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Sample records for receptors ii cross-reaction

  1. Modeling the interactions of a peptide-major histocompatibility class I ligand with its receptors. II. Cross-reaction between a monoclonal antibody and two alpha beta T cell receptors

    DEFF Research Database (Denmark)

    Rognan, D; Engberg, J; Stryhn, A

    2000-01-01

    -peptide pair into the Fab combining site. Interestingly, the most energetically favored binding mode shows numerous analogies to the recently determined recognition of class I MHC-peptide complexes by alpha beta T cell receptors (TCRs). The pSAN13.4.1 also binds diagonally across the MHC binding groove......The recombinant antibody, pSAN13.4.1, has a unique T cell like specificity; it binds an Influenza Hemagglutinin octapeptide (Ha255-262) in an MHC (H-2Kk)-restricted manner, and a detailed comparison of the fine specificity of pSAN13.4.1 with the fine specificity of two Ha255-262-specific, H-2Kk......-restricted T cell hybridomas has supported this contention. A three-dimensional model of pSAN13.4.1 has been derived by homology modeling techniques. Subsequently, the structure of the pSAN13.4.1 antibody in complex with the antigenic Ha-Kk ligand was derived after a flexible and automated docking of the MHC...

  2. Receptor binding radiotracers for the angiotensin II receptor: radioiodinated [Sar1, Ile8]angiotensin II

    International Nuclear Information System (INIS)

    Gibson, R.E.; Beauchamp, H.T.; Fioravanti, C.; Brenner, N.; Burns, H.D.

    1994-01-01

    The potential for imaging the angiotensin II receptor was evaluated using the radioiodinated peptide antagonist [ 125 I][Sar 1 , Ile 8 ]angiotensin II. The radioligand provides a receptor-mediated signal in several tissues in rat (kidneys, adrenal and liver). The receptor-mediated signal of 3% ID/g kidney cortex should be sufficient to permit imaging, at least via SPECT. The radiotracer is sensitive to reductions in receptor concentration and can be used to define in vivo dose-occupancy curves of angiotensin II receptor ligands. Receptor-mediated images of [ 123 I][Sar 1 , Ile 8 ]angiotensin II were obtained in the rat kidney and Rhesus monkey liver. (author)

  3. Scavenger receptor AI/II truncation, lung function and COPD

    DEFF Research Database (Denmark)

    Thomsen, M; Nordestgaard, B G; Tybjaerg-Hansen, A

    2011-01-01

    The scavenger receptor A-I/II (SRA-I/II) on alveolar macrophages is involved in recognition and clearance of modified lipids and inhaled particulates. A rare variant of the SRA-I/II gene, Arg293X, truncates the distal collagen-like domain, which is essential for ligand recognition. We tested whet...

  4. IGF-II receptors and IGF-II-stimulated glucose transport in human fat cells

    International Nuclear Information System (INIS)

    Sinha, M.K.; Buchanan, C.; Raineri-Maldonado, C.; Khazanie, P.; Atkinson, S.; DiMarchi, R.; Caro, J.F.

    1990-01-01

    Insulin-like growth factor II (IGF-II) receptors have been described in rat but not in human adipocytes. In both species, IGF-II has been reported to stimulate glucose transport by interacting with the insulin receptor. In this study, we have unequivocally demonstrated the presence of IGF-II receptors in human adipocytes. 125I-labeled IGF-II specifically binds to intact adipocytes, membranes, and lectin-purified detergent solubilized extracts. Through the use of 0.5 mM disuccinimidyl suberate, 125I-IGF-II is cross-linked to a 260-kDa protein that is identified as the IGF-II receptor by displacement experiments with unlabeled IGF-II, IGF-I, and insulin and either by immunoprecipitation or by Western blot analysis with mannose 6-phosphate receptor antibodies. The concentrations of IGF-II required for half-maximal and maximal stimulation of glucose transport in human adipocytes are 35 and 100 times more than that of insulin. The possibility of IGF-II stimulating glucose transport by interacting predominantly with the insulin receptor is suggested by the following: (1) the concentration of IGF-II that inhibits half of insulin binding is only 20 times more than that of insulin; (2) the lack of an additive effect of IGF-II and insulin for maximal stimulation of glucose transport; (3) the ability of monoclonal insulin receptor antibodies to decrease glucose transport stimulated by submaximal concentrations of both IGF-II and insulin; and (4) the ability of IGF-II to stimulate insulin receptor autophosphorylation albeit at a reduced potency when compared with insulin

  5. Urolinin: The First Linear Peptidic Urotensin-II Receptor Agonist.

    Science.gov (United States)

    Bandholtz, Sebastian; Erdmann, Sarah; von Hacht, Jan Lennart; Exner, Samantha; Krause, Gerd; Kleinau, Gunnar; Grötzinger, Carsten

    2016-11-23

    This study investigated the role of individual U-II amino acid positions and side chain characteristics important for U-IIR activation. A complete permutation library of 209 U-II variants was studied in an activity screen that contained single substitution variants of each position with one of the other 19 proteinogenic amino acids. Receptor activation was measured using a cell-based high-throughput fluorescence calcium mobilization assay. We generated the first complete U-II substitution map for U-II receptor activation, resulting in a detailed view into the structural features required for receptor activation, accompanied by complementary information from receptor modeling and ligand docking studies. On the basis of the systematic SAR study of U-II, we created 33 further short and linear U-II variants from eight to three amino acids in length, including d- and other non-natural amino acids. We identified the first high-potency linear U-II analogues. Urolinin, a linear U-II agonist (nWWK-Tyr(3-NO 2 )-Abu), shows low nanomolar potency as well as improved metabolic stability.

  6. Receptor Autoradiography Protocol for the Localized Visualization of Angiotensin II Receptors.

    Science.gov (United States)

    Linares, Andrea; Couling, Leena E; Carrera, Eduardo J; Speth, Robert C

    2016-06-07

    This protocol describes receptor binding patterns for Angiotensin II (Ang II) in the rat brain using a radioligand specific for Ang II receptors to perform receptor autoradiographic mapping. Tissue specimens are harvested and stored at -80 °C. A cryostat is used to coronally section the tissue (brain) and thaw-mount the sections onto charged slides. The slide-mounted tissue sections are incubated in (125)I-SI-Ang II to radiolabel Ang II receptors. Adjacent slides are separated into two sets: 'non-specific binding' (NSP) in the presence of a receptor saturating concentration of non-radiolabeled Ang II, or an AT1 Ang II receptor subtype (AT1R) selective Ang II receptor antagonist, and 'total binding' with no AT1R antagonist. A saturating concentration of AT2 Ang II receptor subtype (AT2R) antagonist (PD123319, 10 µM) is also present in the incubation buffer to limit (125)I-SI-Ang II binding to the AT1R subtype. During a 30 min pre-incubation at ~22 °C, NSP slides are exposed to 10 µM PD123319 and losartan, while 'total binding' slides are exposed to 10 µM PD123319. Slides are then incubated with (125)I-SI-Ang II in the presence of PD123319 for 'total binding', and PD123319 and losartan for NSP in assay buffer, followed by several 'washes' in buffer, and water to remove salt and non-specifically bound radioligand. The slides are dried using blow-dryers, then exposed to autoradiography film using a specialized film and cassette. The film is developed and the images are scanned into a computer for visual and quantitative densitometry using a proprietary imaging system and a spreadsheet. An additional set of slides are thionin-stained for histological comparisons. The advantage of using receptor autoradiography is the ability to visualize Ang II receptors in situ, within a section of a tissue specimen, and anatomically identify the region of the tissue by comparing it to an adjacent histological reference section.

  7. Receptors for insulin-like growth factor II (IGF-II) in the rat kidney glomerulus

    International Nuclear Information System (INIS)

    Haskell, J.F.; Pillion, D.J.; Meezan, E.

    1986-01-01

    Renal glomeruli were isolated by a technique involving renal perfusion with a solution containing magnetic iron oxide particles, followed by homogenization, sieving and isolation over a strong magnet. Isolated glomeruli were treated with 1% Triton X-100 to solubilize plasma membrane components while insoluble basement membrane components were removed by centrifugation. [ 125 I]Insulin-like growth factor-II (IGF-II) binding to this preparation was competitively inhibited by increasing amounts of unlabelled IGF-II, with 50% inhibition of binding observed at an IGF-II concentration of 1 ng/ml. [ 125 I]IGF-II was covalently cross-linked to its receptor with disuccinimidyl suberate in two tissues known to contain IGF-II receptors, the rat chondrosarcoma chondrocyte and the rat kidney tubule, as well as in rat renal glomeruli. In all three cases, a specific high-molecular weight (Mr = 255,000) band could be identified on autoradiograms of dodecyl sulfate polyacrylamide gels. These results indicate that the rat glomerulus contains a high-affinity receptor for IGF-II. This finding is consistent with the hypothesis that IGF-II plays a role in glomerular growth and differentiation

  8. Insulin-like growth factor-II (IGF II) receptor from rat brain is of lower apparent molecular weight than the IGF II receptor from rat liver

    International Nuclear Information System (INIS)

    McElduff, A.; Poronnik, P.; Baxter, R.C.

    1987-01-01

    The binding subunits of the insulin and insulin-like growth factor-I (IGF I) receptors from rat brain are of lower molecular weight than the corresponding receptor in rat liver, possibly due to variations in sialic acid content. We have compared the IGF II receptor from rat brain and rat liver. The brain receptor is of smaller apparent mol wt (about 10 K) on sodium dodecyl sulfate polyacrylamide gel electrophoresis. This size difference is independent of ligand binding as it persists in iodinated and specifically immunoprecipitated receptors. From studies of wheat germ agglutinin binding and the effect of neuraminidase on receptor mobility, we conclude that this difference is not simply due to variations in sialic acid content. Treatment with endoglycosidase F results in reduction in the molecular size of both liver and brain receptors and after this treatment the aglycoreceptors are of similar size. We conclude that in rat brain tissue the IGF II receptor like the binding subunits of the insulin and IGF I receptors is of lower molecular size than the corresponding receptors in rat liver. This difference is due to differences in N-linked glycosylation

  9. The angiotensin II type 1 receptor antagonist Losartan binds and activates bradykinin B2 receptor signaling

    DEFF Research Database (Denmark)

    Bonde, Marie Mi; Olsen, Kristine Boisen; Erikstrup, Niels

    2011-01-01

    The angiotensin II type 1 receptor (AT1R) blocker (ARB) Losartan has cardioprotective effects during ischemia-reperfusion injury and inhibits reperfusion arrhythmias -effects that go beyond the benefits of lowering blood pressure. The renin-angiotensin and kallikrein-kinin systems are intricately...

  10. Distinct angiotensin II receptor in primary cultures of glial cells from rat brain

    International Nuclear Information System (INIS)

    Raizada, M.K.; Phillips, M.I.; Crews, F.T.; Sumners, C.

    1987-01-01

    Angiotensin II (Ang-II) has profound effects on the brain. Receptors for Ang-II have been demonstrated on neurons, but no relationship between glial cells and Agn-II has been established. Glial cells (from the hypothalamus and brain stem of 1-day-old rat brains) in primary culture have been used to demonstrate the presence of specific Ang-II receptors. Binding of 125 I-Ang-II to glial cultures was rapid, reversible, saturable, and specific for Ang-II. The rank order of potency of 125 I-Ang-II binding was determined. Scatchard analysis revealed a homogeneous population of high-affinity binding sites with a B/sub max/ of 110 fmol/mg of protein. Light-microscopic autoradiography of 125 I-Ang-II binding supported the kinetic data, documenting specific Ang-II receptors on the glial cells. Ang-II stimulated a dose-dependent hydrolysis of phosphatidylinositols in glial cells, an effect mediated by Ang-II receptors. However, Ang-II failed to influence [ 3 H] norepinephrine uptake, and catecholamines failed to regulate Ang-II receptors, effects that occur in neurons. These observations demonstrate the presence of specific Ang-II receptors on the glial cells in primary cultures derived from normotensive rat brain. The receptors are kinetically similar to, but functionally distinct from, the neuronal Ang-II receptors

  11. Effects of urotensin II receptor antagonist, GSK1440115, in asthma

    Directory of Open Access Journals (Sweden)

    Alison D Portnoy

    2013-04-01

    Full Text Available Background: Urotensin II (U-II is highly expressed in the human lung and has been implicated in regulating respiratory physiology in preclinical studies. Our objective was to test antagonism of the urotensin receptor (UT by GSK1440115, a novel, competitive and selective inhibitor of the UT receptor, as a therapeutic strategy for the treatment of asthma. Methods: Safety, tolerability and pharmacokinetics (PK of single doses of GSK1440115 (1–750 mg were assessed in a Phase I, placebo-controlled study in 70 healthy subjects. In a Phase Ib study, 12 asthmatic patients were randomized into a 2-period, single-blind crossover study and treated with single doses of 750 mg GSK1440115 or placebo and given a methacholine challenge. Results: Administration of GSK1440115 was safe and well-tolerated in healthy subjects and asthmatic patients. In both studies, there was a high degree of variability in the observed PK following oral dosing with GSK1440115 at all doses. There was a marked food effect in healthy subjects at the 50 mg dose. In the presence of food at the 750 mg dose, the time to maximal concentration was between 2 and 6 hours and the terminal half-life was short at approximately 2 hours. All asthmatic patients maintained greater than the predicted concentration levels necessary to achieve predicted 96% receptor occupancy for >=3 hours (between 4-7 hours post-dose. There were no apparent trends or relationships between the systemic plasma exposure of GSK1440115 and pharmacodynamic endpoints, PC20 after methacholine challenge and FEV1, in asthmatics. Conclusion: While GSK1440115 was safe and well-tolerated, it did not induce bronchodilation in asthmatics, or protect against methacholine-induced bronchospasm, suggesting that acute UT antagonism is not likely to provide benefit as an acute bronchodilator in this patient population.

  12. Potential Clinical Implications of the Urotensin II Receptor Antagonists

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    Emilie Kane

    2011-07-01

    Full Text Available Urotensin-II (UII, which binds to its receptor UT, plays an important role in the heart, kidneys, pancreas, adrenal gland and CNS. In the vasculature, it acts as a potent endothelium-independent vasoconstrictor and endothelium-dependent vasodilator. In disease states, this constriction-dilation equilibrium is disrupted. There is an upregulation of the UII system in heart disease, metabolic syndrome and kidney failure. The increase in UII release and UT expression suggest that UII system may be implicated in the pathology and pathogenesis of these diseases by causing an increase in ACAT-1 activity leading to SMC proliferation and foam cell infiltration, insulin resistance (DMII, as well as inflammation, high blood pressure and plaque formation. Recently, UT antagonists such as SB-611812, palosuran, and most recently a piperazino-isoindolinone based antagonist have been developed in the hope of better understanding the UII system and treating its associated diseases.

  13. Simvastatin enhances bone morphogenetic protein receptor type II expression

    International Nuclear Information System (INIS)

    Hu Hong; Sung, Arthur; Zhao, Guohua; Shi, Lingfang; Qiu Daoming; Nishimura, Toshihiko; Kao, Peter N.

    2006-01-01

    Statins confer therapeutic benefits in systemic and pulmonary vascular diseases. Bone morphogenetic protein (BMP) receptors serve essential signaling functions in cardiovascular development and skeletal morphogenesis. Mutations in BMP receptor type II (BMPR2) are associated with human familial and idiopathic pulmonary arterial hypertension, and pathologic neointimal proliferation of vascular endothelial and smooth muscle cells within small pulmonary arteries. In severe experimental pulmonary hypertension, simvastatin reversed disease and conferred a 100% survival advantage. Here, modulation of BMPR2 gene expression by simvastatin is characterized in human embryonic kidney (HEK) 293T, pulmonary artery smooth muscle, and lung microvascular endothelial cells (HLMVECs). A 1.4 kb BMPR2 promoter containing Egr-1 binding sites confers reporter gene activation in 293T cells which is partially inhibited by simvastatin. Simvastatin enhances steady-state BMPR2 mRNA and protein expression in HLMVEC, through posttranscriptional mRNA stabilization. Simvastatin induction of BMPR2 expression may improve BMP-BMPR2 signaling thereby enhancing endothelial differentiation and function

  14. Direct demonstration of rapid insulin-like growth factor II receptor internalization and recycling in rat adipocytes. Insulin stimulates 125I-insulin-like growth factor II degradation by modulating the IGF-II receptor recycling process

    International Nuclear Information System (INIS)

    Oka, Y.; Rozek, L.M.; Czech, M.P.

    1985-01-01

    The photoactive insulin-like growth factor (IGF)-II analogue 4-azidobenzoyl- 125 I-IGF-II was synthesized and used to label specifically and covalently the Mr = 250,000 Type II IGF receptor. When rat adipocytes are irradiated after a 10-min incubation with 4-azidobenzoyl- 125 I-IGF-II at 10 degrees C and immediately homogenized, most of the labeled IGF-II receptors are associated with the plasma membrane fraction, indicating that receptors accessible to the labeling reagent at low temperature are on the cell surface. However, when the photolabeled cells are incubated at 37 degrees C for various times before homogenization, labeled IGF-II receptors are rapidly internalized with a half-time of 3.5 min as evidenced by a loss from the plasma membrane fraction and a concomitant appearance in the low density microsome fraction. The steady state level of cell surface IGF-II receptors in the presence or absence of IGF-II remains constant under these conditions, demonstrating that IGF-II receptors rapidly recycle back to the cell surface at the same rate as receptor internalization. Using the above methodology, it is shown that acute insulin action: 1) increases the steady state number of cell surface IGF-II receptors; 2) increases the number of ligand-bound IGF-II receptors that are internalized per unit of time; and 3) increases the rate of cellular 125 I-IGF-II degradation by a process that is blocked by anti-IGF-II receptor antibody

  15. Macrocyclic receptor showing extremely high Sr(II)/Ca(II) and Pb(II)/Ca(II) selectivities with potential application in chelation treatment of metal intoxication.

    Science.gov (United States)

    Ferreirós-Martínez, Raquel; Esteban-Gómez, David; Tóth, Éva; de Blas, Andrés; Platas-Iglesias, Carlos; Rodríguez-Blas, Teresa

    2011-04-18

    Herein we report a detailed investigation of the complexation properties of the macrocyclic decadentate receptor N,N'-Bis[(6-carboxy-2-pyridil)methyl]-4,13-diaza-18-crown-6 (H(2)bp18c6) toward different divalent metal ions [Zn(II), Cd(II), Pb(II), Sr(II), and Ca(II)] in aqueous solution. We have found that this ligand is especially suited for the complexation of large metal ions such as Sr(II) and Pb(II), which results in very high Pb(II)/Ca(II) and Pb(II)/Zn(II) selectivities (in fact, higher than those found for ligands widely used for the treatment of lead poisoning such as ethylenediaminetetraacetic acid (edta)), as well as in the highest Sr(II)/Ca(II) selectivity reported so far. These results have been rationalized on the basis of the structure of the complexes. X-ray crystal diffraction, (1)H and (13)C NMR spectroscopy, as well as theoretical calculations at the density functional theory (B3LYP) level have been performed. Our results indicate that for large metal ions such as Pb(II) and Sr(II) the most stable conformation is Δ(δλδ)(δλδ), while for Ca(II) our calculations predict the Δ(λδλ)(λδλ) form being the most stable one. The selectivity that bp18c6(2-) shows for Sr(II) over Ca(II) can be attributed to a better fit between the large Sr(II) ions and the relatively large crown fragment of the ligand. The X-ray crystal structure of the Pb(II) complex shows that the Δ(δλδ)(δλδ) conformation observed in solution is also maintained in the solid state. The Pb(II) ion is endocyclically coordinated, being directly bound to the 10 donor atoms of the ligand. The bond distances to the donor atoms of the pendant arms (2.55-2.60 Å) are substantially shorter than those between the metal ion and the donor atoms of the crown moiety (2.92-3.04 Å). This is a typical situation observed for the so-called hemidirected compounds, in which the Pb(II) lone pair is stereochemically active. The X-ray structures of the Zn(II) and Cd(II) complexes show that

  16. Effects of a novel bradykinin B1 receptor antagonist and angiotensin II receptor blockade on experimental myocardial infarction in rats.

