interacts_with DB05239?
P08908 receptor-mediated regulation of mitogen-activated protein kinase phosphorylation in rat brain . Mitogen-activated protein kinases ( MAPKs ) , a family of signal transduction mediators important in a host of cellular activities , include the extracellular signal-regulated kinases Erk1 and Erk2 . We determined whether 5-HT(1A) receptors activate Erk1/2 in rat brain in vivo , as they do in recombinant cell lines . In contrast to the effect in cells , the 5-HT(1A) receptor agonist 8-hydroxy-N,N-diproylaminotetralin ( 8-OH-DPAT ) dose- and time-dependently decreased basal levels of phosphorylated Erk1/2 ( phospho-Erk1/2 ) in rat hippocampus ( ED(50) approximately 0.1 mg/kg , maximum approximately 90 % ) without altering total Erk1/2 . The effects were kinase-specific , as 8-OH-DPAT did not modify phosphorylated or total levels of the MAPKs c-Jun-N-terminal kinase/stress-activated protein kinase ( JNK/SAPK ) and p38 MAPK . Moreover , 8-OH-DPAT did not modify phospho-Erk1/2 in striatum or frontal cortex . The effect of 8-OH-DPAT was blocked by pretreatment with the selective 5-HT(1A) receptor antagonists N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide ( WAY 100635 ) , 1-(2-methoxyphenyl)-4-(4-[2-phthalimido]butyl)piperazine ( NAN-190 ) and 4-fluoro-N-(2-[4-(2-methoxyphenyl)1-piperazinyl]ethyl)-N-(2-pyridinyl)benzamide dihydrochloride ( p-MPPF ) , but not by the weak partial agonist/antagonist 8-(2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl)-8-azaspiro(4.5)decane-7,9-dione dihydrochloride ( BMY 7378 ) . Other 5-HT(1A) receptor agonists ( buspirone , gepirone and ipsapirone ) also reduced phospho-Erk1/2 levels in hippocampus . 8-OH-DPAT also reduced the levels of the upstream activator of Erk1/2 , phosphorylated extracellular signal-regulated kinase kinase ( phospho- Q02750 /2 ) , and at least one potential downstream target , the nuclear transcription factor phospho-Elk-1 . The region- and kinase-specific effects suggest that the Erk1/2 signal transduction cascade is likely an important differential mediator of 5-HT(1A) receptor-regulated events in the central nervous system . Tumor-derived exosomes promote tumor progression and T-cell dysfunction through the regulation of enriched exosomal microRNAs in human nasopharyngeal carcinoma . Tumor-derived exosomes contain biologically active proteins and messenger and microRNAs ( miRNAs ) . These particles serve as vehicles of intercellular communication and are emerging mediators of tumorigenesis and immune escape . Here , we isolated 30-100 nm exosomes from the serum of patients with nasopharyngeal carcinoma ( NPC ) or the supernatant of TW03 cells . Increased circulating exosome concentrations were correlated with advanced lymphoid node stage and poor prognosis in NPC patients ( P < 0.05 ) . TW03-derived exosomes impaired T-cell function by inhibiting T-cell proliferation and Th1 and Th17 differentiation and promoting Treg induction by NPC cells in vitro . These results are associated with decreases in P29323 , P42224 , and P40763 phosphorylation and increases in P42229 phosphorylation in exosome-stimulated T-cells . TW03-derived exosomes increased the proinflammatory cytokines IL-1β , P05231 , and P22301 but decreased IFNγ , P60568 , and Q16552 release from P01730 + or CD8+ T-cells . Furthermore , five commonly over-expressed miRNAs were identified in the exosomes from patient sera or NPC cells : hsa-miR-24-3p , hsa-miR-891a , hsa-miR-106a-5p , hsa-miR-20a-5p , and hsa-miR-1908 . These over-expressed miRNA clusters down-regulated the Q9P0L2 signaling pathway to alter cell proliferation and differentiation . Overall , these observations reveal the clinical relevance and prognostic value of tumor-derived exosomes and identify a unique intercellular mechanism mediated by tumor-derived exosomes to modulate T-cell function in NPC . Beyond statins : new lipid lowering strategies to reduce cardiovascular risk . Statins are the first-line therapy in LDL- DB04540 ( LDL-C ) reduction and its clinical use has contributed to significant prevention and treatment of atherosclerotic vascular disease . Yet , a significant proportion of patients remain at high risk . Recently , a number of new therapies have been developed to further lower LDL-C . These agents may provide clinical benefit on top of statin therapy in patients with high residual risk , severe hypercholesterolemia or as an alternative for patients who are intolerant to statins . We review four novel approaches based on the inhibition of proprotein convertase subtilisin/kexin type 9 ( Q8NBP7 ) , apolipoprotein-B100 ( apoB ) , Cholesteryl ester transport protein ( P11597 ) and microsomal triglyceride transfer protein ( P55157 ) . ApoB and P55157 inhibitors ( DB05528 and DB08827 ) are indicated only for homozygous familial hypercholesterolemia patients . The results of ongoing trials with P11597 and Q8NBP7 inhibitors may warrant a wider employment in different categories of patients at high risk for cardiovascular disease . DB00644 induction of extracellular-signal regulated kinase is blocked by inhibition of calmodulin . Our previous studies demonstrate that DB00644 -induced P29323 activation required influx of extracellular Ca2+ in alphaT3-1 and rat pituitary cells . In the present studies , we examined the hypothesis that calmodulin ( Cam ) plays a fundamental role in mediating the effects of Ca2+ on P29323 activation . Cam inhibition using W7 was sufficient to block DB00644 -induced reporter gene activity for the c-Fos , murine glycoprotein hormone alpha-subunit , and MAPK phosphatase ( MKP ) -2 promoters , all shown to require P29323 activation . Inhibition of Cam ( using a dominant negative ) was sufficient to block DB00644 -induced P29323 but not c-Jun N-terminal kinase activity