MH_dev_292

P08235 REA antagonists do not block rapid P29323 REA activation by aldosterone . DB04630 MEN can elicit rapid nongenomic effects both in vivo and in vitro , often mediated by signal transduction cascades . However , it is not understood how these rapid effects are initiated . In this study we show that aldosterone leads to rapid activation of mitogen activated protein kinases P27361 REA / 2 in the cortical collecting duct cell line M - 1 . Inhibitors of transcription and translation could not block this activation , which suggests an extranuclear ( nongenomic ) mechanism . Although it is known that M - 1 cells do not contain a transcriptionally functional MR , it is not known whether a closely related protein still could mediate the effects , or an unrelated nonclassic receptor . To test this hypothesis , the effects of four classical mineralocorticoid receptor antagonists were studied . None of the compounds could block the response to aldosterone . Altogether , the data suggest that rapid aldosterone effects in M - 1 cells are initiated by a receptor different from the classical mineralocorticoid receptor .

Vampire bat plasminogen activator DB04925 MEN - alpha - 1 ( desmoteplase ) : a thrombolytic drug optimized by natural selection . P00747 REA activators are enzymes found in all vertebrate species investigated so far . Their physiological function is the generation of localized proteolysis in the context of tissue remodeling , wound healing and neuronal plasticity . The common vampire bat ( Desmodus rotundus ) is a New World species that feeds exclusively on blood . Its saliva contains highly potent plasminogen activators , specialized in rapid lysis of fresh blood clots . Biochemical and pharmacological evidence indicates that these plasminogen activators represent a new class of thrombolytics with pharmacological and toxicological properties superior to human tissue-type plasminogen activator , the clot dissolving agent now most frequently used in medicine . A form of the enzyme produced by recombinant DNA technology is currently employed to test this hypothesis in clinical studies .

Augmentation by citalopram of risperidone-induced monoamine release in rat prefrontal cortex . RATIONALE : A typical antipsychotics ( APDs ) , e . g . olanzapine and risperidone , have been reported to be effective adjunctive treatment for depression if selective serotonin ( 5 - HT ) reuptake inhibitors ( SSRIs ) alone are ineffective . OBJECTIVES AND METHODS : We utilized microdialysis in awake , freely moving rats to study the effect of risperidone in combination with citalopram , an SSRI , on extracellular 5 - HT , dopamine ( DA ) , and norepinephrine ( NE ) efflux in rat medial prefrontal cortex ( mPFC ) . RESULTS : DB00734 MENMAX DB00734 MEN ( 1.0 mg / kg , s . c . ) , given alone , significantly increased 5 - HT , DA , and NE concentrations in the mPFC . DB00215 ( 10 mg / kg , s . c . ) , by itself , produced a significant increase in 5 - HT levels only . The combination of risperidone and citalopram produced significantly greater increases in efflux of both DA and NE than risperidone alone . However , the effect of this combination on extracellular 5 - HT concentrations was not significantly different than that of citalopram alone . The augmentation of DA and NE efflux induced by risperidone plus citalopram could be partially blocked by the selective P08908 REA antagonist , WAY 100635 ( 0.2 mg / kg , s . c . ) . CONCLUSIONS : The results suggest that the ability of atypical APDs to augment the therapeutic efficacy of SSRIs in major depression and treatment-resistant depression may be due , at least in part , to potentiation of SSRI-induced increases in cortical DA and NE . The contributions of P08908 REA receptor stimulation and 5 - Q13049 REA and alpha 2 adrenergic receptor antagonism to this augmentation are discussed .