    Directory of Open Access Journals (Sweden)

    Dongmei Wu

    Full Text Available The aim of the present study was to evaluate the cardiovascular effects of the novel bradykinin B1 receptor antagonist BI-113823 following myocardial infarction (MI and to determine whether B1 receptor blockade alters the cardiovascular effects of an angiotensin II type 1 (AT1 receptor antagonist after MI in rats.Sprague Dawley rats were subjected to permanent occlusion of the left descending coronary artery. Cardiovascular function was determined at 7 days post MI. Treatment with either B1 receptor antagonist (BI-113823 or AT1 receptor antagonist (irbesartan alone or in combination improved post-MI cardiac function as evidenced by attenuation of elevated left ventricular end diastolic pressure (LVEDP; greater first derivative of left ventricular pressure (± dp/dt max, left ventricle ejection fraction, fractional shorting, and better wall motion; as we as reductions in post-MI up-regulation of matrix metalloproteinases 2 (MMP-2 and collagen III. In addition, the cardiac up-regulation of B1 receptor and AT1 receptor mRNA were markedly reduced in animals treated with BI 113823, although bradykinin B2 receptor and angiotensin 1 converting enzyme (ACE1 mRNA expression were not significantly affected by B1 receptor blockade.The present study demonstrates that treatment with the novel B1 receptor antagonist, BI-113823 improves post-MI cardiac function and does not influence the cardiovascular effects of AT1 receptor antagonist following MI.

  17. Insulin-like growth factor-II receptors in cultured rat hepatocytes: regulation by cell density

    International Nuclear Information System (INIS)

    Scott, C.D.; Baxter, R.C.

    1987-01-01

    Insulin-like growth factor-II (IGF-II) receptors in primary cultures of adult rat hepatocytes were characterized and their regulation by cell density examined. In hepatocytes cultured at 5 X 10(5) cells per 3.8 cm2 plate [ 125 I]IGF-II bound to specific, high affinity receptors (Ka = 4.4 +/- 0.5 X 10(9) l/mol). Less than 1% cross-reactivity by IGF-I and no cross-reactivity by insulin were observed. IGF-II binding increased when cells were permeabilized with 0.01% digitonin, suggesting the presence of an intracellular receptor pool. Determined by Scatchard analysis and by polyacrylamide gel electrophoresis after affinity labeling, the higher binding was due solely to an increase in binding sites present on 220 kDa type II IGF receptors. In hepatocytes cultured at low densities, the number of cell surface receptors increased markedly, from 10-20,000 receptors per cell at a culture density of 6 X 10(5) cells/well to 70-80,000 receptors per cell at 0.38 X 10(5) cells/well. The increase was not due simply to the exposure of receptors from the intracellular pool, as a density-related increase in receptors was also seen in cells permeabilized with digitonin. There was no evidence that IGF binding proteins, either secreted by hepatocytes or present in fetal calf serum, had any effect on the measurement of receptor concentration or affinity. We conclude that rat hepatocytes in primary culture contain specific IGF-II receptors and that both cell surface and intracellular receptors are regulated by cell density

  18. Therapeutic targeting of angiotensin II receptor type 1 to regulate androgen receptor in prostate cancer.

    Science.gov (United States)

    Takahashi, Satoru; Uemura, Hiroji; Seeni, Azman; Tang, Mingxi; Komiya, Masami; Long, Ne; Ishiguro, Hitoshi; Kubota, Yoshinobu; Shirai, Tomoyuki

    2012-10-01

    With the limited strategies for curative treatment of castration-resistant prostate cancer (CRPC), public interest has focused on the potential prevention of prostate cancer. Recent studies have demonstrated that an angiotensin II receptor blocker (ARB) has the potential to decrease serum prostate-specific antigen (PSA) level and improve performance status in CRPC patients. These facts prompted us to investigate the direct effects of ARBs on prostate cancer growth and progression. Transgenic rat for adenocarcinoma of prostate (TRAP) model established in our laboratory was used. TRAP rats of 3 weeks of age received ARB (telmisartan or candesartan) at the concentration of 2 or 10 mg/kg/day in drinking water for 12 weeks. In vitro analyses for cell growth, ubiquitylation or reporter gene assay were performed using LNCaP cells. We found that both telmisartan and candesartan attenuated prostate carcinogenesis in TRAP rats by augmentation of apoptosis resulting from activation of caspases, inactivation of p38 MAPK and down-regulation of the androgen receptor (AR). Further, microarray analysis demonstrated up-regulation of estrogen receptor β (ERβ) by ARB treatment. In both parental and androgen-independent LNCaP cells, ARB inhibited both cell growth and AR-mediated transcriptional activity. ARB also exerted a mild additional effect on AR-mediated transcriptional activation by the ERβ up-regulation. An intervention study revealed that PSA progression was prolonged in prostate cancer patients given an ARB compared with placebo control. These data provide a new concept that ARBs are promising potential chemopreventive and chemotherapeutic agents for prostate cancer. Copyright © 2012 Wiley Periodicals, Inc.

  19. New basic science initiatives with the angiotensin II receptor blocker valsartan

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    Marc de Gasparo

    2000-06-01

    Full Text Available Summary Angiotensin II (Ang II plays a key role in the regulation of blood pressure and fluid homeostasis. Valsartan is a highly selective Ang II receptor blocker that specifically and selectively blocks Ang II at the AT1-receptor. In animal models, valsartan has shown positive effects on vasoconstriction, proliferation, remodelling, endothelial function and thrombogenesis, inflammation and atherosclerosis. These data are likely to be confirmed by the results of current clinical trials and valsartan is set to provide improved cardiovascular therapy in the future.

  20. Macrophage-to-sensory neuron crosstalk mediated by Angiotensin II type-2 receptor elicits neuropathic pain

    OpenAIRE

    Krause, Eric; Shepherd, Andrew; Mickle, Aaron; Copits, Bryan; Karlsson, Pall; Kadunganattil, Suraj; Golden, Judith; Tadinada, Satya; Mack, Madison; Haroutounian, Simon; De Kloet, Annette; Samineni, Vijay; Valtcheva, Manouela; Mcilvried, Lisa; Sheahan, Tayler

    2017-01-01

    Peripheral nerve damage initiates a complex series of cellular and structural processes that culminate in chronic neuropathic pain. Our study defines local angiotensin signaling via activation of the Angiotensin II (Ang II) type-2 receptor (AT2R) on macrophages as the critical trigger of neuropathic pain. An AT2R-selective antagonist attenuates neuropathic, but not inflammatory pain hypersensitivity in mice, and requires the cell damage-sensing ion channel transient receptor potential family-...

  1. Direct stimulation of angiotensin II type 2 receptor enhances spatial memory

    DEFF Research Database (Denmark)

    Jing, Fei; Mogi, Masaki; Sakata, Akiko

    2012-01-01

    We examined the possibility that direct stimulation of the angiotensin II type 2 (AT(2)) receptor by a newly generated direct AT(2) receptor agonist, Compound 21 (C21), enhances cognitive function. Treatment with C21 intraperitoneal injection for 2 weeks significantly enhanced cognitive function...

  2. Reduced glomerular angiotensin II receptor density in diabetes mellitus in the rat: time course and mechanism

    International Nuclear Information System (INIS)

    Wilkes, B.M.

    1987-01-01

    Glomerular angiotensin II receptors are reduced in number in early diabetes mellitus, which may contribute to hyperfiltration and glomerular injury. The time course and role of the renin-angiotensin-aldosterone system in the pathogenesis of the receptor abnormality were studied in male Sprague-Dawley rats made diabetic with streptozotocin (65 mg, iv). Glomerular angiotensin II receptors were measured by Scatchard analysis; insulin, renin activity, angiotensin II, and aldosterone were measured by RIA. Diabetes mellitus was documented at 24 h by a rise in plasma glucose (vehicle-injected control, 133 +/- 4; diabetic, 482 +/- 22 mg/dl and a fall in plasma insulin (control, 53.1 +/- 5.7; diabetic, 35.6 +/- 4.0 microIU/ml. At 24 h glomerular angiotensin II receptor density was decreased by 26.5% in diabetic rats (control, 75.5 +/- 9.6 X 10(6); diabetic, 55.5 +/- 8.3 X 10(6) receptors/glomerulus. Receptor occupancy could not explain the defect, because there was reduced binding in diabetic glomeruli after pretreatment with 3 M MgCl 2 , a maneuver that caused dissociation of previously bound hormone. There was a progressive return of the receptor density toward normal over the 60 days following induction of diabetes, with diabetic glomeruli measuring 22.7%, 14.8%, and 3.7% fewer receptors than age-matched controls at 11 days, 1 month, and 2 months, respectively

  3. Does protein binding modulate the effect of angiotensin II receptor antagonists?

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    Marc P Maillard

    2001-03-01

    Full Text Available IntroductionAngiotensin II AT 1-receptor antagonists are highly bound to plasma proteins (≥ 99%. With some antagonists, such as DuP-532, the protein binding was such that no efficacy of the drug could be demonstrated clinically. Whether protein binding interferes with the efficacy of other antagonists is not known. We have therefore investigated in vitro how plasma proteins may affect the antagonistic effect of different AT1-receptor antagonists.MethodsA radio-receptor binding assay was used to analyse the interaction between proteins and the ability of various angiotensin II (Ang II antagonists to block AT1-receptors. In addition, the Biacore technology, a new technique which enables the real-time monitoring of binding events between two molecules, was used to evaluate the dissociation rate constants of five AT1-receptor antagonists from human serum albumin.ResultsThe in vitro AT 1-antagonistic effects of different Ang II receptor antagonists were differentially affected by the presence of human plasma, with rightward shifts of the IC50 ranging from one to several orders of magnitude. The importance of the shift correlates with the dissociation rate constants of these drugs from albumin. Our experiments also show that the way that AT1-receptor antagonists bind to proteins differs from one compound to another. These results suggest that the interaction with plasma proteins appears to modulate the efficacy of some Ang II antagonists.ConclusionAlthough the high binding level of Ang II receptor antagonist to plasma proteins appears to be a feature common to this class of compounds, the kinetics and characteristics of this binding is of great importance. With some antagonists, protein binding interferes markedly with their efficacy to block AT1-receptors.

  4. Inactivation of the transforming growth factor beta type II receptor in human small cell lung cancer cell lines

    DEFF Research Database (Denmark)

    Hougaard, S; Nørgaard, P; Abrahamsen, N

    1999-01-01

    Transforming growth factor beta (TGF-beta) exerts a growth inhibitory effect on many cell types through binding to two types of receptors, the type I and II receptors. Resistance to TGF-beta due to lack of type II receptor (RII) has been described in some cancer types including small cell lung...

  5. Insulin-like growth factor II: complexity of biosynthesis and receptor binding

    DEFF Research Database (Denmark)

    Gammeltoft, S; Christiansen, Jan; Nielsen, F C

    1991-01-01

    Insulin-like growth factor II (IGF-II) belongs to the insulin family of peptides and acts as a growth factor in many fetal tissues and tumors. The gene expression of IGF-II is initiated at three different promoters which gives rise to multiple transcripts. In a human rhabdomyosarcoma cell line......, Man-6-P induces cellular responses. We have studied rat brain neuronal precursor cells where Man-6-P acted as a mitogen suggesting that phosphomannosylated proteins may act as growth factors via the Man-6-P/IGF-II receptor. In conclusion, the gene expression and mechanism of action of IGF-II is very...

  6. Scavenger receptor AI/II truncation, lung function and COPD: a large population-based study

    DEFF Research Database (Denmark)

    Thomsen, M; Nordestgaard, B G; Tybjærg-Hansen, Anne

    2011-01-01

    The scavenger receptor A-I/II (SRA-I/II) on alveolar macrophages is involved in recognition and clearance of modified lipids and inhaled particulates. A rare variant of the SRA-I/II gene, Arg293X, truncates the distal collagen-like domain, which is essential for ligand recognition. We tested...... whether the Arg293X variant is associated with reduced lung function and risk of chronic obstructive pulmonary disease (COPD) in the general population....

  7. beta-Arrestin 1 and 2 stabilize the angiotensin II type I receptor in distinct high-affinity conformations

    DEFF Research Database (Denmark)

    Sanni, S J; Hansen, J T; Bonde, M M

    2010-01-01

    The angiotensin II type 1 (AT(1)) receptor belongs to family A of 7 transmembrane (7TM) receptors. The receptor has important roles in the cardiovascular system and is commonly used as a drug target in cardiovascular diseases. Interaction of 7TM receptors with G proteins or beta-arrestins often...

  8. Nonpeptidic urotensin-II receptor antagonists I: in vitro pharmacological characterization of SB-706375

    Science.gov (United States)

    Douglas, Stephen A; Behm, David J; Aiyar, Nambi V; Naselsky, Diane; Disa, Jyoti; Brooks, David P; Ohlstein, Eliot H; Gleason, John G; Sarau, Henry M; Foley, James J; Buckley, Peter T; Schmidt, Dulcie B; Wixted, William E; Widdowson, Katherine; Riley, Graham; Jin, Jian; Gallagher, Timothy F; Schmidt, Stanley J; Ridgers, Lance; Christmann, Lisa T; Keenan, Richard M; Knight, Steven D; Dhanak, Dashyant

    2005-01-01

    SB-706375 potently inhibited [125I]hU-II binding to both mammalian recombinant and ‘native' UT receptors (Ki 4.7±1.5 to 20.7±3.6 nM at rodent, feline and primate recombinant UT receptors and Ki 5.4±0.4 nM at the endogenous UT receptor in SJRH30 cells). Prior exposure to SB-706375 (1 μM, 30 min) did not alter [125I]hU-II binding affinity or density in recombinant cells (KD 3.1±0.4 vs 5.8±0.9 nM and Bmax 3.1±1.0 vs 2.8±0.8 pmol mg−1) consistent with a reversible mode of action. The novel, nonpeptidic radioligand [3H]SB-657510, a close analogue of SB-706375, bound to the monkey UT receptor (KD 2.6±0.4 nM, Bmax 0.86±0.12 pmol mg−1) in a manner that was inhibited by both U-II isopeptides and SB-706375 (Ki 4.6±1.4 to 17.6±5.4 nM) consistent with the sulphonamides and native U-II ligands sharing a common UT receptor binding domain. SB-706375 was a potent, competitive hU-II antagonist across species with pKb 7.29–8.00 in HEK293-UT receptor cells (inhibition of [Ca2+]i-mobilization) and pKb 7.47 in rat isolated aorta (inhibition of contraction). SB-706375 also reversed tone established in the rat aorta by prior exposure to hU-II (Kapp∼20 nM). SB-706375 was a selective U-II antagonist with ⩾100-fold selectivity for the human UT receptor compared to 86 distinct receptors, ion channels, enzymes, transporters and nuclear hormones (Ki/IC50>1 μM). Accordingly, the contractile responses induced in isolated aortae by KCl, phenylephrine, angiotensin II and endothelin-1 were unaltered by SB-706375 (1 μM). In summary, SB-706375 is a high-affinity, surmountable, reversible and selective nonpeptide UT receptor antagonist with cross-species activity that will assist in delineating the pathophysiological actions of U-II in mammals. PMID:15852036

  9. Characterization of Angiotensin II Molecular Determinants Involved in AT1 Receptor Functional Selectivity.

    Science.gov (United States)

    Domazet, Ivana; Holleran, Brian J; Richard, Alexandra; Vandenberghe, Camille; Lavigne, Pierre; Escher, Emanuel; Leduc, Richard; Guillemette, Gaétan

    2015-06-01

    The octapeptide angiotensin II (AngII) exerts a variety of cardiovascular effects through the activation of the AngII type 1 receptor (AT1), a G protein-coupled receptor. The AT1 receptor engages and activates several signaling pathways, including heterotrimeric G proteins Gq and G12, as well as the extracellular signal-regulated kinases (ERK) 1/2 pathway. Additionally, following stimulation, βarrestin is recruited to the AT1 receptor, leading to receptor desensitization. It is increasingly recognized that specific ligands selectively bind and favor the activation of some signaling pathways over others, a concept termed ligand bias or functional selectivity. A better understanding of the molecular basis of functional selectivity may lead to the development of better therapeutics with fewer adverse effects. In the present study, we developed assays allowing the measurement of six different signaling modalities of the AT1 receptor. Using a series of AngII peptide analogs that were modified in positions 1, 4, and 8, we sought to better characterize the molecular determinants of AngII that underlie functional selectivity of the AT1 receptor in human embryonic kidney 293 cells. The results reveal that position 1 of AngII does not confer functional selectivity, whereas position 4 confers a bias toward ERK signaling over Gq signaling, and position 8 confers a bias toward βarrestin recruitment over ERK activation and Gq signaling. Interestingly, the analogs modified in position 8 were also partial agonists of the protein kinase C (PKC)-dependent ERK pathway via atypical PKC isoforms PKCζ and PKCι. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

  10. Specific, high affinity receptors for insulin-like growth factor II in the rat kidney glomerulus

    International Nuclear Information System (INIS)

    Haskell, J.F.; Pillion, D.J.; Meezan, E.

    1988-01-01

    Rat renal glomeruli were isolated by a technique involving kidney perfusion with a solution containing magnetic iron oxide particles, followed by homogenization, sieving, and concentration over a strong magnet. Isolated glomeruli were treated with 1% Triton X-100 to solubilize plasma membrane components, while insoluble basement membrane components were removed by centrifugation. [ 125 I]Insulin-like growth factor II (IGF-II) binding to this preparation was competitively inhibited by increasing amounts of unlabeled IGF-II, with 50% inhibition at an IGF-II concentration of 1 ng/ml. [ 125 I]IGF-II was covalently cross-linked with disuccinimidyl suberate to its receptor in rat renal glomeruli and a specific high mol wt (255,000) band could be identified on autoradiograms of dodecyl sulfate-polyacrylamide gels. [ 125 I]IGF-II binding and cross-linking to this band was inhibited by a polyclonal antibody against the type II IGF receptor. These results demonstrate for the first time that the isolated rat renal glomerulus contains a high affinity receptor for IGF-II

  11. Angiotensin-II type 1 receptor gene polymorphism and diabetic microangiopathy

    DEFF Research Database (Denmark)

    Tarnow, L; Cambien, Francois; Rossing, P

    1996-01-01

    with proliferative retinopathy and without diabetic retinopathy was found either: 77 (50%) / 66 (42%) / 13 (8%) vs. 42 (63%) / 22 (33%) / 3 (4%) had AA/AC/CC genotypes, respectively. CONCLUSIONS: The A1166-->C polymorphism in the angiotensin-II type 1 receptor gene does not contribute to the genetic susceptibility...... is present particularly in vascular smooth muscle cells, myocardium and the kidney. A transversion of adenine to cytosine at nucleotide position 1166 in the gene coding for the angiotensin-II type 1 receptor has been associated with hypertension in the non-diabetic population. METHODS: We studied...... the relationship between the A1166-->C polymorphism in the angiotensin-II type 1 receptor gene in patients with insulin dependent diabetes mellitus (IDDM) and diabetic nephropathy (121 men, 77 women, age 41 +/- 10 years, diabetes duration 27 +/- 8 years) and in IDDM patients with normoalbuminuria (116 men, 74...

  12. Quantitative autoradiographic mapping of serotonin receptors in the rat brain. II. Serotonin-2 receptors

    International Nuclear Information System (INIS)

    Pazos, A.; Cortes, R.; Palacios, J.M.

    1985-01-01

    The distribution of serotonin-2 (5-HT 2 ) receptors in the rat brain was studied by light microscopic quantitative autoradiography. Receptors were labeled with four ligands: [ 3 H]ketanserin, [ 3 H]mesulergine, [ 3 H]LSD and [ 3 H]spiperone, which are reported to show high affinity for 5-HT 2 receptors. Very high concentrations were localized in the claustrum, olfactory tubercle and layer IV of the neocortex. The anterior olfactory nucleus, piriform cortex and layer I of neocortex were also rich in 5-HT 2 receptors. The specificity of the different ligands used is discussed in terms of the other populations of sites recognized by them. The distribution of 5-HT 2 receptors here reported is discussed in correlation with (a) the known distribution of serotoninergic terminals, (b) the specific anatomical systems and (c) the central effects reported to be mediated by 5-HT 2 -selective drugs. (Auth.)