activation . The Cam-dependent protein kinase ( CamK ) II inhibitor KN62 did not recapitulate these findings . DB00644 -induced phosphorylation of Q02750 and c-Raf kinase was blocked by Cam inhibition , whereas activity of phospholipase C was unaffected , suggesting that Ca2+/Cam modulation of the P29323 cascade potentially at the level of c-Raf kinase . Enrichment of Cam-interacting proteins using a Cam agarose column revealed that c-Raf kinase forms a complex with Cam . Reconstitution studies reveal that recombinant c-Raf kinase can associate directly with Cam in a Ca2+-dependent manner and this interaction is reduced in vitro by addition of W7 . Cam was localized in lipid rafts consistent with the formation of a Ca2+-sensitive signaling platform including the P30968 and c-Raf kinase . These data support the conclusion that Cam may have a critical role as a Ca2+ sensor in specifically linking Ca2+ flux with P29323 activation within the DB00644 signaling pathway . [ The effect of blood pressure-reducing therapy with captopril on tubular marker excretion in type-1 diabetics with nephropathy ] . A prospective open clinical trial was carried out with 23 hypertensive type I diabetics ( 13 men , ten women , mean age 49 +/- 9.1 years , duration of diabetes 18 +/- 9.1 years ) with early nephropathy . Glomerular and tubular renal function and metabolic parameters were monitored during 8 months ' treatment with the angiotensin converting enzyme ( P12821 ) inhibitor , captopril , in addition to previous antihypertensive treatment with one or more drugs . Blood pressure control tended to improve on captopril ( systolic pressures 152 +/- 13 vs 140 +/- 13 mm Hg , P < 0.05 ; diastolic pressures 89 +/- 10 vs 87 +/- 10 mm Hg , not significant ) . Proteinuria ( > 0.5 g/24 hours ) fell into the microalbuminuria range ( albumin excretion 2-20 mg/mmol creatinine ) in four out of 13 patients , and microalbuminuria disappeared in four out of ten patients . Urinary levels of the brush border enzyme O60502 ( NAG ) , a marker of tubular dysfunction , were initially raised and fell significantly after 8 months ' treatment with captopril ( 20.3 +/- 14.4 vs 8.8 +/- 8.1 U/g creatinine ; P < 0.01 ) . DB01197 did not affect metabolic control ( HbA1 , total , HDL and LDL cholesterol , triglycerides , apolipoproteins A1 and B ) or the insulin dosage . These results show that long-term treatment with captopril may favourably influence both albumin excretion and NAG activity , a marker of tubular dysfunction , in type I diabetics with nephropathy . Lectin-like oxidized P01130 -1 ( P78380 ) acts as a receptor for remnant-like lipoprotein particles ( RLPs ) and mediates RLP-induced migration of vascular smooth muscle cells . OBJECTIVE : Remnant-like lipoprotein particles ( RLPs ) have been implicated in atherogenesis especially by diabetic dyslipidemia ; however , their receptor(s) and effects on vascular smooth muscle cells ( VSMCs ) remain unclear . In this study , we examined if lectin-like oxidized P01130 -1 ( P78380 ) acts as a receptor for RLPs and its biological effects in VSMCs . METHODS AND RESULTS : RLPs were isolated from human plasma by immunoaffinity gel containing anti-apolipoprotein A-I and anti-apolipoprotein B-100 monoclonal antibodies . DiI-labeled RLPs were taken up by CHO- P04264 cells stably expressing P78380 but not by wild-type CHO- P04264 cells . RLPs induced P78380 expression and cell migration in bovine VSMCs ( BVSMCs ) , which were significantly suppressed by transfection with P78380 specific siRNAs . Inhibitors of metalloproteinases , epidermal growth factor ( P01133 ) receptor tyrosine kinase , heparin-binding P01133 -like growth factor ( HB- P01133 ) , p38 mitogen-activated protein kinase ( p38 MAPK ) , MAPK kinase ( Q02750 ) and phosphoinositide 3-kinase ( PI3K ) significantly blocked RLP-induced P78380 expression and cell migration of BVSMCs . CONCLUSIONS : The present study provides direct evidence that P78380 is a novel receptor for RLPs in VSMCs . P78380 -mediated uptake of RLPs may thus play important roles in atherogenesis by inducing P78380 expression and VSMC migration especially in the settings of postprandial hyperlipidemia , diabetes and metabolic syndrome . Differential regulation of cystic fibrosis transmembrane conductance regulator by interferon gamma in mast cells and epithelial cells . P13569 ( P13569 ) is a P13569 in epithelial cells ; recently , we identified it in mast cells . Previous work that we confirmed showed that interferon gamma ( IFNgamma ) down-regulated P13569 expression in epithelial cells ( T84 ) , but by contrast , we found that IFNgamma up-regulated P13569 mRNA and protein expression in rat and human mast cells . IFNgamma up-regulation of P13569 in mast cells was inhibited by p38 and extracellular signal-regulated kinase ( P29323 ) kinase inhibitors but not a Janus tyrosine kinase (JAK)2 inhibitor , whereas in T84 cells IFNgamma-mediated down-regulation of P13569 was O60674 -dependent and P29323 - and p38-independent . Furthermore , IFNgamma down-regulation of P13569 in T84 epithelial cells was P42224 -dependent , but up-regulation of P13569 in mast cells was P42224 -independent . Thus , differential regulatory pathways of P13569 expression in mast cells and epithelial cells exist that depend upon either p38/ P29323 or JAK/ P35610 pathways , respectively . Surprisingly , IFNgamma treatment of mast cells inhibited Cl(-) efflux , in contrast to up-regulation of P13569 /mRNA and protein expression . However , down-regulation of Cl(-) flux correlated with IFNgamma-mediated inhibition of mediator secretion . This and other work suggests that the effect of IFNgamma on P13569 expression in mast cells is important for their function . Serotonergic mechanisms in human allergic contact dermatitis . Expression