MH_dev_178

[ Anti-inflammatory effect of Urtica dioica folia extract in comparison to caffeic malic acid ] . Urtica dioica extract is a traditionary used adjuvant therapeutic in rheumatoid arthritis . The antiphlogistic effects of the urtica dioica folia extract P22304 REA 23 ( Extractum Urticae dioicae foliorum ) and the main phenolic ingredient caffeic malic acid were tested concerning the inhibitory potential on biosynthesis of arachidonic acid metabolites in vitro . The caffeic malic acid was isolated from Urtica folia extract using gel exclusion - and high performance liquid chromatography and identified by mass spectroscopy and nuclear magnetic resonance . Concerning the P09917 REA products P22304 REA 23 showed a partial inhibitory effect . The isolated phenolic acid inhibited the synthesis of the leukotriene B4 in a concentration dependent manner . The concentration for halfmaximal inhibition ( IC50 ) was 83 microns / ml in the used assay . P22304 REA 23 showed a strong concentration dependent inhibition of the synthesis of cyclooxygenase derived reactions . The IC50 were 92 micrograms / ml for P22304 REA 23 and 38 micrograms / ml for the caffeic malic acid . Calculating the content in P22304 REA 23 the caffeic malic acid is a possible but not the only active ingredient of the plant extract in the tested assay systems . It is demonstrated that the phenolic component showed a different enzymatic target compared with P22304 REA 23 . The antiphlogistic effects observed in vitro may give an explanation for the pharmacological and clinical effects of P22304 REA 23 in therapie of rheumatoid diseases .

Altered gene expression by low-dose arsenic exposure in humans and cultured cardiomyocytes : assessment by real-time PCR arrays . Chronic arsenic exposure results in higher risk of skin , lung , and bladder cancer , as well as cardiovascular disease and diabetes . The purpose of this study was to investigate the effects on expression of selected genes in the blood lymphocytes from 159 people exposed chronically to arsenic in their drinking water using a novel RT-PCR TaqMan low-density array ( TLDA ) . We found that expression of tumor necrosis factor-α ( P01375 REA - α ) , which activates both inflammation and NF-κB-dependent survival pathways , was strongly associated with water and urinary arsenic levels . Expression of P22460 REA , which encodes a potassium ion channel protein , was positively associated with water and toe nail arsenic levels . Expression of 2 and 11 genes were positively associated with nail and urinary arsenic , respectively . Because arsenic exposure has been reported to be associated with long QT intervals and vascular disease in humans , we also used this TLDA for analysis of gene expression in human cardiomyocytes exposed to arsenic in vitro . Expression of the ion-channel genes CACNA 1 , Q12809 REA , P51787 REA and P15382 REA were down-regulated by 1 - μM arsenic . Alteration of some common pathways , including those involved in oxidative stress , inflammatory signaling , and ion-channel function , may underlay the seemingly disparate array of arsenic-associated diseases , such as cancer , cardiovascular disease , and diabetes .

The low-potency , voltage-dependent Q12809 REA blocker propafenone - - molecular determinants and drug trapping . The molecular determinants of high-affinity human ether-a-go-go-related gene ( Q12809 REA ) potassium channel blockade by methanesulfonanilides include two aromatic residues ( Phe 656 and Tyr 652 ) on the inner helices ( S6 ) and residues on the pore helices that face into the inner cavity , but determinants for lower-affinity Q12809 REA blockers may be different . In this study , alanine-substituted Q12809 REA channel mutants of inner cavity residues were expressed in Xenopus laevis oocytes and were used to characterize the Q12809 REA channel binding site of the antiarrhythmic propafenone . DB01182 SUB ' s blockade of Q12809 REA was strongly dependent on residue Phe 656 but was insensitive or weakly sensitive to mutation of Tyr 652 , Thr 623 , Ser 624 , Val 625 , Gly 648 , or Val 659 and did not require functional inactivation . Homology models of Q12809 REA based on KcsA and MthK crystal structures , representing the closed and open forms of the channel , respectively , suggest propafenone is trapped in the inner cavity and is unable to interact exclusively with Phe 656 in the closed state ( whereas exclusive interactions between propafenone and Phe 656 are found in the open-channel model ) . These findings are supported by very slow recovery of wild-type Q12809 REA channels from block at - 120 mV , but extremely rapid recovery of D540K channels that reopen at this potential . The experiments and modeling suggest that the open-state propafenone binding-site may be formed by the Phe 656 residues alone . The binding site for propafenone ( which may involve pi-stacking interactions with two or more Phe 656 side-chains ) is either perturbed or becomes less accessible because of closed-channel gating . This provides further evidence for the existence of gating-induced changes in the spatial location of Phe 656 side chains .