  13. Angiotensin II Type 2 Receptor and Receptor Mas Are Colocalized and Functionally Interdependent in Obese Zucker Rat Kidney

    DEFF Research Database (Denmark)

    Patel, Sanket N; Ali, Quaisar; Samuel, Preethi

    2017-01-01

    The actions of angiotensin II type 2 receptor (AT2R) and the receptor Mas (MasR) are complex but show similar pronatriuretic function; particularly, AT2R expression and natriuretic function are enhanced in obese/diabetic rat kidney. In light of some reports suggesting a potential positive...... interaction between these receptors, we tested hypothesis that renal AT2R and MasR physically interact and are interdependent to stimulate cell signaling and promote natriuresis in obese rats. We found that infusion of AT2R agonist C21 in obese Zucker rats (OZR) increased urine flow and urinary Na excretion...... coimmunoprecipitated with MasR in cortical homogenate of OZR. Immunoblotting of cortical homogenate cross-linked with zero-length oxidative (sulfhydryl groups) cross-linker cupric-phenanthroline revealed a shift of AT2R and MasR bands upward with overlapping migration for their complexes which were sensitive...

  14. Takifugu rubripes cation independent mannose 6-phosphate receptor: Cloning, expression and functional characterization of the IGF-II binding domain.

    Science.gov (United States)

    A, Ajith Kumar; Nadimpalli, Siva Kumar

    2018-07-01

    Mannose 6-phosphate/IGF-II receptor mediated lysosomal clearance of insulin-like growth factor-II is significantly associated with the evolution of placental mammals. The protein is also referred to as the IGF-II receptor. Earlier studies suggested relatively low binding affinity between the receptor and ligand in prototherian and metatherian mammals. In the present study, we cloned the IGF-II binding domain of the early vertebrate fugu fish and expressed it in bacteria. A 72000Da truncated receptor containing the IGF-II binding domain was obtained. Analysis of this protein (covering domains 11-13 of the CIMPR) for its affinity to fish and human IGF-II by ligand blot assays and ELISA showed that the expressed receptor can specifically bind to both fish and human IGF-II. Additionally, a peptide-specific antibody raised against the region of the IGF-II binding domain also was able to recognize the IGF-II binding regions of mammalian and non-mammalian cation independent MPR protein. These interactions were further characterized by Surface Plasma resonance support that the receptor binds to fish IGF-II, with a dissociation constant of 548nM. Preliminary analysis suggests that the binding mechanism as well as the affinity of the fish and human receptor for IGF-II may have varied according to different evolutionary pressures. Copyright © 2018. Published by Elsevier B.V.

  15. IGF-II receptors in luminal and basolateral membranes isolated from pars convoluta and pars recta of rabbit proximal tubule

    DEFF Research Database (Denmark)

    Jacobsen, Christian; Jessen, H; Flyvbjerg, A

    1995-01-01

    the inhibitory effect of beta-galactosidase. Analyses of 125I-IGF-II binding curves in the presence of beta-galactosidase or D-mannose 6-phosphate demonstrated that none of these compounds changed the binding affinity of 125I-IGF-II for the membrane vesicles. The IGF-II/M6P receptor content in the luminal...... membranes was in the range 0.21-0.34 pmol IGF-II/M6P receptor per mg protein and very low compared to 2.27-2.86 pmol IGF-II/M6P receptor per mg protein in basolateral membranes. Udgivelsesdato: 1995-Apr-12...

  16. Nonpeptidic angiotensin II AT₁ receptor antagonists derived from 6-substituted aminocarbonyl and acylamino benzimidazoles.

    Science.gov (United States)

    Zhang, Jun; Wang, Jin-Liang; Yu, Wei-Fa; Zhou, Zhi-Ming; Tao, Wen-Chang; Wang, Yi-Cheng; Xue, Wei-Zhe; Xu, Di; Hao, Li-Ping; Han, Xiao-Feng; Fei, Fan; Liu, Ting; Liang, Ai-Hua

    2013-11-01

    Both 6-substituted aminocarbonyl and acylamino benzimidazole derivatives were designed and synthesized as nonpeptidic angiotensin II AT₁ receptor antagonists. Compounds 6f, 6g, 11e, 11f, 11g, and 12 showed nanomolar AT₁ receptor binding affinity and high AT₁ receptor selectivity over AT₂ receptor in a preliminary pharmacological evaluation. Among them, the two most active compounds 6f (AT₁ IC₅₀ = 3 nM, AT₂ IC₅₀ > 10,000 nM, PA₂ = 8.51) and 11g (AT₁ IC₅₀ = 0.1 nM, AT₂ IC₅₀ = 149 nM, PA₂ = 8.43) exhibited good antagonistic activity in isolated rabbit aortic strip functional assay. In addition, they were orally active AT₁ receptor antagonists in spontaneous hypertensive rats. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  17. Angiotensin II Regulates Th1 T Cell Differentiation Through Angiotensin II Type 1 Receptor-PKA-Mediated Activation of Proteasome.

    Science.gov (United States)

    Qin, Xian-Yun; Zhang, Yun-Long; Chi, Ya-Fei; Yan, Bo; Zeng, Xiang-Jun; Li, Hui-Hua; Liu, Ying

    2018-01-01

    Naive CD4+ T cells differentiate into T helper cells (Th1 and Th2) that play an essential role in the cardiovascular diseases. However, the molecular mechanism by which angiotensin II (Ang II) promotes Th1 differentiation remains unclear. The aim of this study was to determine whether the Ang II-induced Th1 differentiation regulated by ubiquitin-proteasome system (UPS). Jurkat cells were treated with Ang II (100 nM) in the presence or absence of different inhibitors. The gene mRNA levels were detected by real-time quantitative PCR analysis. The protein levels were measured by ELISA assay or Western blot analysis, respectively. Ang II treatment significantly induced a shift from Th0 to Th1 cell differentiation, which was markedly blocked by angiotensin II type 1 receptor (AT1R) inhibitor Losartan (LST). Moreover, Ang II significantly increased the activities and the expression of proteasome catalytic subunits (β1, β1i, β2i and β5i) in a dose- and time-dependent manner. However, Ang II-induced proteasome activities were remarkably abrogated by LST and PKA inhibitor H-89. Mechanistically, Ang II-induced Th1 differentiation was at least in part through proteasome-mediated degradation of IκBα and MKP-1 and activation of STAT1 and NF-κB. This study for the first time demonstrates that Ang II activates AT1R-PKA-proteasome pathway, which promotes degradation of IκBα and MKP-1 and activation of STAT1 and NF-κB thereby leading to Th1 differentiation. Thus, inhibition of proteasome activation might be a potential therapeutic target for Th1-mediated diseases. © 2018 The Author(s). Published by S. Karger AG, Basel.

  18. Distortion of maternal-fetal angiotensin II type 1 receptor allele transmission in pre-eclampsia.

    Science.gov (United States)

    Morgan, L; Crawshaw, S; Baker, P N; Brookfield, J F; Broughton Pipkin, F; Kalsheker, N

    1998-01-01

    OBJECTIVE: To investigate the fetal angiotensin II type 1 receptor genotype in pre-eclampsia. DESIGN: Case-control study. POPULATION: Forty-one maternal-fetal pairs from pre-eclamptic pregnancies and 80 maternal-fetal pairs from normotensive pregnancies. METHODS: Maternal and fetal DNA was genotyped at three diallelic polymorphisms, at nucleotides 573, 1062, and 1166, in the coding exon of the angiotensin II type 1 receptor gene, and at a dinucleotide repeat polymorphism in its 3' flanking region. RESULTS: Allele and genotype frequencies at the four polymorphic regions investigated did not differ between pre-eclamptic and normotensive groups, in either fetal or maternal samples. Mothers heterozygous for the dinucleotide repeat allele designated A4 transmitted this allele to the fetus in 15 of 18 informative pre-eclamptic pregnancies and in eight of 26 normotensive pregnancies. This was greater than the expected probability in pre-eclamptic pregnancies (p=0.04) and less than expected in normotensive pregnancies (p<0.005). The 573T variant, which is in partial linkage disequilibrium with the A4 allele, showed a similar distortion of maternal-fetal transmission. CONCLUSION: Angiotensin II type 1 receptor gene expression in the fetus may contribute to the aetiology of pre-eclampsia. It is unclear whether susceptibility is conferred by the fetal genotype acting alone, or by allele sharing by mother and fetus. Possible mechanisms for the effect of the angiotensin II type 1 receptor gene are suggested by the association of the 573T variant with low levels of surface receptor expression on platelets. If receptor expression is similarly genetically determined in the placenta, responsiveness to angiotensin II may be affected, with the potential to influence placentation or placental prostaglandin secretion. PMID:9719367

  19. Angiotensin II, hypertension and angiotensin II receptor antagonism: Roles in the behavioural and brain pathology of a mouse model of Alzheimer's disease

    NARCIS (Netherlands)

    Wiesmann, M.; Roelofs, M.; Lugt, R. Van Der; Heerschap, A.; Kiliaan, A.J.; Claassen, J.A.H.R.

    2017-01-01

    Elevated angiotensin II causes hypertension and contributes to Alzheimer's disease by affecting cerebral blood flow. Angiotensin II receptor blockers may provide candidates to reduce (vascular) risk factors for Alzheimer's disease. We studied effects of two months of angiotensin II-induced

  20. Receptors for insulin-like growth factors I and II: autoradiographic localization in rat brain and comparison to receptors for insulin

    International Nuclear Information System (INIS)

    Lesniak, M.A.; Hill, J.M.; Kiess, W.; Rojeski, M.; Pert, C.B.; Roth, J.

    1988-01-01

    Receptors for insulin-like growth factor I (IGF-I) in rat brain were visualized using autoradiography with [125I]IGF-I. The binding of the labeled peptide was competed for fully by high concentrations of unlabeled IGF-I. At intermediate concentrations of unlabeled peptide the binding of [125I]IGF-I was competed for by unlabeled IGF-I more effectively than by IGF-II or insulin, which is typical of receptors for IGF-I. Essentially every brain section shows specific binding of IGF-I, and the pattern of binding of IGF-I to its receptors correlated well with the cytoarchitectonic structures. In parallel studies we showed that [125I]IGF-II was bound to tissue sections of rat brain and that the binding was competed for by an excess of unlabeled IGF-II. However, intermediate concentrations of unlabeled peptides gave inconclusive results. To confirm that the binding of [125I]IGF-II was to IGF-II receptors, we showed that antibodies specific for the IGF-II receptor inhibited the binding of labeled IGF-II. Furthermore, the binding of the antibody to regions of the brain section, visualized by the application of [125I]protein-A, gave patterns indistinguishable from those obtained with [125I]IGF-II alone. Again, the binding was very widely distributed throughout the central nervous system, and the patterns of distribution corresponded well to the underlying neural structures. Densitometric analysis of the receptors enabled us to compare the distribution of IGF-I receptors with that of IGF-II receptors as well as retrospectively with that of insulin receptors

  1. Uterine-embryonic interaction in pit : activin, follistatin, and activin receptor II in uterus and embryo during early gestation

    NARCIS (Netherlands)

    Pavert, van de S.A.; Boerjan, M.L.; Stroband, H.W.J.; Taverne, M.A.M.; Hurk, van der R.

    2001-01-01

    The mRNA expression patterns of activin A and follistatin in the uterus and embryo, the mRNA expression of the activin receptor II in the embryo, and the localization in the uterus of the immunoreactive activin A and the receptor II proteins in the uterus were examined at gestation days 7-12 after

  2. Overexpression of the human angiotensin II type 1 receptor in the rat heart augments load induced cardiac hypertrophy

    NARCIS (Netherlands)

    Hoffmann, S.; Krause, T.; van Geel, P. P.; Willenbrock, R.; Pagel, I.; Pinto, Y. M.; Buikema, H.; van Gilst, W. H.; Lindschau, C.; Paul, M.; Inagami, T.; Ganten, D.; Urata, H.

    2001-01-01

    Angiotensin II is known to stimulate cardiac hypertrophy and contractility. Most angiotensin II effects are mediated via membrane bound AT1 receptors. However, the role of myocardial AT1 receptors in cardiac hypertrophy and contractility is still rarely defined. To address the hypothesis that

  3. Overexpression of the human angiotensin II type 1 receptor in the rat heart augments load induced cardiac hypertrophy

    NARCIS (Netherlands)

    Hoffmann, S; van Geel, PP; Willenbrock, R; Pagel, [No Value; Pinto, YM; Buikema, H; van Gilst, WH; Lindschau, C; Paul, M; Inagami, T; Ganten, D; Urata, H

    2001-01-01

    Angiotensin II is known to stimulate cardiac hypertrophy and contractility. Most angiotensin II effects are mediated via membrane bound AT(1) receptors. However, the role of myocardial AT(1) receptors in cardiac hypertrophy and contractility is still rarely defined. To address the hypothesis that

  4. Identification of type II and type III pyoverdine receptors from Pseudomonas aeruginosa.

    Science.gov (United States)

    de Chial, Magaly; Ghysels, Bart; Beatson, Scott A; Geoffroy, Valérie; Meyer, Jean Marie; Pattery, Theresa; Baysse, Christine; Chablain, Patrice; Parsons, Yasmin N; Winstanley, Craig; Cordwell, Stuart J; Cornelis, Pierre

    2003-04-01

    Pseudomonas aeruginosa produces, under conditions of iron limitation, a high-affinity siderophore, pyoverdine (PVD), which is recognized at the level of the outer membrane by a specific TonB-dependent receptor, FpvA. So far, for P. aeruginosa, three different PVDs, differing in their peptide chain, have been described (types I-III), but only the FpvA receptor for type I is known. Two PVD-producing P. aeruginosa strains, one type II and one type III, were mutagenized by a mini-TnphoA3 transposon. In each case, one mutant unable to grow in the presence of the strong iron chelator ethylenediaminedihydroxyphenylacetic acid (EDDHA) and the cognate PVD was selected. The first mutant, which had an insertion in the pvdE gene, upstream of fpvA, was unable to take up type II PVD and showed resistance to pyocin S3, which is known to use type II FpvA as receptor. The second mutant was unable to take up type III PVD and had the transposon insertion in fpvA. Cosmid libraries of the respective type II and type III PVD wild-type strains were constructed and screened for clones restoring the capacity to grow in the presence of PVD. From the respective complementing genomic fragments, type II and type III fpvA sequences were determined. When in trans, type II and type III fpvA restored PVD production, uptake, growth in the presence of EDDHA and, in the case of type II fpvA, pyocin S3 sensitivity. Complementation of fpvA mutants obtained by allelic exchange was achieved by the presence of cognate fpvA in trans. All three receptors posses an N-terminal extension of about 70 amino acids, similar to FecA of Escherichia coli, but only FpvAI has a TAT export sequence at its N-terminal end.

  5. Erratum Aldosterone synthase C-344T, angiotensin II type 1 receptor ...

    Indian Academy of Sciences (India)

    Aldosterone synthase C-344T, angiotensin II type 1 receptor A1166C and 11-β hydroxysteroid dehydrogenase G534A gene polymorphisms and essential hypertension in the population of Odisha, India. Manisha Patnaik, Pallabi Pati, Surendra N. Swain, Manoj K. Mohapatra, Bhagirathi Dwibedi, Shantanu K. Kar.

  6. Centrally Mediated Cardiovascular Actions of the Angiotensin II Type 2 Receptor

    DEFF Research Database (Denmark)

    Steckelings, U Muscha; Kloet, Annette de; Sumners, Colin

    2017-01-01

    Sustained increases in the activity of the sympathetic neural pathways that exit the brain and which increase blood pressure (BP) are a major underlying factor in resistant hypertension. Recently available information on the occurrence of angiotensin II type 2 receptors (AT2Rs) within or adjacent...

  7. Autoradiographic visualization of insulin-like growth factor-II receptors in rat brain

    International Nuclear Information System (INIS)

    Mendelsohn, L.G.; Kerchner, G.A.; Clemens, J.A.; Smith, M.C.

    1986-01-01

    The documented presence of IGF-II in brain and CSF prompted us to investigate the distribution of receptors for IGF-II in rat brain slices. Human 125 -I-IGF-II (10 pM) was incubated for 16 hrs at 4 0 C with slide-mounted rat brain slices in the absence and presence of unlabeled human IGF-II (67 nM) or human insulin (86 nM). Slides were washed, dried, and exposed to X-ray film for 4-7 days. The results showed dense labeling in the granular layers of the olfactory bulbs, deep layers of the cerebral cortex, pineal gland, anterior pituitary, hippocampus (pyramidal cells CA 1 -CA 2 and dentate gyrus), and the granule cell layers of the cerebellum. Unlabeled IGF-II eliminated most of the binding of these brain regions while insulin produced only a minimal reduction in the amount of 125 I-IGF-II bound. These results indicate that a specific neural receptor for IGS-II is uniquely distributed in rat brain tissue and supports the notion that this peptide might play an important role in normal neuronal functioning

  8. Troglitazone stimulates β-arrestin-dependent cardiomyocyte contractility via the angiotensin II type 1A receptor

    International Nuclear Information System (INIS)

    Tilley, Douglas G.; Nguyen, Anny D.; Rockman, Howard A.

    2010-01-01

    Peroxisome proliferator-activated receptor γ (PPARγ) agonists are commonly used to treat cardiovascular diseases, and are reported to have several effects on cardiovascular function that may be due to PPARγ-independent signaling events. Select angiotensin receptor blockers (ARBs) interact with and modulate PPARγ activity, thus we hypothesized that a PPARγ agonist may exert physiologic effects via the angiotensin II type 1 A receptor (AT1 A R). In AT1 A R-overexpressing HEK 293 cells, both angiotensin II (Ang II) and the PPARγ agonist troglitazone (Trog) enhanced AT1 A R internalization and recruitment of endogenous β-arrestin1/2 (βarr1/2) to the AT1 A R. A fluorescence assay to measure diacylglycerol (DAG) accumulation showed that although Ang II induced AT1 A R-G q protein-mediated DAG accumulation, Trog had no impact on DAG generation. Trog-mediated recruitment of βarr1/2 was selective to AT1 A R as the response was prevented by an ARB- and Trog-mediated βarr1/2 recruitment to β1-adrenergic receptor (β1AR) was not observed. In isolated mouse cardiomyocytes, Trog increased both % and rate of cell shortening to a similar extent as Ang II, effects which were blocked with an ARB. Additionally, these effects were found to be βarr2-dependent, as cardiomyocytes isolated from βarr2-KO mice showed blunted contractile responses to Trog. These findings show for the first time that the PPARγ agonist Trog acts at the AT1 A R to simultaneously block G q protein activation and induce the recruitment of βarr1/2, which leads to an increase in cardiomyocyte contractility.

  9. Modulation of type II TGF-β receptor degradation by integrin-linked kinase.

    Science.gov (United States)

    Vi, Linda; Boo, Stellar; Sayedyahossein, Samar; Singh, Randeep K; McLean, Sarah; Di Guglielmo, Gianni M; Dagnino, Lina

    2015-03-01

    Cutaneous responses to injury, infection, and tumor formation involve the activation of resident dermal fibroblasts and subsequent transition to myofibroblasts. The key for induction of myofibroblast differentiation is the activation of transforming growth factor-β (TGF-β) receptors and stimulation of integrins and their associated proteins, including integrin-linked kinase (ILK). Cross-talk processes between TGF-β and ILK are crucial for myofibroblast formation, as ILK-deficient dermal fibroblasts exhibit impaired responses to TGF-β receptor stimulation. We now show that ILK associates with type II TGF-β receptors (TβRII) in ligand- and receptor kinase activity-independent manners. In cells with targeted Ilk gene inactivation, cellular levels of TβRII are decreased, through mechanisms that involve enhanced ubiquitination and proteasomal degradation. Partitioning of TGF-β receptors into membrane has been linked to proteasome-dependent receptor degradation. We found that interfering with membrane raft formation in ILK-deficient cells restored TβRII levels and signaling. These observations support a model whereby ILK functions in fibroblasts to direct TβRII away from degradative pathways during their differentiation into myofibroblasts.

  10. The effect of serum angiotensin II and angiotensin II type 1 receptor ...

    African Journals Online (AJOL)

    Ehab

    2012-06-18

    Jun 18, 2012 ... case-control cross sectional study which included 24 patients with pLN ..... significantly high levels (1000-fold) of Ang II .... initial validation of the Systemic Lupus International ... Fyhrquist F, Metsärinne K, Tikkanen I. Role of.

  11. A macrocyclic ligand as receptor and Zn(II)-complex receptor for anions in water: binding properties and crystal structures.