Counteraction between angiotensin II and angiotensin - ( 1-7 ) via activating angiotensin type I and Mas receptor on rat renal mesangial cells . In the updated concept of renin-angiotensin system ( DB01367 ) , it contains the angiotensin converting enzyme ( P12821 REA ) - angiotensin ( Ang ) II-angtiogensin type 1 receptor ( AT1 ) axis and the angiotensin-converting enzyme-related carboxypeptidase ( Q9BYF1 ) - Ang - ( 1-7 ) - Mas axis . The former axis has been well demonstrated performing the vasoconstrictive , proliferative and pro-inflammatory functions by activation of AT1 receptors , while the later new identified axis is considered counterbalancing the effects of the former . The present study is aimed at observing the interaction between Ang - ( 1-7 ) and Ang II on cultured rat renal mesangial cells ( MCs ) . RT-PCR , Western blot and immunofluorescent staining and confocal microscopy results showed that both AT1 and Mas receptor were co-distributed in rat renal MCs . Ang - ( 1-7 ) showed similar effects on Ang II in cultured MCs that stimulated phosphorylated extracellular signal-regulated kinase ( P29323 REA ) 1/2 phosphorylation and transforms growth factor-β 1 synthesis , and cell proliferation and extracellular matrix synthesis . Co-treatment of the cell with Ang - ( 1-7 ) and Ang II , Ang - ( 1-7 ) counteracted AngII-induced effects in a concentration dependent manner , but failed to alter the changes induced by endothelin - 1 . The stimulating effect of Ang II was mediated by AT1 receptor while all the effects of Ang - ( 1-7 ) were blocked by Mas receptor antagonist A - 779 , but not by AT1 receptor antagonist losartan or P50052 REA receptor antagonist PD123319 . These results suggest that Ang - ( 1-7 ) and Ang II specifically interact with each other on rat renal MCs via activation of their specific receptors , Mas and AT1 receptor respectively .

Agonism of human pregnane X receptor by rilpivirine and etravirine : comparison with first generation non-nucleoside reverse transcriptase inhibitors . DB08864 MEN and etravirine are second generation non-nucleoside reverse transcriptase inhibitors approved recently by the United States Food and Drug Administration for the treatment of human immunodeficiency virus - 1 infection . O75469 REA ( O75469 REA ) is a member of the superfamily of nuclear receptors that regulate the expression of various genes controlling diverse biological functions . The present study investigated the effects of rilpivirine and etravirine on the activity of human O75469 REA ( hPXR ) , including the mode of activation , and compared them to those of efavirenz , nevirapine , and delavirdine , which are first generation non-nucleoside reverse transcriptase inhibitors . In transiently transfected HepG 2 cells , rilpivirine , etravirine , and efavirenz , but not nevirapine or delavirdine , activated human , mouse , and rat O75469 REA . Results from mechanistic studies indicated that rilpivirine , etravirine , and efavirenz , but not nevirapine or delavirdine , bound to the ligand-binding domain of hPXR , as assessed by a transactivation assay and by a competitive ligand-binding assay using time-resolved fluorescence resonance energy transfer ; triggered nuclear translocation of a green fluorescence protein-tagged hPXR , as visualized by confocal imaging ; and recruited steroid receptor coactivator - 1 ( Q15788 REA ) , P12931 REA - 2 , and Q9Y6Q9 REA to hPXR , as demonstrated by mammalian two-hybrid assays . DB08864 MEN , etravirine , and efavirenz , but not nevirapine or delavirdine , increased hPXR target gene ( P08684 REA ) expression in primary cultures of human hepatocytes . In summary , select non-nucleoside reverse transcriptase inhibitors activated human and rodent O75469 REA . DB08864 MEN , etravirine , and efavirenz , but not nevirapine or delavirdine , were identified as agonists of hPXR , as assessed in mechanistic experiments , and inducers of P08684 REA , as determined in primary cultures of human hepatocytes .

Inhibition of farnesyl pyrophosphate synthase attenuates angiotensin II-induced cardiac hypertrophy and fibrosis in vivo . P14324 REA ( FPPS ) , as a key branchpoint of the mevalonate pathway , catalyzes the synthesis of isoprenoid intermediates . The isoprenoid intermediates are needed for protein isoprenylation to participate in cardiac remodeling . We have previously demonstrated that both knockdown of FPPS with small interfering RNA and inhibition of FPPS by alendronate could prevent Ang II-induced hypertrophy in cultured cardiomyocytes . In this study , we evaluated the effects of FPPS inhibition in Ang II-mediated cardiac hypertrophy and fibrosis in vivo . Wild type mice were separately treated with saline , Ang II ( 2.88 mg / kg per day ) , FPPS inhibitor alendronate ( 0.1 mg / kg per day ) , or the combination of Ang II ( 2.88 mg / kg per day ) and alendronate ( 0.1 mg / kg per day ) for 4 weeks . The results showed that Ang II increased FPPS expression , and the increases of Ang II-induced synthesis of the isoprenoid intermediates , FPP and GGPP , were significantly inhibited by FPPS inhibitor . In the meantime , FPPS inhibition attenuated Ang II-mediated cardiac hypertrophy and fibrosis as indexed by the heart weight to body weight ratio , echocardiographic parameters , histological examinations and expression of P01160 REA and DB04899 mRNA . Furthermore , it was also found that FPPS inhibitor attenuated Ang II-induced increases of RhoA activity and p - 38 MAPK phosphorylation and TGF-β 1 mRNA expression . In conclusion , FPPS might play an important role in Ang II-induced cardiac hypertrophy and fibrosis in vivo , at least in part through RhoA , p - 38 MAPK and TGF-β 1 .

