonin ( 5-HT ) (2A) receptors are involved in cytokine production in infection or sepsis . Therefore , 5-HT(2A) receptor antagonist might be useful to treat sepsis . The present study investigates the effects of a 5-HT(2A) receptor antagonist , sarpogrelate on endotoxin shock . Catheters were inserted into the femoral artery and vein of Sprague-Dawley rats . First , sarpogrelate 0 ( control ) , 3 , or 10 mg/kg dissolved in 0.5 ml of distilled water has been given , followed by endotoxin 10 mg/kg in saline 0.5 ml 5 min later . Blood pressure , pulse rate and survival rate were monitored in 20 rats per dose . Blood gas and plasma cytokine concentrations were measured in 8 rats per dose . In four rats each of sarpogrelate 0 , 3 , or 10 mg/kg , and sham operation , the lung histology was examined . Zero , 15 , and 12 rats survived for 8 h in the control , 3 mg/kg , and 10 mg/kg groups , respectively . The control group had the lowest blood pressure , pulse rate , pH and arterial oxygen tension , and the highest arterial carbon dioxide tension and plasma IL-1beta concentration . The increase of P01375 was significantly lower in 3 mg/kg group than in the control group . Pathological changes of the lung were inhibited in 3 and 10 mg/kg groups . In conclusion , sarpogrelate might be effective to decrease production of pro-inflammatory cytokines , to keep hemodynamics , to inhibit lung damage , and to decrease mortality in endotoxin shock . 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 . Allele frequencies of single nucleotide polymorphisms ( SNPs ) in 40 candidate genes for gene-environment studies on cancer : data from population-based Japanese random samples . Knowledge of genetic polymorphisms in gene-environment studies may contribute to more accurate identification of avoidable risks and to developing tailor-made preventative measures . The aim of this study was to describe the allele frequencies of single nucleotide polymorphisms ( SNPs ) of select genes , which may be included in future gene-environment studies on cancer in Japan . SNP typing was performed on middle-aged Japanese men randomly selected from the general population in five areas of Japan . We genotyped and calculated allele frequencies of 153 SNPs located on 40 genes : P04798 , Q16678 , P11712 , P33261 , P05181 , P05093 , P11511 , P35869 , P03372 , Q92731 , ERRRG , P06401 , P07099 , P34913 , P37059 , P37058 , P28161 , P21266 , GSTT2 , P09211 , NAT1 , NAT2 , P21964 , P07327 , P00325 , P00326 , P05091 , P35228 , NOS3 , P01583 , P01584 , O15527 , P36639 [ P36639 ] , P14416 , P35462 , P21917 , P31645 , P04150 [ GCCR ] , P42898 , and P15559 . In the present study , the Japanese allele frequencies were verified by using nationwide population samples . P01375 polymorphisms as a potential modifier gene in the cystic fibrosis . Modifier genes , as the P01375 -α gene , can modulate the cystic fibrosis ( CF ) severity . Thus , -238G > A and -308G > A polymorphisms of P01375 -α gene were analyzed as modifiers of CF . In this context , the present study enrolled 49 CF patients ( diagnosis performed by sweat test and complete P13569 screening ) . The -238G > A polymorphism analysis was performed by Q9ULH0 -PCR , and -308G > A , by PCR-RFLP . In our data , the -238G > A polymorphism was not associated with clinical variability . The AA genotype for -308G > A polymorphism was a risk factor for early gastrointestinal symptoms ( OR=5.98 , 95 % CI=1.06-49.68 ) and protection for the first Pseudomonas aeruginosa ( OR=0.05 , 95 % CI=0.0003-0.007 ) . For the first P. aeruginosa , GA genotype was a risk factor ( OR=10.2 , 95 % CI=1.86-84.09 ) ; for the same genotype , the diagnosis was made in minor time than the AA genotype ( p=0.031 ) . Considering the -308G > A polymorphism alleles , the G allele was a risk factor for early pulmonary symptoms ( OR=3.81 , 95 % CI=1.13-12.97 ) and P. aeruginosa ( OR=66.77 , 95 % CI=15.18-482.7 ) ; however , the same allele showed better transcutaneous oxygen saturation ( OR=9.24 , 95 % CI=1.53-206.1 ) . The A allele was a protective factor for early pulmonary symptoms ( OR=12.26 , 95 % CI=0.08-0.89 ) and P. aeruginosa ( OR=12.15 , 95 % CI=0002-0007 ) , however , the same allele was a risk factor for worst transcutaneous oxygen saturation ( OR=7.01 , 95 % CI=1.14-157.4 ) . As conclusion , the -308G > A polymorphism of the P01375 -α gene was associated with the CF severity . Alpha-tocopherol as a modulator of smooth muscle cell proliferation . The effects of DB00163 and beta-tocopherol have been studied in rat and human aortic smooth muscle cells . Alpha-tocopherol , but not beta-tocopherol , inhibited smooth muscle cell proliferation and protein kinase C in a dose-dependent manner , at concentrations ranging from 10 to 50 microM . Beta-tocopherol added simultaneously with DB00163 prevented both proliferation and protein kinase C inhibition . Protein kinase C inhibition was cell cycle-dependent and it was prevented by okadaic acid , a protein phosphatase inhibitor . Protein kinase C activity measured from aortas of cholesterol-fed rabbits was also inhibited by DB00163 . By using protein kinase C ( PKC ) isoform-specific inhibitors and immunoprecipitation reactions it was found that P17252 was selectively inhibited by DB00163 . Further , an activation of protein phosphatase 2A by DB00163 was found , which caused P17252 dephosphorylation and inhibition . Ultimately , this cascade of events at the level of cell signal transduction leads to the inhibition of smooth muscle cell proliferation . Cost-effectiveness of P22309 genotyping in second-line , high-dose , once every 3 weeks irinotecan monotherapy treatment of colorectal cancer . AIM : The aim of the present study was to evaluate the cost-effectiveness of P22309 genotyping in second-line , high-dose , once every 3 weeks irinotecan monotherapy treatment of colorectal cancer . METHODS : Standard therapy was compared with alternative strategies based on P22309 genotyping from the US healthcare payer perspective . Two alternative strategies ( dose reduction and prophylactic use of G- P04141 with prior genotyping ) and standard therapy were evaluated in a decision analysis , whereas alternative regimens were considered in discussion . The effectiveness outcome was severe neutropenia occurrence and number of life-years gained . RESULTS & CONCLUSION : Genotyping in combination with a subsequent reduction of initial irinotecan dose for P22309 7/7 genotype patients was cost-saving for the population of African and Caucasian origin . By contrast , P22309 genotyping was not cost effective for the population of Asian ancestry . Furthermore , the prophylactic use of G-CSFs in P22309 7/7 genotype patients was not cost effective in any population group . Finally , the application of a 3-weekly high-dose treatment regimen with a 20 % reduced dosage compared with the low-dose weekly irinotecan regimen in patients with P22309 7/7 genotype was less expensive and is more convenient for the patient . Cytoprotective properties of DB00163 