MH_dev_320

Comparative effects of azimilide and ambasilide on the human ether-a-go-go-related gene ( Q12809 REA ) potassium channel . OBJECTIVE : To evaluate the effects of azimilide and ambasilide on the biophysical properties of the human-ether-a-go-go-related ( Q12809 REA ) channel . METHODS : Q12809 REA was stably transfected into Chinese hamster ovary ( CHO - P04264 REA ) cells and currents were measured using a whole cell , voltage-clamp technique . RESULTS : DB04957 MEN had a ' dual effect ' , inhibiting current at voltage steps above - 40 mV and augmenting current at - 40 and - 50 mV . Tail current inhibition following a step to + 30 mV did not vary with temperature ( IC ( 50 ) 610 nM at 22 degrees C and 560 nM at 37 degrees C ) . The agonist effect at - 50 mV was concentration-dependent and correlated with a hyperpolarizing shift in the V ( 1/2 ) of activation ( r = 0.98 , P < 0.05 ) . Time constants of inactivation were faster and there was a - 10 mV shift in the V ( 1/2 ) of steady state inactivation suggestive of open and inactivated state binding . By comparison , ambasilide inhibited Q12809 REA channels with lower potency ( IC ( 50 ) 3.6 microM ) , in a voltage - and time-dependent but frequency-independent manner ( 0.03- 1 Hz ) . Ambasilide had no effect on activation or inactivation gating but prolonged both fast and slow components of deactivation consistent with unbinding from the open state . The net effect of both drugs was similar during a voltage ramp which simulated a cardiac action potential . CONCLUSIONS : Inhibition of Q12809 REA channels by azimilide and ambasilide exhibits a similar time and voltage-dependence . While both exhibit affinity for the open state , azimilide also binds to inactivated channels .

Evaluation of cytotoxicity of bevacizumab on P15692 REA - enriched corneal endothelial cells . PURPOSE : To evaluate the cytotoxicity of varying doses of DB00112 MEN on corneal endothelial cells in the presence of a range of concentrations of vascular endothelial growth factor ( P15692 REA ) . DB00112 MEN , a drug widely used in the treatment of neovascular glaucoma neutralizes all isoforms of P15692 REA and ameliorates neovascularization after intracameral administration . However , the safety of intracameral administration of DB00112 MEN and dose-dependent toxicity on corneal endothelial cells has not been established . METHODS : Bovine corneal endothelial ( BCE ) cells were treated with P15692 REA ( 50 ng / ml ) and / or DB00112 MEN ( 0.1- 2 mg / ml ) for 72 h . Cell proliferation was measured with the water soluble tetrazolium salts ( WST - 1 ) assay . Morphological changes were recorded by bright-field microscopy of cells . Cytotoxicity in response to DB00112 MEN was evaluated by trypan blue exclusion , as well as annexin V / propidium iodide ( PI ) staining . RESULTS : DB00112 MEN was not cytotoxic at the concentrations tested and the percentage of DB00112 MEN - treated cells staining positively for both PI and P08758 REA was less than 1 % . The anti-proliferative effects of DB00112 MEN on BCE cells were dose-dependent ; a dose of 1.5 mg / ml or 2 mg / ml produced a 33 % ( p= 0.005 ) or 47 % ( p= 0.001 ) decrease in cell proliferation compared to controls . Similar results were obtained in cells treated with a combination of DB00112 MEN and P15692 REA . P15692 REA ( 50 ng / ml ) had no significant effect on cell proliferation compared to controls . Morphology of cells was unchanged after treatment with DB00112 MEN and / or P15692 REA compared to controls . CONCLUSIONS : DB00112 MEN was safe and not toxic to BCE cells at concentrations commonly used in clinical practice .