P12821 REA inhibition suppresses plasminogen activator inhibitor - 1 expression in the neointima of balloon-injured rat aorta . BACKGROUND : P00747 REA activator inhibitor - 1 ( P05121 REA ) , an important regulator of fibrinolysis and extracellular matrix turnover , has been implicated in a number of vascular diseases . Studies demonstrating angiotensin II ( Ang II ) to be a potent stimulator of P05121 REA expression in cultured vascular cells suggests that the renin-angiotensin system may modulate vascular P05121 REA expression . METHODS AND RESULTS : We examined the effects of the P12821 REA inhibitor captopril on P05121 REA expression in control and balloon-injured rat aorta . Northern blot analysis demonstrated that aortic P05121 REA mRNA expression was 7.6- fold elevated 3 hours ( P < . 05 ) after balloon injury , back to baseline at 2 days , increased again at 4 days , and by 7 days after balloon injury was 3.2- fold elevated ( P < . 05 ) when compared with control . In captopril-treated rats , the induction of P05121 REA expression by balloon injury was significantly suppressed by 44 % ( P < . 05 ) in the 7 day group but was not altered in the 3 - hour group . DB01197 SUB also reduced baseline aortic P05121 REA mRNA . In situ hybridization and immunohistochemistry revealed dense P05121 REA staining of 7 - day neointima in untreated rats and a dramatic decrease in P05121 REA in neointima of captopril-treated rats . CONCLUSIONS : This report demonstrates that balloon injury results in both a rapid P12821 REA inhibitor-independent induction of aortic P05121 REA expression and a later increase in P05121 REA in the neointima that is significantly suppressed by captopril . This provides the first evidence that the renin-angiotensin system regulates neointimal P05121 REA expression and that P12821 REA inhibitors can reduce P05121 REA in the vessel wall in vivo .

DB05229 MEN sodium , prostacyclin analogue , attenuates glomerular hyperfiltration and glomerular macrophage infiltration by modulating ecNOS expression in diabetic rats . Stable prostacyclin analogue , beraprost sodium ( BPS ) has recently been reported to attenuate glomerular hyperfiltration in diabetic rats , however , the mechanism has been still unknown . We previously reported that overexpression of endothelial cell nitric oxide synthase ( ecNOS ) in afferent arterioles and glomeruli induce inappropriate dilatation of afferent arterioles and glomerular hyperfiltration through overproduction of nitric oxide in early stage of diabetic nephropathy . In this study , we tested the hypothesis that BPS ameliorates glomerular hyperfiltration through modulating ecNOS expression in diabetic nephropathy . Furthermore , we examined the effects of BPS on the expression of intercellular adhesion molecule - 1 ( P05362 REA ) and macrophage infiltration in diabetic glomeruli , because glomerular hyperfiltration induces the expression of P05362 REA resulting in macrophage infiltration . Male Sprague-Dawley ( SD ) rats were administered continuously with BPS for 4 weeks after induction of diabetes by streptozotocin . In diabetic rats , the diameters of afferent arterioles , glomerular volume , creatinine clearance and urinary excretion of albumin and NO2 / NO3 were increased as compared with non-diabetic control rats . Treatment with BPS improved these changes . The expression of ecNOS was increased in afferent arterioles and glomeruli in diabetic rats and suppressed by BPS . P43119 REA was expressed along afferent arterioles . Our results suggest that BPS attenuates glomerular hyperfiltration by modulating ecNOS expression in early stage of diabetic nephropathy . Moreover , BPS may inhibit P05362 REA - dependent infiltration of macrophages in diabetic glomeruli .