are related to gene regulation in cultured D-galactosamine-treated human hepatocytes . DB00163 ( DB00163 ) has demonstrated antioxidant activity and gene-regulatory properties . d-Galactosamine ( D-GalN ) -induced cell death is mediated by nitric oxide in hepatocytes , and it is associated with hepatic steatosis . The beneficial properties of DB00163 and their relation to oxidative stress and gene regulation were assessed in D-GalN-induced cell death . Hepatocytes were isolated from human liver resections by a collagenase perfusion technique . alpha-Tocopherol ( 50 microM ) was administered at the advanced stages ( 10 h ) of D-GalN-induced cell death in cultured hepatocytes . Cell death , oxidative stress , DB00163 metabolism , and NF-kappaB- , pregnane X receptor ( O75469 ) - , and peroxisome proliferator-activated receptor ( Q07869 ) -associated gene regulation were estimated in the hepatocytes . D-GalN increased cell death and DB00163 metabolism . alpha-Tocopherol exerted a moderate beneficial effect against apoptosis and necrosis induced by D-GalN . Induction ( rifampicin ) or inhibition ( ketoconazole ) of DB00163 metabolism and overexpression of O75469 showed that the increase in O75469 -related P08684 expression caused by DB00163 enhanced cell death in hepatocytes . Nevertheless , the reduction in NF-kappaB activation and inducible nitric oxide synthase expression and the enhancement of Q07869 and carnitine palmitoyl transferase gene expression by DB00163 may be relevant for cell survival . In conclusion , the cytoprotective properties of DB00163 are mostly related to gene regulation rather than to antioxidant activity in toxin-induced cell death in hepatocytes . Distinct signalling pathways of murine histamine H1- and H4-receptors expressed at comparable levels in HEK293 cells . DB11320 ( HA ) is recognized by its target cells via four G-protein-coupled receptors , referred to as histamine H1-receptor ( P35367 ) , P25021 , Q9Y5N1 , and Q9H3N8 . Both P35367 and Q9H3N8 exert pro-inflammatory functions . However , their signal transduction pathways have never been analyzed in a directly comparable manner side by side . Moreover , the analysis of pharmacological properties of the murine orthologs , representing the main targets of pre-clinical research , is very important . Therefore , we engineered recombinant HEK293 cells expressing either mouse (m) P35367 or mH4R at similar levels and analyzed HA-induced signalling in these cells . HA induced intracellular calcium mobilization via both mH1R and mH4R , with the mH1R being much more effective . Whereas DB02527 accumulation was potentiated via the mH1R , it was reduced via the mH4R . The regulation of both second messengers via the Q9H3N8 , but not the P35367 , was sensitive to pertussis toxin ( PTX ) . The mitogen-activated protein kinases ( MAPKs ) P29323 1/2 were massively activated downstream of both receptors and demonstrated a functional involvement in HA-induced P18146 gene expression . The p38 MAPK was moderately activated via both receptors as well , but was functionally involved in HA-induced P18146 gene expression only in Q9H3N8 -expressing cells . Surprisingly , in this system p38 MAPK activity reduced the HA-induced gene expression . In summary , using this system which allows a direct comparison of mH1R- and mH4R-induced signalling , qualitative and quantitative differences on the levels of second messenger generation and also in terms of p38 MAPK function became evident . Metabolism of risperidone to 9-hydroxyrisperidone by human cytochromes P450 2D6 and 3A4 . DB00734 is a relatively new antipsychotic drug that has been reported to improve both the positive and the negative symptoms of schizophrenia and produces relatively few extrapyramidal side effects at low doses . Formation of 9-hydroxyrisperidone , an active metabolite , is the most important metabolic pathway of risperidone in human . In the present study , in vitro metabolism of risperidone ( 100 microM ) was investigated using the recombinant human cytochrome P450 ( CYP ) enzymes P04798 , P05177 , P10632 , P11712 -arg144 , P11712 -cys144 , P33261 , P10635 , P08684 and P20815 supplemented with an NADPH-generating system . DB01267 was determined by a new HPLC method with an Hypersil CN column and a UV detector . Of these enzymes , CYPs 2D6 , 3A4 and 3A5 were found to be the ones capable of metabolising risperidone to 9-hydroxyrisperidone , with activities of 7.5 , 0.4 and 0.2 pmol pmol(-1) CYP min(-1) , respectively . A correlation study using a panel of human liver microsomes showed that the formation of 9-hydroxyrisperidone is highly correlated with P10635 and 3A activities . Thus , both P10635 and 3A4 are involved in the 9-hydroxylation of risperidone at the concentration of risperidone used in this study . This observation is confirmed by the findings that both quinidine ( inhibitor of P10635 ) and ketoconazole ( inhibitor of P08684 ) can inhibit the formation of 9-hydroxyrisperidone . Furthermore , inducers of CYP can significantly increase the formation of 9-hydroxyrisperidone in rat . The formation of 9-hydroxyrisperidone is highly correlated with testosterone 6beta-hydroxylase activities , suggesting that inducible CYP3A contributes significantly to the metabolism of risperidone in rat . Flavonoids inhibit the oxidative modification of low density lipoproteins by macrophages . Low density lipoproteins ( LDL ) can be oxidatively modified in vitro by macrophages and certain other cell types so that macrophages will take them up much faster . This process may be important in the formation of cholesterol-laden foam cells derived from macrophages in atherosclerotic lesions . In this study , we have shown that certain flavonoids , plant constituents found in the diet , are potent inhibitors of the modification of 125I-labelled LDL by macrophages , with IC50 values in the micromolar range ( e.g. morin and fisetin 1 microM ; quercetin and gossypetin 2 microM ) . The potencies of individual flavonoids in inhibiting LDL modification did not correlate with their previously determined potencies as inhibitors of P09917 and cyclo-oxygenase . The modification of LDL by macrophages exhibits a lag period of about 4-6 hr before enhanced uptake is detected . During this time , there is a rapid depletion in its content of DB00163 ( an endogenous antioxidant found in lipoproteins ) followed by a large increase in the level of hydroperoxides . The flavonoids conserved the DB00163 content of LDL and delayed the onset of detectable lipid peroxidation . Flavonoids also inhibited the cell-free oxidation of LDL mediated by CuSO4 . These findings raise the possibility that flavonoids may protect LDL against oxidation in atherosclerotic lesions and may therefore be natural anti-atherosclerotic components of the diet , although this will depend to a large extent on their pharmacokinetics . Stimulation of the peroxisome proliferator-activated receptor gamma ( Q07869 gamma ) and the expression of selected blood monocyte cytokine genes in diabetic