of serotonin ( 5-hydroxytryptamine ; 5-HT ) , 5-HT receptors 1A ( 5-HT1AR ) and 2A , and serotonin transporter protein ( P31645 ) was studied in positive epicutaneous reactions to nickel sulphate in nickel-allergic patients , at 72 h post-challenge with the antigen . In addition , the effects of 5-HT2AR agonist 2,5-dimethoxy-4-iodoamphetamine ( DOI ) , and the selective serotonin reuptake inhibitors ( SSRIs ) citalopram and fluoxetine , were tested on nickel-stimulated peripheral blood mononuclear cells from nickel-allergic patients , regarding their proliferation and interleukin ( IL ) -2 production , as well as the effect of these SSRIs on a murine Langerhans ' cell-like line ( XS52 ) , regarding its IL-1beta production . Serotonin-positive platelets were increased in the inflamed skin compared with control skin . A decrease ( p < 0.01 ) in 5-HT1AR-positive mononuclear cells was evident in the eczematous skin compared with control skin , whereas 5-HT2AR- and P31645 -positive cells were increased ( p < 0.001 for both ) in the eczematous skin . Treatment of nickel-stimulated peripheral blood mononuclear cells with 5x10(-5) mol/l of DOI inhibited ( p < 0.01 ) the proliferation of nickel-stimulated peripheral blood mononuclear cells , while no effect was found regarding P60568 production . DB00215 at 10(-6) mol/l tended to inhibit the production of IL-1beta by the XS52 cell line . These results indicate the implication of the serotonergic system in the contact allergic reaction . JTT-705 blocks cell proliferation and angiogenesis through p38 kinase/p27(kip1) and Ras/ P38936 (waf1) pathways . The excessive proliferation and migration of vascular smooth muscle cells ( SMCs ) participate in the growth and instability of atherosclerotic plaque . We examined the direct role of a newly developed chemical inhibitor of cholesteryl ester transfer protein , JTT-705 , on SMC proliferation and angiogenesis in endothelial cells ( ECs ) . JTT-705 inhibited human coronary artery SMC proliferation . JTT-705 induced the phosphorylation of p38 mitogen-activated protein kinase ( MAPK ) and extracellular-signal-regulated kinases ( P29323 ) in SMCs . In addition , the anti-proliferative effects of JTT-705 in SMCs were blocked by p38 MAPK inhibitor . JTT-705 induced the upregulation of p- P38936 (waf1) , and this effect was blocked by dominant-negative Ras ( N17 ) , but not by inhibitors of p38 MAPK or P29323 . In addition , JTT-705 also induced the upregulation of p27(kip1) , and this effect was blocked by p38 MAPK inhibitor . Interestingly , culture medium from JTT-705-treated SMCs blocked human coronary artery EC tube formation in an in vitro model of angiogenesis indirectly via a decrease in vascular endothelial growth factor ( P15692 ) from SMCs and directly via an anti-proliferative effect in ECs . JTT-705 blocked the proliferation of SMCs through the activation of p38 kinase/p27(kip1) and Ras/ P38936 (waf1) pathways , and simultaneously blocked EC tube formation associated with a decrease in P15692 production from SMCs and an anti-proliferative effect in ECs . Our results indicate that JTT-705 may induce a direct anti-atherogenic effect in addition to its inhibitory effect of P11597 activity . A comparative study of the effects of inhibitory cytokines on human natural killer cells and the mechanistic features of transforming growth factor-beta . The major factors and mechanisms by which natural killer ( NK ) cells are inhibited in cancer patients have not yet been well defined . In this study , we conducted a comparative analysis of the effects of TGF-β , P22301 , and P05112 on primary NK cells , and it was demonstrated that ( 1 ) TGF-β most potently inhibited the overall function of NK cells . ( 2 ) It appears that TGF-β reduced the tyrosine phosphorylation of Syk and the expression of c-myc . ( 3 ) It was also found that the P60568 -induced promoter-binding activities of C-myb , AP-1 , CREB , and AR were also completely suppressed upon TGF-β treatment . Interestingly , TGF-β also completely suppressed other transcription factors , which are constitutively activated . Among these factors , we further confirmed roles of AP-1 in NK-92 cell activation through c-jun and Q02750 inhibitor assay . Our study provides insight into the effects of TGF-β in modulating NK cell functions . DB09280 - DB08820 in Patients with Cystic Fibrosis Homozygous for Phe508del P13569 . Phosphorylation of Grainy head by P29323 is essential for wound-dependent regeneration but not for development of an epidermal barrier . Grainy head ( P01148 ) is a key transcription factor responsible for epidermal barrier formation and repair , whose function is highly conserved across diverse animal species . However , it is not known how P01148 function is reactivated to repair differentiated epidermal barriers after wounding . Here , we show that P01148 is directly regulated by extracellular signal-regulated kinase ( P29323 ) phosphorylation , which is required for wound-dependent expression of P01148 target genes in epidermal cells . DB00133 91 is the principal residue in P01148 that is phosphorylated by P29323 . Although mutations of the P29323 phosphorylation sites in P01148 do not impair its DNA binding function , the P29323 sites in P01148 are required to activate Dopa decarboxylase ( Ddc ) and misshapen ( msn ) epidermal wound enhancers as well as functional regeneration of an epidermal barrier upon wounding . This result indicates that the phosphorylation sites are essential for damaged epidermal barrier repair . However , P01148 with mutant P29323 phosphorylation sites can still promote barrier formation during embryonic epidermal development , suggesting that P29323 sites are dispensable for the P01148 function in establishing epidermal barrier integrity . These results