DB01184 treatment for gastroparesis : demographic and pharmacogenetic characterization of clinical efficacy and side-effects . BACKGROUND : DB01184 is a useful alternative to metoclopramide for treatment of gastroparesis due to better tolerability . Effectiveness and side-effects from domperidone may be influenced by patient-related factors including polymorphisms in genes encoding drug-metabolizing enzymes , drug transporters , and domperidone targets . AIMS : The aim of this study was to determine if demographic and pharmacogenetic parameters of patients receiving domperidone are associated with response to treatment or side-effects . METHODS : Patients treated with domperidone for gastroparesis provided saliva samples from which DNA was extracted . Fourteen single-nucleotide polymorphisms ( SNPs ) in seven candidate genes ( P08183 REA , P10635 REA , P14416 REA , P15382 REA , Q9Y6J6 REA , Q12809 REA , P51787 REA ) were used for genotyping . SNP microarrays were used to assess single-nucleotide polymorphisms in the ADRA 1A , P35368 REA , and P25100 REA loci . RESULTS : Forty-eight patients treated with domperidone participated in the study . DNA was successfully obtained from each patient . Age was associated with effectiveness of domperidone ( p= 0.0088 ) . Genetic polymorphism in Q12809 REA was associated with effectiveness of domperidone ( p= 0.041 ) . The efficacious dose was associated with polymorphism in P08183 REA gene ( p= 0.0277 ) . The side-effects of domperidone were significantly associated with the SNPs in the promoter region of P25100 REA gene . CONCLUSIONS : Genetic characteristics associated with response to domperidone therapy included polymorphisms in the drug transporter gene P08183 REA , the potassium channel Q12809 REA gene , and α1D - - adrenoceptor P25100 REA gene . Age was associated with a beneficial response to domperidone . If verified in a larger population , this information might be used to help determine which patients with gastroparesis might respond to domperidone and avoid treatment in those who might develop side-effects .

A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors . P10721 REA or alpha-platelet-derived growth factor receptor ( alpha - P09619 REA ) activating mutations are the pathogenic mechanisms that characterize gastrointestinal stromal tumors ( GIST ) . Despite excellent responses to imatinib mesylate ( IM ) , patients are relapsing . We developed an IM-resistant GIST cell line ( GIST-R ) from the IM-sensitive GIST 882 cell line ( GIST-S ) by growing these cells in IM . Gene expression profiling ( GEP ) of GIST-S , GIST-R cells and two IM resistant GIST patients demonstrated that P10721 REA is downregulated implying a major role in IM resistance . Instead , GIST-R cells have acquired IM resistance by overexpressing the oncogenic receptor tyrosine kinase - P30530 REA - in a ' kinase switch ' . Further , the two IM resistant GIST patients express P30530 REA and not c-Kit , seen by immunohistochemistry ( IHC ) . Real time reverse transcriptase-polymerase chain reaction and Western blotting of the GIST-S and GIST-R cells confirmed the switch from Kit to P30530 REA . In GIST-R , P30530 REA is tyrosine phosphorylated and its ligand growth-arrest-specific gene 6 is overexpressed implying autocrine activation . The kinase switch is associated with a morphological change from spindle to epithelioid . Molecular modeling of the kinase domain of mutant c-Kit ( V654A ) and P30530 REA showed no binding to IM but efficient binding to DB05216 MEN , a novel c-Kit / P30530 REA kinase inhibitor . DB05216 MEN synergizes with docetaxel ( taxotere ) and is cytotoxic to GIST cells .

