interacts_with DB01418?
Vitamin D analogues . The plethora of actions attributed to 1,25(OH)2D3 throughout the body have suggested potential therapeutic applications for the treatment of hyperproliferative diseases , immune dysfunction , endocrine disorders , and metabolic bone disease . However , the potent calcemic activity of the natural vitamin D hormone has precluded its use in most cases . New vitamin D analogues are under development that display greater specificity , in most cases , by retaining the therapeutic properties of 1,25(OH)2D3 , but with lower calcemic activity . Two analogues have been approved for use in patients : calcipotriol ( DB02300 from Leo Pharmaceuticals , Copenhagen , Denmark ) for the treatment of psoriasis ; and 19-nor-1,25(OH)2D2 ( DB00910 from Abbott Laboratories , Abbott Park , IL ) for secondary hyperparathyroidism . Many others analogues are currently being tested in preclinical and clinical trials for the treatment of various types of cancer and osteoporosis , and for immunosuppression . The selectivity of the analogues can be attributed to the combined interactions with four proteins : the vitamin D receptor ( P11473 ) , the serum vitamin D binding protein ( DBP ) , the vitamin D-24-hydroxylase and to a newly described membrane receptor . Low DBP affinity has been shown to be responsible for the reduced calcemic actions of calcipotriol and 22-oxacalcitriol ( O75051 ) , which is being tested for secondary hyperparathyroidism . However , the low calcemic activity of other analogues , including 19-nor-1,25(OH)2D2 , involves other , as yet undefined , mechanisms . Understanding of the molecular basis for the selectivity of the vitamin D analogues will allow the design of more effective and safer vitamin D compounds for the treatment of a wide range of clinical disorders . Poly(ADP-ribose) polymerase-1 inhibition prevents eosinophil recruitment by modulating Th2 cytokines in a murine model of allergic airway inflammation : a potential specific effect on P05113 . We recently used a murine model of allergic airway inflammation to show that poly(ADP-ribose) polymerase-1 ( P09874 ) plays an important role in the pathogenesis of asthma-related lung inflammation . In this study , we show that P09874 inhibition , by a novel inhibitor ( TIQ-A ) or by gene deletion , prevented eosinophilic infiltration into the airways of OVA-challenged mice . Such impairment of eosinophil recruitment appeared to take place after IgE production . OVA challenge of wild-type mice resulted in a significant increase in P05112 , P05113 , P22301 , P35225 , and GM- P04141 secretions . Although P05112 production was moderately affected in OVA-challenged P09874 (-/-) mice , the production of P05113 , P22301 , P35225 , and GM- P04141 was completely inhibited in ex vivo OVA-challenged lung cells derived from these animals . A single TIQ-A injection before OVA challenge in wild-type mice mimicked the latter effects . The marked effect P09874 inhibition exerted on mucus production corroborated the effects observed on the Th2 response . Although P09874 inhibition by gene knockout increased the production of the Th1 cytokines P60568 and IL-12 , the inhibition by TIQ-A exerted no effect on these two cytokines . The failure of lung cells derived from OVA-challenged P09874 (-/-) mice to synthesize GM- P04141 , a key cytokine in eosinophil recruitment , was reestablished by replenishment of P05113 . Furthermore , intranasal administration of P05113 restored the impairment of eosinophil recruitment and mucus production in OVA-challenged P09874 (-/-) mice . The replenishment of either P05112 or IgE , however , did not result in such phenotype reversals . Altogether , these results suggest that P09874 plays a critical role in eosinophil recruitment by specifically regulating the cascade leading to P05113 production . Isoenzyme-specific cyclooxygenase inhibitors : a whole cell assay system using the human erythroleukemic cell line HEL and the human monocytic cell line Mono Mac 6 . NSAIDs inhibit the conversion of arachidonic acid into DB03866 and Prostaglandin H2 which is catalyzed by the enzyme cyclooxygenase ( P36551 ) . Two genetically distinct isoforms have been discovered , P23219 and P35354 . While P23219 is thought to account