Identification of Reverb ( alpha ) as a novel ROR ( alpha ) target gene . The nuclear receptor superfamily comprises a large number of ligand-activated transcription factors that are involved in numerous biological processes such as cell proliferation , differentiation , and homeostasis . ROR ( alpha ) ( P35398 REA ) and Reverb ( alpha ) ( P20393 REA ) are two members of this family whose biological functions are largely unknown . In addition , no ligand has been yet identified for these two receptors ; therefore , they are referred as orphan receptors . Here , we show that ROR ( alpha ) and Reverb ( alpha ) are expressed with a similar tissue distribution and are both induced during the differentiation of rat Q9BTT4 myoblastic cells . Ectopic expression of ROR ( alpha ) 1 in Q9BTT4 cells significantly induces Reverb ( alpha ) expression as demonstrated by Northern blot analysis . Using reverse transcription-PCR to analyze Reverb ( alpha ) gene expression from staggerer mice , we found that there was a significant reduction of Reverb ( alpha ) mRNA in the skeletal muscle comparing it with the wild-type mice , which suggests that ROR ( alpha ) is involved in the regulation of Reverb ( alpha ) gene expression . Transient transfection assays using the Reverb ( alpha ) promoter demonstrate that ROR ( alpha ) regulates the Reverb ( alpha ) gene at the transcriptional level . Furthermore , mutagenesis experiments indicate that ROR ( alpha ) regulates Reverb ( alpha ) transcription via a monomeric ROR response element located in the Reverb ( alpha ) gene promoter . Electrophoretic mobility shift assays show that ROR ( alpha ) binds strongly to this site in a specific-manner . Finally , overexpression of Q9Y3R0 REA / Q06418 - 2 , but not Q15788 REA , potentiates ROR ( alpha ) - stimulated Reverb ( alpha ) promoter activity in transient transfection experiments . Together , our results identify Reverb ( alpha ) as a novel target gene for ROR ( alpha ) .

Molecular basis of differential resistance to cycloguanil and pyrimethamine in Plasmodium falciparum malaria . DB01131 MEN and pyrimethamine are antifolate drugs with distinct chemical structures that are used commonly in the prophylaxis and treatment of Plasmodium falciparum malaria . Clinical reports and field studies have suggested that some parasites refractory to proguanil can be treated with pyrimethamine , and vice versa . Analysis of the P . falciparum dihydrofolate reductase ( P00374 REA ) from different parasites reveals the structural basis for differential susceptibility to these antifolate drugs . Parasites harboring a pair of point mutations from Ala - 16 to DB00161 - 16 and from DB00133 - 108 to DB00156 - 108 are resistant to cycloguanil ( the active metabolite of proguanil ) but not to pyrimethamine . A single DB00174 - 108 mutation , on the other hand , confers resistance to pyrimethamine with only a moderate decrease in susceptibility to cycloguanil . Significant cross-resistance to both drugs occurs in parasites having mutations that include DB00133 - 108 - - - DB00174 - 108 and DB00167 - 164 - - - DB00149 - 164 . These results reflect the distinct structures of pyrimethamine and cycloguanil and suggest fine differences in binding within the active site cavity of P00374 REA . Alternative inhibitors , used alone or in combination , may be effective against some strains of cycloguanil - or pyrimethamine-resistant malaria .

Expression of the human concentrative nucleotide transporter 1 ( O00337 REA ) gene correlates with clinical response in patients affected by Waldenström ' s Macroglobulinemia ( WM ) and small lymphocytic lymphoma ( SLL ) undergoing a combination treatment with 2 - chloro - 2 ' - deoxyadenosine ( DB00242 MEN ) and DB00073 . PURPOSE : Resistance to nucleoside analogues agents is likely to be multifactorial and could involve a number of mechanisms affecting drug penetration , metabolism and targeting . In vitro studies of resistant human cell lines have confirmed that human concentrative nucleoside transporter 1 ( O00337 REA ) - deficient cells display resistance . EXPERIMENTAL DESIGN : We applied real-time PCR method to assess the mRNA expression of equilibrative and concentrative nucleoside transporter ( hENT 1 , O00337 REA ) , deoxycytidine and deoxyguanosine kinase ( P27707 REA , Q16854 REA ) , 5 ' - nucleotidase ( 5 ' - NT ) , ribonucleotide reductase catalytic and regulatory ( P23921 REA , P31350 REA ) subunits in bone marrow cells from 32 patients with Waldenström ' s Macroglobulinemia ( WM ) and small lymphocytic lymphoma ( SLL ) who received 2CdA - based chemotherapy . Responses to chemotherapy , were then correlated to the expression of these markers . RESULTS : All 32 patients enrolled expressed lower levels of O00337 REA as compared to healthy donors . In univariate analysis , lower expression level of O00337 REA ( p= 0.0021 ) and P31350 REA ( p= 0.02 ) correlated with response to chemotherapy . In particular , patients with low levels of O00337 REA achieved inferior clinical response . No significant correlation between these genes expression and age , stage of disease was found . This study suggests that nucleotidase expression levels can be used to identify subgroups of WM and SLL patients who will likely respond differently to a 2CdA - based therapy .