Recombinant human prothrombin kringles have potent anti-angiogenic activities and inhibit Lewis lung carcinoma tumor growth and metastases . P00734 REA , a protein involved in blood coagulation , is a plasma glycoprotein composed of the Gla domain , two adjacent kringle domains , and a serine protease domain . Kringles are triple-disulfide-loop folding domains , which are found in several other blood proteins . In this study , we showed that recombinant human prothrombin kringle - 1 , - 2 . and -1-2 ( rk - 1 , - 2 , -1-2 ) all have potent anti-angiogenic activities , which inhibit Lewis lung carcinoma ( LLC ) tumor growth and metastases . Recombinant human prothrombin kringles were expressed by an E . coli expression system and purified to apparent homogeneity from crude E . coli extracts . Purified rk - 1 , - 2 , -1-2 migrated with a molecular mass of 14 , 19 , and 31 kDa , respectively , on sodium dodecyl sulfate-polyacrylamide gel electrophoresis ( SDS-PAGE ) under reducing conditions . rk - 1 , - 2 , -1-2 exhibited potent inhibitory effects on P09038 REA - stimulated bovine capillary endothelial cell growth with half-maximal concentrations ( ED50 ) of approximately 41 , 55 , and 156 nM , respectively . All of the recombinant human prothrombin kringles also inhibited angiogenesis in the chorioallantoic membrane ( P62158 ) of chick embryos at a dose of 20 microg . Systemic administration of rk - 1 , - 2 , -1-2 at a dose of 0.5 mg / kg / day suppressed the growth of primary LLC and at dose of 0.5 and 1.0 mg / kg / day inhibited LLC metastases in C57BL6 / J mice lungs through their anti-angiogenic effects .

Clinical and genetic factors associated with nausea and vomiting in cancer patients receiving opioids . BACKGROUND : This study investigates whether demographical , disease-related and genetic factors contribute to inter-individual differences in nausea and vomiting among patients receiving opioids for cancer pain . METHODS : Cancer patients receiving opioids were included from 17 centres in 11 European countries . Intensities of nausea and vomiting were reported by 1579 patients on four-point categorical scales . In stratified regression models including demographical and disease-related factors as covariates , 96 single nucleotide polymorphisms ( SNPs ) in 16 candidate genes related to opioid - or nausea / vomiting signalling pathways ( P08183 REA , P35372 REA , P41145 REA , P32121 REA , P42226 REA , P21964 REA , P20309 REA , P08912 REA , P35367 REA , P14416 REA , P35462 REA , P25103 REA , P46098 REA , O95264 REA , Q8WXA8 , P21554 REA ) were analysed for association with nausea and vomiting . FINDINGS : Age , body mass index , Karnofsky Performance Status , gender , use of antiemetics , type of opioid , type of cancer and eight SNPs were associated with the inter-individual differences in nausea and vomiting among cancer patients treated with opioids ( p < 0.01 ) . The SNPs were rs1176744 , rs3782025 and rs1672717 in O95264 REA ; rs165722 , rs4680 and rs4633 in P21964 REA ; rs10802789 and rs685550 in P20309 REA . Only the SNP rs1672717 in O95264 REA passed the Benjamini-Hochberg criterion for a 10 % false discovery rate . INTERPRETATION : Clinical characteristics and SNPs within the O95264 REA , P21964 REA and P20309 REA genes may be associated with the variability in nausea and vomiting among cancer patients receiving opioids . This knowledge may help to identify patients at particular risk for nausea and vomiting during treatment with opioids for cancer pain .

The thioredoxin reductase inhibitor auranofin triggers apoptosis through a Bax / Bak-dependent process that involves peroxiredoxin 3 oxidation . P30044 REA ( TrxR ) is a key selenoprotein antioxidant enzyme and a potential target for anti-cancer drugs . One potent inhibitor of TrxR is the gold ( I ) compound auranofin , which can trigger mitochondrial-dependent apoptosis pathways . The exact mechanism of apoptosis induction by auranofin is not yet clear , but there are indications that mitochondrial oxidative stress is a central event . We assessed the redox state of the peroxiredoxins ( Prxs ) in Jurkat T-lymphoma cells treated with auranofin , and found that mitochondrial Prx 3 was considerably more sensitive to oxidation than the cytosolic Prx 1 and 2 , indicating selective mitochondrial stress . Prx 3 oxidation was detected at apoptotic doses of auranofin in several cell types , and occurred before other mitochondrial events including cytochrome c release and mitochondrial depolarisation . DB00995 MEN was also able to sensitise U937 cells to P01375 REA - mediated apoptosis . DB00995 MEN - induced apoptosis was effectively blocked by the overexpression of Bcl - 2 , and Bax / Bak deficient mouse embryonic fibroblasts were also resistant to apoptosis , indicating a central role for the pro-apoptotic proteins of this family in auranofin-triggered apoptosis . DB00995 MEN exposure inhibited the proliferation of apoptosis-resistant cells , and at higher doses of auranofin could cause cell death through necrosis . We conclude that auranofin induces apoptosis in cells through a Bax / Bak-dependent mechanism associated with selective disruption of mitochondrial redox homeostasis in conjunction with oxidation of Prx 3 .