for homeostatic amounts of eicosanoids , P35354 is induced during inflammation leading to pathologic amounts of eicosanoids . Since NSAIDs inhibit both P36551 isoforms , antiinflammatory drug research has refocused to discovering P35354 inhibitors that do not inhibit P23219 . For this purpose , we have developed a whole cell assay system using the human erythroleukemic cell line HEL as a source for P23219 and the human monocytic cell line Mono Mac 6 as a source for P35354 . Mono Mac 6 cells express high amounts of P35354 upon stimulation with lipopolysaccharide ( LPS ) in the absence of any detectable P23219 protein . On the other hand , we find HEL cells to naturally express P23219 protein , but not P35354 . Testing of a panel of NSAIDs as well as some P35354 specific inhibitors showed that this assay system is suitable for identifying compounds that selectively inhibit either P23219 or P35354 . This test system offers the advantage of assessing P23219 and P35354 inhibitors within the human species , within a similar test set-up , and circumvents the need for tedious purification of either platelets or peripheral blood monocytes . Activation of the succinate receptor Q9BXA5 in macula densa cells causes renin release . Macula densa ( MD ) cells of the juxtaglomerular apparatus ( JGA ) are salt sensors and generate paracrine signals that control renal blood flow , glomerular filtration , and release of the prohypertensive hormone renin . We hypothesized that the recently identified succinate receptor Q9BXA5 is present in MD cells and regulates renin release . Using immunohistochemistry , we identified Q9BXA5 in the apical plasma membrane of MD cells . Treatment of MD cells with succinate activated mitogen-activated protein kinases ( MAPKs ; p38 and extracellular signal-regulated kinases 1/2 ) and cyclooxygenase 2 ( P35354 ) and induced the synthesis and release of prostaglandin E(2) , a potent vasodilator and classic paracrine mediator of renin release . Using microperfused JGA and real-time confocal fluorescence imaging of quinacrine-labeled renin granules , we detected significant renin release in response to tubular succinate ( EC(50) 350 microM ) . Genetic deletion of Q9BXA5 ( Q9BXA5 (-/-) mice ) or pharmacologic inhibition of MAPK or P35354 blocked succinate-induced renin release . DB00428 -induced diabetes caused Q9BXA5 -dependent upregulation of renal cortical phospho-p38 , extracellular signal-regulated kinases 1/2 , P35354 , and renin content . Salt depletion for 1 wk increased plasma renin activity seven-fold in wild-type mice but only 3.4-fold in Q9BXA5 (-/-) mice . In summary , MD cells can sense alterations in local tissue metabolism via accumulation of tubular succinate and Q9BXA5 signaling , which involves the activation of MAPKs , P35354 , and the release of prostaglandin E(2) . This mechanism may be integral in the regulation of renin release and activation of the renin-angiotensin system in health and disease . Gender influences the class III and V β-tubulin ability to predict poor outcome in colorectal cancer . PURPOSE : Colorectal cancer is one of the deadliest diseases in Western countries . To predict the outcome of therapy , we assessed the role of class III ( Q13509 ) and class V β-tubulin ( Q9BUF5 ) as predictive biomarkers . EXPERIMENTAL DESIGN : Using immunohistochemistry and nanofluidics , the expression of Q13509 and Q9BUF5 was assessed in two cohorts of 180 and 134 patients , respectively . The P05093 RS743572 was genotyped to identify GG carriers with enhanced androgen levels . Q13509 and Q9BUF5 were investigated in 22 colorectal cancer cell lines in basal conditions and after serum starvation , the latter serving as activator of this prosurvival pathway . To ascertain the role of androgen receptor ( AR ) in such regulation , we silenced AR and checked Q13509 and Q9BUF5 expression and sensitivity to chemotherapy . RESULTS : There was a link between poor survival , the expression of Q13509 / Q9BUF5 , and AR only in females . Conversely , only in males carriers of the GG phenotype exhibited the worst outcome . Importantly , male cell lines were resistant to serum starvation and exhibited higher levels of Q9BUF5 , thereby suggesting that the pathway is activated by androgens . In female