interacts_with DB01045?
Effect of dietary NaCl on tyrosine hydroxylase in the superior cervical ganglia of Dahl rats . To investigate the involvement of peripheral catecholamines in the development of Dahl-Iwai salt-sensitive ( Q8IX12 /Eis ) hypertension , we performed immunohistochemical staining of tyrosine hydroxylase ( TH ) in the superior cervical ganglia ( SCG ) of Q8IX12 /Eis rats and Dahl-Iwai salt-resistant ( P30518 /Eis ) rats , and in situ hybridization histochemistry for demonstration of TH mRNA localization in the SCG of these rats . Q8IX12 /Eis and P30518 /Eis rats were fed on a high ( 8 % ) salt diet or on a low ( 0.3 % ) salt diet for 4 weeks . Nerve cells in the SCG of Q8IX12 /Eis high salt rats exhibited more intense TH-immunoreactivity ( P < 0.01 ) and hybridization signals ( P < 0.01 ) than those of the other experimental groups . These findings suggest that activation of peripheral sympathetic nerves may account for hypertension in Q8IX12 /Eis rats on a high salt diet . Intracellular volume and apparent diffusion constants of perfused cancer cell cultures , as measured by NMR . Diffusion NMR spectroscopy was used to study intracellular volume and apparent water diffusion constants in different cell lines ( DU145 , human prostate cancer ; P01008 , rat prostate cancer ; MCF-7 , human breast cancer ; Q9HBH0 -1 , mouse fibrosacroma ) . The cells were grown on various matrices ( collagen sponge , collagen beads , polystyrene beads ) which enabled continuous growth in perfused high density cell culture suitable for NMR studies . In perfused cell systems , the attenuation of the water signal versus the squared gradient strength was fitted by the sum of two decaying exponentials . For the slowly decaying component the apparent water diffusion constant at 37 degrees C was 0.22 ( +/-0.02 ) x 10(-9) s/m2 for all cell lines at diffusion times > 100 ms . It continuously increased up to 0.47 ( +/-0.05 ) x 10(-9) s/m2 when the diffusion time was decreased to 8 ms , indicating restricted diffusion . No significant effect of the matrices was observed . The fractional volume of the slow component as determined from the biexponential diffusion curve correlated with the relative intracellular volume , as obtained from the cell density in the sample and the cell size as measured by light microscopy . Therefore , this simple NMR approach can be used to determine intracellular volume in perfused cell cultures suitable for NMR studies . Using this information in combination with spectroscopic data , changes in intracellular metabolite concentration can be detected even when the cellular volume is changing during the experiment . The apparent diffusion constant for the fast diffusing component varied with growth matrix , cell density and cell type and also showed the typical characteristics of restricted diffusion ( increase of apparent diffusion constant with time ) . P35367 occupancy in human brains after single oral doses of histamine H1 antagonists measured by positron emission tomography . 1. P35367 occupancy in the human brain was measured in 20 healthy young men by positron emission tomography ( PET ) using [ 11C ] -doxepin . 2 . (+)- DB01114 , a selective and classical antihistamine , occupied 76.8 +/- 4.2 % of the averaged values of available histamine H1 receptors in the frontal cortex after its administration in a single oral dose of 2 mg . Intravenous administration of 5 mg (+)-chlorpheniramine almost completely abolished the binding of [ 11C ] -doxepin to H1 receptors ( H1 receptor occupancy : 98.2 +/- 1.2 % ) . 3 . Terfenadine , a nonsedative antihistamine , occupied 17.2 +/- 14.2 % of the available H1 receptors in the human frontal cortex after its administration in a single oral dose of 60 mg . 4 . There was no correlation between H1 receptor occupancy by terfenadine and the plasma concentration of the active acid metabolite of terfenadine in each subject . 5 . PET data on human brain were essentially compatible with those on H1 receptor occupancy in guinea-pig brain determined by in vivo binding techniques , although for the same H1 receptor occupancy the dose was less in human subjects than in guinea-pigs . 6 . The PET studies demonstrated the usefulness of measuring H1 receptor occupancy with classical and second-generation antihistamines in human brain to estimate their unwanted side effects such as sedation and drowsiness quantitatively . Involvement of transcription factor P24468 in human trophoblast differentiation . BACKGROUND : During the in vitro differentiation of human villous cytotrophoblast ( Q01459 ) cells to a syncytiotrophoblast ( STB ) phenotype , mRNA levels for the nuclear hormone receptor P24468 ( P24468 , COUP-TFII ) increase rapidly , reaching a peak at day 1 of differentiation that is 8.8-fold greater than that in undifferentiated Q01459 cells . To examine whether P24468 is involved in the regulation of villous Q01459 cell differentiation , studies were performed to determine whether P24468 regulates the expression of P05549 ( AP-2alpha ) , a transcription factor that is critical for the terminal differentiation of these cells to a STB phenotype . METHODOLOGY/PRIMARY FINDINGS : Overexpression of P24468 in primary cultures of human Q01459 cells and JEG-3 human choriocarcinoma cells induced dose-dependent increases in P05549 promoter activity . Conversely , siRNA mediated silencing of the P24468 gene in villous Q01459 undergoing spontaneous differentiation blocked the induction of the mRNAs for P05549 and several STB cell specific marker genes , including human placental lactogen ( hPL ) , pregnancy specific glycoprotein 1 ( P11464 ) and corticotropin releasing hormone ( P06850 ) by 51-59 % . The induction of P05549 promoter activity by P24468 was potentiated by the nuclear hormone receptors retinoic acid receptor alpha ( P10276 ) and retinoid X receptor alpha ( P19793 ) . CONCLUSIONS/SIGNIFICANCE : Taken together , these results strongly suggest that P24468 is involved in villous Q01459 cell differentiation and that P24468 acts , at least in part , by directly activating P05549 gene expression and by potentiating the transactivation of P05549 by P10276 and P19793 . Ectopic DB01285 syndrome caused by bronchial carcinoid tumor indistinguishable from Cushing 's disease . A 75-year-old woman was admitted to our hospital because of a poor glycemic control . She was found to have Cushingoid feature and dynamic endocrine tests showed elevated plasma DB01285 and cortisol levels , lack of their circadian rhythm , non-suppressibility to high-dose dexamethasone , responsiveness to P06850 , but not to DB00035 , and suppression to octreotide . Pituitary Q9BWK5 showed an equivocal small lesion . CT scan of the chest showed two nodular lesions in the right lung ( S5 , S7 ) , while a mild uptake was noted only in S5 lesion by DB09150 -PET , but positive uptake was only in S7 lesion by somatostatin receptor scintigraphy ( SRS ) . Inferior petrosal sinus sampling revealed a gradient of plasma DB01285 after P06850 stimulation , consistent with the diagnosis of Cushing ' s disease . She underwent middle and inferior lobectomy of the right lung . The resected tumor in S7 was consistent with the diagnosis of a bronchial carcinoid tumor with positive DB01285 immunoreactivity , while that of S5 was cryptococcal granuloma . RT-PCR revealed abundant expressions of P01189 and SSTR ( -1 , -2 , -5 ) , but not of P34998 and P47901 . Postoperatively , abnormal endocrine data were normalized along with improvement of hypertension and diabetes . This was a diagnostic challenging case with ectopic DB01285 syndrome indistinguishable from Cushing ' s disease by various endocrine and imaging tests , among which SRS successfully localized the tumor responsible for ectopic DB01285 secretion . A Q8NBP7 -binding antibody that structurally mimics the P01133 (A) domain of LDL-receptor reduces LDL cholesterol in vivo . Proprotein convertase subtilisin-like/kexin type 9 ( Q8NBP7 ) regulates LDL cholesterol levels by inhibiting P01130 ( LDLr ) -mediated cellular LDL uptake . We have identified a fragment antigen-binding ( Fab ) 1D05 which binds Q8NBP7 with nanomolar affinity . The fully human antibody 1D05-IgG2 completely blocks the inhibitory effects of wild-type Q8NBP7 and two gain-of-function human Q8NBP7 mutants , S127R and D374Y . The crystal structure of 1D05-Fab bound to Q8NBP7 reveals that 1D05-Fab binds to an epitope on the Q8NBP7 catalytic domain which includes the entire LDLr P01133 (A) binding site . Notably , the 1D05-Fab CDR-H3 and CDR-H2 loops structurally mimic the P01133 (A) domain of LDLr . In a transgenic mouse model ( P11597 /LDLr-hemi ) , in which plasma lipid and Q8NBP7 profiles are comparable to those of humans , 1D05-IgG2 reduces plasma LDL cholesterol to 40 % and raises hepatic LDLr protein levels approximately fivefold . Similarly , in healthy rhesus monkeys , 1D05-IgG2 effectively reduced LDL cholesterol 20 % -50 % for over 2 weeks , despite its relatively short terminal half-life ( t(1/2) = 3.2 days ) . Importantly , the decrease in circulating LDL cholesterol corresponds closely to the reduction in free Q8NBP7 levels . Together these results clearly demonstrate that the LDL-lowering effect of the neutralizing anti- Q8NBP7 1D05-IgG2 antibody is mediated by reducing the amount of Q8NBP7 that can bind to the LDLr . Organic anion transporting polypeptide-C mediates arsenic uptake in P29320 -293 cells . Arsenic is an established human carcinogen . The role of aquaglyroporins ( AQPs ) in arsenic disposition was recently identified . In order to examine whether organic anion transporting polypeptide-C ( Q9Y6L6 ) also plays a role in arsenic transport , Q9Y6L6 cDNA was transfected into cells of a human embryonic kidney cell line ( P29320 -293 ) . Transfection increased uptake of the model Q9Y6L6 substrate , estradiol-17beta-D-glucuronide , by 10-fold . In addition , we measured uptake and cytotoxicity of arsenate , arsenite , monomethylarsonate(MMA(V)) , and dimethylarsinate ( P28067 (V) ) . Transfection of Q9Y6L6 increased uptake and cytotoxicity of arsenate and arsenite , but not of MMA(V) or P28067 (V) . DB01045 and taurocholic acid ( a substrate of Q9Y6L6 ) reversed the increased toxicity of arsenate and arsenite seen in Q9Y6L6 -transfected cells . The increase in uptake of inorganic arsenic was not as great as that of estradiol-17beta-D-glucuronide . Our results suggest that Q9Y6L6 can transport inorganic arsenic in a ( DB00143 ) -dependent manner . However , this may not be the major pathway for arsenic transport . Mass spectrometry and hydrogen/deuterium exchange measurements of alcohol-induced structural changes in cellular retinol-binding protein type I . To bind and release its ligand , cellular retinol-binding protein type I ( P09455 ) needs to undergo conformational and dynamic changes to connect the inner , solvent-shielded cavity , where retinol is found to bind , and the outside medium . DB00162 dissociation in vitro is favoured by water/alcohol mixtures whose moderately low dielectric constants mimic a property characteristic of the membrane microenvironment where this process occurs in vivo . Apo- and holo- P09455 , in either water/methanol or water/trifluoroethanol ( TFE ) mixtures , were analyzed at equilibrium by electrospray ionization with orthogonal quadrupole time-of-flight mass spectrometry ( P19957 -Q-TOFMS ) to identify the alcohol-induced species . The questions were asked whether the presence of alcohols affects protein dynamics , as reflected by hydrogen/deuterium ( H/D ) exchange monitored by continuous-labelling experiments , and to which extent retinol dissociation influences the process . With increasing methanol , at pH near neutrality , apo- P09455 exhibits a progressively more compact conformation , resulting in reduced H/D exchange with respect to the native protein in water . DB00162 dissociation from the holo-protein did not promote hydrogen replacement . Similarly , in the presence of the low TFE concentration sufficient to cause retinol dissociation , the hydrogen exchange of the resulting apo-protein was not exalted . However , in contrast with the alkanol , higher TFE concentrations induced a transition of apo- P09455 to a new alpha-helix conformation capable of exchanging all available hydrogen atoms . DB01045 Does not Significantly Affect the Expression of Small Heterodimer Partner in Primary Human Hepatocytes . The small/short heterodimer partner ( Q15466 , Q15466 ) is a nuclear receptor corepressor lacking a DNA binding domain . Q15466 is induced by bile acid-activated farnesoid X receptor ( Q96RI1 ) resulting in P22680 gene suppression . In contrast , O75469 ( O75469 ) activation by its ligands was recently suggested to inhibit Q15466 gene transactivation to maximize the induction of O75469 target genes . However , there are also conflicting reports in literature whether O75469 or rodent Pxr activation down-regulates Q15466 /Shp expression . Moreover , the O75469 -mediated regulation of the Q15466 gene has been studied only at the Q15466 mRNA and transactivation ( gene reporter assay ) levels . In this study , we studied the effect of rifampicin , a prototype O75469 ligand , on Q15466 mRNA , and protein expression in three primary human hepatocyte cultures . We found that Q15466 mRNA is not systematically down-regulated in hepatocyte in culture after 24 h treatment with rifampicin . Consistently , we did not observe down-regulation of Q15466 protein in primary human hepatocytes after 24 and 48 h of incubation with rifampicin . We can conclude that although we observed slight down-regulation of Q15466 mRNA and protein in several hepatocyte preparations , the phenomenon is unlikely critical for O75469 -mediated induction of its target genes . Serotonin skews human macrophage polarization through P41595 and P34969 . Besides its role as a neurotransmitter , serotonin ( 5-hydroxytryptamine , 5HT ) regulates inflammation and tissue repair via a set of receptors ( 5HT(1-7) ) whose pattern of expression varies among cell lineages . Considering the importance of macrophage polarization plasticity for inflammatory responses and tissue repair , we evaluated whether 5HT modulates human macrophage polarization . 