New insights into the role of serum - and glucocorticoid-inducible kinase O00141 REA in the regulation of renal function and blood pressure . PURPOSE OF REVIEW : The serum and glucocorticoid inducible kinase 1 ( O00141 REA ) is induced in the aldosterone sensitive distal nephron ( ASDN ) where it may stimulate Na reabsorption , partly by inhibiting ubiquitin ligase Q96PU5 - mediated retrieval of epithelial Na + channel ENaC from the luminal membrane . We describe recent advances in our understanding of O00141 REA function in the regulation of renal function and blood pressure . RECENT FINDINGS : Thiazolidinediones , i . e . activators of peroxisome proliferator-activated receptor gamma ( Q07869 REA gamma ) , upregulate O00141 REA and ENaC mRNA expression and increase cell-surface expression of ENaC alpha in a human cortical-collecting-duct cell line . DB02527 / protein kinase A can induce phosphorylation and inhibition of Q96PU5 - independent of O00141 REA . Part of ENaC stimulation by O00141 REA appears dependent on a O00141 REA consensus motif in ENaC alpha and independent of Q96PU5 . O00141 REA - dependent upregulation of Na + reabsorption in ASDN contributes to upregulation of renal K + excretion . In oocytes , O00141 REA activates various renal transport proteins including Na + / glucose cotransporter P13866 REA , Na + - coupled dicarboxylate transporter Q13183 REA , epithelial Ca + channel Q9NQA5 , renal outer medullary K + channel ROMK and voltage gated K + channels P15382 REA / P51787 REA and Kv1 . 3 . A variant of the O00141 REA gene associates with increased blood pressure and body mass index . SUMMARY : Q07869 REA gamma activators may increase renal Na reabsorption by stimulating O00141 REA and ENaC . Q96PU5 integrates influences of DB02527 / protein kinase A and O00141 REA . O00141 REA can activate ENaC in part directly and independent of Q96PU5 . K + homeostasis requires O00141 REA - dependent Na + reabsorption in ASDN . O00141 REA may affect renal transport mechanisms beyond Na + reabsorption and K + secretion in ASDN . Polymorphisms of O00141 REA may be relevant to the pathophysiology of hypertension and other diseases .

Inhibition of platelet-derived growth factor receptor tyrosine kinase by atrial natriuretic peptide . Atrial natriuretic peptide ( P01160 REA ) is known to suppress platelet-derived growth factor ( PDGF ) - stimulated proliferation of rat cultured vascular smooth muscle cells . The present study examined whether P01160 REA inhibits the PDGF receptor ( P09619 REA ) tyrosine kinase activation , an initial event for PDGF cellular signaling . P01160 REA reduced the in vivo tyrosine phosphorylation of P09619 REA stimulated by PDGF in a dose-dependent manner . This effect was not due to the reduction in P09619 REA protein as detected by immunoblot analysis . 8 - Bromo-cyclic GMP , a membrane-permeable 3 ' , 5 ' - cyclic monophosphate ( cGMP ) derivative , mimicked the action of P01160 REA . HS -142-1 , an antagonist for guanylate cyclase A ( P16066 REA ) and B , co-incubated with P01160 REA , restored the PDGF-induced P09619 REA autophosphorylation . The effect of P01160 REA was also observed in the presence of a protein tyrosine phosphatase inhibitor , sodium orthovanadate . To confirm that P01160 REA exerts its action by inhibiting protein tyrosine kinase ( PTK ) , an in vitro kinase assay was performed . Cyclic GMP inhibited PTK activity of P09619 REA partially purified by lectin affinity chromatography . In contrast , PTK activity in immobilized P09619 REA immunocomplexes was not inhibited by cGMP . However , exogenous cGMP dependent protein kinase ( PKG ) reduced the PTK activity in the presence of cGMP . These results demonstrate that P01160 REA suppresses P09619 REA PTK through P16066 REA probably by activating PKG . This may be an important mechanism by which P01160 REA exerts its anti-proliferative action antagonizing PDGF .