cells this phenomenon was absent . In both genders , AR was the main driver of Q13509 / Q9BUF5 expression , as constitutive silencing of AR was associated with downregulation of Q13509 / Q9BUF5 expression and increased sensitivity to oxaliplatin and SN-38 . CONCLUSIONS : The involvement of androgens in the Q13509 pathway opens the way for clinical trials to assess the efficacy of antiandrogens for increasing the efficacy of chemotherapy in male colorectal cancer patients . DB00139 modulates Ca(2+) transient and cardiomyocyte viability through PKA-dependent pathway . Q9BXA5 is an orphan G-protein-coupled receptor ( GPCR ) that has been characterized as a receptor for succinate , a citric acid cycle intermediate , in several tissues . In the heart , the role of succinate is unknown . We now report that rat ventricular cardiomyocytes express Q9BXA5 . We found that succinate , through Q9BXA5 , increases the amplitude and the rate of decline of global Ca(2+) transient , by increasing the phosphorylation levels of ryanodine receptor and phospholamban , two well known Ca(2+) handling proteins . The effects of succinate on Ca(2+) transient were abolished by pre-treatment with adenylyl cyclase and DB02527 -dependent protein kinase ( PKA ) inhibitors . Direct PKA activation by succinate was further confirmed using a FRET-based A-kinase activity reporter . Additionally , succinate decreases cardiomyocyte viability through a caspase-3 activation pathway , effect also prevented by PKA inhibition . Taken together , these observations show that succinate acts as a signaling molecule in cardiomyocytes , modulating global Ca(2+) transient and cell viability through a PKA-dependent pathway . Creating a genotype-based dosing algorithm for acenocoumarol steady dose . DB01418 is a commonly prescribed anticoagulant drug for the prophylaxis and treatment of venous and arterial thromboembolic disorders in several countries . In counterpart of warfarin , there is scarce information about pharmacogenetic algorithms for steady acenocoumarol dose estimation . The aim of this study was to develop an algorithm of prediction for acenocoumarol.The algorithm was created using the data from 973 retrospectively selected anticoagulated patients and was validated in a second independent cohort adding up to 2,683 patients . The best regression model to predict stable dosage in the Primary Cohort included clinical factors ( age and body mass index , BSA ) and genetic variants ( Q9BQB6 , P11712 * and P78329 polymorphisms ) and explained up to 50 % of stable dose . In the validation study the clinical algorithm yielded an adjusted R²=0.15 ( estimation´s standard error=4.5 ) and the genetic approach improved the dose forecast up to 30 % ( estimation´s standard error=4.6 ) . Again , the best model combined clinical and genetic factors ( R² = 0.48 ; estimation´s standard error=4 ) which provided the best results of doses estimates within 20 % of the real dose in patients taking lower ( ≤ 7 mg/week ) or higher ( ≥ 25 mg/week ) acenocoumarol doses . In conclusion , we developed a prediction algorithm using clinical data and three polymorphisms in Q9BQB6 , P11712 * and P78329 genes that provided a steady acenocoumarol dose for about 50 % of patients in the Validation Cohort . Such algorithm was especially useful to patients who need higher or lower acenocoumarol doses , those patients with higher time required until their stabilisation and are more prone to suffer a treatment derived complication . Allele frequencies of single nucleotide polymorphisms ( SNPs ) in 40 candidate genes for gene-environment studies on cancer : data from population-based Japanese random samples . Knowledge of genetic polymorphisms in gene-environment studies may contribute to more accurate identification of avoidable risks and to developing tailor-made preventative measures . The aim of this study was to describe the allele frequencies of single nucleotide polymorphisms ( SNPs ) of select genes , which may be included in future gene-environment studies on cancer in Japan . SNP typing was performed on middle-aged Japanese men randomly selected from the general population in five areas of Japan . We genotyped and calculated allele frequencies of 153 SNPs located on 40 genes : P04798 , Q16678 , P11712 , P33261 , P05181 , P05093 , P11511 , P35869 , P03372 , Q92731 , ERRRG , P06401 , P07099 , P34913 , P37059 , P37058 , P28161 , P21266 , GSTT2 , P09211 , NAT1 , NAT2 , P21964 , P07327 , P00325 , P00326 , P05091 , P35228 , NOS3 , P01583 , P01584 , O15527 , P36639 [ P36639 ] , P14416 , P35462 , P21917 , P31645 , P04150 [ GCCR ] , P42898 , and P15559 . In the present study , the Japanese allele frequencies were verified by using nationwide population samples . Interleukin-1β causes excitotoxic neurodegeneration and multiple sclerosis disease progression by activating the apoptotic protein p53 . BACKGROUND : Understanding how inflammation causes neuronal damage is of paramount importance in multiple sclerosis ( MS ) and in other neurodegenerative diseases . Here we addressed the role of the apoptotic cascade in the synaptic abnormalities and neuronal loss caused by the proinflammatory cytokines interleukin-1β ( IL-1β ) and tumor necrosis factor ( P01375 -α ) in brain tissues , and disease progression caused by inflammation in relapsing-remitting MS ( RRMS ) patients . RESULTS : The effect of IL-1β , but not of P01375 -α , on glutamate-mediated excitatory postsynaptic currents was blocked by pifithrin-α ( DB00522 ) , inhibitor of p53 . The protein kinase C ( PKC ) /transient receptor potential vanilloid 1 ( Q8NER1 ) pathway was involved in IL-1β-p53 interaction at glutamatergic synapses , as pharmacological modulation of this inflammation-relevant molecular pathway affected DB00522 effects on the synaptic action of IL-1β . IL-1β-induced neuronal swelling was also blocked by DB00522 , and IL-1β increased the expression of P38936 , a canonical downstream target of activated p53.Consistent with these in vitro results , the Pro/Pro genotype of p53 , associated with low efficiency of transcription of p53-regulated genes , abrogated the association between IL-1β cerebrospinal fluid ( P04141 ) levels and disability progression in RRMS patients . The interaction between p53 and P04141 IL-1β was also evaluated at the optical coherence tomography ( O75051 ) , showing that IL-1β-driven neurodegenerative damage , causing alterations of macular volume and of retinal nerve fibre layer thickness , was modulated by the p53 genotype . CONCLUSIONS : Inflammatory synaptopathy and neurodegeneration caused by IL-1β in RRMS patients involve the apoptotic cascade . Targeting IL-1β-p53 interaction might result in significant neuroprotection in MS . Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis/metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long-term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 *4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P=0.003 and P=0.007 ) and were 2.2- and 2.5-fold more likely to develop P42126 and CND ( P=0.039 and P=0.041 ) , respectively . P34913 55Arg , P51589 *7 , P10632 *1B , and P10632 g.36785A allele carriers had lower EET and DHET P04141 levels . P10632 g.25369T and P10632 g.36755A allele carriers had higher EET levels . Patients with P10632 *2C and P34913 404del variants had worse long-term outcomes while those with P34913 287Gln , P51589 *7 , and P11712 g.816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3-month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis/metabolic pathway and the pathophysiology of aSAH . A case study of acenocoumarol sensitivity and genotype-phenotype discordancy explained by combinations of polymorphisms in Q9BQB6 and P11712 . To determine the cause of a genotype-phenotype discordancy for acenocoumarol sensitivity . Methods A patient , highly sensitive to acenocoumarol , and previously determined to carry only a single P11712 *3 allele , was genotyped for additional functionally defective alleles in the P11712 and Q9BQB6 genes . Family members were also analyzed to trace the pedigree . Results The acenocoumarol-sensitive patient was found to possess , in addition to P11712 *3 allele , a P11712 *11 allele and the Q9BQB6 AA diplotype which were all traced back through the parental lines . Conclusions DB01418 sensitivity in this subject is the consequence of inheritance of multiple functionally defective alleles in both the P11712 and Q9BQB6 genes . The study provides additional data in support of diminished P11712 activity due to