provide mechanistic insight into how tissue repair can be initiated by posttranslational modification of a key transcription factor that normally mediates the developmental generation of that tissue . Downregulation of angiotensin converting enzyme II is associated with pacing-induced sustained atrial fibrillation . Atrial fibrillation ( AF ) , the most common cardiac arrhythmia , is frequently accompanied by atrial interstitial fibrosis . Angiotensin II ( Ang II ) dependent signaling pathways have been implicated in interstitial fibrosis during the development of AF . However , Ang II could be further degraded by angiotensin converting enzyme II ( Q9BYF1 ) . We examined expression of Q9BYF1 in the fibrillating atria of pigs and its involvement in fibrotic pathogenesis during AF . Nine adult pigs underwent continuous rapid atrial pacing to induce sustained AF and six pigs were sham controls ( i.e. , sinus rhythm ; SR ) . In the histological examinations , extensive accumulation of extracellular matrix in the interstitial space of the atria , as evidenced by Masson 's trichrome stain , were found in fibrillating atria . The relative amount of collagen type I in the atria with AF was significantly increased as compared with that in the SR . Local P12821 activity in the fibrillating atria was also markedly higher than that in the SR subjects . Q9BYF1 gene and protein expression in the AF subjects were significantly decreased compared with those in the SR subjects , whereas expression of mitogen-activated/ P29323 kinase 1/2 ( Q02750 /2 ) , extracellular signal-regulated protein kinase 2 ( P28482 ) , and activated P28482 were significantly greater in the AF subjects . We propose that decreasing Q9BYF1 expression during AF may affect the Ang II-dependent signaling pathway . In addition , our results suggest that atrial fibrosis in AF may be induced by antagonistic regulation between P12821 and Q9BYF1 expression . Absolute bioavailability and effect of formulation change , food , or elevated pH with rabeprazole on cobimetinib absorption in healthy subjects . DB05239 is a potent and highly selective inhibitor of Q02750 /2 . Since cobimetinib exhibited absorption variability in cancer patients , a series of single-dose studies in healthy subjects were conducted to determine absolute bioavailability and elucidate potential effects of formulation , food , and elevated gastric pH on cobimetinib bioavailability . Three crossover trials were performed with a 20 mg cobimetinib oral dose : absolute bioavailability using a 2 mg intravenous infusion ( n = 13 ) , relative bioavailability of tablets versus capsules and food effect ( n = 20 ) , and drug interaction with a proton pump inhibitor ( 20 mg of rabeprazole daily for 5 days prior to cobimetinib administration ; n = 20 ) . Absolute bioavailability of cobimetinib was 46.2 % ( 24.2 , CV % ) , likely due to metabolism rather than incomplete absorption . The mean systemic clearance of cobimetinib was low ( 11.7 L/h [ 28.2 , CV % ] ) . Administration of cobimetinib tablets with a high-fat meal delayed drug absorption ( prolonged tmax ) but had no statistically significant effect on cobimetinib exposure ( Cmax and AUC0-∞ ) . Tablet and capsule formulations of cobimetinib showed comparable exposures . DB05239 exhibited delayed absorption ( tmax ) in the presence of rabeprazole , with no statistically significant effects on drug exposure ( Cmax and AUC0-∞ ) in the fasted state . In conclusion , cobimetinib oral absorption was not affected by change in formulation , food , or elevated gastric pH . Menadione reduction by pharmacological doses of ascorbate induces an oxidative stress that kills breast cancer cells . Oxidative stress generated by ascorbate-driven menadione redox cycling kills MCF7 cells by a concerted mechanism including glycolysis inhibition , loss of calcium homeostasis , DNA damage and changes in mitogen activated protein kinases ( MAPK ) activities . Cell death is mediated by necrosis rather than apoptosis or macroautophagy . Neither 3-methyladenine nor Z-VAD affects cytotoxicity by ascorbate/menadione ( Asc/Men ) . BAPTA-AM , by restoring cellular capacity to reduce MTT , underlines the role of calcium in the necrotic process . Oxidative stress-mediated cell death is shown by the opposite effects of DB06151 and 3-aminotriazole . Moreover , oxidative stress induces DNA damage ( protein poly-ADP-ribosylation and gamma- P16104 phosphorylation ) and inhibits glycolysis . Asc/Men deactivates extracellular signal-regulated kinase ( P29323 ) while activating p38 , suggesting an additional mechanism to kill MCF7 cells . Since ascorbate is taken up by cancer cells and , due to their antioxidant enzyme deficiency , oxidative stress should affect cancer cells to a greater extent than normal cells . This differential sensitivity may have clinical applications . Determination of cobimetinib in human plasma using protein precipitation extraction and high-performance liquid chromatography coupled to mass spectrometry . Inhibition of Q96HU1 / P29323 kinase ( MEK ) is a promising strategy to control the growth of tumors that are dependent on aberrant signaling in the MEK pathway . DB05239 ( P16260 -0973 ) ( S ) -[3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-phenyl]- ( ( S ) -3-hydroxy-3-piperidin-2-yl-azetidin-1-yl ) -methanone ) inhibits proliferation of a variety of human tumor cell lines by inhibiting Q02750 and P36507 . A specific high performance liquid chromatography-mass spectrometric assay was developed and validated for the determination of cobimetinib in human plasma . The overall mean recovery using protein precipitation extraction with acetonitrile was found to be 54.1 % . The calibration curve was ranged from 0.20 to 100ng/mL . The LLOQ was sensitive enough to detect terminal