Substituted benzamides with conformationally restricted side chains . 5 . Azabicyclo [ x . y . z ] derivatives as Q13639 REA receptor agonists and gastric motility stimulants . The syntheses of benzamides containing azabicyclo [ x . y . z ] side chains and their Q13639 REA receptor agonist and 5 - Q9H205 REA receptor antagonist properties are described . These compounds were designed to mimic higher energy conformations of quinolizidine and indolizidine . High potency was achieved for both activities although an exactly paralleling SAR was not apparent . Introduction of O and S resulted in only marginal differences in potency which was more apparent for 5 - Q9H205 REA antagonism . The introduction of a methyl group alpha to the basic nitrogen resulted in a reduction in Q13639 REA receptor agonist potency . DB04917 MEN ( 5f ) was identified for further evaluation for which both enantiomers had an identical pharmacological profile , as did an azatricyclic 9b , which contained a combination of the steric bulk of the two separate enantiomers .

In utero and lactational exposure to 2,3 , 7,8- tetrachlorodibenzo-p-dioxin alters postnatal development of seminal vesicle epithelium . 2,3 , 7,8- Tetrachlorodibenzo-p-dioxin ( TCDD ) has been shown to alter male reproductive development of laboratory animals through in utero and lactational exposure . As a result of exposure , the accessory glands of the male reproductive tract , including the seminal vesicle , are decreased in size as determined by total weight of the tissue . Analysis of seminal vesicle weights over time suggests that the changes may be transient . Administration of 1.0 microg / kg TCDD during gestation caused a significant decrease in seminal vesicle weights of offspring 8-11 months of age . We examined the effects of TCDD on seminal vesicles from rats exposed in utero and lactationally . Pregnant Long Evans rats were gavaged on gestation day 15 with 1.0 microg / kg TCDD in corn oil . Male pups were euthanized and necropsied on postnatal days ( P01160 REA ) 15 , 25 , 32 , 49 , 63 , and 120 . Seminal vesicles were weighed and then fixed in 10 % neutral buffered formalin and processed for microscopic examination . Seminal vesicle weights were not significantly decreased until P01160 REA 32 . P10275 REA mRNA expression in P01160 REA 25 seminal vesicles was not different from control . In the present study , TCDD exposure decreased seminal vesicle epithelial branching and differentiation . Control epithelial cells had tall columnar morphology with relatively abundant cytoplasm , whereas TCDD-treated cells had rounded nuclei and less cytoplasm . In addition , immunolocalization of proliferating nuclear antigen was confined to undifferentiated basal epithelial cells of controls but was found in both basal and luminal cells of the treated seminal vesicle . Results indicate that the TCDD-induced impaired growth of the rat seminal vesicles is associated with a dramatic decrease in the development of the epithelium .

Regional selective neuronal degeneration after protein phosphatase inhibition in hippocampal slice cultures : evidence for a Q96HU1 kinase-dependent mechanism . The regional selectivity and mechanisms underlying the toxicity of the serine / threonine protein phosphatase inhibitor okadaic acid ( OA ) were investigated in hippocampal slice cultures . Image analysis of propidium iodide-labeled cultures revealed that okadaic acid caused a dose - and time-dependent injury to hippocampal neurons . Pyramidal cells in the P07451 REA region and granule cells in the dentate gyrus were much more sensitive to okadaic acid than the pyramidal cells in the P00915 REA region . Electron microscopy revealed ultrastructural changes in the pyramidal cells that were not consistent with an apoptotic process . Treatment with okadaic acid led to a rapid and sustained tyrosine phosphorylation of the mitogen-activated protein kinases P27361 REA and P28482 REA ( Q8TCB0 / 42 ( mapk ) ) . The phosphorylation was markedly reduced after treatment of the cultures with the microbial alkaloid DB02152 MEN ( a nonselective protein kinase inhibitor ) or the Q96HU1 kinase kinase ( Q02750 REA / 2 ) inhibitor PD98059 . DB02152 MEN and PD98059 also ameliorated the okadaic acid-induced cell death . Inhibitors of protein kinase C , Ca2 + / calmodulin-dependent protein kinase II , or tyrosine kinase were ineffective . These results indicate that sustained activation of the Q96HU1 kinase pathway , as seen after e . g . , ischemia , may selectively harm specific subsets of neurons . The susceptibility to Q96HU1 kinase activation of the P07451 REA pyramidal cells and dentate granule cells may provide insight into the observed relationship between cerebral ischemia and dementia in Alzheimer ' s disease .