the presence of the rare *11 allele . Secretory phospholipase A₂-mediated progression of hepatotoxicity initiated by acetaminophen is exacerbated in the absence of hepatic P35354 . We have previously reported that among the other death proteins , hepatic secretory phospholipase A₂ ( sPLA₂ ) is a leading mediator of progression of liver injury initiated by CCl₄ in rats . The aim of our present study was to test the hypothesis that increased hepatic sPLA₂ released after acetaminophen ( DB00316 ) challenge mediates progression of liver injury in wild type ( WT ) and P35354 knockout ( KO ) mice . P35354 WT and KO mice were administered a normally non lethal dose ( 400 mg/kg ) of acetaminophen . The P35354 KO mice suffered 60 % mortality compared to 100 % survival of the WT mice , suggesting higher susceptibility of P35354 KO mice to sPLA₂-mediated progression of acetaminophen hepatotoxicity . Liver injury was significantly higher at later time points in the KO mice compared to the WT mice indicating that the abatement of progression of injury requires the presence of P35354 . This difference in hepatotoxicity was not due to increased bioactivation of acetaminophen as indicated by unchanged cyp2E1 protein and covalently bound ¹⁴C- DB00316 in the livers of KO mice . Hepatic sPLA₂ activity and plasma P01375 -α were significantly higher after DB00316 administration in the KO mice . This was accompanied by a corresponding fall in hepatic PGE₂ and lower compensatory liver regeneration and repair ( ³H-thymidine incorporation ) in the KO mice . These results suggest that hindered compensatory tissue repair and poor resolution of inflammation for want of beneficial prostaglandins render the liver very vulnerable to sPLA₂-mediated progression of liver injury . These findings are consistent with the destructive role of sPLA₂ in the progression and expansion of tissue injury as a result of continued hydrolytic breakdown of plasma membrane phospholipids of perinecrotic hepatocytes unless mitigated by sufficient co-induction of P35354 . Differential in vitro sensitivity to patupilone versus paclitaxel in uterine and ovarian carcinosarcoma cell lines is linked to tubulin-beta-III expression . OBJECTIVE : To compare the in vitro sensitivity/resistance to patupilone versus paclitaxel in uterine and ovarian carcinosarcomas ( CS ) . METHODS : Five primary carcinosarcoma cell lines , two from uterine and three of ovarian origin , were evaluated for growth rate and tested for their in vitro sensitivity/resistance to patupilone versus paclitaxel by MTS assays . To identify potential mechanisms underlying the differential sensitivity/resistance to patupilone , expression levels of β-tubulin III ( Q13509 ) were determined with quantitative-real-time-polymerase-chain-reaction ( q-RT-PCR ) in primary uterine and ovarian CS cell lines and in 26 uterine and 9 ovarian CS fresh-frozen-tissues . RESULTS : No appreciable difference in sensitivity to patupilone versus paclitaxel was noted in ovarian CS cell lines , or when uterine and ovarian CS cell lines were compared in their response to paclitaxel . In contrast , uterine CS cell lines were found to be significantly more sensitive to patupilone than to paclitaxel ( P < 0.002 ) and demostrated lower IC(50s) to patupilone ( range 0.76-0.93nM ) when compared to ovarian CS ( range 1.9-3.4 nM , p < 0.05 ) . Higher levels of Q13509 were detected in uterine CS cell lines and fresh frozen tissues when compared to ovarian CS ( P < 0.05 ) . CONCLUSIONS : Uterine CS cell lines are significantly more sensitive than ovarian CS cell lines to patupilone versus paclitaxel . High expression of Q13509 is associated with sensitivity to patupilone in primary CS cell lines and may act as a genetic marker to predict chemotherapy efficacy . DB03010 may represent a promising drug in the treatment of this subset of rare but highly aggressive gynecological tumors . Interactions Between Ataxia Telangiectasia Mutated Kinase Inhibition , Poly(ADP-ribose) Polymerase-1 Inhibition and P38398 Status in Breast Cancer Cells . BACKGROUND : Cells harboring P38398 / P51587 mutations are hypersensitive to inhibition of poly(ADP-ribose) polymerase-1 ( P09874 ) . We recently showed that interference with P09874 activity by DB02690 is strongly