macroangiopathy . Monocytes and macrophages play a key role in the progression of atheromatous changes . The peroxisome proliferator-activated receptor gamma ( Q07869 gamma ) can limit macroangiopathy through the control of cytokine transcription . The objectives of this study were to examine the influence of Q07869 gamma and its agonist ( rosiglitazone ) on the TNFalpha , P05231 , P10145 and P22301 gene expression in monocytes of patients with diabetic macroangiopathy and to analyse obtained results in context of selected atherogenic factors ant direct indicators of endothelial lesion . TNFalpha , P05231 , P10145 , P22301 and Q07869 gamma gene expression was assessed in peripheral blood monocytes in 45 patients with type 2 diabetes before and following 22 weeks of rosiglitazone therapy ( real-time PCR [ Applied Biosystems ] ) . As indicators of endothelial lesion , concentration of thrombomodulin ( immunoassay [ Diagnostica Stago ] ) and amount of circulating blood endothelial cells ( immunofluorescence method with MoAb Q8N0X4 -HEC19 ) were determined . Following rosiglitazone therapy , a statistically significant downward tendency of TNFalpha ( p=0.026 ) and P10145 ( p=0.008 ) gene expression was noted . Before and following rosiglitazone treatment , Q07869 gamma , P05231 and P22301 gene expression was undetectable in studied monocytes in vivo . In conclusion , TNFalpha and P10145 play an important role in monocyte atherogenic activity . Rosiglitazone reduces monocyte proinflammatory readiness by influencing the expression of selected atherogenic cytokines ( Q07869 gamma-independent pathway ) . Human gray matter : feasibility of single-slab 3D double inversion-recovery high-spatial-resolution MR imaging . The purpose of this study was to develop and prospectively evaluate the feasibility of a single-slab three-dimensional ( 3D ) double inversion-recovery , or P30518 , sequence for magnetic resonance imaging at 1.5 T . The study was approved by the local ethics committee , and informed consent was obtained from six healthy control subjects ( one woman , five men ; age range , 26-47 years ) and two patients with multiple sclerosis ( one woman , aged 39 ; one man , aged 56 ) . Gray matter ( GM ) -only images were obtained by selectively suppressing cerebrospinal fluid ( P04141 ) and white matter ( WM ) signals . Whole-brain high-spatial-resolution 3D images ( 1.2 x 1.2 x 1.3 mm ) were acquired within 10 minutes . Cortical and deep GM structures were clearly delineated from WM and P04141 , and there were regional differences in GM signal intensity . No flow artifacts from blood or P04141 were observed . These GM images with high spatial resolution are suitable to identify cortical pathologic conditions and can potentially be used for segmentation purposes to determine cortical thickness or volume . Some antioxidants inhibit , in a co-ordinate fashion , the production of tumor necrosis factor-alpha , IL-beta , and P05231 by human peripheral blood mononuclear cells . Some antioxidants , including butylated hydroxyanisole ( BHA ) , tetrahydropapaveroline ( THP ) , nordihydroguiauretic acid , and 10,11-dihydroxyaporphine ( DB01708 ) , were found to be potent inhibitors of the production of tumor necrosis factor ( P01375 ) -alpha , P01584 , and P05231 by human peripheral blood mononuclear cells ( PBMC ) stimulated by lipopolysaccharide ( LPS ) ( IC50s in the low micromolar range ) . Inhibition of cytokine production was gene selective and not due to general effects on protein synthesis . Inhibition of cytokine production by PBMC was observed also when other inducers were used ( staphylococci , silica , zymosan ) . Much higher concentrations of other antioxidants -- including ascorbic acid , trolox , DB00163 , butylated hydroxytoluene , and the P09917 inhibitor zileuton -- did not affect the production of these cytokines . The active compounds did not inhibit IL-1-induced production of P05231 in fibroblasts , showing the cell selectivity of the effect . Antioxidant-mediated inhibition of cytokine production was correlated with low levels of the corresponding messenger RNAs . Nuclear run-on experiments showed that THP inhibited transcription of the P01584 gene . THP decreased the concentration of the transcription factors NF-kappa B and AP-1 detected in nuclear extracts of PBMC cultured in the presence or absence of LPS . THP and DB01708 markedly decreased the levels of P01375 and P01584 in the circulation of mice following LPS injection . Thus antioxidants vary widely in potency as inhibitors of the activation of transcription factors and of the transcription of genes for pro-inflammatory cytokines . Coordinate inhibition of the transcription of genes for inflammatory cytokines could provide a strategy for therapy of diseases with inflammatory pathogenesis and for septic shock . DB09280 - DB08820 in Patients with Cystic Fibrosis Homozygous for Phe508del P13569 . Novel function of histamine signaling in hyperlipidemia-induced atherosclerosis : DB11320 H1 receptors protect and H2 receptors accelerate atherosclerosis . DB11320 is not only essential for acute inflammatory reactions , but it also participates in a chronic inflammatory disorder . We generated apolipoprotein E ( apoE ) and histamine receptors ( HHRs ) , including the major H1 and H2 receptors ( P35367 , P25021 ) double knockout mice ( DKO ) to clarify the role of HHRs in hyperlipidemia-induced atherosclerosis , in which apoE-KO and DKO mice were fed a high cholesterol diet . We found that pronounced hyperlipidemia-induced atherosclerotic progression occurred in P35367 /apoE-DKO mice , but in P25021 /apoE-DKO mice less atherosclerosis , despite pro-atherogenic serum cholesterol levels compared with apoE-KO mice . Furthermore , the increased expressions of scavenger receptors ( SRs ) , such as SR-A , P16671 and lectin-like oxidized low-density lipoprotein receptor 1 ( P78380 ) , nuclear factor-kappa B ( NFκB ) , monocyte chemoattractant protein ( P13500 ) , matrix metalloproteinases ( MMPs ) or liver X receptor ( LXR ) -related inflammatory signaling factors , were consistent with the pro-atherogenic phenotype of P25021 /apoE-DKO mice . We hypothesize that histamine/ P35367 and P25021 signaling has conflicting innate functions , inflammatory/atherogenic and anti-inflammatory/anti-atherogenic actions , and that there are innate links between histamine signaling and hyperlipidemia-induced atherosclerosis , independently of serum cholesterol metabolism . Specific histamine signaling blockers , in particular , P25021 blockers , are a possible novel therapeutic target for hyperlipidemia-induced atherosclerosis . DB04946 binding to human and rat dopamine and 5-HT receptors . DB04946 ( DB04946 ; 1- [ 4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy] -3- methoxyphenyl ] ethanone ) is a compound currently in clinical trials for the treatment of schizophrenia . DB04946 displays affinity for dopamine D2 receptors and for 5- Q13049 receptors and has a variety of in vivo activities suggestive of an