P09917 REA pathway promotes cell proliferation in human glioma cell lines . OBJECTIVE : P09917 REA ( P09917 REA ) is a key enzyme in the synthesis of leukotrienes ( LTs ) , that might promote carcinogenesis . We investigated P09917 REA expression and examined whether the P09917 REA pathway is associated with the proliferation of human brain tumors . METHODS : We immunohistochemically evaluated the profile of P09917 REA expression in various types of brain tumors obtained from 42 patients , and examined the proliferative effects of the P09917 REA pathway in human glioma cell lines using a proliferation assay . RESULTS : Immunohistochemistry of glioblastomas , astrocytomas , meningiomas , medulloblastomas , craniopharyngiomas , ependymomas , neurinomas , oligodendrogliomas , malignant lymphomas , dysembryoplastic neuroepithelial and metastatic brain tumors revealed P09917 REA expression in the cytoplasm and nuclei or nuclear envelopes of tumor cells . The P09917 REA inhibitor A861 and the P09960 REA hydrolase inhibitor DB03424 MEN dose-dependently suppressed the proliferation of A172 cells , a glioma cell line . CONCLUSIONS : We confirmed the expression of P09917 REA in various human brain tumors and demonstrated the partial suppression of tumor growth by inhibitors of the P09917 REA - P09960 REA hydrolase pathway in human glioma cell lines . The P09917 REA - P09960 REA pathway might play roles in the proliferation of human glioma cells .

Design , synthesis , and biological evaluation of 3,4- diarylmaleimides as angiogenesis inhibitors . The new analogue 2 of combretastatin A - 4 was discovered to be an inhibitor of tubulin polymerization with an IC50 of 7.6 microM and reduced angiogenesis in the in vivo chick embryo model . Interestingly , in a series of 2,3- diarylmaleimides closely related to this lead , no other compound was found to be active in the tubulin polymerization assay . However , by screening in the in vivo chick embryo assay 10 was identified as a potent angiogenesis inhibitor indicating an alternative target . Indeed , molecular modeling studies suggest a reasonable binding mode of 10 at the DB00171 - binding site of the model kinase P24941 REA . Motivated by these results , analogues of 10 were screened for inhibitory activity in a panel of 12 selected protein kinases and a high affinity of 10 to P15692 REA - R2 was found showing an IC50 of 2.5 nM . Structure-activity relationships ( SAR ) for this compound series with the isolated enzyme and equivalent antiangiogenic activity in the chick embryo assay are presented herein .

Coadministrating luteolin minimizes the side effects of the aromatase inhibitor letrozole . P11511 REA inhibitors ( AIs ) have been used as adjuvant therapeutic agents for breast cancer . Their adverse side effect on blood lipid is well documented . Some natural compounds have been shown to be potential AIs . In the present study , we compared the efficacy of the flavonoid luteolin to the clinically approved AI letrozole ( DB01006 MEN ; Novartis Pharmaceuticals , East Hanover , NJ ) in a cell and a mouse model . In the in vitro experimental results for aromatase inhibition , the Ki values of luteolin and letrozole were estimated to be 2.44 µM and 0.41 nM , respectively . Both letrozole and luteolin appeared to be competitive inhibitors . Subsequently , an animal model was used for the comparison . P11511 REA - expressing MCF - 7 cells were transplanted into ovariectomized athymic mice . Luteolin was given by mouth at 5 , 20 , and 50 mg / kg , whereas letrozole was administered by intravenous injection . Similar to letrozole , luteolin administration reduced plasma estrogen concentrations and suppressed the xenograft proliferation . The regulation of cell cycle and apoptotic proteins-such as a decrease in the expression of Bcl-xL , cyclin-A / D1 / E , P24941 REA / 4 , and increase in that of Bax-was about the same in both treatments . The most significant disparity was on blood lipids . In contrast to letrozole , luteolin increased fasting plasma high-density lipoprotein concentrations and produced a desirable blood lipid profile . These results suggested that the flavonoid could be a coadjuvant therapeutic agent without impairing the action of AIs .