Antihistamine effects on prefrontal cortex activity during working memory process in preschool children : a near-infrared spectroscopy ( NIRS ) study . P35367 REA antagonists ( antihistamines ) are widely used for the treatment of allergic disorders in young children . This study examined the effects of antihistamine on prefrontal cortex activity in preschool children using near-infrared spectroscopy ( NIRS ) , an emerging brain-imaging method suitable for psychological experiments , especially in young children . We examined the changes of oxygenated hemoglobin concentration in the prefrontal cortex while children performed a spatial working memory task , 3h after taking a first-generation antihistamine ( ketotifen ) , second-generation antihistamine ( epinastine ) , or placebo . Fifteen healthy preschool children ( mean age , 5.5 years ) participated . DB00920 MEN significantly impaired behavioral performance and cortical activation at the lateral prefrontal cortex in the working memory task , compared with epinastine and placebo . There were no sedative effects on neural response or behavioral performance after epinastine administration . This paper demonstrates for the first time differential sedation effects of first - and second-generation antihistamines on brain hemodynamic response in young children . Also discussed is the utility of the NIRS technique in neuropsychopharmacological studies of children .

Very early-onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation . BACKGROUND : Atrial fibrillation ( AF ) is the most common cardiac arrhythmia . Currently , 14 genes important for ion channel function , intercellular signaling , and homeostatic control have been associated with AF . OBJECTIVE : We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early-onset lone AF patients than in the background population . METHODS : Sequencing results of P51787 REA , Q12809 REA , Q14524 REA , P22460 REA , Q9UK17 , P15382 REA , 2 , 5 , P63252 REA , P35498 REA - 3B , P01160 REA , and P36382 REA from 192 early-onset lone AF patients were compared with data from the National Heart , Lung , and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies . RESULTS : Among the lone AF patients , 29 ( 7.6 % ) alleles harbored a novel or very rare variant ( minor allele frequency < 0.1 in the Exome Variant Server ) , a frequency that was significantly higher than what was found in the reference database ( 4.1 % ; with minor allele frequency < 0.1 ; P = . 0012 ) . Previously published electrophysiological data showed that 96 % ( n = 23 ) of the rare variants that has been functionally investigated ( n = 24 ) displayed significant functional changes . CONCLUSIONS : We report a much higher prevalence of rare variants in genes associated with AF in early-onset lone AF patients than in the background population . By presenting these data , we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF .

Effects of DB00482 and DB00744 MEN on liver metastasis and lipidperoxidation in pancreatic cancer in Syrian hamsters . Selective inhibition of eicosanoid synthesis is thought to have effects on carcinogenesis in lung and colon cancer . However , it is still unknown whether pancreatic cancer might also be influenced . Therefore we evaluated the impact of selective cyclooxygenase - 2 inhibitor DB00482 and selective P09917 REA inhibitor DB00744 MEN on liver metastasis in a solid model of pancreatic adenocarcinoma in Syrian hamster . In week 33 , the animals were sacrificed and incidence of pancreatic carcinomas and number and size of liver metastases were determined . Activities of antioxidative enzymes ( GSHPX / SOD ) and concentrations of products of lipidperoxidation were measured in liver metastases and non-metastatic hepatic tissue . The incidence ( 54.5 vs . 100 % ) , number ( 3.17 + / - 0.98 vs . 6.75 + / - 0.71 ) and size ( 2.67 + / - 1.97 vs . 11.75 + / - 1.98 mm2 ) of liver metastases were decreased by combined therapy of DB00744 MEN and DB00482 ( P < 0.05 ) . Furthermore , activities of GSHPX ( [ 73.77 + / - 5.67 ] * 10 ( 5 ) vs . [ 15.49 + / - 4.02 ] * 10 ( 5 ) U / mg prot . ; P < 0.05 ) and SOD ( 474.92 + / - 108.8 vs . 127.89 + / - 38.75 U / mg prot . ; P < 0.05 ) were increased , while lipidperoxidation ( 0.31 + / - 0.08 nmol / mg prot . vs . 1.54 + / - 0.55 nmol / mg prot . ; P < 0.05 ) was decreased by combination therapy , in non-metastatic hepatic tissue . Moreover , combined therapy increased lipidperoxidation in liver metastases ( 0.47 + / - 0.09 vs . 1.95 + / - 0.12 nmol / mg prot . ; P < 0.05 ) . Thus , a combination of DB00482 and DB00744 MEN might be a new concept to decrease tumour growth in liver metastases in advanced pancreatic cancer .