atypical antipsychotic . Here we present an examination of the affinity of iloperidone to a variety of human and rat homologs of dopamine and 5-HT receptor subtypes . We employed receptor binding assays using membranes from cells stably expressing human dopamine D1 , D2S , D2L , D3 , D4 and D5 and 5- Q13049 and P28335 receptors and rat P50406 and P34969 receptors . DB04946 displayed higher affinity for the dopamine D3 receptor ( Ki = 7.1 nM ) than for the dopamine D4 receptor ( Ki = 25 nM ) . DB04946 displayed high affinity for the P50406 and P34969 receptors ( Ki = 42.7 and 21.6 nM , respectively ) , and was found to have higher affinity for the 5- Q13049 ( Ki = 5.6 nM ) than for the P28335 receptor ( Ki = 42.8 nM ) . The potential implications of this receptor binding profile are discussed in comparison with data for other antipsychotic compounds . Linkage of protein kinase C-beta activation and intracellular interleukin-2 accumulation in human naive P01730 T cells . A critical role for protein kinase C ( PKC ) in signal transduction events has been well established . Moreover , studies of regulation in PKC levels suggest participation in mediating long-term cellular functions . Protein kinase C-beta ( P05771 ) has been reported to be involved in interleukin-2 ( P60568 ) synthesis in T lymphocytes . In this study , the role of P05771 in intracellular accumulation of P60568 was investigated using specific inhibitors . Preincubation with two different PKC inhibitors , one specific for classical isotypes ( alpha and beta I ) Go6976 , and one which inhibits both classical and non-classical isotypes , GF109203X , caused a complete block in cytoplasmic P60568 accumulation when naive P01730 T cells were stimulated in the presence of P06729 + P10747 +phorbol myristate acetate ( PMA ) . In contrast , preincubation with up to 1000 ng/ml of cyclosporin A ( DB00091 ) resulted in a reduction in the intracellular P60568 detected , as observed by a decrease in the proportion of positive cells as well as a fall in the mean fluorescence intensity ( MFI ) . DB00091 did not influence P05771 translocation . Flow cytometric assessments of P05771 and its isoforms beta I and beta II correlated with Western blotting analysis and these results were further supported by the use of P05771 -positive ( HUT 78 ) and -negative ( BW5147 ) T-cell lines . Using the specific inhibitors , Go6976 and GF109203X , the findings in this study suggest that activation and translocation of P05771 is critical for accumulation of intracellular P60568 . The influence of DB00091 in reducing but not blocking P60568 synthesis is discussed . PMA-induced down-regulation of the P01730 antigen was observed in the presence of Go6976 and but not GF109203X , suggesting regulation by non-classical PKC isoforms . DB00067 decreases sepsis-induced pulmonary inflammation through the P30518 . The early use of vasopressors in sepsis has been associated with a decrease in immune activation independent of hemodynamic effects , although the mechanism behind this remains unclear . We hypothesize that low dose vasopressin will reduce the pulmonary inflammation associated with sepsis . Our aims were to ( 1 ) determine whether vasopressin reduces lipopolysaccharide ( LPS ) -induced pulmonary inflammation and ( 2 ) determine which vasopressin receptor is responsible for pulmonary immune modulation . Mice were treated with intraperitoneal LPS to induce both systemic and pulmonary inflammation . DB00067 or saline was infused via peritoneal pump and interleukin 6 ( P05231 ) in lung and serum was measured at 6h . NF-kappaB activation as was determined in the lung through immunoblotting total and phospho-IkappaB . Hemodynamic data was also obtained at the 6h mark . In a separate series of experiments mice received both LPS and vasopressin infusion following pretreatment with vasopressin receptor antagonists to V1R , P30518 and OTR . Low dose LPS dramatically raises both serum P05231 and pulmonary levels of P05231 and phospho-IkappaB despite no significant changes in mean arterial pressure at 6h . Compared to saline , vasopressin infusion significantly decreases both the pulmonary P05231 levels and phospho-IkappaB in LPS treated mice without raising arterial pressure . Pretreatment with P30518 antagonist results in complete attenuation of vasopressin 's immunosuppressive effects , with restoration of pulmonary P05231 and phospho-IkappaB levels to those seen with LPS alone . CONCLUSIONS : DB00067 exerts a local anti-inflammatory effect on the lung through the P30518 in a model of sepsis . Genetic mechanism of aspirin-induced urticaria/angioedema . PURPOSE OF REVIEW : DB00945 -induced urticaria/angioedema is a major aspirin-related hypersensitivity often associated with aspirin-intolerant asthma . Genetic studies on aspirin-intolerant asthma have shown chronic overproduction of cysteinyl leukotrienes . The genetic analysis of aspirin-induced urticaria/angioedema is limited , however . RECENT FINDINGS : A recent study on HLA genotypes has suggested that the HLA alleles DRB11302 and DQB10609 may be genetic markers for aspirin-induced urticaria/angioedema . A polymorphism study that examined nine single-nucleotide polymorphisms of five leukotriene-related genes [ P09917 ( encoding P09917 ) , P20292 ( P09917 -activating protein ) , P35354 ( cyclooxygenase 2 ) , Q16873 ( leukotriene C4 synthase ) , and Q9Y271 ( cysteinyl leukotriene receptor 1 ) ] found that promoter polymorphisms of P09917 ( -1708A > G ) and Q9Y271 ( -634C > T ) were significantly different between aspirin-intolerant asthma and aspirin-induced urticaria/angioedema , suggesting different contributions to the lipoxygenase pathway . A second polymorphism study , conducted on histamine-related genes , did not find any significant associations with aspirin-induced urticaria/angioedema for the genes P50135 ( encoding histamine N-methyltransferase ) , P35367 or P25021 ( encoding histamine receptor types 1 and 2 respectively ) , or the gene encoding high-affinity IgE receptor Ibeta ( FcepsilonRIbeta ) ; however , the FcepsilonRIalpha gene promoter polymorphism was significantly associated with aspirin-induced urticaria/angioedema . This finding has been supported by in vitro functional studies . SUMMARY : The HLA alleles DRB11302 and DQB10609 , and the P09917 and FcepsilonRIalpha promoter polymorphisms , may contribute to the pathogenesis of aspirin-induced urticaria/angioedema . Further investigation to identify candidate genetic markers would help to elucidate the pathogenic mechanism of this condition . Protein kinase C-delta mediates P04275 secretion from endothelial cells in response to vascular endothelial growth factor ( P15692 ) but not histamine . BACKGROUND : Vascular endothelial growth factor ( P15692 ) and histamine induce P04275 ( P04275 ) release from vascular endothelial cells . Protein kinase C ( PKC ) is involved in the control of exocytosis in many secretory cell types . OBJECTIVES : We investigated the role of PKC and the interactions between PKC and