Regulatory regions of growth-related genes can activate an exogenous gene of the alpha-fetoprotein promoter to a comparable degree in human hepatocellular carcinoma cells . We examined the transcriptional activation by the regulatory regions of the midkine ( MK ) , survivin ( Q09428 REA ) , cyclooxygenase - 2 ( P35354 REA ) , telomerase reverse transcriptase ( O14746 REA ) and alpha-fetoprotein ( AFP ) genes in human hepatocellular carcinoma cells . Luciferase assays showed that the Q09428 REA regulatory region exhibited the greatest activity and that the MK regulatory region activated the reporter gene better than the enhancer-linked AFP promoter even in high-AFP-producing cells . The P35354 REA and O14746 REA regulatory regions also activated the reporter gene better than the AFP enhancer / promoter in intermediate-AFP-producing cells . Combination of the regulatory regions arranged in tandem modulated their transcriptional activities , depending on the arrangement of the promoters and cells examined . These data suggested that the regulatory regions of the growth-related genes could be useful to activate a therapeutic gene in hepatocellular carcinoma cells irrespective of the amounts of AFP production but combinatory use of the promoter regions could not always contribute to enhanced activity .

Titration of KATP channel expression in mammalian cells utilizing recombinant baculovirus transduction . A variety of transfection approaches have been used to deliver plasmids encoding ion channel genes into cells . We have used the baculovirus transduction system , BacMam , to demonstrate transient expression of multi-subunit KATP channels in CHO - P04264 REA and P29320 REA - 293 EBNA cells using sulfonylurea receptor 1 ( Q09428 REA ) , SUR 2A , SUR 2B , and P55040 6.2 genes . [ 3H ] - glyburide binding , patch clamp , and DiBAC 4 ( 3 ) measurements of membrane potential changes were used to monitor channel expression . BacMam delivery of each Q09428 REA isoform with KIR 6.2 was demonstrated based on its pharmacological profiles . Expression levels of Q09428 REA and KIR 6.2 were titrated by varying the viral concentration or time of virus addition , with functional activity measured in as little as 4-6 hours posttransduction . Further increases in BacMam virus induced sufficient KATP expression to dominate membrane potential without pharmacological opening of the channel . Independently altering treatment with virus containing either the Q09428 REA or KIR 6.2 gene revealed interactions among subunits during formation of functional channels in the plasma membrane . This study demonstrates the utility and versatility of BacMam as a valuable gene delivery tool for the study of ion channel function .

Protective effect of treatment with low-dose gliclazide in a model of middle cerebral artery occlusion and reperfusion in rats . The aim of this study was to explore the expression of sulfonylurea receptor 1 ( Q09428 REA ) , the regulatory subunit of the NCCa - DB00171 channel , and to investigate the protective effects of gliclazide following middle cerebral artery occlusion ( MCAO ) / reperfusion in male Wistar rats . Adult rats underwent 2h of the left MCAO using the intraluminal thread technique before reperfusion . The core areas of the infarct at different reperfusion time points were examined for the mRNA level and protein expression of Q09428 REA using reverse transcription-polymerase chain reaction ( RT-PCR ) and western blotting respectively . DB01120 SUB was administered intravenously into the right jugular vein for 12h simultaneously with the reperfusion . The number of apoptotic cells was determined using the TUNEL assay . The neurological functional deficits were evaluated using Bederson ׳ s test , and the cerebral infarction volume was visualized with TTC staining . We found up-regulation of Q09428 REA mRNA and protein levels in ischemic infarct tissues after reperfusion following MCAO , and Q09428 REA mRNA and protein were maximally upregulated 8-12 h after a 2 - hour ischemia . The treatment with low-dose of gliclazide reduced the total number of TUNEL-positive cells , the neurological functional deficits and the brain infarct volume . These results suggest that the Q09428 REA - regulated NCCa - DB00171 channel may be associated with MCAO / reperfusion injury and the infarct-reducing effects of intravenous treatment with gliclazide may be due , in part , to the blocked upregulation of Q09428 REA expression , the decreased infarct size and the reduced apoptosis in the ischemia-reperfusion brain .