Cardiac channelopathies associated with infantile fatal ventricular arrhythmias : from the cradle to the bench . BACKGROUND : Fatal ventricular arrhythmias in the early period of life have been associated with cardiac channelopathies for decades , and postmortem analyses in P22304 REA victims have provided evidence of this association . However , the prevalence and functional properties of cardiac ion channel mutations in infantile fatal arrhythmia cases are not clear . METHODS AND RESULTS : Seven infants with potentially lethal arrhythmias at age < 1 year ( 5 males , age of onset 44.1 ± 72.1 days ) were genetically analyzed for P51787 REA , Q12809 REA , P15382 REA - 5 , P63252 REA , Q14524 REA , P36382 REA , and P62158 by using denaturing high-performance liquid chromatography and direct sequencing . Whole-cell currents of wildtype and mutant channels were recorded and analyzed in Chinese hamster ovary cells transfected with Q14524 REA and Q12809 REA cDNA . In 5 of 7 patients , we identified 4 mutations ( p . N1774D , p . T290fsX53 , p . F1486del and p . N406K ) in Q14524 REA , and 1 mutation ( p . G628D ) in Q12809 REA . N1774D , F1486del , and N406K in Q14524 REA displayed tetrodotoxin-sensitive persistent late Na ( + ) currents . By contrast , Q14524 REA - T290fsX53 was nonfunctional . Q12809 REA - G628D exhibited loss of channel function . CONCLUSION : Genetic screening of 7 patients was used to demonstrate the high prevalence of cardiac channelopathies . Functional assays revealed both gain and loss of channel function in Q14524 REA mutations , as well as loss of function associated with the Q12809 REA mutation .

Atrial natriuretic peptide : a possible mediator involved in dexamethasone ' s inhibition of cell proliferation in multiple myeloma . Atrial natriuretic peptide ( P01160 REA ) has been recognized for several decades for its role of regulating blood pressure . Recently , cumulating evidences show that P01160 REA plays an anticancer role in various solid tumors via blocking the kinase cascade of Ras - Q02750 REA / 2 - P27361 REA / 2 with the result of inhibition of DNA synthesis . P01160 REA , as well as its receptors ( P16066 REA and P17342 ) has been identified present in the embryonic stem cell and a wide range of cancer cells . Various lymphoid organs , such as lymph nodes , have been detected the presence of P01160 REA . Multiple myeloma ( MM ) , though the therapies have evolved significantly , is still an incurable disease as B lymphocyte cell neoplasm . Dexamethasone is the cornerstone in treatment of MM via inactivation of Ras - Q02750 REA / 2 - P27361 REA / 2 cascade reaction . Coincidently , dexamethasone can increase the expression of P01160 REA markedly . Nevertheless , the role of P01160 REA in MM is unclear . Based on these results above , we raise the hypothesis that P01160 REA is involved in mediating dexamethasone ' s inhibition of proliferation in MM cells , which suggests that P01160 REA may be a potential agent to treat MM .

Effects on thrombin generation of single injections of DB02351 MEN in patients with calf vein thrombosis . STUDY OBJECTIVE : To determine whether single injections of DB02351 MEN , a direct thrombin inhibitor , can inhibit thrombin generation in patients with calf vein thrombosis and , if so , if the inhibition is sustained . DESIGN : Phase II open label cohort study . SETTING : Tertiary-care referral centres , university affiliated hospitals . PATIENTS : 10 patients with venographically-demonstrated calf vein thrombosis . INTERVENTION : Patients received a single injection of DB02351 MEN , either 1.0 mg / kg subcutaneously or 0.6 mg / kg as a 15 min intravenous infusion . P00734 REA fragment ( F1 + + 2 ) levels , as an index of thrombin generation , were measured before as well as 6 h post - and 24 h post - DB02351 MEN administration . Patients were followed with non-invasive tests to detect thrombus extension into the proximal veins . RESULTS : There was a significant reduction in the levels of F1 + 2 with both regimens , 6 h after DB02351 MEN . The F1 + 2 levels 24 h post - DB02351 MEN showed a significant increase relative to the 6 h post - DB02351 MEN results . One patient developed thrombus extension into the popliteal vein and was treated with conventional anticoagulants . CONCLUSION : The single injections of DB02351 MEN used in the study produced incomplete and temporary suppression of F1 + 2 . Complete and permanent inhibition of thrombin generation with DB02351 MEN in patients with calf vein thrombosis may require higher doses , multiple subcutaneous injections and / or prolonged intravenous infusion .