    Science.gov (United States)

    Ambrosi, Gianluca; Formica, Mauro; Fusi, Vieri; Giorgi, Luca; Macedi, Eleonora; Micheloni, Mauro; Paoli, Paola; Pontellini, Roberto; Rossi, Patrizia

    2011-02-01

    Binding properties of 24,29-dimethyl-6,7,15,16-tetraoxotetracyclo[19.5.5.0(5,8).0(14,17)]-1,4,9,13,18,21,24,29-octaazaenatriaconta-Δ(5,8),Δ(14,17)-diene ligand L towards Zn(II) and anions, such as the halide series and inorganic oxoanions (phosphate (Pi), sulfate, pyrophosphate (PPi), and others), were investigated in aqueous solution; in addition, the Zn(II)/L system was tested as a metal-ion-based receptor for the halide series. Ligand L is a cryptand receptor incorporating two squaramide functions in an over-structured chain that connects two opposite nitrogen atoms of the Me(2)[12]aneN(4) polyaza macrocyclic base. It binds Zn(II) to form mononuclear species in which the metal ion, coordinated by the Me(2)[12]aneN(4) moiety, lodges inside the three-dimensional cavity. Zn(II)-containing species are able to bind chloride and fluoride at the physiologically important pH value of 7.4; the anion is coordinated to the metal center but the squaramide units play the key role in stabilizing the anion through a hydrogen-bonding network; two crystal structures reported here clearly show this aspect. Free L is able to bind fluoride, chloride, bromide, sulfate, Pi, and PPi in aqueous solution. The halides are bound at acidic pH, whereas the oxoanions are bound in a wide range of pH values ranging from acidic to basic. The cryptand cavity, abundant in hydrogen-bonding sites at all pH values, allows excellent selectivity towards Pi to be achieved mainly at physiological pH 7.4. By joining amine and squaramide moieties and using this preorganized topology, it was possible, with preservation of the solubility of the receptor, to achieve a very wide pH range in which oxoanions can be bound. The good selectivity towards Pi allows its discrimination in a manner not easily obtainable with nonmetallic systems in aqueous environment. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  12. [Functional properties of taste bud cells. Mechanisms of afferent neurotransmission in Type II taste receptor cells].

    Science.gov (United States)

    Romanov, R A

    2013-01-01

    Taste Bud cells are heterogeneous in their morphology and functionality. These cells are responsible for sensing a wide variety of substances and for associating detected compounds with a different taste: bitter, sweet, salty, sour and umami. Today we know that each of the five basic tastes corresponds to distinct cell populations organized into three basic morpho-functional cell types. In addition, some receptor cells of the taste bud demonstrate glia-related functions. In this article we expand on some properties of these three morphological receptor cell types. Main focus is devoted to the Type II cells and unusual mechanism for afferent neurotransmission in these cells. Taste cells of the Type II consist of three populations detecting bitter, sweet and umami tastes, and, thus, evoke a serious scientific interest.

  13. The mechanisms behind decreased internalization of angiotensin II type 1 receptor.

    Science.gov (United States)

    Bian, Jingwei; Zhang, Suli; Yi, Ming; Yue, Mingming; Liu, Huirong

    2018-04-01

    The internalization of angiotensin II type 1 receptor (AT 1 R) plays an important role in maintaining cardiovascular homeostasis. Decreased receptor internalization is closely related to cardiovascular diseases induced by the abnormal activation of AT 1 R, such as hypertension. However, the mechanism behind reduced AT 1 R internalization is not fully understood. This review focuses on four parts of the receptor internalization process (the combination of agonists and receptors, receptor phosphorylation, endocytosis, and recycling) and summarizes the possible mechanisms by which AT 1 R internalization is reduced based on these four parts of the process. (1) The agonist has a large molecular weight or a stronger ability to hydrolyze phosphatidylinositol 4,5-bisphosphate (PtdIns (4,5) P 2 ), which can increase the consumption of PtdIns (4,5) P 2 . (2) AT 1 R phosphorylation is weakened because of an abnormal function of phosphorylated kinase or changes in phospho-barcoding and GPCR-β-arrestin complex conformation. (3) The abnormal formation of vesicles or AT 1 R heterodimers with fewer endocytic receptors results in less AT 1 R endocytosis. (4) The enhanced activity and upregulated expression of small GTP-binding protein 4 (Rab4) and 11 (Rab11), which regulate receptor recycling, and phosphatidylinositol 3-kinase increase AT 1 R recycling. In addition, lower expression of AT 1 R-associated protein (ATRAP) or higher expression of AT 1 R-associated protein 1 (ARAP1) can reduce receptor internalization. Copyright © 2018 Elsevier Inc. All rights reserved.

  14. H pylori receptor MHC class II contributes to the dynamic gastric epithelial apoptotic response

    Science.gov (United States)

    Bland, David A; Suarez, Giovanni; Beswick, Ellen J; Sierra, Johanna C; Reyes, Victor E

    2006-01-01

    AIM: To investigate the role of MHC class II in the modulation of gastric epithelial cell apoptosis induced by H pylori infection. METHODS: After stimulating a human gastric epithelial cell line with bacteria or agonist antibodies specific for MHC class II and CD95, the quantitation of apoptotic and anti-apoptotic events, including caspase activation, BCL-2 activation, and FADD recruitment, was performed with a fluorometric assay, a cytometric bead array, and confocal microscopy, respectively. RESULTS: Pretreatment of N87 cells with the anti-MHC class II IgM antibody RFD1 resulted in a reduction in global caspase activation at 24 h of H pylori infection. When caspase 3 activation was specifically measured, crosslinking of MHC class II resulted in a marked reduced caspase activation, while simple ligation of MHC class II did not. Crosslinking of MHC class II also resulted in an increased activation of the anti-apoptosis molecule BCL-2 compared to simple ligation. Confocal microscope analysis demonstrated that the pretreatment of gastric epithelial cells with a crosslinking anti-MHC class II IgM blocked the recruitment of FADD to the cell surface. CONCLUSION: The results presented here demonstrate that the ability of MHC class II to modulate gastric epithelial apoptosis is at least partially dependent on its crosslinking. Furthermore, while previous research has demonstrated that MHC class II signaling can be pro-apoptotic during extended ligation, we have shown that the crosslinking of this molecule has anti-apoptotic effects during the earlier time points of H pylori infection. This effect is possibly mediated by the ability of MHC class II to modulate the activation of the pro-apoptotic receptor Fas by blocking the recruitment of the accessory molecule FADD, and this delay in apoptosis induction could allow for prolonged cytokine secretion by H pylori-infected gastric epithelial cells. PMID:16981259

  15. Pharmacological characterization of BR-A-657, a highly potent nonpeptide angiotensin II receptor antagonist.

    Science.gov (United States)

    Chi, Yong Ha; Lee, Joo Han; Kim, Je Hak; Tan, Hyun Kwang; Kim, Sang Lin; Lee, Jae Yeol; Rim, Hong-Kun; Paik, Soo Heui; Lee, Kyung-Tae

    2013-01-01

    The pharmacological profile of BR-A-657, 2-n-butyl-5-dimethylamino-thiocarbonyl-methyl-6-methyl-3-{[2-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl}-pyrimidin-4(3H)-one, a new nonpeptide AT1-selective angiotensin receptor antagonist, has been investigated in a variety of in vitro and in vivo experimental models. In the present study, BR-A-657 displaced [(125)I][Sar(1)-Ile(8)]angiotensin II (Ang II) from its specific binding sites to AT1 subtype receptors in membrane fractions of HEK-293 cells with an IC50 of 0.16 nM. In a functional assay using isolated rabbit thoracic aorta, BR-A-657 inhibited the contractile response to Ang II (pD'2: 9.15) with a significant reduction in the maximum. In conscious rats, BR-A-657 (0.01, 0.1, 1 mg/kg; intravenously (i.v.)) dose-dependently antagonized Ang II-induced pressor responses. In addition, BR-A-657 dose-dependently decreased mean arterial pressure in furosemide-treated rats and renal hypertensive rats. Moreover, BR-A-657 given orally at 1 and 3 mg/kg reduced blood pressure in conscious renal hypertensive rats. Taken together, these findings indicate that BR-A-657 is a potent and specific antagonist of Ang II at the AT1 receptor subtype, and reveal the molecular basis responsible for the marked lowering of blood pressure in conscious rats.

  16. Localization and characterization of angiotensin II receptor binding and angiotensin converting enzyme in the human medulla oblongata.

    Science.gov (United States)

    Allen, A M; Chai, S Y; Clevers, J; McKinley, M J; Paxinos, G; Mendelsohn, F A

    1988-03-08

    Angiotensin II receptor and angiotensin converting enzyme distributions in the human medulla oblongata were localised by quantitative in vitro autoradiography. Angiotensin II receptors were labelled with the antagonist analogue 125I-[Sar1, Ile8] AII while angiotensin converting enzyme was labelled with 125I-351A, a derivative of the specific converting enzyme inhibitor, lisinopril. Angiotensin II receptor binding and angiotensin converting enzyme are present in high concentrations in the nucleus of the solitary tract, the dorsal motor nucleus of vagus, the rostral and caudal ventrolateral reticular nucleus, and in a band connecting the dorsal and ventral regions. In the rostral and caudal ventrolateral reticular nucleus, angiotensin II receptors are distributed in a punctate pattern that registers with neuronal cell bodies. The distribution and density of these cell bodies closely resemble those of catecholamine-containing neurones mapped by others. In view of the known interactions of angiotensin II with both central and peripheral catecholamine-containing neurons of laboratory animals, the current anatomical findings suggest similar interactions between these neuroactive compounds in the human central nervous system. The presence of angiotensin II receptors and angiotensin converting enzyme in the nucleus of the solitary tract, dorsal motor nucleus of vagus, and rostral and caudal ventrolateral reticular nucleus demonstrates sites for central angiotensin II to exert its known actions on vasopressin release and autonomic functions including blood pressure control. These data also suggest a possible interaction between angiotensin II and central catecholeminergic systems.

  17. Clathrin-dependent internalization of the angiotensin II AT₁A receptor links receptor internalization to COX-2 protein expression in rat aortic vascular smooth muscle cells.

    Science.gov (United States)

    Morinelli, Thomas A; Walker, Linda P; Velez, Juan Carlos Q; Ullian, Michael E

    2015-02-05

    The major effects of Angiotensin II (AngII) in vascular tissue are mediated by AngII AT1A receptor activation. Certain effects initiated by AT1A receptor activation require receptor internalization. In rat aortic vascular smooth muscle cells (RASMC), AngII stimulates cyclooxygenase 2 protein expression. We have previously shown this is mediated by β-arrestin-dependent receptor internalization and NF-κB activation. In this study, a specific inhibitor of clathrin-mediated endocytosis (CME), pitstop-2, was used to test the hypothesis that clathrin-dependent internalization of activated AT1A receptor mediates NF-κB activation and subsequent cyclooxygenase 2 expression. Radioligand binding assays, real time qt-PCR and immunoblotting were used to document the effects of pitstop-2 on AngII binding and signaling in RASMC. Laser scanning confocal microscopy (LSCM) was used to image pitstop-2׳s effects on AT1 receptor/GFP internalization in HEK-293 cells and p65 NF-κB nuclear localization in RASMC. Pitstop-2 significantly inhibited internalization of AT1A receptor (44.7% ± 3.1% Control vs. 13.2% ± 8.3% Pitstop-2; n=3) as determined by radioligand binding studies in RASMC. Studies utilizing AT1A receptor/GFP expressed in HEK 293 cells and LSCM confirmed these findings. Pitstop-2 significantly inhibited AngII-induced p65 NF-κB phosphorylation and nuclear localization, COX-2 message and protein expression in RASMC without altering activation of p42/44 ERK or TNFα signaling. Pitstop-2, a specific inhibitor of clathrin-mediated endocytosis, confirms that internalization of activated AT1A receptor mediates AngII activation of cyclooxygenase 2 expression in RASMC. These data provide support for additional intracellular signaling pathways activated through β-arrestin mediated internalization of G protein-coupled receptors, such as AT1A receptors. Copyright © 2014 Elsevier B.V. All rights reserved.

  18. Local angiotensin II promotes adipogenic differentiation of human adipose tissue mesenchymal stem cells through type 2 angiotensin receptor

    Directory of Open Access Journals (Sweden)

    Veronika Y. Sysoeva

    2017-12-01

    Full Text Available Obesity is often associated with high systemic and local activity of renin-angiotensin system (RAS. Mesenchymal stem cells of adipose tissue are the main source of adipocytes. The aim of this study was to clarify how local RAS could control adipose differentiation of human adipose tissue derived mesenchymal stem cells (ADSCs. We examined the distribution of angiotensin receptor expressing cells in human adipose tissue and found that type 1 and type 2 receptors are co-expressed in its stromal compartment, which is known to contain mesenchymal stem cells. To study the expression of receptors specifically in ADSCs we have isolated them from adipose tissue. Up to 99% of cultured ADSCs expressed angiotensin II (AngII receptor type 1 (AT1. Using the analysis of Ca2+ mobilization in single cells we found that only 5.2 ± 2.7% of ADSCs specifically respond to serial Ang II applications via AT1 receptor and expressed this receptor constantly. This AT1const ADSCs subpopulation exhibited increased adipose competency, which was triggered by endogenous AngII. Inhibitory and expression analyses showed that AT1const ADSCs highly co-express AngII type 2 receptor (AT2, which was responsible for increased adipose competency of this ADSC subpopulation.

  19. Estimation of the number of angiotensin II AT1 receptors in rat kidney afferent and efferent arterioles

    DEFF Research Database (Denmark)

    Razga, Zsolt; Nyengaard, Jens Randel

    2007-01-01

    of angiotensin II AT1 receptors along the length of the arterioles and per arteriole, we combined immunoelectron microscopy with stereology. RESULTS: The number of AT1 receptor molecules was significantly lower in the renin-positive smooth muscle cells (SMCs) than in the renin-negative SMCs of the afferent...

  20. Mechanism of Ca2+/calmodulin-dependent kinase II regulation of AMPA receptor gating

    DEFF Research Database (Denmark)

    Kristensen, Anders Skov; Jenkins, Meagan A; Banke, Tue G

    2011-01-01

    The function, trafficking and synaptic signaling of AMPA receptors are tightly regulated by phosphorylation. Ca(2+)/calmodulin-dependent kinase II (CaMKII) phosphorylates the GluA1 AMPA receptor subunit at Ser831 to increase single-channel conductance. We show that CaMKII increases the conductanc...

  1. Cross talk between AT1 receptors and Toll-like receptor 4 in microglia contributes to angiotensin II-derived ROS production in the hypothalamic paraventricular nucleus.

    Science.gov (United States)

    Biancardi, Vinicia Campana; Stranahan, Alexis M; Krause, Eric G; de Kloet, Annette D; Stern, Javier E

    2016-02-01

    ANG II is thought to increase sympathetic outflow by increasing oxidative stress and promoting local inflammation in the paraventricular nucleus (PVN) of the hypothalamus. However, the relative contributions of inflammation and oxidative stress to sympathetic drive remain poorly understood, and the underlying cellular and molecular targets have yet to be examined. ANG II has been shown to enhance Toll-like receptor (TLR)4-mediated signaling on microglia. Thus, in the present study, we aimed to determine whether ANG II-mediated activation of microglial TLR4 signaling is a key molecular target initiating local oxidative stress in the PVN. We found TLR4 and ANG II type 1 (AT1) receptor mRNA expression in hypothalamic microglia, providing molecular evidence for the potential interaction between these two receptors. In hypothalamic slices, ANG II induced microglial activation within the PVN (∼65% increase, P receptors and TLR4 in mediating ANG II-dependent microglial activation and oxidative stress within the PVN. More broadly, our results support a functional interaction between the central renin-angiotensin system and innate immunity in the regulation of neurohumoral outflows from the PVN. Copyright © 2016 the American Physiological Society.

  2. Interaction of a non-peptide agonist with angiotensin II AT1 receptor mutants

    DEFF Research Database (Denmark)

    Costa-Neto, Claudio M; Miyakawa, Ayumi A; Pesquero, João B

    2002-01-01

    and inositol phosphate turnover assays in COS-7 cells transiently transfected with the wild-type and mutant forms of the receptor. Mutant receptors bore modifications in the extracellular region: T88H, Y92H, G1961, G196W, and D278E. Compound L-162,313 displaced [125I]-Sar1,Leu8-AngII from the mutants G196I...... and G196W with IC50 values similar to that of the wild-type. The affinity was, however, slightly affected by the D278E mutation and more significantly by the T88H and Y92H mutations. In inositol phosphate turnover assays, the ability of L-162,313 to trigger the activation cascade was compared...... with that of angiotensin II. These assays showed that the G196W mutant reached a relative maximum activation exceeding that of the wild-type receptor; the efficacy was slightly reduced in the G1961 mutant and further reduced in the T88H, Y92H, and D278E mutants. Our data suggest that residues of the extracellular domain...

  3. Metallothionein-I plus II and receptor megalin are altered in relation to oxidative stress in cerebral lymphomas

    DEFF Research Database (Denmark)

    Pedersen, M.O.; Hansen, P.B.; Nielsen, Signe Ledou

    2010-01-01

    . This article characterizes the histopathology and expression profiles of metallothionein-I + II (MT-I + II) and their receptor megalin along with proliferation, oxidative stress, and apoptosis in PCNSL and in central nervous system (CNS) lymphomas due to relapse from DLBCL (collectively referred to as CNS...

  4. Renal graft failure after addition of an angiotensin II receptor antagonist to an angiotensin-converting enzyme inhibitor

    DEFF Research Database (Denmark)

    Kamper, Anne-Lise; Nielsen, Arne Høj; Baekgaard, Niels

    2002-01-01

    Combined treatment with an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin II (Ang II) receptor blocker (ARB) has been suggested in order to achieve a more complete blockade of the renin-angiotensin-aldosterone system in cardiovascular and renal disease. The present report descri...

  5. Expression of angiotensin II receptors in the caprine ovary and improvement of follicular viability in vitro.

    Science.gov (United States)

    Bruno, J B; Lima-Verde, I B; Celestino, J J H; Lima, L F; Matos, M H T; Faustino, L R; Donato, M A M; Peixoto, C A; Campello, C C; Silva, J R V; Figueiredo, J R

    2016-08-01

    This study aimed to evaluate mRNA levels of angiotensin II (ANG II) receptors (AGTR1 and AGTR2) in caprine follicles and to investigate the influence of ANG II on the viability and in vitro growth of preantral follicles. Real-time polymerase chain reaction (PCR) was used to quantify AGTR1 and AGTR2 mRNA levels in the different follicular stages. For culture, caprine ovaries were collected, cut into 13 fragments and then either directly fixed for histological and ultrastructural analysis (fresh control) or placed in culture for 1 or 7 days in α-minumum essential medium plus (α-MEM+) with 0, 1, 5, 10, 50 or 100 ng/ml ANG II. Then, the fragments were destined to morphological, viability and ultrastructural analysis. The results showed that primordial follicles had higher levels of AGTR1 and AGTR2 mRNA than secondary follicles. Granulosa/theca cells from antral follicles had higher levels of AGTR1 mRNA than their respective cumulus-oocyte complex (COCs). After 7 days of culture, ANG II (10 or 50 ng/ml) maintained the percentages of normal follicles compared with α-MEM+. Fluorescence and ultrastructural microscopy confirmed follicular integrity in ANG II (10 ng/ml). In conclusion, a high expression of AGTR1 and AGTR2 is observed in primordial follicles. Granulosa/theca cells from antral follicles had higher levels of AGTR1 mRNA. Finally, 10 ng/ml ANG II maintained the viability of caprine preantral follicles after in vitro culture.

  6. The angiotensin II type 2 receptor agonist Compound 21 is protective in experimental diabetes-associated atherosclerosis

    DEFF Research Database (Denmark)

    Chow, Bryna S M; Koulis, Christine; Krishnaswamy, Pooja

    2016-01-01

    AIMS/HYPOTHESIS: Angiotensin II is well-recognised to be a key mediator in driving the pathological events of diabetes-associated atherosclerosis via signalling through its angiotensin II type 1 receptor (AT1R) subtype. However, its actions via the angiotensin II type 2 receptor (AT2R) subtype...... are still poorly understood. This study is the first to investigate the role of the novel selective AT2R agonist, Compound 21 (C21) in an experimental model of diabetes-associated atherosclerosis (DAA). METHODS: Streptozotocin-induced diabetic Apoe-knockout mice were treated with vehicle (0.1 mol/l citrate...