Signalling pathways involved in retinal endothelial cell proliferation induced by advanced glycation end products : inhibitory effect of gliclazide . AIM : We have previously demonstrated that advanced glycation end products ( AGEs ) stimulate bovine retinal endothelial cell ( BREC ) proliferation through induction of vascular endothelial growth factor ( P15692 REA ) production by these cells . We have also shown that gliclazide , a sulfonylurea which decreases oxidative stress , inhibits this effect . The aim of the present study was to characterize the signalling pathways involved in P51606 REA - induced BREC proliferation and P15692 REA production and mediating the inhibitory effect of gliclazide on these biological events . METHODS : BRECs were treated or not treated with AGEs in the presence or absence of gliclazide , antioxidants , protein kinase C ( PKC ) , mitogen-activated protein kinase ( MAPK ) or nuclear factor-kappaB ( NF-kappaB ) inhibitors . BREC proliferation was assessed by measuring [ 3H ] - thymidine incorporation into DNA . Activation of PKC , MAPK and NF-kappaB signal transduction pathways and determination of P15692 REA expression were assessed by Western blot analysis using specific antibodies . MAPK activity was also determined by an in vitro kinase assay . RESULTS : Treatment of BRECs with AGEs significantly increased cell proliferation and P15692 REA expression . AGEs induced P05771 REA translocation , extracellular signal-regulated protein kinase 1/2 and NF-kappaB activation in these cells . Pharmacological inhibition of these signalling pathways abolished P51606 REA effects on cell proliferation and P15692 REA expression . Exposure of BRECs to gliclazide or antioxidants such as vitamin E or N-acetyl-l-cysteine resulted in a significant decrease in P51606 REA - induced activation of PKC - , MAPK - and NF-kappaB-signalling pathways . CONCLUSIONS : Our results demonstrate the involvement of PKC , MAPK and NF-kappaB in P51606 REA - induced BREC proliferation and P15692 REA expression . DB01120 SUB inhibits BREC proliferation by interfering with these intracellular signal transduction pathways .

Effect of canagliflozin on renal threshold for glucose , glycemia , and body weight in normal and diabetic animal models . BACKGROUND : DB08907 MEN is a sodium glucose co-transporter ( SGLT ) 2 inhibitor in clinical development for the treatment of type 2 diabetes mellitus ( T2DM ) . METHODS : ( 14 ) C-alpha-methylglucoside uptake in Chinese hamster ovary-K cells expressing human , rat , or mouse SGLT 2 or P13866 REA ; ( 3 ) H - 2 - deoxy-d-glucose uptake in Q9BTT4 myoblasts ; and 2 - electrode voltage clamp recording of oocytes expressing human SGLT 3 were analyzed . Graded glucose infusions were performed to determine rate of urinary glucose excretion ( UGE ) at different blood glucose ( BG ) concentrations and the renal threshold for glucose excretion ( RT ( G ) ) in vehicle or canagliflozin-treated Zucker diabetic fatty ( ZDF ) rats . This study aimed to characterize the pharmacodynamic effects of canagliflozin in vitro and in preclinical models of T2DM and obesity . RESULTS : Treatment with canagliflozin 1 mg / kg lowered RT ( G ) from 415 ± 12 mg / dl to 94 ± 10 mg / dl in ZDF rats while maintaining a threshold relationship between BG and UGE with virtually no UGE observed when BG was below RT ( G ) . DB08907 MEN dose-dependently decreased BG concentrations in db / db mice treated acutely . In ZDF rats treated for 4 weeks , canagliflozin decreased glycated hemoglobin ( HbA 1c ) and improved measures of insulin secretion . In obese animal models , canagliflozin increased UGE and decreased BG , body weight gain , epididymal fat , liver weight , and the respiratory exchange ratio . CONCLUSIONS : DB08907 MEN lowered RT ( G ) and increased UGE , improved glycemic control and beta-cell function in rodent models of T2DM , and reduced body weight gain in rodent models of obesity .