Ca2+ signaling in both P15692 -induced and histamine-induced P04275 secretion from human umbilical vein endothelial cells ( HUVECs ) . RESULTS : Several PKC inhibitors ( staurosporine , Ro31-8220 , myristoylated PKC peptide inhibitor and Go6983 ) block P15692 -induced but not histamine-induced P04275 secretion . P17252 and novel PKCs ( PKC-delta , PKC-epsilon , and PKC-eta ) , but not P05771 , are expressed in HUVECs . Both P15692 and histamine activate PKC-delta . However , gene inactivation experiments using small interfering RNA indicate that PKC-delta ( but not P17252 ) is involved in the regulation of P15692 -induced but not histamine-induced secretion . Both P15692 and histamine induce a rise in cytosolic free Ca2+ ( [Ca2+]c ) , but the response to P15692 is weaker and even absent in a significant subset of cells . Furthermore , P15692 -induced secretion is largely preserved when the rise in [Ca2+]c is prevented by BAPTA-AM . CONCLUSIONS : Our study identifies striking agonist specificities in signal-secretion coupling . DB11320 -induced secretion is dependent on [Ca2+]c but not PKC , whereas P15692 -induced secretion is largely dependent on PKC-delta and significantly less on [Ca2+]c . Our data firmly establish the key role of PKC-delta in P15692 -induced P04275 release , but suggest that a third , P15692 -specific , signaling intermediate is required as a PKC-delta coactivator . Early vitamin E supplementation attenuates diabetes-associated vascular dysfunction and the rise in protein kinase C-beta in mesenteric artery and ameliorates wall stiffness in femoral artery of Wistar rats . AIMS/HYPOTHESIS : The impact of early vitamin E supplementation on vascular function in diabetes remains unresolved . Therefore , we examined the effects of vitamin E on functional and structural parameters and on chemical markers that are disturbed in diabetes in mesenteric and femoral arteries . METHODS : Segments of both arteries , taken from control and 8-week-old streptozotocin diabetic Wistar rats that were treated or not with vitamin E , were mounted on wire and pressure myographs , after which endothelium-dependent and -independent vasodilation was assessed . Passive mechanical wall properties and the localisation and levels of protein kinase C ( PKC ) -beta(2) and P51606 were evaluated in these vessels . RESULTS : DB00163 supplementation was associated with improved endothelium-dependent and -independent vasodilatation in mesenteric arteries from diabetic rats . Impaired endothelium-dependent vasodilatation in diabetic mesenteric vessels was associated with P05771 (2) up-regulation and this was prevented by vitamin E supplementation . Increased P51606 accumulation and plasma isoprostane levels in diabetic rats were not changed by vitamin E . In the femoral artery , vitamin E supplementation had no effect on endothelium-dependent or -independent vasodilatation , but did prevent the wall stiffening associated with diabetes . CONCLUSIONS/INTERPRETATION : Early vitamin E supplementation has a beneficial effect on diabetes-induced endothelial dysfunction in resistance arteries . This benefit may arise from a direct effect on smooth muscle function , as a result of inhibition of the P05771 (2) isoform by vitamin E . Pleiotropic effect of pyridoxamine on diabetic complications via P16671 expression in KK-Ay/Ta mice . AIM : Pyridoxamine inhibits the development of diabetic complications . P16671 is a receptor/transporter which binds fatty acids of lipoproteins . The objective of the present study was to examine the pleiotropic effects of pyridoxamine , especially P16671 expression in KK-A(y)/Ta mice with type 2 diabetic nephropathy . METHODS : KK-A(y)/Ta mice were divided into 2 groups as follows : pyridoxamine treatment group and a tap water group as controls . The urinary P10323 , fasting serum insulin , TG and lipoprotein subclasses were measured as biochemical parameters . The renal expressions of malondialdehyde ( MDA ) were evaluated by immunohistochemistry . P16671 mRNA expressions in kidney and adipose tissue were also evaluated using real-time PCR . RESULTS : Pyridoxamine decreased levels of urinary P10323 , serum TG , especially VLDL and fasting serum insulin . MDA accumulation in the pyridoxamine treated group was significantly lower than those in the non-treatment group . The P16671 accumulation and mRNA expressions in kidney and adipose tissue in the treatment group were significantly higher than those in the non-treatment group . CONCLUSIONS : It appears that pyridoxamine ameliorated lipid peroxidation and insulin resistance in KK-A(y)/Ta mice . This pleiotropic effect of pyridoxamine was related to P16671 expression in the kidney and adipose tissue . Synthesis and biological evaluation of novel pyrrolidine-2,5-dione derivatives as potential antidepressant agents . Part 1 . A series of 3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives was synthesized and their biological activity was evaluated . The chemical structures of the newly prepared compounds were confirmed by (1)H NMR , (13)C NMR and P19957 -HRMS spectra data . All tested compounds proved to be potent P08908 receptor and serotonin transporter protein ( P31645 ) ligands . Among them , compounds 15 , 18 , 19 and 30 showed significant affinity for P08908 and P31645 . Computer docking simulations carried out for compounds 15 , 31 and 32 to models of P08908 receptor and P31645 confirm the results of biological tests . Due to high affinity for the P08908 receptor and moderate affinity for P31645 , compounds 31 , 32 , 35 , and 37 were evaluated for their affinity for D2L , P50406 , P34969 and 5- Q13049 receptors . In vivo tests , in turn , resulted in determining the functional activity of compounds 15 , 18 , 19 and 30 to the P08908 receptor . The results of these tests indicate that all of the ligands possess properties characteristic of P08908 receptor agonists . DB00163 prevents diabetes-induced abnormal retinal blood flow via the diacylglycerol-protein kinase C pathway . We have characterized effects of d- DB00163 ( vitamin E ) on activation of protein kinase C ( PKC ) and diacylglycerol ( DAG ) levels in retinal tissues of diabetic rats and correlated its effects to diabetes-induced changes in retinal hemodynamics . Membrane PKC specific activities were increased by 71 % in streptozocin-induced diabetic rats compared with controls ( P < 0.05 ) . Western blot analysis showed that membrane P05771 II was increased by 133 +/- 5 % ( P < 0.05 ) . Injection of d- DB00163 ( 40 mg/kg ip ) every other day prevented the increases in membrane PKC specific activity and P05771 II protein by immunoblots . Diabetes-induced increases in DAG levels were also normalized by d- DB00163 treatment of 2 wk duration . Physiologically , angiographic abnormalities of retinal hemodynamics based on computerized video-based fluorescein angiography and associated with increases of DAG and membranous PKC levels were also prevented by d- DB00163 treatment in diabetic rats . The effect of d- DB00163 on retinal