  7. Effects of LHRH and ANG II on prolactin stimulation are mediated by hypophysial AT1 receptor subtype.

    Science.gov (United States)

    Becú-Villalobos, D; Lacau-Mengido, I M; Thyssen, S M; Díaz-Torga, G S; Libertun, C

    1994-02-01

    We have used the nonpeptide angiotensin II (ANG II) receptor antagonists losartan (receptor subtype AT1) and PD-123319 (AT2) to determine the participation of ANG II receptor subtypes in luteinizing hormone-releasing hormone (LHRH)-induced prolactin release in a perifusion study using intact pituitaries in vitro. LHRH (1.85 x 10(-7) M) released prolactin consistently, whereas losartan (10(-5) M) abolished prolactin response without modifying basal prolactin or luteinizing hormone (LH) and follicle-stimulating hormone (FSH) release. PD-123319 (10(-5) M) had no effect on basal or LHRH-induced prolactin, LH, or FSH release. We also determined that the effect of ANG II on prolactin release was mediated by the same receptor subtype. In adenohypophysial cells dispersed in vitro ANG II (10(-8) M) released prolactin. Losartan (10(-7) and 10(-6) M), but not PD-123319, inhibited this effect. We conclude that in intact hypophyses of 15-day-old female rats the effect of LHRH on prolactin release is readily demonstrated. LHRH-induced prolactin release appears to be mediated by ANG II acting in a paracrine manner on AT1 receptors located on lactotrophs.

  8. The disintegrin and metalloproteinase ADAM12 contributes to TGF-beta signaling through interaction with the type II receptor

    DEFF Research Database (Denmark)

    Atfi, Azeddine; Dumont, Emmanuelle; Colland, Frédéric

    2007-01-01

    Transforming growth factor-beta (TGF-beta) regulates a wide variety of biological processes through two types of Ser/Thr transmembrane receptors: the TGF-beta type I receptor and the TGF-beta type II receptor (TbetaRII). Upon ligand binding, TGF-beta type I receptor activated by TbetaRII propagat......RII protein presumably by suppressing the association of TbetaRII with Smad7. These results define ADAM12 as a new partner of TbetaRII that facilitates its trafficking to early endosomes in which activation of the Smad pathway is initiated....

  9. Increased angiotensin II type 1 receptor expression in temporal arteries from patients with giant cell arteritis

    DEFF Research Database (Denmark)

    Dimitrijevic, Ivan; Malmsjö, Malin; Andersson, Christina

    2009-01-01

    PURPOSE: Currently, giant cell arteritis (GCA) is primarily treated with corticosteroids or immunomodulating agents, but there is interest in identifying other noncorticosteroid alternatives. Similarities exist in the injury pathways between GCA and atherosclerosis. Angiotensin II is a vasoactive......, internal elastic lamina degeneration, and band-shaped infiltrates of inflammatory cells, including lymphocytes, histocytes, and multinucleated giant cells. AT(1) receptor staining was primarily observed in the medial layer of the temporal arteries and was higher in the patients with GCA than in the control...

  10. Renoprotective effects of angiotensin II receptor blockade in type 1 diabetic patients with diabetic nephropathy

    DEFF Research Database (Denmark)

    Andersen, S; Tarnow, L; Rossing, P

    2000-01-01

    BACKGROUND: Angiotensin I-converting enzyme (ACE) inhibitors reduce angiotensin II formation and induce bradykinin accumulation. Animal studies suggest that bradykinin may play a role for the effects of ACE inhibition on blood pressure and kidney function. Therefore, we compared the renal and hem...... inhibition is primarily caused by interference in the renin-angiotensin system. Our study suggest that losartan represents a valuable new drug in the treatment of hypertension and proteinuria in type 1 diabetic patients with diabetic nephropathy....... and hemodynamic effects of specific intervention in the renin-angiotensin system by blockade of the angiotensin II subtype-1 receptor to the effect of ACE inhibition. METHODS: A randomized, double-blind, cross-over trial was performed in 16 type 1 diabetic patients (10 men), age 42 +/- 2 years (mean +/- SEM...

  11. Change of expression of renal alpha1-adrenergic receptor and angiotensin II receptor subtypes with aging in rats.

    Science.gov (United States)

    Li, Yan-Fang; Cao, Xiao-Jing; Bai, Xue-Yuan; Lin, Shu-Peng; Shi, Shu-Tian

    2010-04-01

    It has been considered that the functional decline of renal vasoconstriction during senescence is associated with an alteration in renal alpha1-adrenergic receptor (alpha1-AR) expression. While alterations in renal angiotensin II receptor (ATR) expression was considered to have an effect on renal structure and function, until now little information has been available concerning alpha1-AR and ATR expression variations over the entire aging continuum. The present study was undertaken to examine the expression levels of alpha1-AR and ATR subtypes in renal tissue during the spectrum running from young adulthood, to middle age, to the presenium, and to the senium. Semiquantitative Reverse Transcription Polymerase Chain Reaction (RT-PCR) and Western Blot were used to quantify the messenger RNA (mRNA) and protein levels of alpha1-AR and ATR subtypes in renal tissue in 3-month-old (young adult), 12-month-old (middle age), 18-month-old (presenium) and 24-month-old (senium) Wistar rats. alpha1A-AR expression decreased gradually with aging: it was decreased during middle age, the presenium and the senium, compared, respectively, with young adult values (page and in the senium with respect to the presenium. alpha1B-AR and alpha1D-AR expression were unmodified during senescence. AT1R expression was unaffected by aging during young adulthood and middle age, but exhibited a remarkable downregulation in the presenium and senium periods (prenal alpha1-AR and ATR subtypes during aging. alpha1A-AR expression downregulation may account for the reduced reactivity of renal alpha1-AR to vasoconstrictors and to renal function decline in the senium. Both the downregulation of AT1R and the upregulation of AT2R may be influential in maintaining normal physiological renal function during aging.

  12. IGF-I, IGF-II, and Insulin Stimulate Different Gene Expression Responses through Binding to the IGF-I Receptor

    DEFF Research Database (Denmark)

    Versteyhe, Soetkin; Klaproth, Birgit; Borup, Rehannah

    2013-01-01

    Insulin and the insulin-like growth factors (IGF)-I and -II are closely related peptides important for regulation of metabolism, growth, differentiation, and development. The IGFs exert their main effects through the IGF-I receptor. Although the insulin receptor is the main physiological receptor...... for insulin, this peptide hormone can also bind at higher concentrations to the IGF-I receptor and exert effects through it. We used microarray gene expression profiling to investigate the gene expression regulated by IGF-I, IGF-II, and insulin after stimulation of the IGF-I receptor. Fibroblasts from mice......, knockout for IGF-II and the IGF-II/cation-independent mannose-6-phosphate receptor, and expressing functional IGF-I but no insulin receptors, were stimulated for 4 h with equipotent saturating concentrations of insulin, IGF-I, and IGF-II. Each ligand specifically regulated a group of transcripts...

  13. Identification of transmembrane domain 6 & 7 residues that contribute to the binding pocket of the urotensin II receptor.

    Science.gov (United States)

    Holleran, Brian J; Domazet, Ivana; Beaulieu, Marie-Eve; Yan, Li Ping; Guillemette, Gaétan; Lavigne, Pierre; Escher, Emanuel; Leduc, Richard

    2009-04-15

    Urotensin II (U-II), a cyclic undecapeptide, is the natural ligand of the urotensin II (UT) receptor, a G protein-coupled receptor. In the present study, we used the substituted-cysteine accessibility method to identify specific residues in transmembrane domains (TMDs) six and seven of the rat urotensin II receptor (rUT) that contribute to the formation of the binding pocket of the receptor. Each residue in the R256(6.32)-Q283(6.59) fragment of TMD6 and the A295(7.31)-T321(7.57) fragment of TMD7 was mutated, individually, to a cysteine. The resulting mutants were expressed in COS-7 cells, which were subsequently treated with the positively charged methanethiosulfonate-ethylammonium (MTSEA) or the negatively charged methanethiosulfonate-ethylsulfonate (MTSES) sulfhydryl-specific alkylating agents. MTSEA treatment resulted in a significant reduction in the binding of TMD6 mutants F268C(6.44) and W278C(6.54) and TMD7 mutants L298C(7.34), T302C(7.38), and T303C(7.39) to (125)I-U-II. MTSES treatment resulted in a significant reduction in the binding of two additional mutants, namely L282C(6.58) in TMD6 and Y300C(7.36) in TMD7. These results suggest that specific residues orient themselves within the water-accessible binding pocket of the rUT receptor. This approach, which allowed us to identify key determinants in TMD6 and TMD7 that contribute to the UT receptor binding pocket, enabled us to further refine our homology-based model of how U-II interacts with its cognate receptor.

  14. The Angiotensin II Type 1 Receptor Antagonist Losartan Affects NHE1-Dependent Melanoma Cell Behavior

    Directory of Open Access Journals (Sweden)

    Daniel Navin Olschewski

    2018-03-01

    Full Text Available Background/Aims: The peptide hormone angiotensin II (ATII plays a prominent role in regulating vasoconstriction and blood pressure. Its primary target is the angiotensin II receptor type 1 (AT1, the stimulation of which induces an increase in cytosolic [Ca2+] and calmodulin activation. Ca2+-bound (activated calmodulin stimulates the activity of the Na+/ H+ exchanger isoform 1 (NHE1; and increased NHE1 activity is known to promote melanoma cell motility. The competitive AT1 receptor inhibitor losartan is often used to lower blood pressure in hypertensive patients. Since AT1 mediates ATII-stimulated NHE1 activity, we set out to investigate whether ATII and losartan have an impact on NHE1-dependent behavior of human melanoma (MV3 cells. Methods: ATII receptor expression was verified by PCR, F-actin was visualized using fluorescently labeled phalloidin, and cytosolic [Ca2+] and pH were determined ratiometrically using Fura-2 and BCECF, respectively. MV3 cell behavior was analyzed using migration, adhesion, invasion and proliferation assays. Results: MV3 cells express both AT1 and the angiotensin II receptor type 2 (AT2. Stimulation of MV3 cells with ATII increased NHE1 activity which could be counteracted by both losartan and the Ca2+/ calmodulin inhibitor ophiobolin-A. ATII stimulation induced a decrease in MV3 cell migration and a more spherical cell morphology accompanied by an increase in the density of F-actin. Independently of the presence of ATII, both NHE1 and migratory activity were reduced when AT1 was blocked by losartan. On the other hand, losartan clearly increased cell adhesion to, and the invasion of, a collagen type I substrate. The AT2 inhibitor PD123319 did not affect NHE1 activity, proliferation and migration, but increased adhesion and invasion. Conclusion: Losartan inhibits NHE1 activity and the migration of human melanoma cells. At the same time, losartan promotes MV3 cell adhesion and invasion. The therapeutic use of AT1

  15. An Antibody Blocking Activin Type II Receptors Induces Strong Skeletal Muscle Hypertrophy and Protects from Atrophy

    Science.gov (United States)

    Minetti, Giulia C.; Sheppard, KellyAnn; Ibebunjo, Chikwendu; Feige, Jerome N.; Hartmann, Steffen; Brachat, Sophie; Rivet, Helene; Koelbing, Claudia; Morvan, Frederic; Hatakeyama, Shinji

    2014-01-01

    The myostatin/activin type II receptor (ActRII) pathway has been identified to be critical in regulating skeletal muscle size. Several other ligands, including GDF11 and the activins, signal through this pathway, suggesting that the ActRII receptors are major regulatory nodes in the regulation of muscle mass. We have developed a novel, human anti-ActRII antibody (bimagrumab, or BYM338) to prevent binding of ligands to the receptors and thus inhibit downstream signaling. BYM338 enhances differentiation of primary human skeletal myoblasts and counteracts the inhibition of differentiation induced by myostatin or activin A. BYM338 prevents myostatin- or activin A-induced atrophy through inhibition of Smad2/3 phosphorylation, thus sparing the myosin heavy chain from degradation. BYM338 dramatically increases skeletal muscle mass in mice, beyond sole inhibition of myostatin, detected by comparing the antibody with a myostatin inhibitor. A mouse version of the antibody induces enhanced muscle hypertrophy in myostatin mutant mice, further confirming a beneficial effect on muscle growth beyond myostatin inhibition alone through blockade of ActRII ligands. BYM338 protects muscles from glucocorticoid-induced atrophy and weakness via prevention of muscle and tetanic force losses. These data highlight the compelling therapeutic potential of BYM338 for the treatment of skeletal muscle atrophy and weakness in multiple settings. PMID:24298022

  16. Angiotensin II type 2 receptor stimulation increases the rate of NG108-15 cell migration via actin depolymerization.

    Science.gov (United States)

    Kilian, Peter; Campbell, Shirley; Bilodeau, Lyne; Guimond, Marie-Odile; Roberge, Claude; Gallo-Payet, Nicole; Payet, Marcel Daniel

    2008-06-01

    Angiotensin II (Ang II) has been reported to induce migration in neuronal cell types. Using time-lapse microscopy, we show here that Ang II induces acceleration in NG108-15 cell migration. This effect was antagonized by PD123319, a selective AT2 receptor antagonist, but not by DUP753, a selective AT1 receptor antagonist, and was mimicked by the specific AT2 receptor agonist CGP42112. This Ang II-induced acceleration was not sensitive to the inhibition of previously described signaling pathways of the AT2 receptor, guanylyl cyclase/cyclic GMP or p42/p44 mapk cascades, but was abolished by pertussis toxin treatment and involved PP2A activation. Immunofluorescence studies indicate that Ang II or CGP42112 decreased the amount of filamentous actin at the leading edge of the cells. This decrease was accompanied by a concomitant increase in globular actin levels. Regulation of actin turnover in actin-based motile systems is known to be mainly under the control of the actin depolymerizing factor and cofilin. Basal migration speed decreased by 77.2% in cofilin-1 small interfering RNA-transfected NG108-15 cells, along with suppression of the effect of Ang II. In addition, the Ang II-induced increase in cell velocity was abrogated in serum-free medium as well as by genistein or okadaic acid treatment in a serum-containing medium. Such results indicate that the AT2 receptor increases the migration speed of NG108-15 cells and involves a tyrosine kinase activity, followed by phosphatase activation, which may be of the PP2A type. Therefore, the present study identifies actin depolymerization and cofilin as new targets of AT2 receptor action, in the context of cellular migration.

  17. Interaction of alpha-conotoxin ImII and its analogs with nicotinic receptors and acetylcholine-binding proteins: additional binding sites on Torpedo receptor

    NARCIS (Netherlands)

    Kasheverov, I.E.; Zhmak, M.N.; Fish, A.; Rucktooa, P.; Khruschov, A.Y.; Osipov, A.V.; Ziganshin, R.H.; D'Hoedt, D.; Bertrand, D.; Sixma, T.K.; Smit, A.B.; Tsetlin, V.I.

    2009-01-01

    α-Conotoxins interact with nicotinic acetylcholine receptors (nAChRs) and acetylcholine-binding proteins (AChBPs) at the sites for agonists/competitive antagonists. α-Conotoxins blocking muscle-type or α7 nAChRs compete with α-bungarotoxin. However, α-conotoxin ImII, a close homolog of the α7

  18. The Fifth Transmembrane Domain of Angiotensin II Type 1 Receptor Participates in the Formation of the Ligand-binding Pocket and Undergoes a Counterclockwise Rotation upon Receptor Activation*

    Science.gov (United States)

    Domazet, Ivana; Martin, Stéphane S.; Holleran, Brian J.; Morin, Marie-Ève; Lacasse, Patrick; Lavigne, Pierre; Escher, Emanuel; Leduc, Richard; Guillemette, Gaétan

    2009-01-01

    The octapeptide hormone angiotensin II exerts a wide variety of cardiovascular effects through the activation of the angiotensin II Type 1 (AT1) receptor, which belongs to the G protein-coupled receptor superfamily. Like other G protein- coupled receptors, the AT1 receptor possesses seven transmembrane domains that provide structural support for the formation of the ligand-binding pocket. The role of the fifth transmembrane domain (TMD5) was investigated using the substituted cysteine accessibility method. All of the residues within Thr-190 to Leu-217 region were mutated one at a time to cysteine, and after expression in COS-7 cells, the mutant receptors were treated with the sulfhydryl-specific alkylating agent methanethiosulfonate-ethylammonium (MTSEA). MTSEA reacts selectively with water-accessible, free sulfhydryl groups of endogenous or introduced point mutation cysteines. If a cysteine is found in the binding pocket, the covalent modification will affect the binding kinetics of the ligand. MTSEA substantially decreased the binding affinity of L197C-AT1, N200C-AT1, I201C-AT1, G203C-AT1, and F204C-AT1 mutant receptors, which suggests that these residues orient themselves within the water-accessible binding pocket of the AT1 receptor. Interestingly, this pattern of acquired MTSEA sensitivity was altered for TMD5 reporter cysteines engineered in a constitutively active N111G-AT1 receptor background. Indeed, mutant I201C-N111G-AT1 became more sensitive to MTSEA, whereas mutant G203C-N111G-AT1 lost some sensitivity. Our results suggest that constitutive activation of AT1 receptor causes an apparent counterclockwise rotation of TMD5 as viewed from the extracellular side. PMID:19773549

  19. The fifth transmembrane domain of angiotensin II Type 1 receptor participates in the formation of the ligand-binding pocket and undergoes a counterclockwise rotation upon receptor activation.

    Science.gov (United States)

    Domazet, Ivana; Martin, Stéphane S; Holleran, Brian J; Morin, Marie-Eve; Lacasse, Patrick; Lavigne, Pierre; Escher, Emanuel; Leduc, Richard; Guillemette, Gaétan

    2009-11-13

    The octapeptide hormone angiotensin II exerts a wide variety of cardiovascular effects through the activation of the angiotensin II Type 1 (AT(1)) receptor, which belongs to the G protein-coupled receptor superfamily. Like other G protein- coupled receptors, the AT(1) receptor possesses seven transmembrane domains that provide structural support for the formation of the ligand-binding pocket. The role of the fifth transmembrane domain (TMD5) was investigated using the substituted cysteine accessibility method. All of the residues within Thr-190 to Leu-217 region were mutated one at a time to cysteine, and after expression in COS-7 cells, the mutant receptors were treated with the sulfhydryl-specific alkylating agent methanethiosulfonate-ethylammonium (MTSEA). MTSEA reacts selectively with water-accessible, free sulfhydryl groups of endogenous or introduced point mutation cysteines. If a cysteine is found in the binding pocket, the covalent modification will affect the binding kinetics of the ligand. MTSEA substantially decreased the binding affinity of L197C-AT(1), N200C-AT(1), I201C-AT(1), G203C-AT(1), and F204C-AT(1) mutant receptors, which suggests that these residues orient themselves within the water-accessible binding pocket of the AT(1) receptor. Interestingly, this pattern of acquired MTSEA sensitivity was altered for TMD5 reporter cysteines engineered in a constitutively active N111G-AT(1) receptor background. Indeed, mutant I201C-N111G-AT(1) became more sensitive to MTSEA, whereas mutant G203C-N111G-AT(1) lost some sensitivity. Our results suggest that constitutive activation of AT(1) receptor causes an apparent counterclockwise rotation of TMD5 as viewed from the extracellular side.

  20. Resveratrol prevents angiotensin II-induced hypertrophy of vascular smooth muscle cells through the transactivation of growth factor receptors.

    Science.gov (United States)

    Hossain, Ekhtear; Anand-Srivastava, Madhu B

    2017-08-01

    We previously showed that augmented levels of endogenous angiotensin II (AngII) contribute to vascular smooth muscle cell (VSMC) hypertrophy through the transactivation of growth factor receptors in spontaneously hypertensive rats. Resveratrol (RV), a polyphenolic component of red wine, has also been shown to attenuate AngII-evoked VSMC hypertrophy; however, the molecular mechanism mediating this response is obscure. The present study was therefore undertaken to examine whether RV could prevent AngII-induced VSMC hypertrophy through the transactivation of growth factor receptor and associated signaling pathways. AngII treatment of VSMC enhanced the protein synthesis that was attenuated towards control levels by RV pretreatment as well as by the inhibitors of NADPH oxidase, c-Src, and growth factor receptors. Furthermore, RV pretreatment also inhibited enhanced levels of superoxide anion, NADPH oxidase activity, increased expression of NADPH oxidase subunits, and phosphorylation of c-Src, EGF-R, PDGE-R, ERK1/2, and AKT1/2. In conclusion, these results indicate that RV attenuates AngII-induced VSMC hypertrophy through the inhibition of enhanced oxidative stress and activation of c-Src, growth factor receptors, and MAPK/AKT signaling. We suggest that RV could be used as a therapeutic agent in the treatment of vascular complications associated with hypertension and hypertrophy.