phase concentrations of the drug . The intra- and inter-assay precision ( % CV ) was within 10.3 % and 9.5 % for cobimetinib . The assay accuracy ( % RE ) was within ±13.7 % of the nominal concentration values for cobimetinib with the normal analytical QCs . The developed assay was successfully used to analyze the human plasma samples ( for pharmacokinetic analysis ) from clinical trials . Counteraction between angiotensin II and angiotensin-(1-7) via activating angiotensin type I and Mas receptor on rat renal mesangial cells . In the updated concept of renin-angiotensin system ( DB01367 ) , it contains the angiotensin converting enzyme ( P12821 ) -angiotensin ( Ang ) II-angtiogensin type 1 receptor ( AT1 ) axis and the angiotensin-converting enzyme-related carboxypeptidase ( Q9BYF1 ) -Ang-(1-7)-Mas axis . The former axis has been well demonstrated performing the vasoconstrictive , proliferative and pro-inflammatory functions by activation of AT1 receptors , while the later new identified axis is considered counterbalancing the effects of the former . The present study is aimed at observing the interaction between Ang-(1-7) and Ang II on cultured rat renal mesangial cells ( MCs ) . RT-PCR , Western blot and immunofluorescent staining and confocal microscopy results showed that both AT1 and Mas receptor were co-distributed in rat renal MCs . Ang-(1-7) showed similar effects on Ang II in cultured MCs that stimulated phosphorylated extracellular signal-regulated kinase ( P29323 )1/2 phosphorylation and transforms growth factor-β1 synthesis , and cell proliferation and extracellular matrix synthesis . Co-treatment of the cell with Ang-(1-7) and Ang II , Ang-(1-7) counteracted AngII-induced effects in a concentration dependent manner , but failed to alter the changes induced by endothelin-1 . The stimulating effect of Ang II was mediated by AT1 receptor while all the effects of Ang-(1-7) were blocked by Mas receptor antagonist A-779 , but not by AT1 receptor antagonist losartan or P50052 receptor antagonist PD123319 . These results suggest that Ang-(1-7) and Ang II specifically interact with each other on rat renal MCs via activation of their specific receptors , Mas and AT1 receptor respectively . Loss of both phospholipid and triglyceride transfer activities of microsomal triglyceride transfer protein in abetalipoproteinemia . Mutations in microsomal triglyceride transfer protein ( P55157 ) cause abetalipoproteinemia ( P00519 ) , characterized by the absence of plasma apoB-containing lipoproteins . In this study , we characterized the effects of various P55157 missense mutations found in P00519 patients with respect to their expression , subcellular location , and interaction with protein disulfide isomerase ( P07237 ) . In addition , we characterized functional properties by analyzing phospholipid and triglyceride transfer activities and studied their ability to support apoB secretion . All the mutants colocalized with calnexin and interacted with P07237 . We found that R540H and N780Y , known to be deficient in triglyceride transfer activity , also lacked phospholipid transfer activity . Novel mutants S590I and G746E did not transfer triglycerides and phospholipids and did not assist in apoB secretion . In contrast , D384A displayed both triglyceride and phospholipid transfer activities and supported apoB secretion . These studies point out that P00519 is associated with the absence of both triglyceride and phospholipid transfer activities in P55157 . P01375 induces P15941 gene transcription in lung epithelial cells : its signaling pathway and biological implication . The current study was conducted to elucidate the mechanism through which P01375 stimulates expression of P15941 , a membrane-tethered mucin . A549 human lung alveolar cells treated with P01375 exhibited significantly higher P15941 protein levels in detergent lysates compared with cells treated with vehicle alone . Increased P15941 protein levels were correlated with significantly higher levels of P15941 mRNA in P01375 -treated cells compared with controls . However , P01375 did not alter P15941 transcript stability , implying increased de novo transcription induced by the cytokine . P01375 increased P15941 gene promoter activity in A549 cells transfected with a promoter-luciferase reporter plasmid . Both U0126 , an inhibitor of Q02750 /2 , and dominant negative P27361 prevented P01375 -induced P15941 promoter activation , and anti- P19438 antibody blocked P01375 -stimulated P27361 /2 activation . P15941 promoter activation by P01375 also was blocked by mithramycin A , an inhibitor of Sp1 , as well as either deletion or mutation of a putative Sp1 binding site in the P15941 promoter located between nucleotides -99 and -90 . P01375 -stimulated binding of Sp1 to the P15941 promoter in intact cells was demonstrated by chromatin immunoprecipitation assay . We conclude that P01375 induces P15941 gene transcription through a P19438 --> Q02750 /2 --> P27361 --> Sp1 pathway . Gossypin up-regulates P01130 through activation of P29323 pathway : a signaling mechanism for the hypocholesterolemic effect . Hypercholesterolemia is one of the major risk factors for the development of cardiovascular disease . This study aims to elucidate the effect of gossypin on cholesterol metabolism in HepG2 cells . Results indicated that gossypin significantly reduced the total cholesterol concentration in a dose-dependent manner . There was a time- and dose-dependent increase in the expression of low-density lipoprotein receptor ( P01130 ) protein . However , 3-hydroxy-3-methylglutaryl coenzyme A ( HMG- DB01992 ) reductase , the rate-limiting enzyme in cholesterol synthesis , was not affected by gossypin . Moreover , gossypin had no effect on nuclear sterol regulatory element binding proteins ( SREBP ) -2 abundance . The activity of gossypin on P01130 expression was inhibited by the extracellular signal-regulated kinase ( P29323 ) inhibitor PD98059 . Western blotting analysis revealed that gossypin treatment dose- and time-dependently increased P29323 activation and preceded the up-regulation of P01130 expression . Collectively , these new findings identify gossypin as a new hypocholesterolemic agent that up-regulates P01130 expression independent of Q12772 but is dependent on P29323 activation . DB03419 incorporation into genomic DNA does not predict toxicity caused by chemotherapeutic inhibition of thymidylate synthase . P04818 ( TS ) is an important target of several chemotherapeutic agents , including DB00544 and raltitrexed ( DB00293 ) . During TS inhibition , TTP levels decrease with a subsequent increase in dUTP . DB03419 incorporated into the genome is removed by base excision repair ( BER ) . Thus , BER initiated by uracil DNA glycosylase ( P13051 ) activity has been hypothesized to influence the toxicity induced by TS inhibitors . In this study we created a human cell line expressing the Ugi protein inhibitor of P13051 family of UDGs , which reduces cellular P13051 activity by at least 45-fold . Genomic uracil incorporation was directly measured by mass spectrometry following treatment with TS inhibitors . Genomic uracil levels were increased over 4-fold following TS inhibition in the Ugi-expressing cells , but did not detectably increase in P13051 proficient cells . Despite the difference in genomic uracil levels , there was no difference in toxicity between the P13051 proficient and P13051 -inhibited cells to folate or nucleotide-based inhibitors of TS . Cell cycle analysis showed that P13051 proficient and P13051 -inhibited cells arrested in early S-phase and resumed replication progression during recovery from RTX treatment almost identically . The induction of gamma- P16104 was measured following TS inhibition as a measure of whether uracil excision promoted DNA double strand break formation during S-phase arrest . Although gamma- P16104 was detectable following TS inhibition , there was no difference between P13051 proficient and P13051 -inhibited cells . We therefore conclude that uracil excision initiated by P13051 does not adequately explain the toxicity caused by TS inhibition in this model . Q02750 /2 inhibition attenuates vascular P25101 and ETB receptor alterations after cerebral ischaemia . Cerebral ischaemia is associated with elevated levels of endothelin B ( ETB ) receptors in the ipsilateral middle cerebral artery ( MCA ) . This up-regulation of ET receptors occurs via de novo transcription involving mitogen-activated protein kinases ( MAPK ) . The aim of this study was to examine the effect of inhibition of the Q96HU1 kinase/ P29323 kinase (MEK)1/2 on ET receptor alteration , brain damage , and neurology in experimental cerebral ischaemia . Transient middle cerebral artery occlusion ( MCAO ) was induced in male Wistar rats by the intraluminal filament technique . The animals received 100 mg/kg intraperitoneally of the Q02750 /2 inhibitor U0126 or vehicle in conjunction with the occlusion . After 24 h , the rats were decapitated and the brains removed . The middle cerebral arteries were dissected out and examined with myographs or immunohistochemistry . The ischaemic areas of the brains were compared . After the MCAO , the contractile responses of the P25101 and ETB receptors were augmented in the ipsilateral MCA . U0126 decreased this alteration in ET receptor response . Furthermore , treatment with U0126 significantly decreased the brain damage and improved neurological scores . Immunohistochemistry showed that there were lower protein levels of phosphorylated extracellular signal-regulated kinases ( P29323 )1/2 and phosphorylated transcription factor Elk-1 in the U0126-treated rats compared to control . The results show that treatment with the Q02750 /2 inhibitor U0126 in ischaemic stroke decreases brain damage , neurological symptoms , and ET receptor alteration . The vascular effects of U0126 provide new perspective on possible mechanisms of actions of MAPK inhibition in cerebral ischaemia . Activation of gonadotropin-releasing hormone receptors induces a long-term enhancement of excitatory postsynaptic currents mediated by ionotropic glutamate receptors in the rat hippocampus . Whole-cell patch-clamp recordings were made from P00915 pyramidal neurons of the rat hippocampus to study the modulation of gonadotropin-releasing hormone ( DB00644 ) on synaptic transmission mediated by ionotropic glutamate receptors . DB00007 ( 10(-9)-10(-7) M ) , a specific DB00644 analog , concentration-dependently elicited a long-lasting potentiation of excitatory postsynaptic currents ( EPSCs ) mediated by ionotropic glutamate receptors . P30968 -induced synaptic potentiation was blocked by 1 microM [ Acetyl-3,4-dehydro-Pro1,D-p-F-Phe2,D-Trp3,6 ] - P01148 , a specific P30968 antagonist . Furthermore , P30968 -induced synaptic potentiation was associated with the stimulation of protein kinase C ( PKC ) , being considerably attenuated by a potent PKC inhibitor ( 30 microM H-7 ) . The results suggest a long-term enhanced modulation of DB00644 on synaptic transmission mediated by ionotropic glutamate receptors , possibly via the actions of PKC in the hippocampus that is an important integrative system in the regulation of reproductive processes . Role of endothelin-1 receptor blockers on hemodynamic parameters and oxidative stress . Endothelin ( ET ) was first isolated and described by Yanagisawa et al. and has since been described as one of the most potent known vasoconstrictor compounds . ET-1 mediates its effects via two types of receptors , P25101 and ETB , which are expressed in the vascular smooth