cytotoxic for P38398 -positive BT-20 cells but not P38398 -deficient SKBr-3 cells . These unexpected observations prompted speculation that other P09874 inhibitor(s) may be more cytotoxic towards SKBr-3 cells . In addition , interference with the DNA damage signaling pathway via ( for instance ) Q13315 ( Q13315 ) kinase inhibition may induce synthetic lethality in DNA repair-deficient breast cancer cells and pharmacological interference with Q13315 activity may sensitize breast cancer cells to P09874 inactivation . METHODS : We determined drug cytotoxicity in human MCF-7 and SKBr-3 breast cancer cells using the CellTiterGLO Luminescent cell viability assay and a Tecan multi-label , multitask plate counter to measure generated luminescence . Changes in cell cycle progression were monitored by flow cytometric measurement of DNA content in cells stained with propidium iodide . RESULTS : Unlike DB02690 , AZD2461 , a new P09874 inhibitor , markedly reduced the numbers of living MCF-7 and SKBr-3 cells . Q13315 kinase inhibition ( CP466722 ) was also cytotoxic for both MCF-7 and SKBr-3 cells . Furthermore , AZD2461 enhanced the cytotoxicity of CP466722 in both cell lines by inducing apoptosis , and concurrent inhibition of Q13315 and P09874 reduced cell proliferation more strongly than either single treatment . CONCLUSIONS : Our data show that inhibition of P09874 by AZD2461 is synthetically lethal for DB02690 -resistant MCF-7 and SKBr-3 breast cancer cells . They also indicate that DNA damage signaling is essential for survival of both SKBr-3 and MCF-7 cells , especially after inactivation of P09874 . Cytochromes P450 are differently expressed in normal and varicose human saphenous veins : linkage with varicosis . The expression of cytochrome P450 ( CYP ) enzymes and cyclo-oxygenases ( P36551 ) was investigated in human saphenous veins by reverse transcription-polymerase chain reaction analysis . Non-varicose veins were obtained from patients undergoing aortocoronary bypass grafting , whereas varicose veins were obtained from patients undergoing stripping removal of varicose saphenous veins . In non-varicose veins , Q16678 , CYP2C , P05181 and Q02928 were detected , whereas P51589 , P20815 , P23219 and P35354 were detected almost exclusively in varicose veins . P78329 was not detectable . Except for Q02928 , the levels of individual CYP mRNA were higher in varicose veins than in control veins . Smooth muscle cell volume , determined by a colour image-analysis system , was increased approximately 1.5-fold in varicose veins . Because CYPs and COXs produce various vasoactive compounds , increased expression of these enzymes could be involved in the impairment of vascular tone and may contribute to varicose pathology . Then , CYP or P36551 modulators may be potentially active in the treatment of chronic venous insufficiency . Clinical pharmacology of serotonin-altering medications for decreasing alcohol consumption . Variations in serotonin neurotransmission influence alcohol consumption ( AC ) . Levels of 5-HT and metabolites are low in some brain regions of alcohol preferring rats and in P04141 of alcoholics . Pharmacological treatments which enhance serotonergic neurotransmission ( uptake inhibitors , releasers , agonists ) consistently reduce AC in rats . Serotonin uptake inhibitors ( SUI ; e.g. , citalopram , fluoxetine ) have been studied extensively in humans . In several double-blind randomized , placebo-controlled clinical trials , SUI have consistently decreased AC by averages of 15 % to 20 % in nondepressed mildly/moderately dependent alcoholics who received no other treatment . Effects were dose-dependent and not related to side effects ( few and mild ) or changes in anxiety or depression ( not observed ) . SUI also decreased desire to drink and liking for alcohol , thus suggesting a mechanism for effects . Other drugs acting on the 5-HT system have been tested in humans , but results are difficult to interpret . For example , buspirone , a P08908 receptor partial agonist , reduced anxiety and alcohol craving , but not AC ; a 5-HT partial agonist , m-CPP , increased alcohol craving in abstinent alcoholics ; modest reductions in AC were observed with a 5- Q9H205 antagonist , ondansetron ( 0.5 mg/day , but not 4 