  1. Conserved water-mediated hydrogen bond network between TM-I, -II, -VI, and -VII in 7TM receptor activation

    DEFF Research Database (Denmark)

    Nygaard, Rie; Hansen, Louise Valentin; Mokrosinski, Jacek

    2010-01-01

    Five highly conserved polar residues connected by a number of structural water molecules together with two rotamer micro-switches, TrpVI:13 and TyrVII:20, constitute an extended hydrogen bond network between the intracellular segments of TM-I, -II, -VI, and -VII of 7TM receptors. Molecular dynamics...... to apparently function as a catching trap for water molecules. Mutational analysis of the beta2-adrenergic receptor demonstrated that the highly conserved polar residues of the hydrogen bond network were all important for receptor signaling but served different functions, some dampening constitutive activity...... (AsnI:18, AspII:10, and AsnVII:13), whereas others (AsnVII:12 and AsnVII:16) located one helical turn apart and sharing a water molecule were shown to be essential for agonist-induced signaling. It is concluded that the conserved water hydrogen bond network of 7TM receptors constitutes an extended...

  2. Endothelial microparticle formation by angiotensin II is mediated via Ang II receptor type I/NADPH oxidase/ Rho kinase pathways targeted to lipid rafts.

    Science.gov (United States)

    Burger, Dylan; Montezano, Augusto C; Nishigaki, Nobuhiro; He, Ying; Carter, Anthony; Touyz, Rhian M

    2011-08-01

    Circulating microparticles are increased in cardiovascular disease and may themselves promote oxidative stress and inflammation. Molecular mechanisms underlying their formation and signaling are unclear. We investigated the role of reactive oxygen species (ROS), Rho kinase, and lipid rafts in microparticle formation and examined their functional significance in endothelial cells (ECs). Microparticle formation from angiotensin II (Ang II)-stimulated ECs and apolipoprotein E(-/-) mice was assessed by annexin V or by CD144 staining and electron microscopy. Ang II promoted microparticle formation and increased EC O(2)(-) generation and Rho kinase activity. Ang II-stimulated effects were inhibited by irbesartan (Ang II receptor type I blocker) and fasudil (Rho kinase inhibitor). Methyl-β-cyclodextrin and nystatin, which disrupt lipid rafts/caveolae, blocked microparticle release. Functional responses, assessed in microparticle-stimulated ECs, revealed increased O(2)(-) production, enhanced vascular cell adhesion molecule/platelet-EC adhesion molecule expression, and augmented macrophage adhesion. Inhibition of epidermal growth factor receptor blocked the prooxidative and proinflammatory effects of microparticles. In vitro observations were confirmed in apolipoprotein E(-/-) mice, which displayed vascular inflammation and high levels of circulating endothelial microparticles, effects that were reduced by apocynin. We demonstrated direct actions of Ang II on endothelial microparticle release, mediated through NADPH oxidase, ROS, and Rho kinase targeted to lipid rafts. Microparticles themselves stimulated endothelial ROS formation and inflammatory responses. Our findings suggest a feedforward system whereby Ang II promotes EC injury through its own endothelial-derived microparticles.

  3. Antidiabetic mechanisms of angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists: beyond the renin-angiotensin system

    Czech Academy of Sciences Publication Activity Database

    Kurtz, T. W.; Pravenec, Michal

    2004-01-01

    Roč. 22, č. 12 (2004), s. 2253-2261 ISSN 0263-6352 R&D Projects: GA ČR GA301/03/0751 Grant - others:HHMI(US) HHMI55000331 Institutional research plan: CEZ:AV0Z5011922 Keywords : angiotensin II receptors * metabolic syndrome * peroxisome proliferator activated receptors Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 4.871, year: 2004

  4. Vascular Type 1A Angiotensin II Receptors Control BP by Regulating Renal Blood Flow and Urinary Sodium Excretion.

    Science.gov (United States)

    Sparks, Matthew A; Stegbauer, Johannes; Chen, Daian; Gomez, Jose A; Griffiths, Robert C; Azad, Hooman A; Herrera, Marcela; Gurley, Susan B; Coffman, Thomas M

    2015-12-01

    Inappropriate activation of the type 1A angiotensin (AT1A) receptor contributes to the pathogenesis of hypertension and its associated complications. To define the role for actions of vascular AT1A receptors in BP regulation and hypertension pathogenesis, we generated mice with cell-specific deletion of AT1A receptors in smooth muscle cells (SMKO mice) using Loxp technology and Cre transgenes with robust expression in both conductance and resistance arteries. We found that elimination of AT1A receptors from vascular smooth muscle cells (VSMCs) caused a modest (approximately 7 mmHg) yet significant reduction in baseline BP and exaggerated sodium sensitivity in mice. Additionally, the severity of angiotensin II (Ang II)-dependent hypertension was dramatically attenuated in SMKO mice, and this protection against hypertension was associated with enhanced urinary excretion of sodium. Despite the lower BP, acute vasoconstrictor responses to Ang II in the systemic vasculature were largely preserved (approximately 80% of control levels) in SMKO mice because of exaggerated activity of the sympathetic nervous system rather than residual actions of AT1B receptors. In contrast, Ang II-dependent responses in the renal circulation were almost completely eliminated in SMKO mice (approximately 5%-10% of control levels). These findings suggest that direct actions of AT1A receptors in VSMCs are essential for regulation of renal blood flow by Ang II and highlight the capacity of Ang II-dependent vascular responses in the kidney to effect natriuresis and BP control. Copyright © 2015 by the American Society of Nephrology.

  5. Angiotensin II induces apoptosis in intestinal epithelial cells through the AT2 receptor, GATA-6 and the Bax pathway

    International Nuclear Information System (INIS)

    Sun, Lihua; Wang, Wensheng; Xiao, Weidong; Liang, Hongyin; Yang, Yang; Yang, Hua

    2012-01-01

    Highlights: ► Ang II-induced apoptosis in intestinal epithelial cell through AT2 receptor. ► The apoptosis process involves in the Bax/Bcl-2 intrinsic pathway. ► GATA-6 short hairpin RNA reduced Bax expression, but not Bcl-2. ► GATA-6 may play a critical role in apoptosis in response to the Ang II challenge. -- Abstract: Angiotensin II (Ang II) has been shown to play an important role in cell apoptosis. However, the mechanisms of Ang-II-induced apoptosis in intestinal epithelial cells are not fully understood. GATA-6 is a zinc finger transcription factor expressed in the colorectal epithelium, which directs cell proliferation, differentiation and apoptosis. In the present study we investigated the underlying mechanism of which GATA-6 affects Ang-II induced apoptosis in intestinal epithelial cells. The in vitro intestinal epithelial cell apoptosis model was established by co-culturing Caco-2 cells with Ang II. Pretreatment with Angiotensin type 2 (AT2) receptor antagonist, PD123319, significantly reduced the expression of Bax and prevented the Caco-2 cells apoptosis induced by Ang II. In addition, Ang II up-regulated the expression of GATA-6. Interestingly, GATA-6 short hairpin RNA prevented Ang II-induced intestinal epithelial cells apoptosis and reduced the expression of Bax, but not Bcl-2. Taken together, the present study suggests that Angiotensin II promotes apoptosis in intestinal epithelial cells through GATA-6 and the Bax pathway in an AT2 receptor-dependent manner.

  6. Design, synthesis and biological activity of 6-substituted carbamoyl benzimidazoles as new nonpeptidic angiotensin II AT₁ receptor antagonists.

    Science.gov (United States)

    Zhang, Jun; Wang, Jin-Liang; Zhou, Zhi-Ming; Li, Zhi-Huai; Xue, Wei-Zhe; Xu, Di; Hao, Li-Ping; Han, Xiao-Feng; Fei, Fan; Liu, Ting; Liang, Ai-Hua

    2012-07-15

    A series of 6-substituted carbamoyl benzimidazoles were designed and synthesised as new nonpeptidic angiotensin II AT(1) receptor antagonists. The preliminary pharmacological evaluation revealed a nanomolar AT(1) receptor binding affinity for all compounds in the series, and a potent antagonistic activity in an isolated rabbit aortic strip functional assay for compounds 6f, 6g, 6h and 6k was also demonstrated. Furthermore, evaluation in spontaneous hypertensive rats and a preliminary toxicity evaluation showed that compound 6g is an orally active AT(1) receptor antagonist with low toxicity. Copyright © 2012 Elsevier Ltd. All rights reserved.

  7. Role of angiotensin II and vasopressin receptors within the supraoptic nucleus in water and sodium intake induced by the injection of angiotensin II into the medial septal area

    Directory of Open Access Journals (Sweden)

    Antunes V.R.

    1998-01-01

    Full Text Available In this study we investigated the effects of the injection into the supraoptic nucleus (SON of non-peptide AT1- and AT2-angiotensin II (ANG II receptor antagonists, DuP753 and PD123319, as well as of the arginine-vasopressin (AVP receptor antagonist d(CH25-Tyr(Me-AVP, on water and 3% NaCl intake induced by the injection of ANG II into the medial septal area (MSA. The effects on water or 3% NaCl intake were assessed in 30-h water-deprived or in 20-h water-deprived furosemide-treated adult male rats, respectively. The drugs were injected in 0.5 ml over 30-60 s. Controls were injected with a similar volume of 0.15 M NaCl. Antagonists were injected at doses of 20, 80 and 180 nmol. Water and sodium intake was measured over a 2-h period. Previous administration of the AT1 receptor antagonist DuP753 into the SON decreased water (65%, N = 10, P<0.01 and sodium intake (81%, N = 8, P<0.01 induced by the injection of ANG II (10 nmol into the MSA. Neither of these responses was significantly changed by injection of the AT2-receptor antagonist PD123319 into the SON. On the other hand, while there was a decrease in water intake (45%, N = 9, P<0.01, ANG II-induced sodium intake was significantly increased (70%, N = 8, P<0.01 following injection of the V1-type vasopressin antagonist d(CH25-Tyr(Me-AVP into the SON. These results suggest that both AT1 and V1 receptors within the SON may be involved in water and sodium intake induced by the activation of ANG II receptors within the MSA. Furthermore, they do not support the involvement of MSA AT2 receptors in the mediation of these responses.

  8. No significant effect of angiotensin II receptor blockade on intermediate cardiovascular end points in hemodialysis patients

    DEFF Research Database (Denmark)

    Peters, Christian Daugaard; Kjaergaard, Krista D; Jensen, Jens D

    2014-01-01

    Agents blocking the renin-angiotensin-aldosterone system are frequently used in patients with end-stage renal disease, but whether they exert beneficial cardiovascular effects is unclear. Here the long-term effects of the angiotensin II receptor blocker, irbesartan, were studied in hemodialysis......, and residual renal function. Brachial blood pressure decreased significantly in both groups, but there was no significant difference between placebo and irbesartan. Use of additional antihypertensive medication, ultrafiltration volume, and dialysis dosage were not different. Intermediate cardiovascular end...... points such as central aortic blood pressure, carotid-femoral pulse wave velocity, left ventricular mass index, N-terminal brain natriuretic prohormone, heart rate variability, and plasma catecholamines were not significantly affected by irbesartan treatment. Changes in systolic blood pressure during...

  9. Angiotensin II Type 2 Receptor Agonist Experts Sustained Neuroprotective Effects In Aged Rats

    DEFF Research Database (Denmark)

    Sumners, Colin; Isenberg, Jacob; Harmel, Allison

    2016-01-01

    OBJECTIVE: The renin angiotensin system is a promising target for stroke neuroprotection and therapy through activation of angiotensin type II receptors (AT2R). The selective non-peptide AT2R agonist, Compound 21 (C21), has been shown to exhibit neuroprotection and improve stroke outcomes...... in preclinical studies, effects that likely involve neurotropic actions. However, these beneficial actions of C21 have not been demonstrated to occur beyond 1 week post stroke. The objective of this study was to determine if systemic administration of C21 would exert sustained neuroprotective effects in aged...... min), 24 h, and 48 h after stroke. Infarct size was assessed by magnetic resonance imaging at 21 days post MCAO. Animals received blinded neurological exams at 4 h, 24 h, 72 h, 7d, 14d, and 21d post-MCAO. RESULTS: Systemic treatment with C21 after stroke significantly improved neurological function...

  10. Synthesis of isotopically labelled angiotensin II receptor antagonist GR138950X

    International Nuclear Information System (INIS)

    Carr, R.M.; Cable, K.M.; Newman, J.J.; Sutherland, D.R.

    1996-01-01

    Syntheses of [ 13 C] and [ 14 C]-labelled versions of angiotensin II receptor antagonist GR138950X, labelled in the imidazole carboxamide residue, are described. These involved preparation of an iodoimidazole substrate by a novel iododecarboxylation procedure, followed by cyanation with a mixture of carbon-labelled potassium cyanide and copper (l) iodide in DMF at high temperature. The preparation of a mass-labelled (M+5) version of GR138950X is also described. This involved the synthesis of an [ 13 C 3 , 15 N 2 ]-labelled imidazole from a 1,2,3-tricarbonyl compound, [ 13 C 3 ]propionaldehyde and [ 15 N]ammonia. The labelled imidazole was further elaborated into multiply-labelled GR138950X. (Author)

  11. Experimental diabetes increases insulin-like growth factor I and II receptor concentration and gene expression in kidney

    International Nuclear Information System (INIS)

    Werner, H.; Shen-Orr, Z.; Stannard, B.; Burguera, B.; Roberts, C.T. Jr.; LeRoith, D.

    1990-01-01

    Insulinlike growth factor I (IGF-I) is a mitogenic hormone with important regulatory roles in growth and development. One of the target organs for IGF-I action is the kidney, which synthesizes abundant IGF-I receptors and IGF-I itself. To study the involvement of IGF-I and the IGF-I receptor in the development of nephropathy, one of the major complications of diabetes mellitus, we measured the expression of these genes in the kidney and in other tissues of the streptozocin-induced diabetic rat. The binding of 125I-labeled IGF-I to crude membranes was measured in the same tissues. We observed a 2.5-fold increase in the steady-state level of IGF-I-receptor mRNA in the diabetic kidney, which was accompanied by a 2.3-fold increase in IGF-I binding. In addition to this increase in IGF-I binding to the IGF-I receptor, there was also binding to a lower-molecular-weight material that may represent an IGF-binding protein. No change was detected in the level of IGF-I-peptide mRNA. Similarly, IGF-II-receptor mRNA levels and IGF-II binding were significantly increased in the diabetic kidney. IGF-I- and IGF-II-receptor mRNA levels and IGF-I and IGF-II binding returned to control values after insulin treatment. Because the IGF-I receptor is able to transduce mitogenic signals on activation of its tyrosine kinase domain, we hypothesize that, among other factors, high levels of receptor in the diabetic kidney may also be involved in the development of diabetic nephropathy. Increased IGF-II-receptor expression in the diabetic kidney may be important for the intracellular transport and packaging of lysosomal enzymes, although a role for this receptor in signal transduction cannot be excluded. Finally, the possible role of IGF-binding proteins requires further study

  12. Impact of cell type and epitope tagging on heterologous expression of G protein-coupled receptor: a systematic study on angiotensin type II receptor.

    Directory of Open Access Journals (Sweden)

    Lili Jiang

    Full Text Available Despite heterologous expression of epitope-tagged GPCR is widely adopted for functional characterization, there is lacking of systematic analysis of the impact of expression host and epitope tag on GPCR expression. Angiotensin type II (AT2 receptor displays agonist-dependent and -independent activities, coupling to a spectrum of signaling molecules. However, consensus has not been reached on the subcellular distributions, signaling cascades and receptor-mediated actions. To examine the contributions of host cell and epitope tag on receptor expression and activity, epitope-tagged AT2 receptor variants were transiently or stably expressed in HEK293, CHO-K1 and PC12 cells. The epitope-tagged AT2 receptor variants were detected both on the cell membrane and in the perinuclear region. In transiently transfected HEK293 cells, Myc-AT2 existed predominantly as monomer. Additionally, a ladder of ubiquitinated AT2 receptor proteins was detected. By contrast, stably expressed epitope-tagged AT2 receptor variants existed as both monomer and high molecular weight complexes, and the latter was enriched in cell surface. Glycosylation promoted cell surface expression of Myc-AT2 but had no effect on AT2-GFP in HEK293 cells. In cells that stably expressed Myc-AT2, serum starvation induced apoptosis in CHO-K1 cells but not in HEK293 or PC12 cells. Instead, HEK293 and PC12 cells stably expressing Myc-AT2 exhibited partial cell cycle arrest with cells accumulating at G1 and S phases, respectively. Taken together, these results suggest that expression levels, subcellular distributions and ligand-independent constitutive activities of AT2 receptor were cell type-dependent while posttranslational processing of nascent AT2 receptor protein was modulated by epitope tag and mode of expression.

  13. Angiotensin II up-regulates PAX2 oncogene expression and activity in prostate cancer via the angiotensin II type I receptor.

    Science.gov (United States)

    Bose, Sudeep K; Gibson, Willietta; Giri, Shailendra; Nath, Narender; Donald, Carlton D

    2009-09-01

    Paired homeobox 2 gene (PAX2) is a transcriptional regulator, aberrantly expressed in prostate cancer cells and its down-regulation promotes cell death in these cells. The molecular mechanisms of tumor progression by PAX2 over-expression are still unclear. However, it has been reported that angiotensin-II (A-II) induces cell growth in prostate cancer via A-II type 1 receptor (AT1R) and is mediated by the phosphorylation of mitogen activated protein kinase (MAPK) as well as signal transducer and activator of transcription 3 (STAT3). Here we have demonstrated that A-II up-regulates PAX2 expression in prostate epithelial cells and prostate cancer cell lines resulting in increased cell growth. Furthermore, AT1R receptor antagonist losartan was shown to inhibit A-II induced PAX2 expression in prostate cancer. Moreover, analysis using pharmacological inhibitors against MEK1/2, ERK1/2, JAK-II, and phospho-STAT3 demonstrated that AT1R-mediated stimulatory effect of A-II on PAX2 expression was regulated in part by the phosphorylation of ERK1/2, JAK II, and STAT3 pathways. In addition, we have showed that down-regulation of PAX2 by an AT1R antagonist as well as JAK-II and STAT3 inhibitors suppress prostate cancer cell growth. Collectively, these findings show for the first time that the renin-angiotensin system (RAS) may promote prostate tumorigenesis via up-regulation of PAX2 expression. Therefore, PAX2 may be a novel therapeutic target for the treatment of carcinomas such as prostate cancer via the down-regulation of its expression by targeting the AT1R signaling pathways.

  14. Nonmuscle Myosin II Is Required for Internalization of the Epidermal Growth Factor Receptor and Modulation of Downstream Signaling*

    Science.gov (United States)

    Kim, Jong Hyun; Wang, Aibing; Conti, Mary Anne; Adelstein, Robert S.

    2012-01-01

    Ligand-induced internalization of the epidermal growth factor receptor (EGFR) is an important process for regulating signal transduction, cellular dynamics, and cell-cell communication. Here, we demonstrate that nonmuscle myosin II (NM II) is required for the internalization of the EGFR and to trigger the EGFR-dependent activation of ERK and AKT. The EGFR was identified as a protein that interacts with NM II by co-immunoprecipitation and mass spectrometry analysis. This interaction requires both the regulatory light chain 20 (RLC20) of NM II and the kinase domain of the EGFR. Two paralogs of NM II, NM II-A, and NM II-B can act to internalize the EGFR, depending on the cell type and paralog content of the cell line. Loss (siRNA) or inhibition (25 μm blebbistatin) of NM II attenuates the internalization of the EGFR and impairs EGFR-dependent activation of ERK and AKT. Both internalization of the EGFR and downstream signaling to ERK and AKT can be partially restored in siRNA-treated cells by introduction of wild type (WT) GFP-NM II, but cannot be restored by motor mutant NM II. Taken together, these results suggest that NM II plays a role in the internalization of the EGFR and EGFR-mediated signaling pathways. PMID:22718763

  15. Brain Region-Specific Effects of cGMP-Dependent Kinase II Knockout on AMPA Receptor Trafficking and Animal Behavior

    Science.gov (United States)

    Kim, Seonil; Pick, Joseph E.; Abera, Sinedu; Khatri, Latika; Ferreira, Danielle D. P.; Sathler, Matheus F.; Morison, Sage L.; Hofmann, Franz; Ziff, Edward B.