Inhibition of the renin-angiotensin system downregulates tissue factor and vascular endothelial growth factor in human breast carcinoma cells . INTRODUCTION : The renin-angiotensin system ( DB01367 ) promotes angiogenesis and growth of neoplastic cells . P12821 REA ( P12821 REA ) inhibitors and angiotensin II receptor AT1 blockers may protect against cancer . P13726 REA ( TF ) , for its involvement in tumor growth , angiogenesis , and metastasis is considered a hallmark of cancer progression . In this study we evaluated whether DB01367 blockade modulates TF constitutive expression by the metastatic breast carcinoma MDA-MB - 231 cell line . MATERIALS AND METHODS : Cell TF activity was assessed by one stage clotting time , TF and P15692 REA antigens and mRNA levels by ELISA and RT-PCR , respectively . AT ( 1 ) was detected by flow-cytometry and angiotensin-II levels by EIA . RESULTS : DB01197 SUB reduced in a concentration-dependent way both the strong constitutive TF activity ( 983.2 ± 55.2 vs . 686.7 ± 135.1 U / 5 × 10 ( 5 ) cells with 10μg / ml captopril ) and antigen ( 32.3 ± 5.9 vs . 13.2 ± 6.6 ng / ml ) in MDA-MB - 231 . Similar results were observed with enalapril . AT1 was present on cell membrane and losartan , a competitive inhibitor of AT1 , reduced TF expression to a degree similar as that exerted by P12821 REA inhibitors . Moreover , captopril and losartan downregulated the constitutive mRNA TF expression by ~ 35 % . Similar results were observed with anti-AT 1 and angiotensin II antibodies . In addition , the constitutive P15692 REA antigen and mRNA levels were reduced in the presence of captopril or losartan , and an anti - P15692 REA antibody downregulated cell TF activity by ~ 40 % . CONCLUSIONS : These results could , at least in part , contribute to the discussion about the possible effects of P12821 REA inhibitors and AT1 receptor antagonists in malignancy , and offer new clues to support their use for tumor control .

DB01197 SUB reduced plasminogen activator inhibitor activity in patients with acute myocardial infarction . Recent clinical trials have demonstrated that the administration of angiotensin-converting enzyme ( P12821 REA ) inhibitors to patients with myocardial infarction reduces the incidence of recurrent myocardial infarction . It has also been reported that an elevated level of plasminogen activator inhibitor ( P05121 REA ) appears to constitute a marker of the risk of recurrent coronary thrombosis . To determine whether the P12821 REA inhibitor captopril reduces plasma P05121 REA inhibitor activity , we measured changes in plasma P05121 REA activity ( IU / ml ) , tissue plasminogen activator ( t-PA ) antigen ( ng / ml ) , and serum P12821 REA activity ( IU / L ) in 14 survivors of myocardial infarction receiving captopril therapy ( 37.5 mg daily ) and compared them with the values in 15 placebo-treated patients chosen at random . Blood sampling was performed at 07.00 h . In the captopril-treated group , serum P12821 REA activity decreased significantly , from 14.0 + / - 0.8 to 11.5 + / - 1.2 IU / L 24 h after captopril therapy ( p < 0.01 ) , and those of P05121 REA activity and t-PA antigen also decreased significantly-from 11.9 + / - 2.8 to 5.5 + / - 2.2 IU / ml ( p < 0.02 ) and from 9.9 + / - 1.0 to 7.5 + / - 0.9 ng / ml ( p < 0.05 ) , respectively 48 h after captopril therapy . However , the levels of P12821 REA activity , P05121 REA activity , and t-PA antigen remained unchanged during the study period in the placebo group . Thus , our data indicate that the administration of captopril to patients with acute myocardial infarction may result in a reduced frequency of recurrent coronary thrombosis by increasing fibrinolytic capacity .

Differential regulation of the serotonin 1 A transcriptional modulators five prime repressor element under dual repression - 1 and nuclear-deformed epidermal autoregulatory factor by chronic stress . Chronic stress is known to affect brain areas involved in learning and emotional responses . These changes , thought to be related to the development of cognitive deficits are evident in major depressive disorder and other stress-related pathophysiologies . The serotonin-related transcription factors ( Q6P1N0 / Q6P1N0 ; five prime repressor element under dual repression / coiled-coil P06681 REA domain 1a , and O75398 / Deaf - 1 ; nuclear-deformed epidermal autoregulatory factor ) are two important regulators of the P08908 REA receptor . Using Western blotting and quantitative real-time polymerase chain reaction ( qPCR ) we examined the expression of mRNA and proteins for Q6P1N0 , O75398 , and the P08908 REA receptor in the prefrontal cortex ( P27918 REA ) of male rats exposed to chronic restraint stress ( CRS ; 6 h / day for 21 days ) . After 21 days of CRS , significant reductions in both Q6P1N0 mRNA and protein were observed in the P27918 REA ( 36.8 % and 32 % , respectively ; P < 0.001 ) , while the levels of both O75398 protein and mRNA did not change significantly . Consistent with reduced Q6P1N0 protein , P08908 REA receptor mRNA levels were equally upregulated in the P27918 REA , while protein levels actually declined , suggesting post-transcriptional receptor downregulation . The data suggest that CRS produces distinct alterations in the serotonin system specifically altering Q6P1N0 and the P08908 REA receptor in the P27918 REA of the male rat while having no effect on O75398 . These results point to the importance of understanding the mechanism for the differential regulation of Q6P1N0 and O75398 in the P27918 REA as a basis for understanding the related effects of chronic stress on the serotonin system ( serotonin-related transcription factors ) and stress-related disorders like depression .