5HT inhibited the LPS-induced release of proinflammatory cytokines without affecting P22301 production , upregulated the expression of M2 polarization-associated genes ( P05120 , P07996 , Q9NY15 , Q86Y22 ) , and reduced the expression of M1-associated genes ( P08476 , P41597 , P39900 , P05121 , P29016 , O94788 ) . Whereas only 5HT(7) mediated the inhibitory action of 5HT on the release of proinflammatory cytokines , both 5HT(2B) and 5HT(7) receptors mediated the pro-M2 skewing effect of 5HT . In fact , blockade of both receptors during in vitro monocyte-to-macrophage differentiation preferentially modulated the acquisition of M2 polarization markers . 5HT(2B) was found to be preferentially expressed by anti-inflammatory M2( P09603 ) macrophages and was detected in vivo in liver Kupffer cells and in tumor-associated macrophages . Therefore , 5HT modulates macrophage polarization and contributes to the maintenance of an anti-inflammatory state via 5HT(2B) and 5HT(7) , whose identification as functionally relevant markers for anti-inflammatory/homeostatic human M2 macrophages suggests their potential therapeutic value in inflammatory pathologies . Simultaneous identification of mycobacterial isolates to the species level and determination of tuberculosis drug resistance by PCR followed by electrospray ionization mass spectrometry . Mycobacterium tuberculosis that is resistant to both isoniazid ( DB00951 ) and rifampin ( Q9HBH0 ) is spreading . It has become a public health problem in part because the standard culture methods used to determine the appropriate treatment regimen for patients often take months following the presumptive diagnosis of tuberculosis . Furthermore , the misidentification of nontuberculosis mycobacteria ( Q9P121 ) in patients presumably suffering from tuberculosis results in additional human and health care costs . The mechanisms of resistance for several drugs used to treat Mycobacterium tuberculosis are well understood and therefore should be amenable to determination by rapid molecular methods . We describe here the use of PCR followed by electrospray ionization mass spectrometry ( PCR/ P19957 -MS ) in an assay that simultaneously determines DB00951 and Q9HBH0 resistance in Mycobacterium tuberculosis and identifies and determines the species of NTMs . The assay panel included 16 primer pairs in eight multiplexed reactions and was validated using a collection of 1,340 DNA samples from cultured specimens collected in the New York City area , the Republic of Georgia , and South Africa . Compared with phenotypic data , the PCR/ P19957 -MS assay had 89.3 % sensitivity and 95.8 % specificity in the determination of DB00951 resistance and 96.3 % sensitivity and 98.6 % specificity in the determination of Q9HBH0 resistance . Based on a set of 264 previously characterized liquid culture specimens , the PCR/ P19957 -MS method had 97.0 % sensitivity and 99.9 % specificity for determination of Q9P121 identity . The assay also provides information on ethambutol , fluoroquinolone , and diarylquinoline resistance and lineage-specific polymorphisms , to yield highly discriminative digital signatures potentially suitable for epidemiology tracking . Attenuation of anti-tuberculosis therapy induced hepatotoxicity by Spirulina fusiformis , a candidate food supplement . Therapy using Isoniazid ( DB00951 ) and DB01045 ( Q9HBH0 ) leads to induction of hepatotoxicity in some individuals undergoing anti-tuberculosis treatment . In this study , we assessed the effect of Spirulina fusiformis on DB00951 and Q9HBH0 induced hepatotoxicity in rats compared with hepatoprotective drug Silymarin . Induction of hepatotoxicity was measured by changes in the liver marker enzymes ( aspartate transaminase , alanine transaminase , and alkaline phosphatase ) . The antioxidant status was also analyzed in liver tissue homogenate and plasma by measurement of superoxide dismutase , catalase , glutathione-S-transferase , glutathione reductase , and lipid peroxidation levels . We also aimed to study the binding and interactions of the transcription factors Pregnane X Receptor ( O75469 ) and Farnesoid X Receptor ( Q96RI1 ) with DB00951 , Q9HBH0 , and representative active compounds of Spirulina fusiformis by in silico methods . The administration of DB00951 and Q9HBH0 resulted in significant ( p < 0.05 ) decrease in the antioxidant levels and total protein levels . There was also a significant ( p < 0.05 ) increase in the levels of liver marker enzymes . Spirulina fusiformis was seen to protect the parameters from significant changes upon challenge with DB00951 and Q9HBH0 in a dose-dependent manner . This was corroborated by histological examination of the liver . The results of the in silico analyses further support the wet lab results . DB01197 reduced plasminogen activator inhibitor activity in patients with acute myocardial infarction . Recent clinical trials have demonstrated that the administration of angiotensin-converting enzyme ( P12821 ) inhibitors to patients with myocardial infarction reduces the incidence of recurrent myocardial infarction . It has also been reported that an elevated level of plasminogen activator inhibitor ( P05121 ) appears to constitute a marker of the risk of recurrent coronary thrombosis . To determine whether the P12821 inhibitor captopril reduces plasma P05121 inhibitor activity , we measured changes in plasma P05121 activity ( IU/ml ) , tissue plasminogen activator ( t-PA ) antigen ( ng/ml ) , and serum P12821 activity ( IU/L ) in 14 survivors of myocardial infarction receiving captopril therapy ( 37.5 mg daily ) and compared them with the values in 15 placebo-treated patients chosen at random . Blood sampling was performed at 07.00 h . In the captopril-treated group , serum P12821 activity decreased significantly , from 14.0 +/- 0.8 to 11.5 +/- 1.2 IU/L 24 h after captopril therapy ( p < 0.01 ) , and those of P05121 activity and t-PA antigen also decreased significantly-from 11.9 +/- 2.8 to 5.5 +/- 2.2 IU/ml ( p < 0.02 ) and from 9.9 +/- 1.0 to 7.5 +/- 0.9 ng/ml ( p < 0.05 ) , respectively 48 h after captopril therapy . However , the levels of P12821 activity , P05121 activity , and t-PA antigen remained unchanged during the study period in the placebo group . Thus , our data indicate that the administration of captopril to patients with acute myocardial infarction may result in a reduced frequency of recurrent coronary thrombosis by increasing fibrinolytic capacity . DB01296 sulfate inhibits P01375 and P01579 -induced production of P05362 in human retinal pigment epithelial cells in vitro . PURPOSE : DB01296 sulfate ( GS ) is a naturally occurring sugar that possesses some immunosuppressive effects in vitro and in vivo , but its mechanism is unknown . We investigated whether GS could modulate the proinflammatory cytokine-induced expression of the gene for intercellular adhesion molecule ( ICAM ) -1 , an inflammatory protein in human retinal pigment epithelial ( Q96AT9 ) cells . METHODS : ARPE-19 cells were used as a model to determine the effects of GS on the expression of the P05362 gene upregulated by P01375 or P01579 , by Western blot analysis and semiquantitative reverse transcription polymerase chain reaction ( RT-PCR ) . The activation and nuclear translocation of the nuclear factors NF-kappaB and P42224 were evaluated by immunocytochemistry , Western blot analysis , and electrophoretic mobility shift assay ( EMSA ) . RESULTS : Both P01375 and P01579 increased the expression of P05362 at the mRNA and protein levels in a time- and dose-dependent manner in ARPE-19 cells . GS effectively downregulated the P01375 - or P01579 -induced expression of P05362 in the protein and mRNA level in a dose-dependent manner . GS further inhibited the nuclear translocation of p65 proteins in P01375 and phosphorylated P42224 in P01579 -stimulated ARPE-19 cells . CONCLUSIONS : GS inhibits the expression of the P05362 gene in ARPE-19 cell stimulated with P01375 or P01579 through blockade of NF-kappaB subunit p65 and nuclear translocation of P42224 . This study has demonstrated a potentially important property of GS in reducing P05362 mediated inflammatory mechanisms in the eye . An O95477 truncation shows no dominant negative effect in a familial hypoalphalipoproteinemia pedigree with three O95477 mutations . The DB00171 binding cassette transporter ( O95477 ) A1 is a key determinant of circulating high density lipoprotein cholesterol ( HDL-C ) levels . Mutations in O95477 are a major genetic contributor to low HDL-C levels within the general population . Following the finding of three different O95477 mutations , p.C978fsX988 , p.T1512M and p.N1800H in a subject with hypoalphalipoproteinemia , we aimed to establish whether the p.C978fsX988 truncation exerted a dominant negative effect on the full-length O95477 alleles within family members as has been reported for other O95477 truncations . Characterisation of the p.C978fsX988 mutant in transfected P29320 293 cells showed it to be expressed as a GFP fusion protein but lacking in cholesterol efflux function . This was in keeping with results from cholesterol efflux assays in the fibroblasts of p.C978fsX988 carriers which also showed impaired efflux . Allele- specific quantification of p.C978fsX988 mRNA and analysis of O95477 protein levels in the fibroblasts of p.C978fsX988 heterozygotes showed negligible levels of mRNA and protein expression . There was no evidence of a dominant negative effect on wildtype or p.N1800H protein levels . We conclude that in the case of the p.C978fsX988 truncated mutant a lack of expression precludes it from having a dominant negative effect . Effect of prototypical inducing agents on P-glycoprotein and CYP3A expression in mouse tissues . P-glycoprotein ( P-gp ) and CYP3A have considerable overlap in inducers in vitro . Characterizing P-gp induction in vivo and potential coregulation with CYP3A are important goals for predicting drug interactions . This study examined P-gp expression in mouse tissues and potential coinduction with CYP3A following oral treatment with 1 of 7 prototypical inducing agents for 5 days . P-gp expression in brain or liver was not induced by any treatment as determined by Western blot , whereas dexamethasone , pregnenolone-16alpha-carbonitrile ( Q15149 ) , St . John 's wort ( SJW ) , and rifampin induced hepatic CYP3A expression . In intestine , rifampin and SJW induced P-gp expression 3.7- and 1.6-fold and CYP3A 3.5- and 2.4-fold , respectively , whereas dexamethasone and Q15149 induced CYP3A only . These observations suggest that P-gp in mouse small intestine is inducible by some , but not all , CYP3A inducers , whereas P-gp expression in liver or brain is not readily induced . Intriguingly , rifampin and SJW , both activators of the human pregnane X receptor ( O75469 ) , induced CYP3A in both liver and intestine but induced P-gp only in intestine , whereas Q15149 , an activator of murine O75469 , did not induce P-gp in any tissue . DB01045 disposition was evaluated , and hepatic exposure to rifampin was comparable to intestine ; in contrast , brain concentrations were low . Overall , these observations demonstrate that P-gp induction in vivo is tissue-specific ; furthermore , there is a disconnect between P-gp induction and CYP3A induction that is tissue- and inducer-dependent , suggesting that O75469 activation alone is insufficient for P-gp induction in vivo . Tissue-specific factors and inducer pharmacokinetic/pharmacodynamic properties may underlie these observations . The steroid receptor co-activator-1 ( Q15788 ) potentiates TGF-beta/Smad signaling : role of p300/CBP . The three related 160-kDa proteins , Q15788 , Q06418 -2 and Q9Y6Q9 , were initially identified as factors interacting with nuclear receptors . They have also been reported to potentiate the activity of other transcription factors such as AP-1 or NF-kappaB . The aim of this work was to identify whether Q15788 interferes with the TGF-beta/Smad signaling pathway , and if so , to identify its underlying mechanisms of action . Using transient cell transfection experiments performed in human dermal fibroblasts with the P84022 /4-specific (SBE)4-lux reporter construct , as well as the human P05121 promoter , we determined that Q15788 enhances TGF-beta-induced , Smad-mediated , transcription . Likewise , Q15788 overexpression potentiated TGF-beta-induced upregulation of P05121 steady-state mRNA levels . Using a mammalian two-hybrid system , we demonstrated that Q15788 interacts with the transcriptional co-activators p300/CBP , but not with P84022 . Overexpression of the adenovirus E1A oncoprotein , an inhibitor of CBP/p300 activity , prevented the enhancing effect of Q15788 on P84022 /4-mediated transcription , indicating that p300/CBP may be required for Q15788 effect . Such hypothesis was validated , as expression of a mutant form of Q15788 lacking the CBP/p300-binding site failed to upregulate P84022 /4-dependent transcription , while full-length Q15788 potentiated p300. P84022 interactions . These results identify Q15788 as a novel P84022 /4 transcriptional partner , facilitating the functional link between P84022 and p300/CBP . Molecular dissection of dimethylnitrosamine ( O15061 ) -induced hepatotoxicity by mRNA differential display . Differential display reverse transcription-polymerase chain reaction ( DDRT-PCR ) was used to catalogue altered hepatic transcript expression during dimethylnitrosamine ( O15061 ) exposure in vivo . Mice were administered O15061 ( 1.5 or 5 mg/kg ) or vehicle ( phosphate-buffered saline ) i.p. once daily for up to 7 days , and livers were collected 6 h post-injection . Total RNA was reverse transcribed and cDNA subsets were selectively amplified by PCR . DDRT-PCR products were fractionated on denaturing polyacrylamide gels , and differentially expressed bands were excised , reamplified , and subsequently cloned into a plasmid vector . This study identified 23 cDNAs that were induced and 25 cDNAs that were suppressed during O15061 exposure . Altered expression during O15061 exposure for cDNA clones was confirmed by Northern blotting , RNase protection , or in situ hybridization analyses . DNA sequence information indicated that four cDNAs suppressed during O15061 exposure encode cytochrome P450 isoenzyme-cholesterol 7 alpha-hydroxylase ( P22680 ) , a monokine , a myeloid cell differentiation protein , and mouse major urinary protein ( MUP ) . We further observed a O15061 -induced increase in transcripts for complement factor 3 ( P01024 ) and serum amyloid A ( P0DJI8 ) . In contrast , the remaining differentially expressed transcripts detected by DDRT-PCR during O15061 exposure demonstrated no similarity to sequences present in Genbank , suggesting that they may encode previously unreported gene products . In situ hybridization showed MUP transcripts to be expressed by hepatic centrilobular areas that undergo necrosis during subchronic O15061 exposure . Thus , the utilization of DDRT-PCR has identified several differentially expressed hepatic mRNAs associated with various doses and stages of O15061 exposure . DB01045 -independent interactions between the pregnane X receptor ligand binding domain and peptide fragments of coactivator and corepressor proteins . The pregnane X receptor ( O75469 ) , a member of the nuclear receptor superfamily , regulates the expression of drug-metabolizing enzymes in a ligand-dependent manner . The conventional view of nuclear receptor action is that ligand binding enhances the receptor 's affinity for coactivator proteins , while decreasing its affinity for corepressors . To date , however , no known rigorous biophysical studies have been conducted to investigate the interaction among O75469 , its coregulators , and ligands . In this work , steady-state total internal reflection fluorescence microscopy ( TIRFM ) and total internal reflection with fluorescence recovery after photobleaching were used to measure the thermodynamics and kinetics of the interaction between the O75469 ligand binding domain and a peptide fragment of the steroid receptor coactivator-1 ( Q15788 ) in the presence and absence of the established O75469 agonist , rifampicin . Equilibrium dissociation and dissociation rate constants of ~5 μM and ~2 s(-1) , respectively , were obtained in the presence and absence of rifampicin , indicating that the ligand does not enhance the affinity of the O75469 and Q15788 fragments . Additionally , TIRFM was used to examine the interaction between O75469 and a peptide fragment of the corepressor protein , the silencing mediator for retinoid and thyroid receptors ( Q9Y618 ) . An equilibrium dissociation constant of ~70 μM was obtained for Q9Y618 in the presence and absence of rifampicin . These results strongly suggest that the mechanism of ligand-dependent activation in O75469 differs significantly from that seen in many other nuclear receptors . DB01645 potentiates the P01160 effect on a K(+)-conductance in P29320 -293 cells . P29320 -293 cells are known to reflect many features of the late distal tubule . Furthermore , they have the ability to release urodilatin , the structural analog to P01160 . RT-PCR was performed to test for the expression of natriuretic peptide receptors . While the mRNA for the human P01160 receptor ( P16066 , P16066 ) could be amplified , the P09543 -specific receptor P20594 ( P20594 ) and the receptor specific for guanylins , P25092 , could not be detected . In patch clamp experiments the effects of P01160 ( 10 nM ) on membrane voltage ( V(m) ) were monitored and P29320 -293 cells depolarized by 2.3 +/- 0.5 mV ( n=14 ) . In the presence of the P01133 receptor blocker genistein ( 10 microM ) the effect of P01160 was increased by 65 % to 3.9 +/- 0.8 mV ( n=14 ) . After removal of genistein the P01160 -mediated depolarization further increased by 147 % to 5.7 +/- 1.0 mV ( n=14 ) . P01160 given repetitively without genistein had no increasing depolarizing effect in P29320 -293 cells with time . The P01160 effect could be fully blocked by 1 mM Ba(2+) and by 1 microM of the specific PKG inhibitor KT5823 indicating that P01160 inhibits a K(+)-conductance via a cGMP-dependent protein kinase . DB01645 itself hyperpolarized the membrane voltage of P29320 -293 cells by -3.9 +/- 0.6 mV ( n=11 ) and this effect could also be fully blocked by Ba(2+) ( -0.3 +/- 0.1 mV , n=5 ) , indicating that genistein activates a K(+)-conductance which contributes significantly to the membrane potential of P29320 -293 cells . Effects of DB01045 , a potent inducer of drug-metabolizing enzymes and an inhibitor of Q9Y6L6 /3 transport , on the single dose pharmacokinetics of anacetrapib . Anacetrapib is a novel cholesteryl ester transfer protein ( P11597 ) inhibitor in development for treatment of dyslipidemia . This open-label , fixed-sequence , 3-period study was intended to evaluate the potential of anacetrapib to be a victim of Q9Y6L6 /3 inhibition and strong CYP3A induction using acute and chronic dosing of rifampin , respectively , as a probe . In this study , 16 healthy subjects received 100 mg anacetrapib administered without rifampin ( Day 1 , Period 1 ) , with single-dose ( SD ) 600 mg rifampin ( Day 1 , Period 2 ) , and with multiple-dose ( MD ) 600 mg rifampin for 20 days ( Day 14 , Period 3 ) . Log-transformed anacetrapib AUC0-∞ and Cmax were analyzed by a linear mixed effects model . The GMRs and 90 % CIs for anacetrapib AUC0-∞ and Cmax were 1.25 ( 1.04 , 1.51 ) and 1.43 ( 1.13 , 1.82 ) for SD rifampin ( Period 2/Period 1 ) and 0.35 ( 0.29 , 0.42 ) and 0.26 ( 0.21 , 0.32 ) for MD rifampin ( Period 3/Period 1 ) , respectively . Anacetrapib was generally well tolerated in both the absence/presence of SD and MD rifampin . In conclusion , treatment with SD rifampin , which inhibits the Q9Y6L6 /3 transporter system , did not substantially influence the SD pharmacokinetics of anacetrapib , while chronic ( 20 days ) administration of rifampin , which strongly induces CYP3A isozymes , reduced mean systemic exposure to SD anacetrapib by 65 % . Blood gene expression profiling of breast cancer survivors experiencing fibrosis . PURPOSE : To extend knowledge on the mechanisms and pathways involved in maintenance of radiation-induced fibrosis ( Q9HBH0 ) by performing gene expression profiling of whole blood from breast cancer ( BC ) survivors with and without fibrosis 3-7 years after end of radiotherapy treatment . METHODS AND MATERIALS : Gene expression profiles from blood were obtained for 254 BC survivors derived from a cohort of survivors , treated with adjuvant radiotherapy for breast cancer 3-7 years earlier . Analyses of transcriptional differences in blood gene expression between BC survivors with fibrosis ( n=31 ) and BC survivors without fibrosis ( n=223 ) were performed using R version 2.8.0 and tools from the Bioconductor project . Gene sets extracted through a literature search on fibrosis and breast cancer were subsequently used in gene set enrichment analysis . RESULTS : Substantial differences in blood gene expression between BC survivors with and without fibrosis were observed , and 87 differentially expressed genes were identified through linear analysis . Transforming growth factor-β1 signaling was identified as the most significant gene set , showing a down-regulation of most of the core genes , together with up-regulation of a transcriptional activator of the inhibitor of fibrinolysis , P05121 in the BC survivors with fibrosis . CONCLUSION : Transforming growth factor-β1 signaling was found down-regulated during the maintenance phase of fibrosis as opposed to the up-regulation reported during the early , initiating phase of fibrosis . Hence , once the fibrotic tissue has developed , the maintenance phase might rather involve a deregulation of fibrinolysis and altered degradation of extracellular matrix components . LPS-induced downregulation of Q92887 and O95342 in human liver is due to a posttranscriptional process . Endotoxin-induced cholestasis in rodents is caused by hepatic downregulation of transporters , including the basolateral Na+-dependent taurocholate transporter ( ntcp ) and the canalicular bile salt export pump ( bsep ) and multidrug resistance-associated protein 2 ( mrp2 ) . Details about the regulation of the human transporter proteins during this process are lacking . We used precision-cut human and rat liver slices to study the regulation of transporter expression during LPS-induced cholestasis . We investigated the effect of LPS on nitrate/nitrite and cytokine production in relation to the expression of inducible nitric oxide synthase , Q14973 , O95342 , and Q92887 both at the level of mRNA with RT-PCR and protein using immunofluorescence microscopy . In liver slices from both species , LPS-induced expression of inducible nitric oxide synthase was detected within 1-3 h and remained increased over 24 h . In rat liver slices , this was accompanied by a significant decrease of rat ntcp and mrp2 mRNA levels , whereas bsep levels were not affected . These results are in line with previous in vivo studies and validate our liver slice technique . In LPS-treated human liver slices , Q14973 mRNA was downregulated and showed an inverse correlation with the amounts of P01375 and Il-1beta produced . In contrast , Q92887 and O95342 mRNA levels were not affected under these conditions . However , after 24-h LPS challenge , both proteins were virtually absent in human liver slices , whereas marker proteins remained detectable . In conclusion , we show that posttranscriptional mechanisms play a more prominent role in LPS-induced regulation of human Q92887 and O95342 compared with the rat transporter proteins . Interrelationships in mice of antipyrine half-life , hepatic monooxygenase activities and liver S9-mediated mutagenicity of aflatoxin B1 , benzo[alpha]pyrene 7,8-dihydrodiol , 2-acetylaminofluorene and N-nitrosomorpholine . To evaluate the predictive value of serum antipyrine half-life AP(T1/2) as an index of hepatic carcinogen metabolism , groups of C57BL/6 and DBA/2 mice were treated with various inducers and inhibitors of cytochrome P-450-dependent monooxygenases ( pregnenolone-16 alpha-carbonitrile ( Q15149 ) , phenobarbital ( PB ) , DB06732 ( 5,6-BF ) , 3-methylcholanthrene ( MC ) , disulfiram ( Q8IX12 ) , 7,8-BF ) . Groups of mice were also given ethanol ( 3 % in drinking water ) for 12 days . Within each group , mean serum AP-(T1/2) was compared with ( i ) the in vitro activity of hepatic microsomal benzo[alpha]pyrene ( BP ) 3-hydroxylase , 2-acetylaminofluorene ( AAF ) -N-hydroxylase and aldrin monooxygenase , and ( ii ) the liver S9-mediated mutagenicity of aflatoxin B1 ( AFB ) , trans-7,8-dihydro-7,8-dihydroxybenzo[alpha]pyrene ( BP 7,8-diol ) , 2-acetylaminofluorene and N-nitrosomorpholine ( NMOR ) in Salmonella typhimurium strains . Serum AP(T1/2) was only correlated negatively with the activity of BP 3-hydroxylase ( P less than 0.001 ) and aldrin monooxygenase ( P less than 0.001 ) . No statistically significant correlation was found between serum AP(T1/2) and liver S9-mediated mutagenicity for any of the four carcinogens . On the basis of these results , we conclude that serum AP(T1/2) may not be a reliable index of the capacity of liver to convert carcinogens into reactive intermediates . Down-regulation of cholesterol 7alpha-hydroxylase ( P22680 ) gene expression by bile acids in primary rat hepatocytes is mediated by the c-Jun N-terminal kinase pathway . DB04540 7alpha-hydroxylase ( P22680 ) , the rate-limiting enzyme in the neutral pathway of bile acid biosynthesis , is feedback-inhibited at the transcriptional level by hydrophobic bile acids . Recent studies show that bile acids are physiological ligands for farnesoid X receptor ( Q96RI1 ) . Activated Q96RI1 indirectly represses P22680 transcription through induction of small heterodimer protein ( Q15466 -1 ) . In this study , we provide evidence that bile acids rapidly down-regulate P22680 transcription via activation of the JNK/c-Jun pathway . Furthermore , we demonstrate that Q15466 -1 is also a direct target of activated c-Jun . In primary rat hepatocyte cultures , taurocholate ( TCA ) strongly activated JNK in a time- and concentration-dependent manner . P01375 -alpha , a potent activator of JNK , also rapidly activated JNK and down-regulated P22680 mRNA levels . Overexpression of dominant-negative P45983 or a transactivating domain mutant of c-Jun significantly blocked the ability of TCA to down-regulate P22680 mRNA . In contrast , overexpression of wild-type c-Jun ( c-Jun(wt) ) enhanced the repression of P22680 by TCA . Moreover , overexpression of c-Jun(wt) resulted in increased Q15466 -1 promoter activity . Mutation of a putative AP-1 ( c-Jun ) element suppressed c-Jun-mediated activation of the Q15466 -1 promoter construct . These results indicate that the bile acid-activated JNK pathway plays a pivotal role in regulating P22680 levels in primary rat hepatocytes . Human and mouse trace amine-associated receptor 1 have distinct pharmacology towards endogenous monoamines and imidazoline receptor ligands . TAARs ( trace amine-associated receptors ) are G-protein-coupled receptors that respond to low abundance , endogenous amines such as tyramine and tryptamine , and represent potential targets for neuropsychiatric diseases . However , some members of this receptor subfamily either have no ligand identified or remain difficult to express and characterize using recombinant systems . In the present paper we report the successful expression of human and mouse Q96RJ0 , and the characterization of their responses to various natural and synthetic agonists . In P29320 ( human embryonic kidney ) -293/CRE-bla cells , mouse Q96RJ0 showed a robust response to trace amines as measured using either a DB02527 assay or a beta-lactamase reporter assay , whereas human Q96RJ0 showed a weaker , but still measurable , response . When certain fragments of human Q96RJ0 were replaced with the corresponding regions of mouse Q96RJ0 , the chimaeric receptor showed a much stronger response in DB02527 production . Examination of a series of agonists on these receptors revealed that the human and the chimaeric receptor are almost identical in pharmacology , but distinct from the mouse receptor . We also screened small libraries of pharmacologically active agents on Q96RJ0 and identified a series of synthetic agonists , some of which are also ligands of the enigmatic imidazoline receptor . The findings of the present study not only shed light on the pharmacological species difference of Q96RJ0 , but also raise new possibilities about the mechanism of some of the imidazoline-related agents . DB00909 block of cloned human T-type voltage-gated calcium channels . DB00909 ( ZNS ) is a multi-target antiepileptic drug reported to be efficient in the treatment of both partial and generalized seizures , with T-type Ca(2+) channel blockade being one of its proposed mechanisms of action . In this study , we systematically investigated electrophysiological effects of ZNS on cloned human Ca(v)3.1-3.3 Ca(2+) channels in a heterologous P29320 -293 expression system using whole cell patch-clamp technique . Concentration-response studies were performed in the range from 5 microM to 2mM for Ca(v)3.2 Ca(2+) channels exhibiting a 15.4-30.8 % reduction of Ca(2+) influx within the maximum therapeutic plasma range ( 50-200 microM ZNS ) . The other T-type Ca(2+) channel entities , Ca(v)3.1 and Q9P0X4 , were even less sensitive to ZNS . Both voltage- and concentration-dependence of inactivation kinetics remained unchanged for Ca(v)3.2 VGCC , whereas Ca(v)3.1 and Q9P0X4 exhibited minor , though significant reduction of inactivation-tau . Interestingly , ZNS block of Ca(v)3.2 VGCCs was not use-dependent and remained unaffected by changes in the holding potential . Steady-state inactivation studies did not display a significant shift in steady-state availability of Ca(v)3.2 channels at 100 microM ZNS ( DeltaV(1/2)=3.1mV , p=0.071 ) . Our studies indicate that ZNS is a moderate blocker of human Ca(v)3 T-type Ca(2+) channels with little or no effect on Ca(v)3.2 Ca(2+) channel inactivation kinetics , use- and state-dependence of blockade . These results suggest that T-type Ca(2+) channel inhibition only partially contributes to the anti-absence activity of ZNS antiepileptic drug . Rubella vaccine-induced cellular immunity : evidence of associations with polymorphisms in the Toll-like , vitamin A and D receptors , and innate immune response genes . Toll-like , vitamin A and D receptors and other innate proteins participate in various immune functions . We determined whether innate gene-sequence variations are associated with rubella vaccine-induced cytokine immune responses . We genotyped 714 healthy children ( 11-19 years of age ) after two doses of rubella-containing vaccine for 148 candidate SNP markers . Rubella virus-induced cytokines were measured by ELISA . Twenty-two significant associations ( range of P values 0.002-0.048 ) were found between SNPs in the vitamin A receptor family ( P10276 , P10826 , Q02880 and P13631 ) , vitamin D receptor and downstream mediator of vitamin D signaling ( P19793 ) genes and rubella virus-specific ( P01579 , P60568 , P22301 , P01375 , and GM- P04141 ) cytokine immune responses . A O15455 gene promoter region SNP ( rs5743305 , -8441A > T ) was associated with rubella-specific GM- P04141 secretion . Importantly , SNPs in the Q9C035 gene coding regions , rs3740996 ( His43Tyr ) and rs10838525 ( Gln136Arg ) , were associated with an allele dose-related secretion of rubella virus-specific P01375 and P60568 /GM- P04141 , respectively , and have been previously shown to have functional consequences regarding the antiviral activity and susceptibility to HIV-1 infection . We identified associations between individual SNPs and haplotypes in , or involving , the O95786 ( O95786 ) gene and rubella-specific P01375 secretion . This is the first paper to present evidence that polymorphisms in the TLR , vitamin A , vitamin D receptor , and innate immunity genes can influence adaptive cytokine responses to rubella vaccination . Roles of purinergic receptor P2Y , G protein-coupled 12 in the development of atherosclerosis in apolipoprotein E-deficient mice . OBJECTIVE : The aim of the study was to evaluate the role of purinergic receptor P2Y , G protein-coupled 12 ( Q9H244 ) , an ADP receptor , in the development of atherosclerotic lesions . METHODS AND RESULTS : P02649 -null mice were crossed with P2y12(-/-) mice to generate double knockout mice . The double knockout mice and the control apolipoprotein E-null mice were fed a high-fat diet for 20 weeks . Assessment of the atherosclerotic lesions in the control and double knockout mice demonstrated that Q9H244 deficiency caused a diminished lesion area , an increased fibrous content at the plaque site , and decreased monocyte/macrophage infiltration of the lesions . Polymerase chain reaction studies revealed that white blood cells do not express significant levels of Q9H244 . Bone marrow transplantation experiments confirmed that Q9H244 expressed on platelets is a key factor responsible for atherosclerosis , but do not exclude a role of smooth muscle cell Q9H244 . Supernatant fluid from activated P2y12(+/+) but not P2y12(-/-) platelets was capable of causing monocyte migration . In vitro studies showed that platelet Q9H244 deficiency suppressed platelet factor 4 secretion and P16109 expression . Further work demonstrated that platelet Q9H244 , through inhibition of the DB02527 /protein kinase A pathway , critically regulates the release of platelet factor 4 , and thereby affects monocyte recruitment and infiltration . CONCLUSIONS : These results demonstrate that Q9H244 modulates atherogenesis , at least in part by augmenting inflammatory cell recruitment via regulation of platelet α-granule release . Cytokine profile in the endometrium of normal fertile and women with repeated implantation failure . BACKGROUND : Repeated Implantation Failure ( Q9HBH0 ) is one of the most intricate obstacles in assisted reproduction . The cytokine and chemokine composition of uterine cavity seem to play important roles in the implantation process . OBJECTIVE : To compare the cytokine profile in the endometrium of normal fertile women and those with repeated implantation failure . METHODS : After enzymatic digestion of endometrial tissues , whole endometrial cells and endometrial stromal cells from Q9HBH0 and normal fertile women were cultivated and stimulated for cytokine secretion . The levels of P22301 , TGF-β , IFN-γ , P05231 , P10145 and Q16552 in culture supernatants of the two groups were assayed by ELISA and compared together . RESULTS : Endometrial stromal cells and whole endometrial cells of normal fertile women produced higher levels of P05231 , P10145 and TGF-β compared to Q9HBH0 group , although this difference was statistically significant only in endometrial stromal cells ( p=0.005 , 0.002 and 0.001 , respectively ) . In addition , endometrial stromal cells of normal fertile women produced lower levels of P22301 in comparison with Q9HBH0 group ( p=0.005 ) . CONCLUSION : Disturbances in cytokine production at the feto-maternal interface could be a cause of implantation failure . A pro-inflammatory cytokine milieu seems to be pivotal for successful implantation . Population genomic analyses based on 1 million SNPs in commercial egg layers . Identifying signatures of selection can provide valuable insight about the genes or genomic regions that are or have been under selective pressure , which can lead to a better understanding of genotype-phenotype relationships . A common strategy for selection signature detection is to compare samples from several populations and search for genomic regions with outstanding genetic differentiation . Wright 's fixation index , P19883 , is a useful index for evaluation of genetic differentiation between populations . The aim of this study was to detect selective signatures between different chicken groups based on SNP-wise P19883 calculation . A total of 96 individuals of three commercial layer breeds and 14 non-commercial fancy breeds were genotyped with three different 600K SNP-chips . After filtering a total of 1 million SNPs were available for P19883 calculation . Averages of P19883 values were calculated for overlapping windows . Comparisons of these were then conducted between commercial egg layers and non-commercial fancy breeds , as well as