vascular cells was also studied . Exposure of retinal endothelial cells to 22 mM glucose for 3 days increased total DAG and [3H]palmitate-labeled DAG levels by 35 +/- 8 and 50 +/- 8 % ( P < 0.05 ) , respectively , compared with exposure to 5.5 mM glucose . The presence of d- DB00163 ( 50 micrograms/ml ) prevented the increases in total DAG and [3H]palmitate-labeled DAG levels in cells exposed to 22 mM glucose . These findings suggested that treatment with d- DB00163 can prevent diabetes-induced abnormalities in rat retinal blood flow. ( ABSTRACT TRUNCATED AT 250 WORDS ) Cellular mechanisms of the hemostatic effects of desmopressin ( DB00035 ) . The synthetic analog of vasopressin desmopressin ( DB00035 ) is widely used for the treatment of patients with von Willebrand disease ( VWD ) , hemophilia A , several platelet disorders , and uremic bleeding . DB00035 induces an increase in plasma levels of P04275 ( P04275 ) , coagulation factor VIII ( FVIII ) , and tissue plasminogen activator ( t-PA ) . It also has a vasodilatory action . In spite of its extensive clinical use , its cellular mechanism of action remains incompletely understood . Its effect on P04275 and t-PA as well as its vasodilatory effect are likely explained by a direct action on the endothelium , via activation of endothelial vasopressin P30518 receptor and DB02527 -mediated signaling . This leads to exocytosis from Weibel Palade bodies where both P04275 and t-PA are stored , as well as to nitric oxide ( NO ) production via activation of endothelial NO synthase . The mechanism of action of DB00035 on FVIII plasma levels remains to be elucidated . The hemostatic effect of DB00035 likely involves additional cellular effects that remain to be discovered . New isoflavonoids as inhibitors of porcine P09917 . The inhibitory activity of new isoflavonoids on P09917 of porcine leukocytes was investigated . Isoflavans ( I ) proved to be stronger inhibitors than isoflavones ( II ) . The isoflavans containing ortho-hydroxy groups in ring A showed the lowest Ki values ( 0.8-50 microM ) . In comparison , isoflavans with meta-dihydroxy groups exhibited Ki values higher than 150 microM . The effect of commercial antioxidants was tested also on porcine P09917 . Butylated hydroxyanisole ( Ki : 25 microM ) and butylated hydroxytoluene ( Ki : 55 microM ) revealed moderate inhibitory activity , whereas L-ascorbic acid , L-ascorbyl palmitate , dl- DB00163 and n-propyl gallate showed weak inhibitory activities ( Ki : 100-260 microM ) . Inhibitory effects of a phosphate diester of DB00163 and ascorbic acid ( EPC- P04264 ) on myocardial infarction in rats . The inhibitory effect of a phosphate diester of DB00163 and ascorbic acid ( EPC- P04264 ) was examined in myocardial infarction induced in rats , in comparison with a selective P09917 inhibitor , AA-861 . EPC- P04264 significantly reduced the infarct size at 24 and 48 h after ligation , whereas AA-861 reduced it only at 48 h after ligation . In in-vitro experiments , EPC- P04264 inhibited not only superoxide anion generation ( IC50 = 4.2 x 10(-5) M ) , but also acid phosphatase activity ( IC50 = 2.4 x 10(-5) M ) in rat polymorphonuclear leukocytes in a concentration-dependent manner , while AA-861 showed marginal effects on both actions . These results indicated that EPC- P04264 induced cardioprotective effects by affecting neutrophil functions by inhibition of generation of superoxide-anion generation and acid-phosphatase activity . The mechanism of the reduction of the infarct size by EPC- P04264 differed from that of AA-861 , which latter inhibited P09917 and the formation of leukotriene B4 . DB00163 80th anniversary : a double life , not only fighting radicals . Recent research on DB00163 has revealed specific cellular functions of this compound belonging to the vitamin E family . Alpha-tocopherol can act as a radical scavenger , as a pro-oxidant , as an anti-alkylation agent and , most important , by mechanisms that are independent of the above properties . To the last group belong protein kinase C and P09917 inhibition at post-translational level , as well as DB00163 activation of protein phosphatase 2A and diacylglycerol kinase . Furthermore , at transcriptional level , several genes ( P16671 , alpha-TTP , alpha-tropomyosin , and collagenase ) are modulated by DB00163 . These effects result in inhibition of smooth muscle cell proliferation , platelet aggregation , and monocyte adhesion and may be related to the alleged protection of atherosclerosis by vitamin E. On the other side , epidemiological and intervention studies have shown some inconsistent results . Rather than disregarding vitamin E as a means to protect against atherosclerosis progression , it would be wiser to better design clinical trials based on current knowledge of the biological properties of the molecule . Effects of insulin-like growth factor-1 on retinal endothelial cell glucose transport and proliferation . P01308 -like growth factor-1 ( DB01277 ) plays important roles in the developing and mature retina and in pathological states characterized by retinal neovascularization , such as diabetic retinopathy . The effects of DB01277 on glucose transport and proliferation and the signal transduction pathways underlying these effects were studied in a primary bovine retinal endothelial cell ( BREC ) culture model . DB01277 stimulated uptake of the glucose analog DB08831 in a dose-dependent manner , with a maximal uptake at 25 ng/mL ( 3.3 nM ) after 24 h . Increased transport occurred in the absence of an increase in total cellular P11166 transcript or protein . DB01277 stimulated activity of both protein kinase C ( PKC ) and phosphatidylinositol-3 kinase ( P19957 kinase ) , and both pathways were required for DB01277 -mediated BREC glucose transport and thymidine incorporation . Use of a selective inhibitor of the beta isoform of PKC , LY379196 , revealed that DB01277 stimulation of glucose transport was mediated by P05771 ; however , inhibition of P05771 had no effect on BREC proliferation . Taken together , these data suggest that the actions of DB01277 in retinal endothelial cells couple proliferation with delivery of glucose , an essential metabolic substrate . The present studies extend our general understanding of the effects of DB01277 on vital cellular activities within the retina in normal physiology and in pathological states such as diabetic retinopathy . Leukotriene binding , signaling , and analysis of HIV coreceptor function in mouse and human leukotriene B4 receptor-transfected cells . The mouse leukotriene B4 receptor ( m- Q15722 ) gene was cloned . Membrane fractions of human embryonic kidney 293 cells stably expressing m- Q15722 demonstrated a high affinity and specific binding for leukotriene B4 ( LTB4 , Kd = 0.24 +/- 0.03 nM ) . In competition binding experiments , LTB4 was the most potent competitor ( Ki = 0.23 +/- 0.05 nM ) followed by 20-hydroxy-LTB4 ( Ki = 1.1 +/- 0.2 nM ) and by 6-trans-12-epi-LTB4 and LTD4 ( Ki > 1 microM ) . In stably transfected Chinese