A novel inhibitory mechanism of nitrogen-containing bisphosphonate on the activity of Cl - extrusion in osteoclasts . DB09152 - containing bisphosphonates have been well known to be inhibited farnesyl diphosphate synthase ( P14324 REA ) , an enzyme in mevalonic acid metabolism , resulting in disturbance in polymerization of cytoskeleton structure in bone resorption and promotion of apoptosis in mature osteoclasts . Although bisphosphonates have been reported to activate ion transporters in native epithelium and Xenopus oocytes , little is known whether bisphosphonates affect acid hydrochronic acid extrusion in osteoclasts during bone resorption . The aim of this study was to determine the role of bisphosphonates on inhibition of hydrochronic acid extrusion in osteoclasts . Effects of zoledronic acid , a nitrogen-containing bisphosphonate , on the Cl ( - ) current activated by extracellular acidification were examined in two types of osteoclasts derived from RAW 264.7 cells and mouse bone marrow macrophages ( BMMs ) . Extracellular acidification induced outwardly rectifying Cl ( - ) currents in mouse osteoclasts . DB00399 MEN dose-dependently inhibited the acid-activated Cl ( - ) current . The non-nitrogen bisphosphonate etidronic acid had no effect on the acid-activated Cl ( - ) current . DB00759 - induced P14324 REA silencing caused a significant decrease in the Cl ( - ) current . The inhibitor of geranylgeranyl transferase suppressed the Cl ( - ) current . By contrast , the inhibitory action of zoledronic acid was rescued by addition of geranylgeranyl acid , a derivative of mevalonic acid . The activity of acid-activated Cl ( - ) currents was dependent on expression of P51798 during osteoclastogenesis . These results suggest that nitrogen-containing bisphosphonates suppress the activity of osteoclastic acid-activated Cl ( - ) currents through P14324 REA inhibition , suggesting the inhibition of Cl ( - ) extrusion activity .

Angiotensin-converting-enzyme inhibitors suppress synthesis of tumour necrosis factor and interleukin 1 by human peripheral blood mononuclear cells . Administration of angiotensin-converting-enzyme ( P12821 REA ) inhibitors reduce vascular proliferation following endothelial injury as well as progression of renal disease in various animal models . These effects might be due to interference with cytokines such as interleukin 1 ( IL - 1 ) or tumour necrosis factor alpha ( P01375 REA ) since they have been implicated in regulating the effects of vascular cell growth factors such as fibroblast - and platelet-derived growth factors . We investigated the in vitro synthesis of IL - 1 and P01375 REA from human peripheral blood mononuclear cells ( PBMC ) in the presence of various P12821 REA - inhibitors . DB01197 SUB dose-dependently suppressed the P01584 REA - induced synthesis of P01375 REA by 74 % ( P < 0.01 ) and the P01584 REA - induced synthesis of P01583 REA by 60 % ( P < 0.01 ) . Cytokine synthesis induced by lipopolysaccharide was less affected . At concentrations suppressing P01375 REA and IL - 1 , captopril did not reduce the synthesis of complement P01024 REA in the same cells . Enalapril and cilazapril also suppressed cytokine-induced cytokine synthesis . Ramipril , lisinopril , perindopril and spirapril had no significant effect on P01375 REA synthesis suggesting that the effect was not related specifically to the inhibition of P12821 REA . Accumulation of mRNA for IL - 1 and P01375 REA were not affected by captopril , suggesting a posttranscriptional effect . We conclude that certain P12821 REA - inhibitors suppress IL - 1 and P01375 REA synthesis at a posttranscriptional level and might therefore influence cytokine-mediated cell growth .