between white egg layers and brown egg layers . Comparing non-commercial and commercial breeds resulted in the detection of 630 selective signatures , while 656 selective signatures were detected in the comparison between the commercial egg-layer breeds . Annotation of selection signature regions revealed various genes corresponding to productions traits , for which layer breeds were selected . Among them were Q15788 , Q12772 and Q6GYQ0 associated with reproductive traits , broodiness and egg production . Furthermore , several of the detected genes were associated with growth and carcass traits , including P01189 , O43741 , P10451 , P01344 , P07384 , TGFb2 and P18065 . Our approach demonstrates that including different populations with a specific breeding history can provide a unique opportunity for a better understanding of farm animal selection . Identification of antithrombin-modulating genes . Role of O95461 , a gene encoding a bifunctional glycosyltransferase , in the secretion of proteins ? The haemostatic relevance of antithrombin together with the low genetic variability of P01008 , and the high heritability of plasma levels encourage the search for modulating genes . We used a hypothesis-free approach to identify these genes , evaluating associations between plasma antithrombin and 307,984 polymorphisms in the GAIT study ( 352 individuals from 21 Spanish families ) . Despite no SNP reaching the genome wide significance threshold , we verified milder positive associations in 307 blood donors from a different cohort . This validation study suggested O95461 , a gene encoding a protein with xylosyltransferase and glucuronyltransferase activities that forms heparin-like linear polysaccharides , as a potential modulator of antithrombin based on the significant association of one SNPs , rs762057 , with anti-FXa activity , particularly after adjustment for age , sex and P01008 rs2227589 genotype , all factors influencing antithrombin levels ( p = 0.02 ) . Additional results sustained this association . O95461 silencing inHepG2 and P29320 -EBNA cells did not affect P01008 mRNA levels but significantly reduced the secretion of antithrombin with moderate intracellular retention . Milder effects were observed on α1-antitrypsin , prothrombin and transferrin . Our study suggests O95461 as the first known modifier of plasma antithrombin , and proposes a new role for O95461 in modulating extracellular secretion of certain glycoproteins . Hepatic overexpression of Abcb11 in mice promotes the conservation of bile acids within the enterohepatic circulation . The bile salt export pump , encoded by O95342 , is the predominant canalicular transport protein for biliary bile acid secretion . The level of O95342 expression in humans is widely variable yet the impact of this variability on human disease is not well defined . We aim to determine the effect of hepatic Abcb11 overexpression on the enterohepatic circulation ( EHC ) in mice . We used a stable isotope dilution technique in transgenic mice overexpressing hepatic Abcb11 ( P02766 -Abcb11 ) to determine the pool size , fractional turnover rate ( FTR ) , and synthesis rate of the primary bile acid , cholic acid ( CA ) . The gallbladder was cannulated to determine bile flow , bile acid composition , and the biliary secretion rates of CA , total bile acids , phospholipid , and cholesterol . The combined data allowed for estimation of the CA cycling time and the fraction of CA lost per cycle . Hepatic and intestinal gene and protein expression were determined by qPCR and Western blot . Abcb11 overexpression strongly decreased FTR and synthesis rate of CA . Abcb11 overexpression decreased the fraction of CA that was lost per cycle of the EHC . Hepatic expression of Cyp7a1 was suppressed by nearly 50 % and ileal expression of FGF15 was increased more than eightfold in P02766 -Abcb11 mice . Despite the increased intestinal reabsorption of bile acids , ileal Asbt expression was suppressed . Hepatic Abcb11 overexpression in mice increases the conservation of bile acids within the enterohepatic circulation . These data provide strong evidence for the existence of feed-forward communication between hepatic expression of a bile acid transport protein and the intestine . Common genetic variants contribute to primary hypertriglyceridemia without differences between familial combined hyperlipidemia and isolated hypertriglyceridemia . BACKGROUND : The majority of hypertriglyceridemias are diagnosed as familial combined hyperlipidemia ( FCHL ) and primary isolated hypertriglyceridemias . The contribution of common genetic variants in primary hypertriglyceridemias and the genetic difference between FCHL and isolated hypertriglyceridemias have not been thoroughly examined . METHODS AND RESULTS : This study involved 580 patients with hypertriglyceridemias and 403 controls . Of the 37 single nucleotide polymorphisms examined , 12 located in 10 genes showed allelic and genotype frequency differences between hypertriglyceridemias and controls . The minor alleles of P02649 , Q6Q788 , GALNTN2 , and Q14397 variants were positively correlated with plasma triglycerides , whereas minor alleles of Q86V24 , Q9Y5C1 , P06858 , and Q96RU8 polymorphisms were inversely associated . Body mass index , glucose , sex , rs328 and rs7007797 in P06858 , rs662799 and rs3135506 in Q6Q788 , and rs1260326 in Q14397 explained 36 % of the variability in plasma triglycerides , 7.3 % of which was attributable to the genetic variables . P06858 , Q14397 , and Q6Q788 polymorphisms fit dominant , recessive , and additive inheritance models , respectively . Variants more frequently identified in isolated hypertriglyceridemias were rs7412 in P02649 and rs1800795 in P05231 ; rs2808607 in P22680 and rs3812316 and rs17145738 in Q9NP71 were more frequent in FCHL . The other 32 single nucleotide polymorphisms presented similar frequencies between isolated hypertriglyceridemias and FCHL . CONCLUSIONS : Common genetic variants found in P06858 , Q6Q788 , and Q14397 are associated with triglycerides levels in patients with primary hypertriglyceridemias . FCHL and isolated hypertriglyceridemias are probably trace to an accumulation of genetic variants predisposing to familial and sporadic hypertriglyceridemias or to hypertriglyceridemias and hypercholesterolemia in case of FCHL . O75469 induces Q02318 and regulates cholesterol metabolism in the intestine . Mitochondrial sterol 27-hydroxylase ( Q02318 ) catalyzes oxidative cleavage of the sterol side chain in the bile acid biosynthetic pathway in the liver and 27-hydroxylation of cholesterol in most tissues . Recent studies suggest that 27-hydroxycholesterol ( 27-HOC ) activates liver orphan receptor alpha ( LXRalpha ) and induces the cholesterol efflux transporters O95477 and P45844 in macrophages . The steroid- and bile acid-activated pregnane X receptor ( O75469 ) plays critical roles in the detoxification of bile acids , cholesterol metabolites , and xenobiotics . The role of Q02318 in the intestine is not known . This study investigated O75469 and Q02318 regulation of cholesterol metabolism in the human intestinal cell lines Caco2 and Ls174T . A human O75469 ligand , rifampicin , induced Q02318 mRNA expression in intestine cells but not in liver cells . DB01045 induced Q02318 gene transcription , increased intracellular 27-HOC levels , and induced O95477 and P45844 mRNA expression only in intestine cells . A functional O75469 binding site was identified in the human Q02318 gene . Chromatin immunoprecipitation assays revealed that rifampicin induced the O75469 recruitment of steroid receptor coactivator 1 to Q02318 chromatin . DB04540 loading markedly increased intracellular 27-HOC levels in intestine cells . DB01045 , 27-HOC , and a potent LXRalpha agonist , T0901317 , induced O95477 and P45844 protein expression and stimulated cholesterol efflux from intestine cells to apolipoprotein A-I and HDL . This study suggests an intestine-specific O75469 / Q02318 /LXRalpha pathway that regulates intestine cholesterol efflux and HDL assembly . Angiotensin-converting-enzyme inhibitors suppress synthesis of tumour necrosis factor and interleukin 1 by human peripheral blood mononuclear cells . Administration of angiotensin-converting-enzyme ( P12821 ) inhibitors reduce vascular proliferation following endothelial injury as well as progression of renal disease in various animal models . These effects might be due to interference with cytokines such as interleukin 1 ( IL-1 ) or tumour necrosis factor alpha ( P01375 ) since they have been implicated in regulating the effects of vascular cell growth factors such as fibroblast- and platelet-derived growth factors . We investigated the in vitro synthesis of IL-1 and P01375 from human peripheral blood mononuclear cells ( PBMC ) in the presence of various P12821 -inhibitors . DB01197 dose-dependently suppressed the P01584 -induced synthesis of P01375 by 74 % ( P < 0.01 ) and the P01584 -induced synthesis of P01583 by 60 % ( P < 0.01 ) . Cytokine synthesis induced by lipopolysaccharide was less affected . At concentrations suppressing P01375 and IL-1 , captopril did not reduce the synthesis of complement P01024 in the same cells . Enalapril and cilazapril also suppressed cytokine-induced cytokine synthesis . Ramipril , lisinopril , perindopril and spirapril had no significant effect on P01375 synthesis suggesting that the effect was not related specifically to the inhibition of P12821 . Accumulation of mRNA for IL-1 and P01375 were not affected by captopril , suggesting a posttranscriptional effect . We conclude that certain P12821 -inhibitors suppress IL-1 and P01375 synthesis at a posttranscriptional level and might therefore influence cytokine-mediated cell growth . Therapy with a synthetic retinoid -- ( Ro 10-1670 ) etretin -- increases the cellular retinoic acid-binding protein in nonlesional psoriatic skin . Cellular retinol ( P09455 ) -and retinoic acid ( CRABP ) -binding proteins were determined in samples of lesional and nonlesional skin of psoriatic patients , before and during oral administration of a synthetic retinoid , DB00459 ( Ro 10-1670 ) . A 200 % increase in CRABP levels , measured by the ability of the protein to bind retinoic acid , was observed in the normal skin during treatment . The P09455 levels were not altered during therapy . The results show that P09455 and CRABP are independently regulated in human skin and suggest that synthetic retinoids may exert their pharmacologic effects by interfering with the regulation of natural retinoic acid receptors . Desmopressin ( DB00035 ) induces NO production in human endothelial cells via V2 receptor- and DB02527 -mediated signaling . The hemostatic agent desmopressin ( DB00035 ) also has strong vasodilatory effects . DB00035 is a selective agonist for the vasopressin V2 receptor ( P30518 ) , which is coupled to DB02527 -dependent signaling . DB00035 -induced vasodilation may be due to endothelial NO synthase ( P29474 ) activation . This hypothesis implies DB02527 -mediated P29474 activation . It also implies wide extrarenal , endothelial P30518 expression . We show that in human umbilical vein endothelial cells ( HUVECs ) the DB02527 -raising agents forskolin and epinephrine increase NO production , as measured by a l-NMMA-inhibitable rise in cellular cGMP content . They also increase P29474 enzymatic activity , in a partly calcium-independent manner . DB02527 -mediated P29474 activation is associated with phosphorylation of residue Ser1177 , in a phosphatidyl inositol 3-kinase ( PI3K ) -independent manner . HUVECs do not express P30518 . However , after heterologous P30518 expression , DB00035 induces DB02527 -dependent P29474 activation via Ser1177 phosphorylation . We have previously found P30518 expression in cultured lung endothelial cells . By real time quantitative RT-PCR , we now find a wide P30518 distribution notably in heart , lung and skeletal muscle . These results indicate that DB00035 and other DB02527 -raising agents can activate P29474 via PI3K-independent Ser1177 phosphorylation in human endothelial cells . This mechanism most likely accounts for DB00035 -induced vasodilation . (Pro)renin promotes fibrosis gene expression in P29320 cells through a Nox4-dependent mechanism . The (pro)renin receptor ( PRR ) has recently been demonstrated to bind equally well renin and its precursor , prorenin , leading to a similar intracellular signaling independent of angiotensin II . In this study , we report that human embryonic kidney cells ( P29320 ) exposed to renin or prorenin for 24 h in the presence of a blocking concentration of the angtiotensin-converting enzyme inhibitor perindoprilate