muscle cells , endothelial cells , intestines and brain . Secretion of ET-1 results in long-lasting vasoconstriction , increased blood pressure and , in turn , overproduction of free radicals . As dysregulation of the endothelin system is an important factor in the pathogenesis of several diseases including atherosclerosis , hypertension and endotoxic shock , the P25101 and ETB receptors are attractive therapeutic targets for treatment of these disorders . The biosynthesis and release of ET-1 are regulated at the transcriptional level . Studies have shown that p38MAP kinase , nuclear factor kappaB ( NF-kappaB ) , PKC/ P29323 and JNK/c-Jun all take part in the ROS-activated production of ET-1 . Furthermore , administration of ET(A) significantly reduces the generation of free radicals . However , treatment with ETB receptor blockers does not elicit the same effect . Therefore , the effects of endothelin receptor blockers on blood pressure and the generation of free radicals remain debatable . This review summarizes recent investigations into the role of endothelin receptor blockers with respect to the modulation of hemodynamic parameters and the generation of free radicals . DB08827 : A novel agent for the treatment of homozygous familial hypercholesterolemia . PURPOSE : The pharmacology , pharmacokinetics , and clinical efficacy and safety of lomitapide in the management of homozygous familial hypercholesterolemia ( HoFH ) are reviewed . SUMMARY : DB08827 ( Juxtapid , Aegerion Pharmaceuticals ) is an oral microsomal triglyceride transfer protein ( P55157 ) inhibitor indicated for the treatment of patients with HoFH , a rare form of hypercholesterolemia that can lead to premature atherosclerotic disease . In clinical trials , the use of lomitapide alone or in combination with other lipid-lowering modalities reduced plasma concentrations of low-density lipoprotein cholesterol ( LDL-C ) by a mean of more than 50 % . DB08827 is associated with significant gastrointestinal adverse effects and increases in hepatic fat levels . DB08827 undergoes hepatic metabolism via cytochrome P-450 ( CYP ) isoenzyme 3A4 and interacts with P08684 substrates including atorvastatin and simvastatin ; dose adjustment is recommended when lomitapide is used concurrently with these agents . In patients receiving concomitant warfarin , the International Normalized Ratio ( INR ) should be closely monitored , as lomitapide use may increase INR values . The recommended initial dosage of lomitapide is 5 mg once daily , with subsequent upward dose adjustment at specified intervals according to tolerability . DB08827 is contraindicated in patients with moderate-to-severe liver disease , patients with sustained abnormal liver function tests , patients taking strong or moderate P08684 inhibitors , and pregnant patients . CONCLUSION : DB08827 is an oral P55157 inhibitor approved for the treatment of HoFH . This agent appears to be a realistic option for patients with HoFH who are unable to attain their LDL-C goal or can not tolerate statin therapy . The effectiveness of lurasidone as an adjunct to lithium or divalproex in the treatment of bipolar disorder . The majority of patients with bipolar disorder spend a lot of time in depressive episodes that impose a great burden on patients , caregivers , and society and accounts for the largest part of the morbidity-mortality of the illness . DB08815 is an atypical antipsychotic with a potent binding affinity as antagonist for D2 , 5- Q13049 , P34969 , and partial agonist at P08908 receptors . Affinity for other receptors as H1 and muscarinic were negligible . DB08815 was approved in 2010 for the treatment of schizophrenia and recently , 2013 , for bipolar depression in monotherapy and an adjunct to lithium or valproate . Clinical trials have established that lurasidone adjuvant to lithium or valproate has more efficacy than the placebo and is associated with minimal weight gain and no clinically meaningful alterations in glucose , lipids , or the QT interval . Additional studies are desirable to know the clinical profile of lurasidone in long-term treatment , in patients with bipolar II disorders , and versus other antipsychotic agents . DB00175 -induced changes in receptor-mediated metabolism of low density lipoprotein in guinea pigs . The effect of pravastatin , an inhibitor of P04035 , on the metabolism of human low density lipoprotein ( LDL ) was examined in guinea pigs . DB00175 treatment significantly reduced plasma levels of total cholesterol and LDL-cholesterol by 15.6 mg/dl ( 38.8 % ) and 12.7 mg/dl ( 42.9 % ) , respectively . We investigated the metabolism of LDL in pravastatin-treated and untreated guinea pigs using the simultaneous intravenous injection of 131I-labeled LDL and 125I-labeled , galactose-treated LDL to quantify the P01130 pathway . DB00175 increased the fractional catabolic rate ( FCR ) of the P01130 -dependent pathway . The treatment with pravastatin did not alter the FCR of the P01130 -independent pathway . The FCR of the P01130 -dependent pathway was higher for LDL isolated from pravastatin-treated subjects than for LDL isolated from control subjects . These findings suggest that pravastatin mainly reduced plasma cholesterol levels by accelerated FCR of the P01130 -mediated pathway . Managing the underlying cause of cystic fibrosis : a future role for potentiators and correctors . Cystic fibrosis ( CF ) , a severe genetic disease , is caused by mutations that alter the structure and function of P13569 , a plasma membrane channel permeable to chloride and bicarbonate . Defective anion transport in CF irreversibly damages the lungs , pancreas , liver , and other organs . CF mutations cause loss of P13569 function in multiple ways . In particular , class 3 mutations such as p.Gly551Asp strongly