Altered expression of inflammation-related genes in human carotid atherosclerotic plaques . OBJECTIVE : Inflammation is a pivotal process in atherosclerosis development and progression , but the underlying molecular mechanisms remain largely obscure . We have conducted an extensive expression study of atherosclerotic plaques to identify the inflammatory pathways involved in atherosclerosis . METHODS : We studied 11 human carotid plaques , their respective adjacent regions and 7 control arteries from different subjects . Expression of 92 genes was studied by TaqMan low-density array human inflammation panel . Human aortic endothelial and smooth muscle cells were used for in vitro experiments . RESULTS : The mRNA levels of 44/92 genes ( 48 % ) differed significantly between the tissues examined ( 13 up-regulated and 31 down-regulated ) . Dysregulated genes encode molecules belonging to different functional classes although most of them encode enzymes involved in the eicosanoid synthesis pathway . The expression of Q16647 REA and P43119 REA genes was decreased in human aortic endothelial and smooth muscle cells stimulated with oxLDL and P01375 REA - α . CONCLUSIONS : This study not only reveals several dysregulated genes in human lesions but also focuses the role played by the genes involved in the eicosanoid synthesis pathway during atherosclerotic development . The decrease of Q16647 REA and P43119 REA expression after oxLDL treatment mirrors the decreased mRNA levels in atherosclerotic lesions versus control arteries , which suggests that oxidation is important for Q16647 REA and P43119 REA regulation in human vessel cells during atherosclerosis development .

Expression of angiotensin I-converting enzymes and bradykinin B2 receptors in mouse inner medullary-collecting duct cells . We described in mouse inner medullary-collecting duct cells ( mIMCD - 3 ) the somatic and the N-domain P12821 REA synthesis and its interaction with the kallikrein-kinin system co-localized in the same cells . We purified two P12821 REA forms from culture medium , M1 ( 130 kDa ) and M2 ( N-domain , 60 kDa ) , and cellular lysate , C1 ( 130 kDa ) and P06681 REA ( N-domain , 60 kDa ) . DB01197 SUB and enalaprilat inhibited the purified enzymes . The immunofluorescence studies indicated that P12821 REA is present in the membrane , cytoplasm and in the cell nucleus . Kinin B1 and B2 receptors were detected by immunofluorescence and showed to be activated by BK and DesR 9 BK , increasing the acidification rate which was enhanced in the presence of enalaprilat . The presence of secreted and intracellular P12821 REA in mIMCD - 3 confirmed the hypothesis previously proposed by our group for a new site of P12821 REA secretion in the collecting duct .

[ The effect of blood pressure-reducing therapy with captopril on tubular marker excretion in type - 1 diabetics with nephropathy ] . A prospective open clinical trial was carried out with 23 hypertensive type I diabetics ( 13 men , ten women , mean age 49 + / - 9.1 years , duration of diabetes 18 + / - 9.1 years ) with early nephropathy . Glomerular and tubular renal function and metabolic parameters were monitored during 8 months ' treatment with the angiotensin converting enzyme ( P12821 REA ) inhibitor , captopril , in addition to previous antihypertensive treatment with one or more drugs . Blood pressure control tended to improve on captopril ( systolic pressures 152 + / - 13 vs 140 + / - 13 mm Hg , P < 0.05 ; diastolic pressures 89 + / - 10 vs 87 + / - 10 mm Hg , not significant ) . Proteinuria ( > 0.5 g / 24 hours ) fell into the microalbuminuria range ( albumin excretion 2-20 mg / mmol creatinine ) in four out of 13 patients , and microalbuminuria disappeared in four out of ten patients . Urinary levels of the brush border enzyme O60502 ( NAG ) , a marker of tubular dysfunction , were initially raised and fell significantly after 8 months ' treatment with captopril ( 20.3 + / - 14.4 vs 8.8 + / - 8.1 U / g creatinine ; P < 0.01 ) . DB01197 SUB did not affect metabolic control ( HbA 1 , total , HDL and LDL cholesterol , triglycerides , apolipoproteins A1 and B ) or the insulin dosage . These results show that long-term treatment with captopril may favourably influence both albumin excretion and NAG activity , a marker of tubular dysfunction , in type I diabetics with nephropathy .