mg/day ) . The therapeutic potentials of these medications are being studied . For example , SUI effects on AC were enhanced by a brief psychosocial intervention . Since SUI decrease urge to drink , they may be suitable pharmacological adjuncts in relapse prevention strategies . SUI and other serotonin-altering medications are promising new neuropharmacological treatments for reducing AC . Recent advances in the genetics of schizophrenia . The genetic etiology of schizophrenia , a common and debilitating psychiatric disorder , is supported by a wealth of data . Review of the current findings suggests that considerable progress has been made in recent years , with a number of chromosomal regions consistently implicated by linkage analysis . Three groups have shown linkage to 1q21-22 using similar models , with HLOD scores of 6.5 , 3.2 , and 2.4 . Other replicated loci include 13q32 that has been implicated by two independent groups with significant HLOD scores ( 4.42 ) or Q9BXD5 values ( 4.18 ) , and 5pl4.1-13.1 , 5q21-33 , 8p2l-22 , and 10p11-15 , each of which have been reported as suggestive by at least three separate groups . Different studies have also replicated evidence for a modest number of candidate genes that were not ascertained through linkage . Of these , the greatest support exists for the P35462 ( 3q13.3 ) , P28223 ( 13q14.2 ) , and P36544 ( 15q13-q14 ) genes . The refinement of phenotypes , the use of endophenotypes , reduction of heterogeneity , and extensive genetic mapping have all contributed to this progress . The rapid expansion of information from the human genome project will likely further accelerate this progress and assist in the discovery of susceptibility genes for schizophrenia . A greater understanding of disease mechanisms and the application of pharmacogenetics should also lead to improvements in therapeutic interventions . Effects of an alpha 7-nicotinic agonist on default network activity in schizophrenia . BACKGROUND : 3-(2,4-dimethoxybenzylidene)-anabaseine ( DB05708 ) is a partial agonist at α7 nicotinic acetylcholine receptors that has been evaluated clinically for treatment of schizophrenia . This study examined the effects of DB05708 on default network activity as a biomarker for drug effects on pathologic brain function associated with schizophrenia . METHODS : Placebo and two doses of DB05708 were administered in a random , double-blind crossover design during a Phase 2 study of DB05708 . Functional magnetic resonance imaging was performed on 16 nonsmoking patients with schizophrenia while they performed a simple eye movement task . Independent component analysis was used to identify the default network component . Default network changes were evaluated in the context of a polymorphism in P36544 , the α7-nicotinic acetylcholine receptor subunit gene , which was previously found to be associated with schizophrenia . RESULTS : Compared with placebo , both 150 and 75 mg twice daily DB05708 altered default network activity , including a reduction in posterior cingulate , inferior parietal cortex , and medial frontal gyrus activity and an increase in precuneus activity . The most robust difference , posterior cingulate activity reduction , was affected by P36544 genotype . CONCLUSIONS : The observed DB05708 -related changes are consistent with improved default network function in schizophrenia . Pharmacogenetic analysis indicates mediation of the effect through the α7-nicotinic receptor . These results further implicate nicotinic cholinergic dysfunction in the disease and suggest that default network activity may be a useful indicator of biological effects of novel therapeutic agents . Controlled delivery of DB00102 for myocardial protection using injectable self-assembling peptide nanofibers . Endothelial cells can protect cardiomyocytes from injury , but the mechanism of this protection is incompletely described . Here we demonstrate that protection of cardiomyocytes by endothelial cells occurs through DB00102 signaling . DB00102 induced cardiomyocyte Akt phosphorylation in a time- and dose-dependent manner and prevented apoptosis via PI3K/Akt signaling . Using injectable self-assembling peptide nanofibers , which bound DB00102 in vitro , sustained delivery of DB00102 to the