Comparisons between the beneficial effects of different sulphonylurea treatments on ischemia-induced retinal neovascularization . The aim of this study was to assess the potential beneficial effects of gliclazide and other sulphonylureas on ischemia-induced retinal neovascularization . To produce an animal model of oxygen-induced ischemic retinopathy , 7 - day-old ( Q0GE19 ) mice were exposed to a 75 % oxygen environment for 5 days . On their return to ambient air at P12 , these mice were then treated with gliclazide , glibenclamide , glimepiride , or DB06151 . DB01120 SUB , but not glibenclamide or glimepiride , markedly suppresses retinal neovascularization . N-Acetylcysteine , however , only moderately suppresses retinal neovascularization . The number of neovascular nuclei in the retinal cross sections decreased by 29 % in the gliclazide-treated mice ( P < 0.05 vs control ) . The induction of P15692 REA mRNA expression at P13 is significantly suppressed in the gliclazide group , relative to the control group ( - 44 % , P < 0.05 ) . The P15692 REA protein expression levels at P15 were also suppressed in the gliclazide group ( - 43 % , P < 0.01 ) . The 8 - isoprostane production levels at P15 were suppressed in both the gliclazide group ( - 20 % , P < 0.05 ) and the DB06151 - treated group ( - 31 % , P < 0.01 ) . DB01120 SUB inhibits ischemia-induced retinal neovascularization , and this is likely to be mediated in part through the downregulation of P15692 REA and the suppression of oxidative stress .

Estradiol increases cell growth in human astrocytoma cell lines through ERα activation and its interaction with Q15788 REA and Q9Y6Q9 REA coactivators . Estradiol ( E2 ) regulates several cellular functions through the interaction with estrogen receptor subtypes , ERα and ERβ , which present different functional and regulation properties . ER subtypes have been identified in human astrocytomas , the most common and aggressive primary brain tumors . We studied the role of ER subtypes in cell growth of two human astrocytoma cell lines derived from tumors of different evolution grades : U373 and D54 ( grades III and IV , respectively ) . E2 significantly increased the number of cells in both lines and the co-administration with an ER antagonist ( ICI 182 , 780 ) significantly blocked E2 effects . ERα was the predominant subtype in both cell lines . E2 and ICI 182 , 780 down-regulated ERα expression . The number of U373 and D54 cells significantly increased after PPT ( ERα agonist ) treatment but not after DPN ( ERβ agonist ) one . To determine the role of Q15788 REA and Q9Y6Q9 REA coactivators in ERα induced cell growth , we silenced them with RNA interference . Coactivator silencing blocked the increase in cell number induced by PPT . The content of proteins involved in proliferation and metastasis was also determined after PPT treatment . Western blot analysis showed that in U373 cells the content of PR isoforms ( PR-A and PR-B ) , P00533 REA , P15692 REA and cyclin D1 increased after PPT treatment while in D54 cells only the content of P00533 REA was increased . Our results demonstrate that E2 induces cell growth of human astrocytoma cell lines through ERα and its interaction with Q15788 REA and Q9Y6Q9 REA and also suggest differential roles of ERα on cell growth depending on astrocytoma grade .