increased superoxide anion production as measured by luminescence ( lucigenin ) and electron spin resonance spectroscopy ( hydroxylamine radical transition ) . Also , both renin and prorenin increased Nox4 expression while Nox2 , p47(phox) , and p67(phox) remained unchanged . In an investigation of the effects of renin and prorenin on fibrosis genes , it appeared that both proteins stimulated transforming growth factor-β ( TGF-β ) , fibronectin , and plasminogen activator inhibitor type 1 ( P05121 ) expression and therefore participated to an overall switch toward a profibrotic state of the kidney cells . When the cells were transfected with a siRNA targeting the PRR , Nox4 expression was efficiently prevented as well as the increase in superoxide production , TGF-β , fibronectin , and P05121 . Finally , we demonstrated that transfection of the cells with a Nox4-specific small interfering ( si ) RNA also prevented fibrosis gene expression following treatment with renin or prorenin . The results demonstrate that renin and prorenin , through their specific membrane receptor and independently of angiotensin II , promote fibrosis gene expression via a Nox4-dependent mechanism . Preservation of P09038 bioactivity using heparin-based nanoparticles , and their delivery from electrospun chitosan fibers . Here we present a novel matrix-mimetic nanoassembly based on polysaccharides . Chitosan electrospun fiber networks are decorated with heparin-containing polyelectrolyte complex nanoparticles ( PCNs ) that present basic fibroblast growth factor ( P09038 ) , both stably adsorbed to the surfaces and released into solution . These P09038 / Q15149 complexes can be released from the fibers with zero-order kinetics over a period of 30 days . Further modification of fibers with a single bilayer of polyelectrolyte multilayer ( P15941 ) composed of N,N,N-trimethyl chitosan and heparin completely prevent release , and the P09038 / Q15149 complexes are retained on the fibers for the duration of the release experiment ( 30 days ) . We also compare the mitogenic activity of these P09038 / Q15149 complexes delivered in two different states : adsorbed to a surface and dissolved in solution . P09038 / Q15149 complexes exhibit mitogenic activity with respect to ovine bone marrow-derived DB05914 , even after being preconditioned by incubating for 27 days at 37°C in solution . However , when the P09038 / Q15149 complexes are adsorbed to chitosan and coated with PEMs , the mitogenic activity of the P09038 steadily decreases with increasing preconditioning time . This work demonstrates a new system for stabilizing and controlling the delivery of heparin-binding growth factors , using polysaccharide-based matrix-mimetic nanomaterials . This work also contributes to our understanding of the preferred mode of growth factor delivery from porous scaffolds . Purinergic receptors contribute to early mesangial cell transformation and renal vessel hypertrophy during angiotensin II-induced hypertension . Chronic P03950 II infusions lead to increases in intrarenal P03950 II levels , hypertension , and tissue injury . Increased blood pressure also elicits increases in renal interstitial fluid ( Q9HBH0 ) DB00171 concentrations that stimulate cell proliferation . We evaluated the contribution of purinergic receptor activation to P03950 II-induced renal injury in rats by treating with clopidogrel , a Q9H244 receptor blocker , or with PPADS , a nonselective P2 receptor blocker . alpha-Actin expression in mesangial cells , afferent arteriolar wall thickness ( AAWT ) , cortical cell proliferation , and macrophage infiltration were used as early markers of renal injury . DB00758 and PPADS did not alter blood pressure , renin or kidney P03950 II content . alpha-Actin expression increased from control of 0.6 +/- 0.4 % of mesangial area to 6.3 +/- 1.9 % in P03950 II-infused rats and this response was prevented by clopidogrel ( 0.4 +/- 0.2 % ) and PPADS . The increase in AAWT from 4.7 +/- 0.1 to 6.0 +/- 0.1 mm in P03950 II rats was also prevented by clopidogrel ( 4.8 +/- 0.1 mm ) and PPADS . P03950 II infusion led to interstitial macrophage infiltration ( 105 +/- 16 vs. 62 +/- 4 cell/mm(2) ) and tubular proliferation ( 71 +/- 15 vs. 20 +/- 4 cell/mm(2) ) and these effects were prevented by clopidogrel ( 52 +/- 4 and 36 +/- 3 cell/mm(2) ) and PPADS . Q9HBH0 DB00171 levels were higher in P03950 II-infused rats than in control rats ( 11.8 +/- 1.9 vs. 5.6 +/- 0.6 nmol/l , P < 0.05 ) . The results suggest that activation of vascular and glomerular purinergic P2 receptors may contribute to the mesangial cell transformation , renal inflammation , and vascular hypertrophy observed in P03950 II-dependent hypertension . A novel mutation in P30518 causing congenital nephrogenic diabetes insipidus with complete resistance to antidiuretic hormone . A 6-month-old male infant presented with failure to thrive . Hypernatraemia and elevated serum osmolality in the presence of low urine sodium and osmolality led to the diagnosis of diabetes insipidus . Administration of DB00035 ( dDAVP ) neither decreased urine volume nor increased urine osmolality indicating congenital nephrogenic diabetes insipidus . Molecular analysis in the arginine-vasopressin receptor-2 gene ( P30518 ) located on chromosome Xq28 demonstrated a novel 5-base pair deletion ( c.962-966delACCCC ; g.1429-1433delACCCC ) leading to a shift of the reading frame ( p.Asn321fs ) and a premature termination codon implying an absent or non-functional protein . Treatment with hydrochlorothiazide , amiloride and indomethacin led to a favourable clinical course . Agonism at P41595 receptors is not a class effect of the ergolines . Restrictive cardiac valvulopathies observed in Parkinson patients treated with the ergoline dopamine agonist pergolide have recently been associated with the agonist efficacy of the drug at 5-hydroxytryptamine2B ( P41595 ) receptors . To evaluate whether agonism at P41595 receptors is a phenomenon of the class of the ergolines , we studied P41595 receptor-mediated relaxation in porcine pulmonary arteries to five ergolines which are used as antiparkinsonian drugs . DB01186 and cabergoline were potent full agonists in this tissue ( pEC50 8.42 and 8.72 ) . DB01200 acted as a partial agonist ( pEC50 6.86 ) . Lisuride and terguride , however , failed to relax the arteries but potently antagonized 5-HT-induced relaxation ( pKB 10.32 and 8.49 ) . Thus , agonism at P41595 receptors seems not to be a class effect of the ergolines . Inhibition of histamine H1 receptor activity modulates proinflammatory cytokine production of dendritic cells through c-Rel activity . BACKGROUND : DB11320 exerts diverse effects on immune regulation through four types of histamine receptors ( HRs ) . Among them , type 1 receptor ( P35367 ) plays an important role in allergic inflammation . Dendritic cells ( DCs ) , which express at least three types of HRs , are professional antigen-presenting cells controlling the development of allergic inflammation . However , the molecular mechanisms involved in P35367 -mediated NF-ĸB signaling of DCs remain poorly defined . METHODS : Bone-marrow ( BM ) -derived DCs ( BM-DCs ) were treated with P35367 inverse agonists to interrupt basal P35367 -mediated signaling . The crosstalk of P35367 -mediated signaling and the NF-ĸB pathway was examined by NF-ĸB cellular activity using a luciferase reporter assay , NF-ĸB subunit analysis using Western blotting and P01375 -α promoter activity using chromatin immunoprecipitation . RESULTS : Blockage of P35367 signaling by inverse agonists significantly inhibited P01375 -α and P05231 production of BM-DCs . P35367 -specific agonists were able to enhance P01375 -α production , but this overexpression was significantly inhibited by NF-ĸB inhibitor . The P35367 inverse agonist ketotifen also suppressed cellular NF-ĸB activity , suggesting crosstalk between P35367 and NF-ĸB signaling in DCs . After comprehensive analysis of NF-ĸB subunits , c-Rel protein expression was significantly down-regulated in ketotifen-treated BM-DCs , which led to inhibition of the promoter activity of P01375 -α . Finally , adoptive transfer of the ketotifen-treated BM-DCs did not induce significant allergic airway inflammation compared to that of control cells in vivo . CONCLUSIONS : Our results suggest that c-Rel controls P35367 -mediated proinflammatory cytokine production in DCs . This study provides a potential mechanism of P35367 -mediated signaling and NF-ĸB pathway crosstalk in allergic inflammation . DB11320 stimulates hydrogen peroxide production by bronchial epithelial cells via histamine H1 receptor and dual oxidase . Oxidative stress has been implicated in the pathogenesis of bronchial asthma . Besides granulocytes , the airway epithelium can produce large amounts of reactive oxygen species and can contribute to asthma-related oxidative stress . DB11320 is a major inflammatory mediator present in large quantities in asthmatic airways . Whether histamine triggers epithelium-derived oxidative stress is unknown . We therefore aimed at characterizing human airway epithelial H2O2 production stimulated by histamine . We found that air-liquid interface cultures of primary human bronchial epithelial cells ( BECs ) and an immortalized BEC model ( Cdk4/hTERT HBEC ) produce H2O2 in response to histamine . The main source of airway epithelial H2O2 is an NADPH dual oxidase , Duox1 . Out of the four histamine receptors ( P35367 - Q9H3N8 ) , P35367 has the highest expression in BECs and mediates the H2O2-producing effects of histamine . P05112 induces Duox1 gene and protein expression levels and enhances histamine-induced H2O2 production by epithelial cells . Using P29320 -293 cells expressing Duox1 or Duox2 and endogenous P35367 , histamine triggers an immediate intracellular calcium signal and H2O2 release . Overexpression of P35367 further increases the oxidative output of Duox-expressing P29320 -293 cells . Our observations show that BECs respond to histamine with Duox-mediated H2O2 production . These findings reveal a mechanism that could be an important contributor to oxidative stress characteristic of asthmatic airways , suggesting novel therapeutic targets for treating asthmatic airway disease . A Kaposi 's sarcoma-associated herpesvirus protein that forms inhibitory complexes with type I interferon receptor subunits , Jak and P35610 proteins , and blocks interferon-mediated signal transduction . Type I interferons ( IFNs ) are important mediators of innate antiviral defense and function by activating a signaling pathway through their cognate type I receptor ( P17181 ) . Here we report that lytic replication of Kaposi 's sarcoma-associated herpesvirus ( KSHV ) efficiently blocks type I IFN signaling and that an important effector of this blockade is the viral protein Q9HBH0 , the product of open reading frame 10 . Q9HBH0 blocks IFN signaling by formation of inhibitory complexes that contain P17181 subunits , the Janus kinases Jak1 and Tyk2 , and the P52630 transcription factor . Activation of both Tyk2 and Jak1 is inhibited , and abnormal recruitment of P52630 to P17181 occurs despite the decrement in Tyk2 activity . As a result of these actions , phosphorylation of both P52630 and P42224 is impaired , with subsequent failure of ISGF3 accumulation in the nucleus . The presence in the viral genome of potent inhibitors of type I IFN signaling , along with several viral genes that block IFN induction , highlights the importance of the IFN pathway in the control of this human tumor virus infection . Direct oral anticoagulants in acute coronary syndrome . Patients with acute coronary syndromes ( ACS ) require a specific antithrombotic therapy in the immediate and the post ACS phase . The current antithrombotic therapy in the acute phase of an ACS combines antiplatelet and anticoagulant drugs in order to reduce ischemic cardiovascular events . In the post ACS phase , dual antiplatelet therapy ( DAPT ; aspirin and a Q9H244 receptor antagonist ) is the current mainstay of antithrombotic treatment and is recommended in the guidelines of the major North American and European clinical cardiology associations ( DB00551 , ACC , and ESC ) . Recently , the addition of rivaroxaban , a low dose oral direct factor Xa inhibitor ( 2.5 mg twice daily ) , to DAPT ( aspirin plus second-generation Q9H244 inhibitor ) showed a significant reduction of cardiovascular and overall mortality in the major phase III clinical trial ATLAS ACS 2 TIMI 51 . This led to the approval of low-dose rivaroxaban in addition to aspirin and clopidogrel by the European Medicines Agency ( P15941 ) in 2013 . Other direct oral anticoagulants ( apixaban , dabigatran etexilate ) have also been assessed in phase II ( dabigatran etexilate ) and phase III ( apixaban ) post ACS clinical trials . In the studied dosing regimens , these drugs failed to show a net clinical benefit in addition to dual antiplatelet therapy . The major clinical phase II and III post ACS studies of direct oral anticoagulants are summarized and discussed in this article along with the concept of long-term anticoagulation for the secondary prevention of ischemic events after ACS and implications for the future of antithrombotic therapy in the current era of third-generation Q9H244 receptor inhibitors ( Prasugrel and DB08816 ) . P29474 activation by HDL is impaired in genetic P11597 deficiency . Mutations in the P11597 gene resulting in defective P11597 activity have been shown to cause remarkable elevations of plasma HDL-C levels , with the accumulation in plasma of large , buoyant HDL particles enriched in apolipoprotein E. Genetic P11597 deficiency thus represents a unique tool to evaluate how structural alterations of HDL impact on HDL atheroprotective functions . Aim of the present study was to assess the ability of HDL obtained from P11597 -deficient subjects to protect endothelial cells from the development of endothelial dysfunction . HDL isolated from one homozygous and seven heterozygous carriers of P11597 null mutations were evaluated for their ability to down-regulate cytokine-induced cell adhesion molecule expression and to promote NO production in cultured endothelial cells . When compared at the same protein concentration , HDL and HDL3 from carriers proved to be as effective as control HDL and HDL3 in down-regulating cytokine-induced P19320 , while carrier HDL2 were more effective than control HDL2 in inhibiting P19320 expression . On the other hand , HDL and HDL fractions from carriers of P11597 deficiency were significantly less effective than control HDL and HDL fractions in stimulating NO production , due to a reduced P29474 activating capacity , likely because of a reduced Q14703 content . In conclusion , the present findings support the notion that genetic P11597 deficiency , by affecting HDL particle structure , impacts on HDL vasculoprotective functions . Understanding of these effects might be important for predicting the outcomes of pharmacological P11597 inhibition . P35443 polymorphism ( A387P ) predicts cardiovascular risk in postinfarction patients with high HDL cholesterol and P02741 levels . Few studies are available in human populations investigating involvement of vascular inflammation and oxidative stress-related dysfunctional transformation of high-density lipoprotein ( HDL ) in establishing cardiovascular disease ( CVD ) risk . To this end , the current work investigated a subgroup of post-infarction patients at high-risk for recurrent events defined by high levels of HDL cholesterol ( HDL-C ) and concurrently high levels of P02741 ( CRP ) . P35443 ( P07996 -4 ) , a matricellular protein of vessel walls associated with inflammation , was investigated in terms of CVD risk using multivariable modelling with a well-characterised functional genetic polymorphism of P35443 ( A387P , rs1866389 ) along with previously demonstrated risk-related functional genetic polymorphisms of P13498 ( C242T , rs4673 ) and P11597 ( TaqIB , rs708272 ) , and a set of blood markers . Results revealed risk-association for the gain-of-function P-allele of the P35443 polymorphism ( hazard ratio 2.00 , 95 % confidence interval 1.10-3.65 , p=0.024 ) . Additionally , P04275 was associated with D-dimer levels in the higher-risk P allele patients suggestive of a connection between endothelial dysfunction and thrombogenesis . In conclusion , P07996 -4 , a matricellular protein involved in regulating vascular inflammation , plays a role in establishing recurrent coronary risk in post-infarction patients with high levels of HDL-C and CRP . Further studies should focus on additional effects of vascular inflammatory processes on anti-atherogenic functionality of HDL particles . [ Prominent features of management strategies in acute coronary syndromes with the new oral antiplatelet agents ] . The novel oral Q9H244 inhibitors ( prasugrel and ticagrelor ) have been incorporated into the recently updated acute coronary syndrome ( ACS ) guidelines , as an adjunct antiplatelet treatment to aspirin . The studies involving the use of new oral antiplatelet agents that are more potent , predictable and faster platelet inhibitors than clopidogrel have demonstrated superiority with respect to the primary composite endpoint ( cardiovascular death , non-lethal myocardial infarction , stroke ) for both prasugrel and ticagrelor compared to clopidogrel . The subgroup analysis of the relevant studies showed that these new agents differ in their level of efficacy in different ACS patient subgroups : ( 1 ) Mortality was reduced with ticagrelor ; ( 2 ) DB08816 is especially more effective in intermediate-and high-risk non-ST elevation ACS patients in whom early invasive strategy is selected ; ( 3 ) Prasugrel should be especially preferred in patients with acute ST elevation myocardial infarction undergoing percutaneous coronary intervention ( P05154 ) after diagnostic angiography ; and ( 4 ) Prasugrel is more effective in diabetic patients . While clopidogrel is recommended for ACS patients who are followed with a non-invasive strategy or who have not undergone percutaneous revascularization , it is the last line choice or an alternative to the Q9H244 inhibitor therapy for patients undergoing invasive strategy . Evidence of drug-drug interactions through uptake and efflux transport systems in rat hepatocytes : implications for cellular concentrations of competing drugs . For drugs with hepatobiliary transport across hepatocytes , the interplay between uptake and efflux transporters determines hepatic concentrations of drugs , but the evolution over time of these concentrations is difficult to measure in humans other than with magnetic resonance imaging contrast agents in the liver . DB00743 dimeglumine ( BOPTA ) is a contrast agent used in liver magnetic resonance imaging that enters into human hepatocytes through organic anion transporting polypeptides ( P46721 ) and exits unchanged into bile through the multiple resistance-associated protein 2 ( Q92887 ) . DB01045 ( Q9HBH0 ) is transported by the same membrane proteins and may compete with BOPTA for hepatic uptake . Simultaneous drug-drug interactions through uptake and efflux transport systems in hepatocytes according to the cellular concentrations of competing drugs were never investigated . In perfused rat liver preparations , we demonstrate how the drug-drug interactions through transporters determine cellular concentrations of the competing drugs BOPTA and Q9HBH0 , and we show that the cellular concentrations by modulating transport through membranes regulate the rat Oatp-Mrp2 interplay . Moreover , drug interactions through transporters change greatly over time . Diet induced regulation of genes involved in cholesterol metabolism in rat liver parenchymal and Kupffer cells . BACKGROUND/AIMS : Feeding rodents atherogenic diets enriched in cholesterol or cholic acid changes hepatic cholesterol metabolism . In the present study , the effect of an atherogenic diet enriched in cholesterol and cholic acid on cellular hepatic cholesterol metabolism was studied . METHODS : Gene and protein expression analysis was performed on parenchymal , endothelial , and Kupffer cells isolated from rats fed a chow or atherogenic diet using quantitative real-time PCR and immunoblotting , respectively . RESULTS : The atherogenic diet raised the serum cholesterol concentration 11-fold , mostly in the VLDL fraction , and led to heavy lipid loading of rat liver parenchymal and Kupffer cells . Only moderate changes in the expression of genes involved in cholesterol metabolism were observed in parenchymal cells on the diet , while Q07869 delta expression was 6.8-fold decreased . Kupffer cells , however , showed a highly adaptive response with a 2- to 9-fold induction of Q8WTV0 , O95477 , and Q9H222 / Q9UBA6 , and an 82-fold induction in P22680 mRNA expression , respectively . CONCLUSIONS : Heavy lipid loading of parenchymal cells leads to moderate gene expression changes , while Kupffer cells respond in a highly adaptive fashion by stimulating the expression of genes involved in cholesterol metabolism and transport . Signaling by retinol and its serum binding protein . DB00162 , retinol , circulates in blood bound to retinol-binding protein ( P02753 ) which , in turn , associates with transthyretin ( P02766 ) to form a retinol- P02753 - P02766 ternary complex . At some tissues , retinol-bound ( holo- ) P02753 is recognized by a membrane protein termed Q9BX79 , which transports retinol from extracellular P02753 into cells and , concomitantly , activates a O60674 / P40763 /5 signaling cascade that culminates in induction of P35610 target genes . Q9BX79 -mediated retinol transport and cell signaling are critically inter-dependent , and they both require the presence of cellular retinol-binding protein 1 ( P09455 ) , an intracellular retinol acceptor , as well as a retinol-metabolizing enzyme such as lecithin:retinol acyltransferase ( O95237 ) . Q9BX79 thus functions as a " cytokine signaling transporter " which couples vitamin A homeostasis and metabolism to cell signaling , thereby regulating gene transcription . Recent studies provided molecular level insights into the mode of action of this unique protein . P05231 and MYC collaborate in plasma cell tumor formation in mice . P05231 ( P05231 ) plays a critical role in the natural history of human plasma cell neoplasms ( PCNs ) , such as plasma cell myeloma and plasmacytoma ( PCT ) . P05231 is also at the center of neoplastic plasma cell transformation in BALB/c ( C ) mice carrying a transgene , H2-L(d)- P05231 , that encodes human P05231 under control of the major histocompatibility complex H2-L(d) promoter : strain C.H2-L(d)- P05231 . These mice are prone to PCT , but tumor development is incomplete with long latencies ( approximately 40 % PCT at 12 months of age ) . To generate a more robust mouse model of P05231 -dependent Q15149 , we intercrossed strain C.H2-L(d)- P05231 with strains C.iMyc(Emu) or C.iMyc(Calpha) , 2 interrelated gene-insertion models of the chromosomal T(12;15) translocation causing deregulated expression of Myc in mouse PCT . Deregulation of MYC is also a prominent feature of human Q15149 . We found that double-transgenic C.H2-L(d)- P05231 /iMyc(Emu) and C.H2-L(d)- P05231 /iMyc(Calpha) mice develop PCT with full penetrance ( 100 % tumor incidence ) and short latencies ( 3-6 months ) . The mouse tumors mimic molecular hallmarks of their human tumor counterparts , including elevated P05231 /Stat3/Bcl-X(L) signaling . The newly developed mouse strains may provide a good preclinical research tool for the design and testing of new approaches to target P05231 in treatment and prevention of human PCNs . Reciprocal negative cross-talk between liver X receptors ( LXRs ) and P42224 : effects on IFN-γ-induced inflammatory responses and LXR-dependent gene expression . Liver X receptors ( LXRs ) exert key functions in lipid homeostasis and in control of inflammation . In this study we have explored the impact of LXR activation on the macrophage response to the endogenous inflammatory cytokine IFN-γ . Transcriptional profiling studies demonstrate that ∼38 % of the IFN-γ-induced transcriptional response is repressed by LXR activation in macrophages . LXRs also mediated inhibitory effects on selected IFN-γ-induced genes in primary microglia and in a model of IFN-γ-induced neuroinflammation in vivo . LXR activation resulted in reduced P42224 recruitment to the promoters tested in this study without affecting P42224 phosphorylation . A closer look into the mechanism revealed that SUMOylation of LXRs , but not the presence of nuclear receptor corepressor 1 , was required for repression of the NO synthase 2 promoter . We have also analyzed whether IFN-γ signaling exerts reciprocal effects on LXR targets . Treatment with IFN-γ inhibited , in a P42224 -dependent manner , the LXR-dependent upregulation of selective targets , including DB00171 -binding cassette A1 ( O95477 ) and sterol response element binding protein 1c . Downregulation of O95477 expression correlated with decreased cholesterol efflux to apolipoprotein A1 in macrophages stimulated with IFN-γ . The inhibitory effects of IFN-γ on LXR signaling did not involve reduced binding of LXR/retinoid X receptor heterodimers to target gene promoters . However , overexpression of the