myocardium at the injected sites for 14 days was achieved . A blinded and randomized study in 96 rats showed that injecting nanofibers with DB00102 , but not nanofibers or DB00102 alone , decreased cardiomyocyte death and preserved systolic function after myocardial infarction . A separate blinded and randomized study in 52 rats showed that DB00102 delivered with nanofibers decreased infarct size after ischemia/reperfusion . DB00102 with nanofibers induced P09619 and Akt phosphorylation in cardiomyocytes in vivo . These data demonstrate that endothelial cells protect cardiomyocytes via DB00102 signaling and that this in vitro finding can be translated into an effective in vivo method of protecting myocardium after infarction . Furthermore , this study shows that injectable nanofibers allow precise and sustained delivery of proteins to the myocardium with potential therapeutic benefits . Withacnistin inhibits recruitment of P40763 and P42229 to growth factor and cytokine receptors and induces regression of breast tumours . BACKGROUND : The binding of P40763 and P42229 to growth factor and cytokine receptors such as P00533 and P05231 receptor P40189 is critical to their activation and ability to contribute to malignant transformation . Therefore , interfering with these biochemical processes could lead to the discovery of novel anticancer agents . METHODS : Co-immunoprecipitation , western blotting , microscopy , DNA binding , invasion , and soft agar assays as well as a mouse model were used to investigate the mechanism by which the natural product Withacnistin ( Wit ) inhibits P35610 3/5 tyrosine phosphoryaltion and activation . RESULTS : Wit blocks P01133 - and P05231 -stimulated binding of P40763 and P42229 to P00533 and P40189 . Wit inhibits P01133 - , PDGF- , P05231 - , IFNβ- , and GM- P04141 -stimulation of tyrosine phosphorylation of P40763 and P42229 but not of P00533 or P09619 . The inhibition of P- P40763 and P- P42229 occurred rapidly , within minutes of Wit treatment and growth factor stimulation . Wit also inhibits P40763 nuclear translocation , DNA binding , promoter transcriptional activation , and it suppresses the expression levels of P40763 target genes such as Bcl-xL and Mcl-1 . Finally , Wit induces apoptosis , inhibits anchorage-dependent and -independent growth and invasion , and causes breast tumour regression in an ErbB2-driven transgenic mouse model . CONCLUSIONS : These data warrant further development of Wit as a novel anticancer drug for targeting tumours that harbour hyperactivated P40763 and P42229 . Alteration of contractile properties to serotonin in gastric fundus smooth muscle isolated from streptozotocin ( Q11206 ) -induced diabetic rats . Contractile responses to serotonin ( 5-HT ) of fundic smooth muscle strips isolated from both control and streptozotocin ( Q11206 ) -induced diabetic rats were investigated . Contrary to carbachol ( CCh ) which causes contractile hyperactivity in DM , 5-HT response tended to decrease in DM compared to that of the control . Pindolol ( 10(-5)M ) increased the value of EC50 of the concentration-response to 5-HT about 2.5 times in both the control and DM . After treatment with pindolol , the maximal tension to 5-HT in DM significantly decreased compared to that of the control . Pindolol showed no effect on the contractile response to CCh . Pindolol significantly inhibited the relaxation caused by isoproterenol in DM more than in the control . DB06148 ( 10(-5) M ) increased the EC50 of the response to 5-HT about 2-2.5 times in both groups , but did not cause a significant difference between the control and DM . The Ca(2+)-induced contraction caused hyperreactivity in DM in the presence of 10(-6) M CCh , but that in DM was not significantly different from the control in the presence of 10(-6) M 5-HT . Pretreatment of phorbol 12-myristate 13-acetate ( PMA , 10(-5) M ) significantly attenuated the response to 5-HT in the control , but not in DM . Results suggest that the contractile response to 5-HT in DM is related to the altered Ca2+ signal transduction system via disturbed protein kinase C ( PKC ) activity , and that there are alterations of receptor characteristics and of the density in 5-HT receptor subtypes , especially P08908 , during DM development .