Renal changes induced by a cyclooxygenase - 2 inhibitor during normal and low sodium intake . P35354 REA ( P35354 REA ) has been identified in renal tissues under normal conditions , with its expression enhanced during sodium restriction . To evaluate the role of P35354 REA - derived metabolites in the regulation of renal function , we infused a selective inhibitor ( nimesulide ) in anesthetized dogs with normal or low sodium intake . The renal effects elicited by nimesulide and a non-isozyme-specific inhibitor ( meclofenamate ) were compared during normal sodium intake . In ex vivo assays , meclofenamate , but not nimesulide , prevented the platelet aggregation elicited by arachidonic acid . During normal sodium intake , nimesulide infusion ( n = 6 ) had no effects on arterial pressure or renal hemodynamics but did reduce urinary sodium excretion , urine flow rate , and fractional lithium excretion . In contrast , nimesulide administration increased arterial pressure and decreased renal blood flow , urine flow rate , and fractional lithium excretion during low sodium intake ( n = 6 ) . P35354 REA inhibition reduced urinary prostaglandin E ( 2 ) excretion in both groups but did not modify plasma renin activity in dogs with low ( 8.1+ / -1.1 ng angiotensin I . mL ( - 1 ) . h ( - 1 ) ) or normal ( 1.8+ / -0.4 ng angiotensin I . mL ( - 1 ) . h ( - 1 ) ) sodium intake . DB00939 MEN infusion in dogs with normal sodium intake ( n = 8 ) induced a greater renal hemodynamic effect than nimesulide infusion . These results suggest that P35354 REA - derived metabolites ( 1 ) are involved in the regulation of sodium excretion in dogs with normal sodium intake , ( 2 ) play an important role in the regulation of renal hemodynamic and excretory function in dogs with low sodium intake , and ( 3 ) are not involved in the maintenance of the high renin levels during a long-term decrease in sodium intake .

Antidepressant properties of the Q13639 REA receptor partial agonist , SL65 . 0155 : behavioral and neurochemical studies in rats . This study was undertaken to investigate the potential antidepressant-like properties of SL65 . 0155 , a serotonin 5 - HT ( 4 ) receptor partial agonist , in male rats of the Wistar strain tested in the forced swim test ( P19883 REA ) , an experimental model widely used to assess antidepressant-like activity . The expression of hippocampal neurotrophic factors , such as the brain-derived neurotrophic factor ( P23560 REA ) , the phosphorilated DB02527 response element-binding protein ( p-CREB ) , the B cell lymphoma - 2 ( Bcl - 2 ) , the Bax and the vascular endothelium growth factor ( P15692 REA ) were also evaluated by Western Blot analysis . Different groups of rats received intraperitoneally ( i . p . ) injections of SL65 . 0155 ( 0.1 , 0.5 and 1 mg / kg ) , clomipramine ( 50 mg / kg ) , citalopram ( 15 mg / kg ) or vehicle , respectively , 24 , 5 and 1 h prior to the P19883 REA . Compared to the control group , SL65 . 0155 ( 0.5 and 1 mg / kg ) , clomipramine or citalopram injected animals showed an increased swimming and climbing behavior and reduced immobility time in the P19883 REA . Interestingly , this effect was not due to changes in the locomotor activity since all treated groups failed to show any change in motor ability as assessed in the open field test . Western blot analysis of hippocampal homogenates showed an enhancement of p-CREB , P23560 REA Bcl - 2 and P15692 REA protein levels in SL65 . 0155 treated groups , but not in citalopram or clomipramine treated groups , used here as positive control . No change was found in Bax expression in any treated group . These findings give further support to the hypothesis that the stimulation of serotonin 5 - HT ( 4 ) receptors may be a therapeutic target for depression .

Suppression of tumor growth and metastasis by a P17948 REA antagonizing peptide identified from a phage display library . Although the P15692 REA - Flk - 1 - pathway has been known as the major driving force of angiogenesis , new evidence has shown that P17948 REA / Flt - 1 plays important roles during the neovascularization under pathological conditions including tumor , atherosclerosis and arthritis . In search of Flt - 1 receptor antagonizing peptides , we screened a phage display 12 - mer-peptide library with recombinant Flt - 1 protein . Seven candidate peptides were identified that specifically bound to P15692 REA receptor Flt - 1 , of which peptide F56 ( WHSDMEWWYLLG ) almost abolished P15692 REA binding to receptor Flt - 1 in vitro . In vivo , F56 fused with P00374 REA ( P00374 REA - F56 ) inhibited angiogenesis in a P62158 assay . Moreover , P00374 REA - F56 significantly inhibited the growth of nodules of human gastric cancer cell line MGC - 803 in BALB / c nude mice . Histological analyses showed that necrosis of the implanted tumor was markedly enhanced following treatment with P00374 REA - F56 . In the severe combined immunodeficiency disease ( SCID ) mouse model for studying metastasis of the human breast cancer cell line BICR-H 1 , synthetic peptide F56 significantly inhibited tumor growth and lung metastases . Taken together , our results have demonstrated that peptide F56 , as a Flt - 1 receptor antagonist , fulfilled the antiangiogenic and antimetastatic effects by specifically interfering with the interaction between P15692 REA and receptor Flt - 1 . Thus , short peptide F56 may have clinical potential in tumor therapy .