coactivator Q92793 /p300 reduced the inhibitory actions of IFN-γ on the Abca1 promoter , suggesting that competition for Q92793 may contribute to P42224 -dependent downregulation of LXR targets . The results from this study suggest an important level of bidirectional negative cross-talk between IFN-γ/ P42224 and LXRs with implications both in the control of IFN-γ-mediated immune responses and in the regulation of lipid metabolism . Cloning of chick cellular retinol-binding protein , type II and comparison to that of some mammals : expression of the gene at different developmental stages , and possible involvement of RXRs and Q07869 . We cloned chick cellular retinol-binding protein , type two ( P09455 II ) cDNA and compared it with those of some mammals . The deduced amino acid sequence showed that chick P09455 II was one amino acid greater in size than those of mammals , and the nucleotide sequence of chick P09455 II shared 72 % -75 % similarity with those of mammals . RNA blot hybridization analysis showed that P09455 II transcript of 0.7 kb was first detected in the duodenum of day-18 embryonic chick , and exhibited a rapid increase during 24 hr around the hatching . Northern blot hybridization also revealed that the transcripts of two types of retinoid X receptors ( RXR alpha and RXR gamma ) and peroxisome proliferator-activated receptor ( Q07869 ) were expressed in the chick duodenum at hatching . The organ culture of day 16 embryonic chick duodenum showed that the addition of 9-cis retinoic acid in the medium caused a significant increase in P09455 II mRNA levels . In addition , arachidonic acid , from which putative ligands for Q07869 were supposed to be generated , was accumulated around hatching in the duodenum . The results may suggest that the abrupt increase of the P09455 II gene expression in the chick duodenum around hatching may be related with RXRs and/or Q07869 . Augmentation of methamphetamine-induced behaviors in transgenic mice lacking the trace amine-associated receptor 1 . The trace amine-associated receptor 1 ( Q96RJ0 ) is a G protein-coupled receptor that is functionally activated by amphetamine-based psychostimulants , including amphetamine , methamphetamine and DB01454 . Previous studies have shown that in transgenic mice lacking the Q96RJ0 gene ( Q96RJ0 knockout ; KO ) a single injection of amphetamine can produce enhanced behavioral responses compared to responses evoked in wild-type ( WT ) mice . Further , the psychostimulant effects of cocaine can be diminished by selective activation of Q96RJ0 . These findings suggest that Q96RJ0 might be implicated in the rewarding properties of psychostimulants . To investigate the role of Q96RJ0 in the rewarding effects of drugs of abuse , the psychomotor stimulating effects of amphetamine and methamphetamine and the conditioned rewarding effects of methamphetamine and morphine were compared between WT and Q96RJ0 KO mice . In locomotor activity studies , both single and repeated exposure to DB01576 or methamphetamine generated significantly higher levels of total distance traveled in Q96RJ0 KO mice compared to WT mice . In conditioned place preference ( CPP ) studies , Q96RJ0 KO mice acquired methamphetamine-induced CPP earlier than WT mice and retained CPP longer during extinction training . In morphine-induced CPP , both WT and KO genotypes displayed similar levels of CPP . Results from locomotor activity studies suggest that Q96RJ0 may have a modulatory role in the behavioral sensitization to amphetamine-based psychostimulants . That methamphetamine-but not morphine-induced CPP was augmented in Q96RJ0 KO mice suggests a selective role of Q96RJ0 in the conditioned reinforcing effects of methamphetamine . Collectively , these findings provide support for a regulatory role of Q96RJ0 in methamphetamine signaling . Genetic determinants of serum lipid levels in Chinese subjects : a population-based study in Shanghai , China . We examined the associations between 21 single nucleotide polymorphisms ( SNPs ) of eight lipid metabolism genes and lipid levels in a Chinese population . This study was conducted as part of a population-based study in China with 799 randomly selected healthy residents who provided fasting blood and an in-person interview . Associations between variants and mean lipid levels were examined using a test of trend and least squares mean test in a general linear model . Four SNPs were associated with lipid levels : P01130 rs1003723 was associated with total cholesterol ( P-trend = 0.002 ) and LDL ( P-trend = 0.01 ) , P01130 rs6413503 was associated with total cholesterol ( P-trend = 0.05 ) , P04114 rs1367117 was associated with apoB ( P-trend = 0.02 ) , and O95342 rs49550 was associated with total cholesterol ( P-trend = 0.01 ) , triglycerides ( P-trend = 0.01 ) , and apoA ( P-trend = 0.01 ) . We found statistically significant effects on lipid levels for P01130 rs6413503 among those with high dairy intake , P06858 rs263 among those with high allium vegetable intake , and P02649 rs440446 among those with high red meat intake . We identified new associations between SNPs and lipid levels in Chinese previously found in Caucasians . These findings provide insight into the role of lipid metabolism genes , as well as the mechanisms by which these genes may be linked with disease . The mechanism of the G0/ P55008 cell cycle phase arrest induced by activation of O75469 in human cells . CONTEXT : O75469 ( O75469 ) is an important transcriptional regulator that plays important roles in the cell metabolism and cell growth by regulating the transcriptional of a sort of metabolizing enzymes . OBJECTIVE : To investigate whether rifampicin effected HepG2 cells growth and the inhibition was due to the G0/ P55008 phase arrest . METHODS : O75469 -knockdown experiments using RNAi showed that the cell cycle phase arrest mediated by rifampicin based on activation of O75469 . The results also indicated that cell phase arrest by rifampicin could protect cells form UVB-induced DNA damage . P19793 ( RXRα ) expression level in cells is another key factor for cell cycle phase arrest mediated by rifampicin . Both over expression and lacking expression of RXRα in cell reduced the cell arrest efficiency mediated by rifampicin . In the study , we found that rifampicin inhibited HepG2 cells growth and demonstrated that the inhibition is due to the G0/ P55008 phase arrest through flow cytometry analysis . CONCLUSION : The results showed that RXRα promote cell cycle phase transition rate of HepG2 . Competitive bind of rifampicin-activated O75469 with RXRα is one main reason to arrest cell cycle phase through inhibiting combination of RXRα with other partners . DB01045 could promote cell growth rate when RXRα expressed more excessively than O75469 in cells . Regulation of P61073 gene expression in breast cancer cells under diverse stress conditions . Chronic inflammation is a critical component in breast cancer progression . Pro-inflammatory mediators along with growth/survival factors within the tumor microenvironment potentiate the expression of pro-inflammatory cytokines ( IL-1 , P05231 , P01375 -α ) , chemotactic cytokines and their receptors ( P61073 , P48061 , P10145 ) and angiogenic factors ( P15692 ) that often overcome the effect of anti-inflammatory molecules ( P05112 , P22301 ) thus evading the host 's antitumor immunity . Detailed knowledge , therefore , of the regulatory mechanisms determining cytokine levels is essential to understand the pathogenesis of breast cancer . HIF-1α and NF-κB transcription factors are important players for the establishment of a pro-inflammatory and potentially oncogenic environment . HIF-1α is the key mediator of the cellular response to oxygen deprivation and induces the expression of genes involved in survival and angiogenesis within solid hypoxic tumors . The expression of these genes is often modulated by the p53 tumor suppressor protein that induces apoptosis or cell cycle arrest in neoplastic cells . Functional crosstalk between HIF-1α and p53 pathways mediated by modulators shared between the two transcription factors such as Q15788 and SIRT-1 differentially regulate the expression of distinct subsets of their target genes under variable stress conditions . In an attempt to shed light on the complex regulatory mechanisms involved in cancer-related inflammation , we investigated the role of the two common p53 and HIF-1α co-regulators Q15788 and SIRT-1 , in the expression of the highly potent metastatic chemokine receptor P61073 . Both Q15788 and SIRT-1 overexpression in DSFX-treated MCF-7 cells reduced P61073 cellular levels implying that both co-regulators are crucial factors in the determination of the metastatic potential of breast cancer cells . Molecular mechanisms governing different pharmacokinetics of ginsenosides and potential for ginsenoside-perpetrated herb-drug interactions on Q9NPD5 . BACKGROUND AND PURPOSE : Ginsenosides are bioactive saponins derived from Panax notoginseng roots ( Sanqi ) and ginseng . Here , the molecular mechanisms governing differential pharmacokinetics of 20(S)-protopanaxatriol-type ginsenoside Rg1 , ginsenoside Re and notoginsenoside Q96GN5 and 20(S)-protopanaxadiol-type ginsenosides Rb1 , Rc and Rd were elucidated . EXPERIMENTAL APPROACH : Interactions of ginsenosides with human and rat hepatobiliary transporters were characterized at the cellular and vesicular levels . A rifampin-based inhibition study in rats evaluated the in vivo role of organic anion-transporting polypeptide (Oatp)1b2 . Plasma protein binding was assessed by equilibrium dialysis . Drug-drug interaction indices were calculated to estimate potential for clinically relevant ginsenoside-mediated interactions due to inhibition of human OATP1Bs . KEY RESULTS : All the ginsenosides were bound to human Q9NPD5 and rat Oatp1b2 but only the 20(S)-protopanaxatriol-type ginsenosides were transported . Human multidrug resistance-associated protein (MRP)2/breast cancer resistance protein ( Q9UNQ0 ) /bile salt export pump ( O95342 ) /multidrug resistance protein-1 and rat Mrp2/Bcrp/Bsep also mediated the transport of the 20(S)-protopanaxatriol-type ginsenosides . Glomerular-filtration-based renal excretion of the 20(S)-protopanaxatriol-type ginsenosides was greater than that of the 20(S)-protopanaxadiol-type counterparts due to differences in plasma protein binding . DB01045 -impaired hepatobiliary excretion of the 20(S)-protopanaxatriol-type ginsenosides was effectively compensated by the renal excretion in rats . The 20(S)-protopanaxadiol-type ginsenosides were potent inhibitors of Q9NPD5 . CONCLUSION AND IMPLICATIONS : Differences in hepatobiliary and in renal excretory clearances caused markedly different systemic exposure and different elimination kinetics between the two types of ginsenosides . Caution should be exercised with the long-circulating 20(S)-protopanaxadiol-type ginsenosides as they could induce hepatobiliary herb-drug interactions , particularly when patients receive long-term therapies with high-dose i.v. Sanqi or ginseng extracts . Resistance to killing by tumor necrosis factor in an adipocyte cell line caused by a defect in arachidonic acid biosynthesis . We have found that Q96RJ0 -R6 , which are resistant to the cytotoxic effects of tumor necrosis factor ( P01375 ) in the presence of cycloheximide ( Reid , T. R. , Torti , F. , and Ringold , G. M. ( 1989 ) J. Biol. Chem. 264 , 4583-4589 ) , have reduced ability to release arachidonic acid ( 20:4 ) from membrane phospholipids in response to either P01375 or the calcium ionophore A23187 treatment . However , no defect in the activity of phospholipase A2 , the principal enzyme responsible for the release of 20:4 from phospholipids , was observed in these cells . Detailed biochemical characterization of these P01375 -resistant cells has revealed that these cells are unable to synthesize 20:4 endogenously because of a defect in delta 6-desaturase , the rate-limiting enzyme of 20:4 biosynthesis . This deficiency leads to a marked decrease in the steady-state levels of 20:4 present in choline-containing phospholipid ( PC ) and ethanolamine-containing phospholipid ( PE ) . The Q96RJ0 -R6 cells , however , are capable of incorporating exogenous 20:4 into PC and PE , and when loaded in such manner they become significantly more sensitive to the cytotoxic effects of P01375 in the presence of cycloheximide . Therefore , the release of arachidonic acid from phospholipids appears to be a critical element in the signaling pathway utilized by P01375 and is essential to the rapid cytotoxic response elicited by P01375 in the absence of protein synthesis in wild-type Q96RJ0 cells .