Targeting vascular endothelial growth factor receptor - 1 and - 3 with cediranib ( DB04849 MEN ) : effects on migration and invasion of gastrointestinal cancer cell lines . The effect of vascular endothelial growth factor ( P15692 REA ) ligands and cediranib on tumor cell proliferation , migration , and invasion was determined . It has recently been suggested that autocrine signaling through the P15692 REA receptor ( VEGFR ) pathway may play a role in tumor cell survival , invasion , and migration . The purpose of the present study was to determine the expression of VEGFRs and VEGFR ligands in a panel of gastrointestinal carcinoma cells . Additionally , we evaluated the effects of P15692 REA autocrine signaling on tumor cell proliferation , migration , and invasion utilizing cediranib ( DB04849 MEN ) , a pan-VEGFR inhibitor . Five colorectal , three pancreatic , and two hepatocellular carcinoma cell lines were screened for VEGFR and P15692 REA expression by several methods . Expression of P17948 REA and P35916 REA was cell line-dependent , whereas P35968 REA was not detected . Secretion of P15692 REA was detected in the supernatants of all cell lines whereas P49767 REA secretion was detected in the Panc - 1 , MiaPaca 2 , and Hep 1 cells only . Tumor cells showed increased migratory activity , but not proliferation , when stimulated with VEGFs . The pan-VEGFR inhibitor cediranib ( 100 nmol / L ) inhibited tumor cell migration and invasion , with no effects on proliferation . Cediranib decreased P17948 REA and P35916 REA phosphorylation as well as activation of downstream effectors . P17948 REA and P35916 REA expression was detected in all the gastrointestinal carcinoma cells evaluated . Although activation of the P15692 REA pathway did not affect cell proliferation , our data indicate that this pathway seems to play a role in tumor cell migration and invasion in these cell lines . Therefore , inhibition of VEGFR by cediranib may represent a clinically relevant treatment option for gastrointestinal tumors .

Novel function of androgen receptor-associated protein 55 / O43294 as a negative regulator of P8 4022 signaling . P10275 REA - associated protein 55 ( O43294 / O43294 ) belongs to the LIM protein superfamily and is featured by three or four N-terminal LD motifs and four C-terminal zinc finger-like LIM domains . Both LD motifs and LIM domains can serve as protein-protein interaction interfaces . Recently , we found that enforced expression of O43294 inhibits transforming growth factor-beta-mediated up-regulation of Smad binding element-luciferase reporter activity in NRP - 154 and NRP - 152 rat prostate and LNCaP human prostate cell lines . Moreover , O43294 also inhibits the induction of Smad-binding element 4 - luciferase and 3TP - luciferase ( a plasminogen activator inhibitor - 1 ( P05121 REA ) promoter construct ) reporters by constitutively active ( CA ) - P8 4022 in these cell lines . Co-immunoprecipitation studies suggest an interaction between O43294 and either CA - P8 4022 or wild-type P8 4022 in HEK 293 cells that occurs through the MH2 domain of P8 4022 and the C terminus of O43294 with wild-type P8 4022 having stronger affinity than CA - P8 4022 to O43294 . O60760 REA pull-down assays demonstrate that this interaction can occur in a cell-free system . These results are consistent with the luciferase data showing that the C terminus of O43294 is critical for suppression of P8 4022 activity . Furthermore , using a mammalian two-hybrid system , we confirmed that O43294 interacts with the MH2 domain of P8 4022 and suppresses CA - P8 4022 - induced transcriptional responses . In conclusion , these results support that O43294 selectively intercepts transforming growth factor-beta signaling through an interaction of the LIM domain of O43294 with the MH2 domain of P8 4022 .

[ The effect of bunazosin vs captopril on hemodynamic and neurohumoral parameters in patients with congestive heart failure ] . The hemodynamic parameters ( right atrial pressure , mean pulmonary artery pressure , pulmonary capillary wedge pressure , cardiac index , heart rate , blood pressure ) and neurohumoral responses ( alpha - P01160 REA , plasma renin activity , aldosterone , angiotensin II ) of DB01197 SUB , oral P12821 REA inhibitor , and Bunazosin , oral alpha 1 - blocker , were investigated in 28 patients with congestive heart failure at rest and after exercise . These data were analysed in both acute and chronic phases . 1 ) Acute effect . DB01197 SUB produced significant improvement of neurohumoral factors at rest and also after exercise . Bunazosin reduced alpha - P01160 REA , but other neurohumoral factors did not change . Bunazosin produced significant hemodynamic improvement both at rest and after exercise . 2 ) Chronic effect . DB01197 SUB produced significant hemodynamic improvement both at rest and after exercise . Improvement of neurohumoral factors in acute phase was also preserved at chronic phase . On Bunazosin , improvement of hemodynamics at acute phase was also preserved at chronic phase without deterioration of neurohumoral factors .