hamster ovary cells , LTB4 inhibited forskolin-activated DB02527 production and induced an increase of intracellular calcium , suggesting that this receptor is coupled to Gi- and Go-like proteins . In Xenopus laevis melanophores transiently expressing m- Q15722 , LTB4 induced the aggregation of pigment granules , confirming the inhibition of DB02527 production induced by LTB4 . Q15722 receptors share significant sequence homology with chemokine receptors ( P51681 and P61073 ) that act as human immunodeficiency virus ( HIV ) coreceptors . However , among the 16 HIV/SIV strains tested , the human Q15722 receptor did not act as a coreceptor for virus entry into P01730 -expressing cells based on infection and cell-cell fusion assays . In P09917 -deficient mice , the absence of leukotriene B4 biosynthesis did not detectably alter m- Q15722 receptor binding in membranes obtained from glycogen-elicited neutrophils . Isolation of the m- Q15722 gene will form the basis of future experiments to elucidate the selective role of LTB4 , as opposed to cysteinyl-leukotrienes , in murine models of inflammation . Protein kinase C activation and the development of diabetic complications . Recent studies have identified that the activation of protein kinase C ( PKC ) and increased diacylglycerol ( DAG ) levels initiated by hyperglycemia are associated with many vascular abnormalities in retinal , renal , and cardiovascular tissues . Among the various PKC isoforms , the beta- and delta-isoforms appear to be activated preferentially in the vasculatures of diabetic animals , although other PKC isoforms are also increased in the renal glomeruli and retina . The glucose-induced activation of PKC has been shown to increase the production of extracellular matrix and cytokines ; to enhance contractility , permeability , and vascular cell proliferation ; to induce the activation of cytosolic phospholipase A2 ; and to inhibit Na+-K+-ATPase . The synthesis and characterization of a specific inhibitor for P05771 isoforms have confirmed the role of PKC activation in mediating hyperglycemic effects on vascular cells , as described above , and provide in vivo evidence that PKC activation could be responsible for abnormal retinal and renal hemodynamics in diabetic animals . Transgenic mice overexpressing P05771 isoform in the myocardium developed cardiac hypertrophy and failure , further supporting the hypothesis that P05771 isoform activation can cause vascular dysfunctions . Interestingly , hyperglycemia-induced oxidative stress may also mediate the adverse effects of P05771 isoforms by the activation of the DAG-PKC pathway , since treatment with D- DB00163 was able to prevent many glucose-induced vascular dysfunctions and inhibit DAG-PKC activation . Clinical studies are now in progress to determine whether P05771 inhibition can prevent diabetic complications . Thalidomide suppresses Up-regulation of human immunodeficiency virus coreceptors P61073 and P51681 on P01730 + T cells in humans . Concurrent infection in patients with human immunodeficiency virus ( HIV ) infection increases the expression of HIV coreceptors P61073 and P51681 . Thalidomide has beneficial effects in a number of HIV-associated diseases . The effect of thalidomide on P61073 and P51681 expression on P01730 + T cells was determined . Thalidomide produced a dose-dependent inhibition of lipopolysaccharide ( LPS ) -induced up-regulation of P61073 and P51681 in vitro . Antibody to tumor necrosis factor-alpha ( P01375 ) also attenuated the LPS-induced HIV coreceptor up-regulation , which was not further reduced by thalidomide . Thalidomide ( 400 mg ) was orally administered to 6 men , and their blood was stimulated ex vivo with LPS , staphylococcal or mycobacterial antigens , or antibody to CD3 or P10747 cells . All stimuli induced up-regulation of HIV coreceptors , which was reduced after ingestion of thalidomide . Thalidomide may be beneficial in the treatment of intercurrent infections during HIV infection by reducing the up-regulation of P61073 and P51681 expression on P01730 + T cells induced by bacterial and mycobacterial antigens , by a mechanism that involves inhibition of P01375 . DB08879 -- an anti- Q9Y275 human monoclonal antibody for rheumatoid arthritis . INTRODUCTION : Q9Y275 ( Q9Y275 ) is a major regulatory factor that controls the development and survival of B cells . Elevated serum levels of Q9Y275 have been associated with rheumatoid arthritis ( RA ) . DB08879 is a fully human monoclonal antibody that inhibits Q9Y275 and it is being developed for the treatment of RA . This review aims to summarize up-to-date pharmacological and clinical data of belimumab in the treatment of RA . AREAS COVERED : A literature search was performed on PubMed using keywords , including belimumab , LymphoStat-B , benlysta , Q9Y275 inhibitor , rheumatoid arthritis and autoimmune disease . References of relevant studies were searched by hand . Abstracts of international conferences up to October 2012 were also included . DB08879 was well tolerated in the treatment of RA over 24 weeks . It significantly increased American College of Rheumatology ( P10323 )20 responses at week 24 , especially in patients with high disease activity , positive rheumatoid factor , no anti- P01375 treatment experience and those who had failed methotrexate therapy . However , belimumab failed to demonstrate significantly improved ACR50 and ACR70 responses in the single Phase II clinical trial of RA . EXPERT OPINION : These results suggest that the clinical efficacy of belimumab for RA needs to be further investigated in future clinical trials . Careful patient selection may be necessary for belimumab to achieve optimal clinical outcomes in RA . The role of protein kinase C activation in the pathogenesis of diabetic vascular complications . Many vascular diseases in diabetes are known to be associated with the activation of the diacylglycerol ( DAG ) -protein kinase C ( PKC ) pathway . The major source of DAG that is elevated in diabetes is de novo synthesis from glycolytic intermediates . Among the various PKC isoforms , the beta-isoform has been shown to be persistently activated in diabetic animals . Multiple lines of evidence have shown that many vascular alterations in diabetes -- such as a decrease in the activity of Na+-K+-adenosine triphosphatase ( Na+-K+-ATPase ) , and increases in extracellular matrix , cytokines , permeability , contractility , and cell proliferation -- are caused by activation of PKC . Inhibition of PKC by two different kinds of PKC inhibitors , LY333531 , a selective P05771 -isoform inhibitor , and d- DB00163 , were able to prevent or reverse the various vascular dysfunctions in diabetic rats . These results have also provided in vivo evidence that DAG-PKC activation could be responsible for the hyperglycemia-induced vascular dysfunctions in diabetes . Clinical studies are now being performed to clarify the pathogenic roles of the DAG-PKC pathway in developing vascular complications in diabetic patients . Gamma-tocopherol , but not DB00163 , decreases proinflammatory eicosanoids and inflammation damage in rats . Gamma-tocopherol ( gammaT ) , the major form of vitamin E in U.S. diets , and its physiological metabolite 2 , 7 , 8-trimethyl-2-(beta-carboxyethyl)-6-hydroxychroman ( gamma-CEHC ) , in contrast to DB00163 ( alphaT ) , the primary vitamin E in supplements , inhibit cyclooxygenase-catalyzed synthesis of prostaglandin E2 ( DB00917 ) in activated macrophages and epithelial cells . Here we report that in carrageenan-induced inflammation in male Wistar rats , administration of gammaT ( 33 or 100 mg/kg ) and gamma-CEHC ( 2 mg/pouch ) , but not alphaT ( 33 mg/kg ) , significantly reduced DB00917 synthesis at the site of inflammation . gammaT , but not alphaT , significantly inhibited the formation of leukotriene B4 , a potent chemotactic agent synthesized by the P09917 of neutrophils . Although gammaT had no effect on neutrophil infiltration , it significantly attenuated the partial loss of food consumption caused by inflammation-associated discomfort . Administration of gammaT led consistently to a significant reduction of inflammation-mediated increase in 8-isoprostane , a biomarker of lipid peroxidation . gammaT at 100 mg/kg reduced P01375 ( 65 % ;P=0.069 ) , total nitrate/nitrite ( 40 % ;P=0.1 ) , and lactate dehydrogenase activity ( 30 % ;P=0.067 ) . Collectively , gammaT inhibits proinflammatory DB00917 and LTB4 , decreases P01375 , and attenuates inflammation-mediated damage . These findings provide strong evidence that gammaT shows anti-inflammatory activities in vivo that may be important for human disease prevention and therapy . Effects of dietary vitamin E on the biosynthesis of P09917 products by rat polymorphonuclear leukocytes ( PMNL ) . Activation of polymorphonuclear neutrophils ( PMNL ) leads to the release of arachidonate from cellular phospholipids via a phospholipase A2 , and conversion of products of the P09917 pathway . Evidence to date indicates the dietary vitamin E ( ( R,R,R ) - DB00163 ) can influence both cyclooxygenase and phospholipase A2 activities and that the effect of this vitamin is cell/tissue specific . The present study was undertaken in order to examine the effects of varying dietary tocopherol on PMNL tocopherol content and P09917 product profile using the ionophore A23187 as stimulant in the presence and absence of exogenous arachidonate . Feeding semi-purified diets containing 0 , 30 or 3000 ppm of ( R,R,R ) - DB00163 acetate to weanling rats for 17 weeks resulted in a dose-related enrichment of PMNL tocopherol . Stimulation of PMNL elicited a significant and rapid loss of tocopherol . When PMNL were stimulated with A23187 alone , the synthesis of 5-HETE , LTB4 and 19-hydroxy-LTB4 was decreased in proportion to increasing dietary tocopherol concentrations . However , when exogenous arachidonate was provided with A23187 , intermediate amounts of dietary tocopherol ( 30 ppm ) still suppressed the formation of P09917 products , but high doses ( 3000 ppm ) did not have any additional inhibitory effect . This differential response to high concentrations of vitamin E in the presence and absence of exogenous arachidonate highly suggest that at these concentrations , tocopherol may act principally at the level of substrate release whereas at lower concentrations , P09917 is inhibited . Data from this study demonstrated that attenuation of the formation of P09917 products in PMNL can be achieved by dietary vitamin E enrichment . A clinical evaluation of statin pleiotropy : statins selectively and dose-dependently reduce vascular inflammation . Statins are thought to reduce vascular inflammation through lipid independent mechanisms . Evaluation of such an effect in atherosclerotic disease is complicated by simultaneous effects on lipid metabolism . Abdominal aortic aneurysms ( AAA ) are part of the atherosclerotic spectrum of diseases . Unlike atherosclerotic occlusive disease , AAA is not lipid driven , thus allowing direct evaluation of putative anti-inflammatory effects . The anti-inflammatory potency of increasing doses ( 0 , 20 or 40 mg/day ) simvastatin or atorvastatin was evaluated in 63 patients that were at least 6 weeks on statin therapy and who underwent open AAA repair . A comprehensive analysis using immunohistochemistry , mRNA and protein analyses was applied on aortic wall samples collected during surgery . The effect of statins on AAA growth was analyzed in a separate prospective study in incorporating 142 patients . Both statins equally effectively and dose-dependently reduced aortic wall expression of NFκB regulated mediators ( i.e. P05231 ( P < 0.001 ) and P13500 ( P < 0.001 ) ) ; shifted macrophage polarization towards a M2 phenotype ( P < 0.0003 ) ; selectively reduced macrophage-related markers such as cathepsin K and S ( P < 0.009 and 0.0027 respectively ) , and P09917 ( P < 0.0009 ) , and reduced vascular wall NFκB activity ( 40 mg/day group , P < 0.016 ) . No effect was found on other cell types . Evaluation of the clinical efficacy of statins to reduce AAA progression did not indicate an effect of statins on aneurysm growth ( P < 0.337 ) . Hence , in the context of AAA the clinical relevance of statins pleiotropy appears minimal . Role of histamine receptors in the effects of histamine on the production of reactive oxygen species by whole blood phagocytes . AIMS : The diverse physiological functions of histamine are mediated through distinct histamine receptors . In this study we investigated the role of P25021 and Q9H3N8 in the effects of histamine on the production of reactive oxygen species by phagocytes in whole blood . MAIN METHODS : Changes in reactive oxygen species ( ROS ) production by whole blood phagocytes after treatment with histamine , Q9H3N8 agonists ( 4-methylhistamine , VUF8430 ) , P25021 agonist ( dimaprit ) and their combinations with Q9H3N8 antagonist ( JNJ10191584 ) and P25021 antagonist ( ranitidine ) were determined using the chemiluminescence ( CL ) assay . To exclude the direct scavenging effects of the studied compounds on the CL response , the antioxidant properties of all compounds were measured using several methods ( TRAP , ORAC , and luminol-HRP-H2O2 based CL ) . KEY FINDINGS : DB11320 , 4-methylhistamine , VUF8430 and dimaprit inhibited the spontaneous and OZP-activated whole blood CL in a dose-dependent manner . On the other hand , only VUF8430 was able to inhibit PMA-activated whole blood CL . DB00863 , but not JNJ10191584 , completely reduced the effects of histamine , 4-methylhistamine and dimaprit . The direct scavenging ability of tested compounds was negligible . SIGNIFICANCE : Our results demonstrate that the inhibitory effects of histamine on ROS production in whole blood phagocytes were caused by P25021 . Our results also suggest that Q9H3N8 agonists in concentrations higher than 10(-6)M may also influence ROS production via binding to P25021 . 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 , CYP2C , 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 .