DB01079 MENMAX DB01079 MEN and other serotonergic agents : what is the evidence ? Through effects on gastrointestinal motor and secretory function as well as visceral sensation , serotonin ( 5 - HT ) plays a key role in the pathogenesis of irritable bowel syndrome ( IBS ) . In particular , 5 - Q9H205 REA and Q13639 REA receptors appear to be very important in IBS . This article critically appraises the evidence supporting the use of the 5 - Q9H205 REA receptor antagonist alosetron in the treatment of women with diarrhea-predominant IBS . The safety profile and restricted-use program for alosetron is also reviewed . This discussion is followed by a comprehensive review of the efficacy and safety data in support of tegaserod for women with constipation-predominant IBS .

A synthetic dl-nordihydroguaiaretic acid ( Nordy ) , inhibits angiogenesis , invasion and proliferation of glioma stem cells within a zebrafish xenotransplantation model . The zebrafish ( Danio rerio ) and their transparent embryos represent a promising model system in cancer research . Compared with other vertebrate model systems , we had previously shown that the zebrafish model provides many advantages over mouse or chicken models to study tumor invasion , angiogenesis , and tumorigenesis . In this study , we systematically investigated the biological features of glioma stem cells ( GSCs ) in a zebrafish model , such as tumor angiogenesis , invasion , and proliferation . We demonstrated that several verified anti-angiogenic agents inhibited angiogenesis that was induced by xenografted-GSCs . We next evaluated the effects of a synthetic dl-nordihydroguaiaretic acid compound ( dl-NDGA or " Nordy " ) , which revealed anti-tumor activity against human GSCs in vitro by establishing parameters through studying its ability to suppress angiogenesis , tumor invasion , and proliferation . Furthermore , our results indicated that Nordy might inhibit GSCs invasion and proliferation through regulation of the arachidonate P09917 REA ( Alox - 5 ) pathway . Moreover , the combination of Nordy and a P15692 REA inhibitor exhibited an enhanced ability to suppress angiogenesis that was induced by GSCs . By contrast , even following treatment with 50 µM Nordy , there was no discernible effect on zebrafish embryonic development . Together , these results suggested efficacy and safety of using Nordy in vivo , and further demonstrated that this model should be suitable for studying GSCs and anti - P56915 drug evaluation .

Novel DNA-binding properties of the RNA-binding protein TIAR . P31483 REA related protein binds avidly to uridine-rich elements in mRNA and pre-mRNAs of a wide range of genes , including interleukin ( IL ) - 8 and vascular endothelial growth factor ( P15692 REA ) . The protein has diverse regulatory roles , which in part depend on the locus of binding within the transcript , including translational control , splicing and apoptosis . Here , we observed selective and potent inhibition of TIAR - Q96LT9 complex formation with P10145 REA and P15692 REA 3 ' - untranslated regions ( 3 ' - UTRs ) using thymidine-rich deoxyoligonucleotide ( ODN ) sequences derived from the VEFG 3 ' - UTR . We show by ultraviolet crosslinking and electrophoretic mobility shift assays that TIAR can bind directly to single-stranded , thymidine-rich ODNs but not to double-stranded ODNs containing the same sequence . TIAR had a nearly 6 - fold greater affinity for DNA than RNA ( K ( d ) app = 1.6 x10 ( - 9 ) M versus 9.4 x 10 ( - 9 ) M ) . Truncation of TIAR indicated that the high affinity DNA-binding site overlaps with the RNA-binding site involving RNA recognition motif 2 ( P31350 REA ) . However , P23921 REA alone could also bind to DNA . Finally , we show that TIAR can be displaced from single-stranded DNA by active transcription through the binding site . These results provide a potential mechanism by which TIAR can shuttle between RNA and DNA ligands .