decrease the time spent by P13569 in the open state ( gating defect ) . Instead , class 2 mutations impair the maturation of P13569 protein and its transport from the endoplasmic reticulum to the plasma membrane ( trafficking defect ) . The deletion of phenylalanine 508 ( p.Phe508del ) , the most frequent mutation among CF patients ( 70-90 % ) , destabilizes the P13569 protein , thus causing both a trafficking and a gating defect . These two defects can be overcome with drug-like molecules generically called correctors and potentiators , respectively . The potentiator Kalydeco™ ( also known as DB08820 or VX-770 ) , developed by Vertex Pharmaceuticals , has been recently approved by the US FDA and the European Medicines Agency ( P15941 ) for the treatment of CF patients carrying at least one P13569 allele with the p.Gly551Asp mutation ( 2-5 % of all patients ) . In contrast , the corrector VX-809 , which significantly improves p.Phe508del- P13569 trafficking in vitro , is still under study in clinical trials . Because of multiple defects caused by the p.Phe508del mutation , it is probable that rescue of the mutant protein will require combined treatment with correctors having different mechanisms of action . This review evaluates the status of experimental and clinical research in pharmacotherapy for the CF basic defect . Coadministration of P55089 -01 with Q02750 /2 inhibitors potently induces apoptosis in P11274 / P00519 + leukemia cells sensitive and resistant to ST1571 . Interactions between the PKC and Chk1 inhibitor P55089 -01 and pharmacologic Q02750 /2 inhibitors ( e.g. , U0126 , PD184352 ) were examined in Bcr/Abl(+) = human leukemia cells ( K562 , P25391 84 ) sensitive and resistant to the Bcr/Abl kinase inhibitor STI571 . Coexposure of K562 cells to P55089 -01 ( e.g. , 100 nM ) or U0126 ( 30 microM ) resulted in a marked increase in mitochondrial injury ( e.g. , release of cytochrome c ; loss of deltapsi(m) ) and apoptosis . Similar results were obtained in other Bcr/Abl(+) cells ( e.g. , P25391 84 , BV-173 ) and with other Q02750 /2 inhibitors ( e.g. , PD184352 ) . Exposure of K562 cells to P55089 -01 resulted in activation of P29323 , an effect that was abrogated by co-administration of Q02750 /2 inhibitors . Coadminstration of P55089 -01 with U0126 produced multiple perturbations in signal transduction/cell cycle regulatory pathways , including diminished expression of Bcr/Abl , Mcl-1 , cylin D(1) , and activation of JNK and p34(cdc2) . Coadministration of the JNK inhibitor SP600125 attenuated P55089 -01/MEK inhibitor- associated lethality , suggesting a functional role for JNK activation in enhanced lethality . Finally , P55089 -01 and Q02750 /2 inhibitors effectively induced apoptosis in Bcr/Abl(+) cells ( e.g. , K562 and P25391 84 ) overexpressing Bcr/Abl and resistant to STI571 . These findings indicate that BcrAbl(+) leukemia cells are sensitive to a strategy combining P55089 -01 with MEK/ P29323 inhibitors that simultaneously disrupts two signaling pathways . Blood flow alterations in TNBS-induced colitis : role of endothelin receptors . OBJECTIVES : The aim of the present study was to investigate the time dependent changes in hemodynamic parameters and to assess the role of endothelin ( ET ) receptors in trinitrobenzene sulfonic acid ( TNBS ) induced colitis . MATERIALS : Inferior mesenteric artery ( IMA ) hemodynamics , myeloperoxidase activity ( P05164 ) and damage scores were measured immediately or 1 , 3 , 5 and 14 days after colitis . TREATMENTS : Another group of rats received a nonselective ET receptor antagonist DB00559 ( 30 mg/kg/day ) , P25101 receptor antagonist BQ485 ( 60 microg/rat/day ) or P24530 receptor antagonist BQ788 ( 60 microg/rat/day ) prior to and on the 1st , 2nd and 3rd days after TNBS administration . RESULTS : IMA flow significantly increased at 90 min followed by a substantial decrease through days 1-5 . Tissue P05164 activity and macroscopic damage score increased on 1st day after the induction of colitis and remained elevated 3 , 5 and 14 days following colitis . Treatment with DB00559 or P25101 receptor antagonist largely prevented the colitis-induced reduction in blood flow and tissue injury whereas P24530 receptor antagonist did not attenuate tissue injury or reductions in blood flow . CONCLUSIONS : Our results demonstrate that time-dependent abnormalities occur in IMA hemodynamics following TNBS administration . Our findings also indicate that P25101 receptors but not P24530 receptors play an important role in the colonic inflammation following TNBS administration . PARP and CHK inhibitors interact to cause DNA damage and cell death in mammary carcinoma cells . The present studies examined viability and DNA damage levels in mammary carcinoma cells following P09874 and O14757 inhibitor drug combination exposure . P09874 inhibitors [ AZD2281 ; ABT888 ; DB02690 ; AG014699 ] interacted with O14757 inhibitors [ P55089 -01 ; AZD7762 ; LY2603618 ] to kill mammary carcinoma cells . P09874 and O14757 inhibitors interacted to increase both single strand and double strand DNA breaks that correlated with increased γ P16104 phosphorylation . Treatment of cells with O14757 inhibitors increased the phosphorylation of O14757 and P27361 /2 . Knock down of Q13315 suppressed the drug-induced increases in O14757 and P27361 /2 phosphorylation and enhanced tumor cell killing by P09874 and O14757 inhibitors . Expression of dominant negative Q02750 enhanced drug-induced DNA damage whereas expression of activated Q02750 suppressed both the DNA damage response and tumor cell killing . Collectively our data demonstrate that P09874 and O14757 inhibitors interact to kill mammary carcinoma cells and that increased DNA damage is a surrogate marker for the response of cells to this drug combination .