P10275 REA repression of gonadotropin-releasing hormone gene transcription via enhancer 1 . DB00644 ( DB00644 ) plays a major role in the hypothalamic-pituitary-gonadal ( HPG ) axis , and synthesis and secretion of DB00644 are regulated by gonadal steroid hormones . Disruptions in androgen levels are involved in a number of reproductive defects , including hypogonadotropic hypogonadism and polycystic ovarian syndrome . Androgens down-regulate DB00644 mRNA synthesis in vivo and in vitro via an androgen receptor ( AR ) - dependent mechanism . DB02998 MEN ( R1881 ) , a synthetic AR agonist , represses DB00644 expression through multiple sites in the proximal promoter . In this study , we show AR also represses DB00644 transcription via the major enhancer ( DB00644 - E1 ) . A multimer of the - 1800 / - 1766 region was repressed by R1881 treatment . Mutation of two bases , - 1792 and - 1791 , resulted in decreased basal activity and a loss of AR-mediated repression . AR bound to the - 1796 / - 1791 sequence in electrophoretic mobility shift assays , indicating a direct interaction with DNA or other transcription factors in this region . We conclude that AR repression of DB00644 - E1 acts via multiple AR-responsive regions , including the site at - 1792 / - 1791 .

P10275 REA in Sertoli cells is not required for testosterone-induced suppression of spermatogenesis , but contributes to Sertoli cell organization in Utp 14b jsd mice . DB00624 MEN acting through the androgen receptor ( AR ) maintains the arrest of spermatogonial differentiation in juvenile spermatogonial depletion ( jsd mutation in the Utp 14b gene ) mutant adult male mice . It is not known which of the somatic cell types expressing AR mediates this inhibition . To determine whether Sertoli cells are responsible , we selectively eliminated AR in Sertoli cells in jsd mice containing a floxed-Ar gene and an anti-Müllerian hormone-Cre transgene . In these Sertoli AR-knockout ( SCARKO ) - jsd mice , spermatogonial differentiation did not recover . However , the normal organization of Sertoli cell nuclei was drastically disrupted in SCARKO-jsd mice compared with SCARKO or jsd mice . In addition , the extent of ectoplasmic specializations was reduced ; tight junctions were not found ; vinculin , an anchoring protein found in ectoplasmic specializations , became uniformly distributed in the cytoplasm ; and the adult Sertoli cells showed excess heterochromatin subjacent to their nuclear envelope . Despite the abnormalities in Sertoli cells in SCARKO-jsd mice , global suppression of testosterone action and levels was still effective in restoring the differentiated germ cells , and this was accompanied by an improved arrangement of Sertoli cell nuclei . We conclude that Sertoli cells are not targets for the testosterone-mediated inhibition of spermatogonial differentiation in jsd mice , and that both AR in Sertoli cells and the presence of differentiated germ cells contribute to maintaining the organization of Sertoli cells within the seminiferous tubules .

P00747 REA activator inhibitor - 1 is increased in colonic epithelial cells from patients with colitis-associated cancer . BACKGROUND : Patients with long-term ulcerative colitis are at risk for developing colorectal cancer . METHODS : Archival formalin-fixed paraffin-embedded tissue from ulcerative colitis patients who underwent a colectomy for high-grade dysplasia or carcinoma was examined for changes in expression of plasminogen activator inhibitor - 1 ( P05121 REA ) as well as other mediators of inflammation-associated cancer . Epithelia from areas of colons that showed histologic evidence of carcinoma , high-grade dysplasia , and epithelia that were not dysplastic or malignant but did contain evidence of prior inflammation ( quiescent colitis ) was microdissected using laser capture microscopy . mRNA was extracted from the microdissected tissue and PCR array analysis was performed . To extend our findings , P05121 REA protein levels were determined using immunohistochemistry . RESULTS : The mRNA expression of P05121 REA is increased 6 - fold ( p= 0.02 ) when comparing the carcinoma group to the quiescent colitis group ; increases were also observed in Q00653 REA , Q04864 REA , P12931 REA , and P15692 REA . The protein levels of P05121 REA are increased by 50 % ( p < 0.001 ) in high-grade dysplasia and by 60 % ( p < 0.001 ) in carcinoma when compared to the quiescent colitis group . CONCLUSIONS : The increase in P05121 REA in high-grade dysplasia and carcinoma suggests a functional role for P05121 REA in malignant transformation in colitis-associated cancer . P05121 REA could also prove a useful diagnostic marker to identify patients at risk for neoplasia and it may be a useful therapeutic target to treat colitis-associated cancer .