Effect of DB01708 MEN on endocrine functions of adipose tissue , the involvement of Q07869 REA gamma . DB01708 MEN ( DB01708 MEN ) , an adrenal steroid , is known to decrease body fat . Thus , it may also alter the endocrine functions of adipose tissue . The aim of this study was to determine if administration of DB01708 MEN might influence adiponectin gene expression and secretion from adipose tissue . We demonstrate here the inducing effect of exogenously administered DB01708 MEN on adiponectin gene expression in epididymal WAT and adiponectin levels in serum of rats fed a DB01708 MEN - containing diet ( 0.6 % , w / w ) for 2 weeks , accompanied by a reduction in epididymal adipose tissue mass . A corresponding increase in peroxisome proliferator-activated receptor gamma ( Q07869 REA ( gamma ) ) mRNA expression suggests that Q07869 REA ( gamma ) may be involved in the up-regulation of adiponectin gene expression after DB01708 MEN treatment . The presented observations indicate that the positive effects of DB01708 MEN , which seems to play a protective role against insulin resistance and atherosclerosis , may be in fact indirect and due to up-regulation of adiponectin gene expression and stimulation of adiponectin secretion from adipose tissue .

Identification of novel androgen receptor antagonists using structure - and ligand-based methods . P10275 REA ( AR ) plays a critical role in the development and progression of prostate cancer ( PCa ) . The AR hormone-binding site ( HBS ) is intensively studied and represents the target area for current antiandrogens including DB01128 and structurally related DB08899 MENMAX DB08899 MEN . As resistance to antiandrogens invariably emerges in advanced prostate cancer , there exists a high medical need for the identification and development of novel AR antagonists of different chemotypes . Given the wealth of structural information on the AR in complex with a variety of ligands , we have applied an integrated structure - and ligand-based virtual screening methodology to identify novel AR antagonists . Virtual hits generated by a consensus voting approach were experimentally evaluated and resulted in the discovery of a number of structurally diverse submicromolar antagonists of the AR . In particular , one identified compound demonstrated anti-AR potency in vitro that is comparable to the clinically used DB01128 . These results set a ground for the development of novel classes of PCa drugs that are structurally different from current AR antagonists .

Chronic atrial fibrillation alters the functional properties of If in the human atrium . INTRODUCTION : Despite the evidence that the hyperpolarization-activated current ( If ) is highly modulated in human cardiomyopathies , no definite data exist in chronic atrial fibrillation ( cAF ) . We investigated the expression , function , and modulation of If in human cAF . METHODS AND RESULTS : Right atrial samples were obtained from sinus rhythm ( SR , n = 49 ) or cAF ( duration > 1 year , n = 31 ) patients undergoing corrective cardiac surgery . Among f-channel isoforms expressed in the human atrium ( O60741 REA , 2 and 4 ) , Q9Y3Q4 REA mRNA levels measured by RT-PCR were significantly reduced . However , protein expression was preserved in cAF compared to SR ( + 85 % for Q9Y3Q4 REA ) ; concurrently , miR - 1 expression was significantly reduced . In patch-clamped atrial myocytes , current-specific conductance ( gf ) was significantly increased in cAF at voltages around the threshold for If activation ( - 60 to - 80 mV ) ; accordingly , a 10 - mV rightward shift of the activation curve occurred ( P < 0.01 ) . β-Adrenergic and Q13639 REA receptor stimulation exerted similar effects on If in cAF and SR cells , while the P01160 REA - mediated effect was significantly reduced ( P < 0.02 ) , suggesting downregulation of natriuretic peptide signaling . CONCLUSIONS : In human cAF modifications in transcriptional and posttranscriptional mechanisms of HCN channels occur , associated with a slight yet significant gain-of-function of If , which may contribute to enhanced atrial ectopy .