    2016-01-01

    Phosphorylation of GluA1, a subunit of AMPA receptors (AMPARs), is critical for AMPAR synaptic trafficking and control of synaptic transmission. cGMP-dependent protein kinase II (cGKII) mediates this phosphorylation, and cGKII knockout (KO) affects GluA1 phosphorylation and alters animal behavior. Notably, GluA1 phosphorylation in the KO…

  16. ANG II type 1 receptor antagonist irbesartan inhibits coronary angiogenesis stimulated by chronic intermittent hypoxia in neonatal rats

    Czech Academy of Sciences Publication Activity Database

    Rakusan, K.; Chvojková, Zuzana; Oliviero, P.; Ošťádalová, Ivana; Kolář, František; Chassagne, C.; Samuel, J. L.; Ošťádal, Bohuslav

    2007-01-01

    Roč. 292, č. 3 (2007), H1237-H1244 ISSN 0363-6135 R&D Projects: GA MŠk 1M0510 Institutional research plan: CEZ:AV0Z50110509 Keywords : angiogenesis neonatal rat * ANG II type 1 receptor antagonist heart * ischemic tolerance Subject RIV: ED - Physiology Impact factor: 3.973, year: 2007

  17. Protection against inhaled oxidants through scavenging of oxidized lipids by macrophage receptors MARCO and SR-AI/II

    DEFF Research Database (Denmark)

    Dahl, Morten; Bauer, Alison K; Arredouani, Mohamed

    2007-01-01

    Alveolar macrophages (AMs) express the class A scavenger receptors (SRAs) macrophage receptor with collagenous structure (MARCO) and scavenger receptor AI/II (SRA-I/II), which recognize oxidized lipids and provide innate defense against inhaled pathogens and particles. Increased MARCO expression...... in lungs of ozone-resistant mice suggested an additional role protecting against inhaled oxidants. After ozone exposure, MARCO-/- mice showed greater lung injury than did MARCO+/+ mice. Ozone is known to generate oxidized, proinflammatory lipids in lung lining fluid, such as 5beta,6beta......-epoxycholesterol (beta-epoxide) and 1-palmitoyl-2-(9'-oxo-nonanoyl)-glycerophosphocholine (PON-GPC). Intratracheal instillation of either lipid caused substantial neutrophil influx in MARCO-/- mice, but had no effect in MARCO+/+ mice. Normal AMs showed greater uptake in vitro of beta-epoxide compared with MARCO-/- AMs...

  18. Blockade of group II metabotropic glutamate receptors produces hyper-locomotion in cocaine pre-exposed rats by interactions with dopamine receptors.

    Science.gov (United States)

    Yoon, Hyung Shin; Jang, Ju Kyong; Kim, Jeong-Hoon

    2008-09-01

    It was previously reported that blockade of group II metabotropic glutamate receptors (mGluRs) produces hyper-locomotion in rats previously exposed to amphetamine, indicating that group II mGluRs are well positioned to modulate the expression of behavioral sensitization by amphetamine. The present study further examined the locomotor activating effects of specific blockade of these receptors after cocaine pre-exposures. First, rats were pre-exposed to seven daily injections of cocaine (15mg/kg, IP). When challenged the next day with an injection of either saline or the group II mGluR antagonist LY341495 (0.5, 1.0 or 2.5mg/kg, IP), they produced hyper-locomotor activity, measured by infrared beam interruptions, to LY341495 compared to saline in a dose-dependent manner. Second, rats were pre-exposed to either saline or seven daily injections of cocaine (15mg/kg, IP). Three weeks later, when they were challenged with an injection of either saline or LY341495 (1.0mg/kg, IP), only rats pre-exposed to cocaine produced hyper-locomotor activity to LY341495 compared to saline. These effects, however, were not present when dopamine D1 (SCH23390; 5 or 10microg/kg), but not D2 (eticlopride; 10 or 50microg/kg), receptor antagonist was pre-injected, indicating that this cocaine-induced hyper-locomotor activity to LY341495 may be mediated in dopamine D1 receptor-dependent manner. These results suggest that group II mGluRs may be adapted to interact with dopaminergic neuronal signaling in mediating the sensitized locomotor activity produced by repeated cocaine pre-exposures.

  19. Protease-activated receptor 1 and 2 contribute to angiotensin II-induced activation of adventitial fibroblasts from rat aorta

    Energy Technology Data Exchange (ETDEWEB)

    He, Rui-Qing; Tang, Xiao-Feng; Zhang, Bao-Li [State Key Laboratory of Medical Genetics, Shanghai Key Laboratory of Hypertension and Department of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (China); Shanghai Institute of Hypertension, Shanghai (China); Li, Xiao-Dong [State Key Laboratory of Medical Genetics, Shanghai Key Laboratory of Hypertension and Department of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (China); Laboratory of Vascular Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai (China); Shanghai Institute of Hypertension, Shanghai (China); Hong, Mo-Na [State Key Laboratory of Medical Genetics, Shanghai Key Laboratory of Hypertension and Department of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (China); Shanghai Institute of Hypertension, Shanghai (China); Chen, Qi-Zhi [Shanghai Institute of Hypertension, Shanghai (China); Han, Wei-Qing, E-mail: whan020@gmail.com [State Key Laboratory of Medical Genetics, Shanghai Key Laboratory of Hypertension and Department of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (China); Laboratory of Vascular Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai (China); Shanghai Institute of Hypertension, Shanghai (China); Gao, Ping-Jin, E-mail: gaopingjin@sibs.ac.cn [State Key Laboratory of Medical Genetics, Shanghai Key Laboratory of Hypertension and Department of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (China); Laboratory of Vascular Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai (China); Shanghai Institute of Hypertension, Shanghai (China)

    2016-04-29

    Adventitial fibroblasts (AFs) can be activated by angiotensin II (Ang II) and exert pro-fibrotic and pro-inflammatory effects in vascular remodeling. Protease-activated receptor (PAR) 1 and 2 play a significant role in fibrogenic and inflammatory diseases. The present study hypothesized that PAR1 and PAR2 are involved in Ang II-induced AF activation and contribute to adventitial remodeling. We found that direct activation of PAR1 and PAR2 with PAR1-AP and PAR2-AP led to AF activation, including proliferation and differentiation of AFs, extracellular matrix synthesis, as well as production of pro-fibrotic cytokine TGF-β and pro-inflammatory cytokines IL-6 and MCP-1. Furthermore, PAR1 and PAR2 mediated Ang II-induced AF activation, since both PAR1 and PAR2 antagonists inhibited Ang II-induced proliferation, migration, differentiation, extracellular matrix synthesis and production of pro-fibrotic and pro-inflammatory cytokines in AFs. Finally, mechanistic study showed that Ang II, via Ang II type I receptor (AT1R), upregulated both PAR1 and PAR2 expression, and transactivated PAR1 and PAR2, as denoted by internalization of both proteins. In conclusion, our results suggest that PAR1 and PAR2 play a critical role in Ang II-induced AF activation, and this may contribute to adventitia-related pathological changes. - Highlights: • Direct activation of PAR1 and PAR2 led to adventitial fibroblast (AF) activation. • PAR1 and PAR2 antagonists attenuated Ang II-induced AF activation. • Ang II induced the upregulation and transactivation of PAR1/PAR2 in AFs.

  20. Protease-activated receptor 1 and 2 contribute to angiotensin II-induced activation of adventitial fibroblasts from rat aorta

    International Nuclear Information System (INIS)

    He, Rui-Qing; Tang, Xiao-Feng; Zhang, Bao-Li; Li, Xiao-Dong; Hong, Mo-Na; Chen, Qi-Zhi; Han, Wei-Qing; Gao, Ping-Jin

    2016-01-01

    Adventitial fibroblasts (AFs) can be activated by angiotensin II (Ang II) and exert pro-fibrotic and pro-inflammatory effects in vascular remodeling. Protease-activated receptor (PAR) 1 and 2 play a significant role in fibrogenic and inflammatory diseases. The present study hypothesized that PAR1 and PAR2 are involved in Ang II-induced AF activation and contribute to adventitial remodeling. We found that direct activation of PAR1 and PAR2 with PAR1-AP and PAR2-AP led to AF activation, including proliferation and differentiation of AFs, extracellular matrix synthesis, as well as production of pro-fibrotic cytokine TGF-β and pro-inflammatory cytokines IL-6 and MCP-1. Furthermore, PAR1 and PAR2 mediated Ang II-induced AF activation, since both PAR1 and PAR2 antagonists inhibited Ang II-induced proliferation, migration, differentiation, extracellular matrix synthesis and production of pro-fibrotic and pro-inflammatory cytokines in AFs. Finally, mechanistic study showed that Ang II, via Ang II type I receptor (AT1R), upregulated both PAR1 and PAR2 expression, and transactivated PAR1 and PAR2, as denoted by internalization of both proteins. In conclusion, our results suggest that PAR1 and PAR2 play a critical role in Ang II-induced AF activation, and this may contribute to adventitia-related pathological changes. - Highlights: • Direct activation of PAR1 and PAR2 led to adventitial fibroblast (AF) activation. • PAR1 and PAR2 antagonists attenuated Ang II-induced AF activation. • Ang II induced the upregulation and transactivation of PAR1/PAR2 in AFs.

  1. Edaravone inhibits pressure overload-induced cardiac fibrosis and dysfunction by reducing expression of angiotensin II AT1 receptor

    Directory of Open Access Journals (Sweden)

    Zhang WW

    2017-10-01

    Full Text Available Wei-Wei Zhang,1,2 Feng Bai,1 Jin Wang,1 Rong-Hua Zheng,1 Li-Wang Yang,1 Erskine A James,3 Zhi-Qing Zhao1,4 1Department of Physiology, Shanxi Medical University, 2Department of Anesthesiology, Shanxi Provincial People’s Hospital, Taiyuan, Shanxi, China; 3Department of Internal Medicine, Navicent Health, Macon, 4Department of Basic Biomedical Sciences, Mercer University School of Medicine, Savannah, GA, USA Abstract: Angiotensin II (Ang II is known to be involved in the progression of ventricular dysfunction and heart failure by eliciting cardiac fibrosis. The purpose of this study was to demonstrate whether treatment with an antioxidant compound, edaravone, reduces cardiac fibrosis and improves ventricular function by inhibiting Ang II AT1 receptor. The study was conducted in a rat model of transverse aortic constriction (TAC. In control, rats were subjected to 8 weeks of TAC. In treated rats, edaravone (10 mg/kg/day or Ang II AT1 receptor blocker, telmisartan (10 mg/kg/day was administered by intraperitoneal injection or gastric gavage, respectively, during TAC. Relative to the animals with TAC, edaravone reduced myocardial malonaldehyde level and increased superoxide dismutase activity. Protein level of the AT1 receptor was reduced and the AT2 receptor was upregulated, as evidenced by the reduced ratio of AT1 over AT2 receptor (0.57±0.2 vs 3.16±0.39, p<0.05 and less locally expressed AT1 receptor in the myocardium. Furthermore, the protein level of angiotensin converting enzyme 2 was upregulated. In coincidence with these changes, edaravone significantly decreased the populations of macrophages and myofibroblasts in the myocardium, which were accompanied by reduced levels of transforming growth factor beta 1 and Smad2/3. Collagen I synthesis was inhibited and collagen-rich fibrosis was attenuated. Relative to the TAC group, cardiac systolic function was preserved, as shown by increased left ventricular systolic pressure (204±51 vs 110±19

  2. The effects of angiotensin II receptor antagonist (candesartan on rat renal vascular resistance

    Directory of Open Access Journals (Sweden)

    Supatraviwat, J

    2004-05-01

    Full Text Available The present study aimed to investigate the action of angiotensin II (AII on renal perfusion pressure and renal vascular resistance using noncompetitive AT1-receptor antagonist (candesartan or CV 11974. Experiments were performed in isolated kidney of adult male Wistar rats. Kreb's Henseleit solution was perfused into the renal artery at the rate of 3.5 ml/min. This flow rate was designed in order to maintain renal perfusion pressure between 80-120 mm Hg. Dose-response relationship between perfusion flow rate and AII concentration were studied. Renal perfusion pressure in response to 1, 10 and 100 nM AII were increased from basal perfusion pressure of 94±8 mm Hg to 127±6, 157±12 and 190±16 mm Hg, respectively. Administration of perfusate containing 11.4 μM candesartan for 30 min had no effect on the basal perfusion pressure. However, this significantly reduced renal perfusion pressure in the presence of AII (1, 10 and 100 nM by 39%, 47% and 61%, (n=7, P<0.05 respectively. At the basal perfusion pressure, calculated renal vascular resistance was 27±2 mm Hg · min · ml-1. However, the vascular resistance were found to be 41±1, 45±2 and 47±2 mm Hg · min · ml-1 when 1, 10 and 100 nM AII were added. Moreover, this dose of candesartan also showed a significant decrease in renal vascular resistance at the corresponding doses of AII by 38%, 48% and 43%, (n=7, P<0.05 respectively. The higher dose of candesartan (22.7 μM completely inhibited the action of 1, 10 and 100 nM AII on renal vasoconstriction. These results may indicate that the action of AII on renal vascular resistance is via AT1-receptor, at least in rat isolated perfusion kidney.

  3. Spinal antinociceptive effects of [D-Ala2]deltorphin II, a novel and highly selective delta-opioid receptor agonist.

    Science.gov (United States)

    Improta, G; Broccardo, M

    1992-01-01

    Pharmacological assays in isolated tissues and binding tests have recently shown that two peptides, with the sequence Tyr-D-Ala-Phe-Asp-(or Glu)- Val-Val-Gly-NH2, isolated from skin extracts of Phyllomedusa bicolor and named [D-Ala2]deltorphin I and II, respectively, possess a higher affinity and selectivity for delta-opioid receptors than any other known natural compound. Since much evidence supports the role of spinal delta-opioid sites in producing antinociceptive effects, we investigated whether analgesia might be detected by direct spinal cord administration of [D-Ala2]deltorphin II (DADELT II) in the rat. The thermal antinociceptive effects of intrathecal DADELT II and dermorphin, a potent mu-selective agonist, were compared at different postinjection times by means of the tail-flick test. The DADELT II produced a dose-related inhibition of the tail-flick response, which lasted 10-60 min depending on the dose and appeared to be of shorter duration than the analgesia produced in rats after intrathecal injection of dermorphin (20-120 min). The analgesic effect of infused or injected DADELT II was completely abolished by naltrindole, the highly selective delta antagonist. These results confirm the involvement of delta receptors in spinal analgesic activity in the rat.

  4. Angiotensin II type 1a receptor-deficient mice develop angiotensin II-induced oxidative stress and DNA damage without blood pressure increase.

    Science.gov (United States)

    Zimnol, Anna; Amann, Kerstin; Mandel, Philipp; Hartmann, Christina; Schupp, Nicole

    2017-12-01

    Hypertensive patients have an increased risk of developing kidney cancer. We have shown in vivo that besides elevating blood pressure, angiotensin II causes DNA damage dose dependently. Here, the role of blood pressure in the formation of DNA damage is studied. Mice lacking one of the two murine angiotensin II type 1 receptor (AT1R) subtypes, AT1aR, were equipped with osmotic minipumps, delivering angiotensin II during 28 days. Parameters of oxidative stress and DNA damage of kidneys and hearts of AT1aR-knockout mice were compared with wild-type (C57BL/6) mice receiving angiotensin II, and additionally, with wild-type mice treated with candesartan, an antagonist of both AT1R subtypes. In wild-type mice, angiotensin II induced hypertension, reduced kidney function, and led to a significant formation of reactive oxygen species (ROS). Furthermore, genomic damage was markedly increased in this group. All these responses to angiotensin II could be attenuated by concurrent administration of candesartan. In AT1aR-deficient mice treated with angiotensin II, systolic pressure was not increased, and renal function was not affected. However, angiotensin II still led to an increase of ROS in kidneys and hearts of these animals. Additionally, genomic damage in the form of double-strand breaks was significantly induced in kidneys of AT1aR-deficient mice. Our results show that angiotensin II induced ROS production and DNA damage even without the presence of AT1aR and independently of blood pressure changes. Copyright © 2017 the American Physiological Society.

  5. Angiotensin II-AT1–receptor signaling is necessary for cyclooxygenase-2–dependent postnatal nephron generation

    DEFF Research Database (Denmark)

    Frölich, Stefanie; Slattery, Patrick; Thomas, Dominique

    2017-01-01

    was achievable. Plasma renin concentration in mouse pups showed a birth peak and a second peak around day P8 during the first 10 days post birth. Administration of the angiotensin II receptor AT1 antagonist telmisartan from day P1 to P3 did not result in cortical damage. However, telmisartan treatment from day P...... development. Inhibition of the renin angiotensin system by aliskiren and enalapril caused similar glomerular defects as telmisartan. Administration of the AT1 receptor agonist L162313 to COX-2-/- pups improved kidney growth, ameliorated renal defects, but had no beneficial effect on reduced cortical mass. L...

  6. The Role of Vasodilator Receptors of Renin-angiotensin System on Nitric Oxide Formation and Kidney Circulation after Angiotensin II Infusion in Renal Ischemia/Reperfusion Rats.

    Science.gov (United States)

    Maleki, Maryam; Hasanshahi, Jalal; Moslemi, Fatemeh

    2018-01-01

    Nitric oxide (NO) as a vasodilator factor has renoprotective effect against renal ischemia. The balance between angiotensin II (Ang II) and NO can affect kidney homeostasis. The aim of this study was to determine NO alteration in response to renin-Ang system vasodilator receptors antagonists (PD123319; Ang II type 2 receptor antagonist and A779; Mas receptor antagonist) in renal ischemia/reperfusion injury (IRI) in rats. Sixty-three Wistar male and female rats were used. Animals from each gender were divided into four groups received saline, Ang II, PD123319 + Ang II, and A779 + Ang II after renal IRI. Renal IRI induced with an adjustable hook. Blood pressure and renal blood flow (RBF) measured continuously. The nitrite levels were measured in serum, kidney, and urine samples. In female rats, the serum and kidney nitrite levels increased significantly by Ang II ( P < 0.05) and decreased significantly ( P < 0.05) when PD123319 was accompanied with Ang II. Such observation was not seen in male. Ang II decreased RBF significantly in all groups ( P < 0.05), while PD + Ang II group showed significant decrease in RBF in comparison with the other groups in female rats ( P < 0.05). Males show more sensibility to Ang II infusion; in fact, it is suggested that there is gender dimorphism in the Ang II and NO production associated with vasodilator receptors.

  7. Endoglin-mediated suppression of prostate cancer invasion is regulated by activin and bone morphogenetic protein type II receptors.

    Directory of Open Access Journals (Sweden)

    Michael J Breen

    Full Text Available Mortality from prostate cancer (PCa is due to the formation of metastatic disease. Understanding how that process is regulated is therefore critical. We previously demonstrated that endoglin, a type III transforming growth factor β (TGFβ superfamily receptor, suppresses human PCa cell invasion and metastasis. Endoglin-mediated suppression of invasion was also shown by us to be dependent upon the type I TGFβ receptor, activin receptor-like kinase 2 (ALK2, and the downstream effector, Smad1. In this study we demonstrate for the first time that two type II TGFβ receptors are required for endoglin-mediated suppression of invasion: activin A receptor type IIA (ActRIIA and bone morphogenetic protein receptor type II (BMPRII. Downstream signaling through these receptors is predominantly mediated by Smad1. ActRIIA stimulates Smad1 activation in a kinase-dependent manner, and this is required for suppression of invasion. In contrast BMPRII regulates Smad1 in a biphasic manner, promoting Smad1 signaling through its kinase domain but suppressing it through its cytoplasmic tail. BMPRII's Smad1-regulatory effects are dependent upon its expression level. Further, its ability to suppress invasion is independent of either kinase function or tail domain. We demonstrate that ActRIIA and BMPRII physically interact, and that each also interacts with endoglin. The current findings demonstrate that both BMPRII and ActRIIA are necessary for endoglin-mediated suppression of human PCa cell invasion, that they have differential effects on Smad1 signaling, that they make separate contributions to regulation of invasion, and that they functionally and physically interact.

  8. Angiotensin II type 1 receptor blockers increase tolerance of cells to copper and cisplatin

    Directory of Open Access Journals (Sweden)

    Pieter Spincemaille

    2014-10-01

    Full Text Available The human pathology Wilson disease (WD is characterized by toxic copper (Cu accumulation in brain and liver, resulting in, among other indications, mitochondrial dysfunction and apoptosis of hepatocytes. In an effort to identify novel compounds that can alleviate Cu-induced toxicity, we screened the Pharmakon 1600 repositioning library using a Cu-toxicity yeast screen. We identified 2 members of the drug class of Angiotensin II Type 1 receptor blockers (ARBs that could increase yeast tolerance to Cu, namely Candesartan and Losartan. Subsequently, we show that specific ARBs can increase yeast tolerance to Cu and/or the chemotherapeutic agent cisplatin (Cp. The latter also induces mitochondrial dysfunction and apoptosis in mammalian cells. We further demonstrate that specific ARBs can prevent the prevalence of Cu-induced apoptotic markers in yeast, with Candesartan Cilexetil being the ARB which demonstrated most pronounced reduction of apoptosis-related markers. Next, we tested the sensitivity of a selection of yeast knockout mutants affected in detoxification of reactive oxygen species (ROS and Cu for Candesartan Cilexetil rescue in presence of Cu. These data indicate that Candesartan Cilexetil increases yeast tolerance to Cu irrespectively of major ROS-detoxifying proteins. Finally, we show that specific ARBs can increase mammalian cell tolerance to Cu, as well as decrease the prevalence of Cu-induced apoptotic markers. All the above point to the potential of ARBs in preventing Cu-induced toxicity in yeast and mammalian cells.

  9. The influence of certain molecular descriptors of fecal elimination of angiotensin II receptor antagonists

    Directory of Open Access Journals (Sweden)

    Trbojević-Stanković Jasna B.

    2015-01-01

    Full Text Available Angiotensin II receptor antagonists (ARBs modulate the function of the renin-angiotensin-aldosterone system and are commonly prescribed antihypertensive drugs, especially in patients with renal failure. In this study, the relationship between several molecular properties of seven ARBs (candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan and their fecal elimination data obtained from the literature were investigated. The ARB molecular descriptors were calculated using three software packages. Simple linear regression analysis showed the best 2 correlation between fecal elimination data and lipophilicity descriptor, ClogP values (R2 = 0.725. Multiple linear regression was applied to examine the correlation of ARBs’ fecal elimination data with their lipophilicity and one additional, calculated descriptor. The best correlation (R2 = 0.909 with an acceptable probability value, P <0.05 was established between the ARB fecal elimination data and their lipophilicity and aqueous solubility data. Applying computed molecular descriptors for evaluating drug elimination is of great importance in drug research.

  10. Angiotensin II type 1 receptor (A1166C gene polymorphism and essential hypertension in Egyptian population

    Directory of Open Access Journals (Sweden)

    Marium M. Shamaa

    2016-09-01

    Full Text Available The pathogenesis of essential hypertension (EH is affected by genetic and environmental factors. Mutations in hypertension-related genes can affect blood pressure (BP via alteration of salt and water reabsorption by the nephron. The genes of the renin-angiotensin system (RAS have been extensively studied because of the well documented role of this system in the control of BP. It has been previously shown that Angiotensin II type 1 receptor (ATR1 gene polymorphism could be associated with increased risk of EH. So, in the current study, we evaluated the frequency of ATR1 (A1166C polymorphism in relation to EH in a group of Egyptian population. The study population included 83 hypertensive patients and 60 age and sex matched healthy control subjects. Restriction fragment length polymorphism – Polymerase chain reaction (RFLP – PCR was used for the analysis of A1166C polymorphism of ATR1 genes in peripheral blood samples of all patients and controls. The results revealed that there was a positive risk of developing EH when having the T allele whether in homozygous or heterozygous state. From this work, it was concluded that there was an association between ATR1 (A1166C gene polymorphism and the risk of developing EH.

  11. Randomised trial on episodic cluster headache with an angiotensin II receptor blocker

    DEFF Research Database (Denmark)

    Tronvik, Erling; Wienecke, Troels; Monstad, Inge

    2013-01-01

    OBJECTIVES: The aim of this study was to evaluate the angiotensin II receptor antagonist candesartan as prophylactic medication in patients with episodic cluster headache. METHODS: This study comprised a prospective, placebo-controlled, double-blind, parallel-designed trial performed in seven cen...... the candesartan and placebo group was not significant with the pre-planned non-parametric ranking test, but a post-hoc exact Poisson test, which takes into account the temporal properties of the data, revealed a significant result ( P  ...... (primary efficacy variable) during the three-week treatment period was reduced from 14.3 ± 9.2 attacks in week 1 to 5.6 ± 7.0 attacks in week 3 (-61%) in the candesartan group and from 16.8 ± 14.1 attacks in week 1 to 10.5 ± 11.3 attacks in week 3 (-38%) in the placebo group. The difference between...

  12. Type II and III Taste Bud Cells Preferentially Expressed Kainate Glutamate Receptors in Rats.

    Science.gov (United States)

    Lee, Sang-Bok; Lee, Cil-Han; Kim, Se-Nyun; Chung, Ki-Myung; Cho, Young-Kyung; Kim, Kyung-Nyun

    2009-12-01

    Glutamate-induced cobalt uptake reveals that non-NMDA glutamate receptors (GluRs) are present in rat taste bud cells. Previous studies involving glutamate induced cobalt staining suggest this uptake mainly occurs via kainate type GluRs. It is not known which of the 4 types of taste bud cells express subunits of kainate GluR. Circumvallate and foliate papillae of Sprague-Dawley rats (45~60 days old) were used to search for the mRNAs of subunits of non-NMDA GluRs using RT-PCR with specific primers for GluR1-7, KA1 and KA2. We also performed RT-PCR for GluR5, KA1, PLCbeta2, and NCAM/SNAP 25 in isolated single cells from taste buds. Taste epithelium, including circumvallate or foliate papilla, express mRNAs of GluR5 and KA1. However, non-taste tongue epithelium expresses no subunits of non-NMDA GluRs. Isolated single cell RT-PCR reveals that the mRNAs of GluR5 and KA1 are preferentially expressed in Type II and Type III cells over Type I cells.

  13. Association analysis of class II cytokine and receptor genes in vitiligo patients.

    Science.gov (United States)

    Traks, Tanel; Karelson, Maire; Reimann, Ene; Rätsep, Ranno; Silm, Helgi; Vasar, Eero; Kõks, Sulev; Kingo, Külli

    2016-05-01

    The loss of melanocytes in vitiligo is mainly attributed to defective autoimmune mechanisms and lately autoinflammatory mediators have become more emphasized. Among these, a number of class II cytokines and their receptors have displayed altered expression patterns in vitiligo. Thus, we selected 30 SNPs from the regions of respective genes to be genotyped in Estonian case-control sample (109 and 328 individuals, respectively). For more precise analyses, patients were divided into subgroups based on vitiligo progression activity, age of onset, sex, occurrence of vitiligo among relatives, extent of depigmented areas, appearance of Köbner's phenomenon, existence of halo nevi, occurrence of spontaneous repigmentation, and amount of thyroid peroxidase antibodies. No associations appeared in whole vitiligo group. In subgroups, several allelic and haplotype associations were found. The strongest involved SNPs rs12301088 (near IL26 gene), that was associated with familial vitiligo and existence of halo nevi, and rs2257167 (IFNAR1 gene), that was associated with female vitiligo. Additionally, haplotypes consisting of rs12301088 and rs12321603 alleles (IL26-IL22 genes), that were associated with familial vitiligo and existence of halo nevi. In conclusion, several genetic associations with vitiligo subphenotypes were revealed and functional explanations to these remain to be determined in respective studies. Copyright © 2016. Published by Elsevier Inc.

  14. Angiotensin II type 2 receptors and cardiac hypertrophy in women with hypertrophic cardiomyopathy

    NARCIS (Netherlands)

    J. Deinum (Jacob); J.M. van Gool (Jeanette); M.J.M. Kofflard (Marcel); A.H.J. Danser (Jan); F.J. ten Cate (Folkert)

    2001-01-01

    textabstractThe development of left ventricular hypertrophy in subjects with hypertrophic cardiomyopathy (HCM) is variable, suggesting a role for modifying factors such as angiotensin II. Angiotensin II mediates both trophic and antitrophic effects, via angiotensin II type 1

  15. Role of epidermal growth factor receptor and endoplasmic reticulum stress in vascular remodeling induced by angiotensin II.

    Science.gov (United States)

    Takayanagi, Takehiko; Kawai, Tatsuo; Forrester, Steven J; Obama, Takashi; Tsuji, Toshiyuki; Fukuda, Yamato; Elliott, Katherine J; Tilley, Douglas G; Davisson, Robin L; Park, Joon-Young; Eguchi, Satoru

    2015-06-01

    The mechanisms by which angiotensin II (AngII) elevates blood pressure and enhances end-organ damage seem to be distinct. However, the signal transduction cascade by which AngII specifically mediates vascular remodeling such as medial hypertrophy and perivascular fibrosis remains incomplete. We have previously shown that AngII-induced epidermal growth factor receptor (EGFR) transactivation is mediated by disintegrin and metalloproteinase domain 17 (ADAM17), and that this signaling is required for vascular smooth muscle cell hypertrophy but not for contractile signaling in response to AngII. Recent studies have implicated endoplasmic reticulum (ER) stress in hypertension. Interestingly, EGFR is capable of inducing ER stress. The aim of this study was to test the hypothesis that activation of EGFR and ER stress are critical components required for vascular remodeling but not hypertension induced by AngII. Mice were infused with AngII for 2 weeks with or without treatment of EGFR inhibitor, erlotinib, or ER chaperone, 4-phenylbutyrate. AngII infusion induced vascular medial hypertrophy in the heart, kidney and aorta, and perivascular fibrosis in heart and kidney, cardiac hypertrophy, and hypertension. Treatment with erlotinib as well as 4-phenylbutyrate attenuated vascular remodeling and cardiac hypertrophy but not hypertension. In addition, AngII infusion enhanced ADAM17 expression, EGFR activation, and ER/oxidative stress in the vasculature, which were diminished in both erlotinib-treated and 4-phenylbutyrate-treated mice. ADAM17 induction and EGFR activation by AngII in vascular cells were also prevented by inhibition of EGFR or ER stress. In conclusion, AngII induces vascular remodeling by EGFR activation and ER stress via a signaling mechanism involving ADAM17 induction independent of hypertension. © 2015 American Heart Association, Inc.

  16. Prevalence of estrogen receptor alpha PvuII and XbaI polymorphism in population of Polish postmenopausal women.

    Directory of Open Access Journals (Sweden)

    Jozef Haczynski

    2008-01-01

    Full Text Available Numerous data indicate that polymorphism of estrogen receptor alpha (ERalpha may predict lipid levels, lipid response to hormone replacement therapy (HRT, myocardial infarction risk, bone fracture risk, bone mineral density (BMD and changes in BMD over time. In this study we aimed to evaluate distribution of ERalpha PvuII and XbaI genotypes in population of Polish postmenopausal women qualified to different protocols of HRT. Subject of the study were 64 consecutive postmenopausal women aged from 45 to 65 years (mean 56.6 assigned to HRT. ERalpha PvuII and XbaI polymorphism was determined by PCR-restriction fragment length polymorphism (RFLP. The absence of PvuII and XbaI restriction sites were indicated by "P" and "X" and presence by "p" and "x", respectively. PvuII genotype was distributed as follows: PP 17.2% (n=11, Pp 50% (n=32, pp 32.83% (n=21. Frequency of XbaI genotype was: XX 6.25% (n=4, Xx 34.4% (n=22, xx 59.4% (n=38. Four haplotypes with following frequencies were recognized: PX 17.3%, px 47.4%, Px 24.4% and pX 10.9%. Prevalence of estrogen receptor alpha PvuII and XbaI polymorphisms in Polish women is similar to previously studied population.

  17. Association between angiotensin II receptor gene polymorphism and serum angiotensin converting enzyme (SACE) activity in patients with sarcoidosis

    OpenAIRE

    Takemoto, Y.; Sakatani, M.; Takami, S.; Tachibana, T.; Higaki, J.; Ogihara, T.; Miki, T.; Katsuya, T.; Tsuchiyama, T.; Yoshida, A.; Yu, H.; Tanio, Y.; Ueda, E.

    1998-01-01

    BACKGROUND—Serum angiotensin converting enzyme (SACE) is considered to reflect disease activity in sarcoidosis. SACE activity is increased in many patients with active sarcoid lesions. The mechanism for the increased SACE activity in this disease has not been clarified. ACE insertion/deletion (I/D) gene polymorphism has been reported to have an association with SACE levels in sarcoidosis, but no evidence of an association between angiotensin II receptor gene polymorphism and SA...

  18. Association between angiotensin II receptor gene polymorphism and serum angiotensin converting enzyme (SACE) activity in patients with sarcoidosis.

    Science.gov (United States)

    Takemoto, Y; Sakatani, M; Takami, S; Tachibana, T; Higaki, J; Ogihara, T; Miki, T; Katsuya, T; Tsuchiyama, T; Yoshida, A; Yu, H; Tanio, Y; Ueda, E

    1998-06-01

    Serum angiotensin converting enzyme (SACE) is considered to reflect disease activity in sarcoidosis. SACE activity is increased in many patients with active sarcoid lesions. The mechanism for the increased SACE activity in this disease has not been clarified. ACE insertion/deletion (I/D) gene polymorphism has been reported to have an association with SACE levels in sarcoidosis, but no evidence of an association between angiotensin II receptor gene polymorphism and SACE in this disease has been found. A study of the association of angiotensin II receptor gene polymorphisms with sarcoidosis was therefore undertaken. ACE (I/D), angiotensin II type 1 receptor (AGTR1), and angiotensin II type 2 receptor (AGTR2) gene polymorphisms were investigated by polymerase chain reaction (PCR) and SACE levels were measured in three groups of patients: those with sarcoidosis or tuberculosis and normal controls. There was no difference in allele frequency of AGTR1 and AGTR2 polymorphism among the three groups. Neither AGTR1 nor AGTR2 polymorphisms were associated with sarcoidosis. SACE activity was higher in patients with sarcoidosis with the AGTR1 A/C genotype than in others. However, this tendency was not detected in patients with tuberculosis. The AGTR1 allele C is associated with high activity of SACE in patients with sarcoidosis. It is another predisposing factor for high levels of SACE in patients with sarcoidosis and is considered to be an independent factor from the ACE D allele for high levels of SACE in sarcoidosis. This fact could be one of the explanations for the increased SACE activity in sarcoidosis.

  19. Dual specificity of activin type II receptor ActRIIb in dorso-ventral patterning during zebrafish embryogenesis.

    Science.gov (United States)

    Nagaso, H; Suzuki, A; Tada, M; Ueno, N

    1999-04-01

    Members of the transforming growth factor-beta (TGF-beta) superfamily are thought to regulate specification of a variety of tissue types in early embryogenesis. These effects are mediated through a cell surface receptor complex, consisting of two classes of ser/thr kinase receptor, type I and type II. In the present study, cDNA encoding zebrafish activin type II receptors, ActRIIa and ActRIIb was cloned and characterized. Overexpression of ActRIIb in zebrafish embryos caused dorsalization of embryos, as observed in activin-overexpressing embryos. However, in blastula stage embryos, ActRIIb induced formation of both dorsal and ventro-lateral mesoderm. It has been suggested that these inducing signals from ActRIIb are mediated through each specific type I receptor, TARAM-A and BMPRIA, depending on activin and bone morphogenetic protein (BMP), respectively. In addition, it was shown that a kinase-deleted form of ActRIIb (dnActRIIb) suppressed both activin- and BMP-like signaling pathways. These results suggest that ActRIIb at least has dual roles in both activin and BMP signaling pathways during zebrafish embryogenesis.

  20. Conformational Profiling of the AT1 Angiotensin II Receptor Reflects Biased Agonism, G Protein Coupling, and Cellular Context.

    Science.gov (United States)

    Devost, Dominic; Sleno, Rory; Pétrin, Darlaine; Zhang, Alice; Shinjo, Yuji; Okde, Rakan; Aoki, Junken; Inoue, Asuka; Hébert, Terence E

    2017-03-31

    Here, we report the design and use of G protein-coupled receptor-based biosensors to monitor ligand-mediated conformational changes in receptors in intact cells. These biosensors use bioluminescence resonance energy transfer with Renilla luciferase (RlucII) as an energy donor, placed at the distal end of the receptor C-tail, and the small fluorescent molecule FlAsH as an energy acceptor, its binding site inserted at different positions throughout the intracellular loops and C-terminal tail of the angiotensin II type I receptor. We verified that the modifications did not compromise receptor localization or function before proceeding further. Our biosensors were able to capture effects of both canonical and biased ligands, even to the extent of discriminating between different biased ligands. Using a combination of G protein inhibitors and HEK 293 cell lines that were CRISPR/Cas9-engineered to delete Gα q , Gα 11 , Gα 12 , and Gα 13 or β-arrestins, we showed that Gα q and Gα 11 are required for functional responses in conformational sensors in ICL3 but not ICL2. Loss of β-arrestin did not alter biased ligand effects on ICL2P2. We also demonstrate that such biosensors are portable between different cell types and yield context-dependent readouts of G protein-coupled receptor conformation. Our study provides mechanistic insights into signaling events that depend on either G proteins or β-arrestin. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  1. Lipid rafts are required for signal transduction by angiotensin II receptor type 1 in neonatal glomerular mesangial cells

    Energy Technology Data Exchange (ETDEWEB)

    Adebiyi, Adebowale, E-mail: aadebiyi@uthsc.edu; Soni, Hitesh; John, Theresa A.; Yang, Fen

    2014-05-15

    Angiotensin II (ANG-II) receptors (AGTRs) contribute to renal physiology and pathophysiology, but the underlying mechanisms that regulate AGTR function in glomerular mesangium are poorly understood. Here, we show that AGTR1 is the functional AGTR subtype expressed in neonatal pig glomerular mesangial cells (GMCs). Cyclodextrin (CDX)-mediated cholesterol depletion attenuated cell surface AGTR1 protein expression and ANG-II-induced intracellular Ca{sup 2+} ([Ca{sup 2+}]{sub i}) elevation in the cells. The COOH-terminus of porcine AGTR1 contains a caveolin (CAV)-binding motif. However, neonatal GMCs express CAV-1, but not CAV-2 and CAV-3. Colocalization and in situ proximity ligation assay detected an association between endogenous AGTR1 and CAV-1 in the cells. A synthetic peptide corresponding to the CAV-1 scaffolding domain (CSD) sequence also reduced ANG-II-induced [Ca{sup 2+}]{sub i} elevation in the cells. Real-time imaging of cell growth revealed that ANG-II stimulates neonatal GMC proliferation. ANG-II-induced GMC growth was attenuated by EMD 66684, an AGTR1 antagonist; BAPTA, a [Ca{sup 2+}]{sub i} chelator; KN-93, a Ca{sup 2+}/calmodulin-dependent protein kinase II inhibitor; CDX; and a CSD peptide, but not PD 123319, a selective AGTR2 antagonist. Collectively, our data demonstrate [Ca{sup 2+}]{sub i}-dependent proliferative effect of ANG-II and highlight a critical role for lipid raft microdomains in AGTR1-mediated signal transduction in neonatal GMCs. - Highlights: • AGTR1 is the functional AGTR subtype expressed in neonatal mesangial cells. • Endogenous AGTR1 associates with CAV-1 in neonatal mesangial cells. • Lipid raft disruption attenuates cell surface AGTR1 protein expression. • Lipid raft disruption reduces ANG-II-induced [Ca{sup 2+}]{sub i} elevation in neonatal mesangial cells. • Lipid raft disruption inhibits ANG-II-induced neonatal mesangial cell growth.

  2. Coordinate expression of activating Fc gamma receptors I and III and inhibiting Fc gamma receptor type II in the determination of joint inflammation and cartilage destruction during immune complex-mediated arthritis.

    NARCIS (Netherlands)

    Nabbe, K.C.A.M.; Blom, A.B.; Holthuysen, A.E.M.; Boross, P.; Roth, J.; Verbeek, S.; Lent, P.L.E.M. van; Berg, W.B. van den

    2003-01-01

    OBJECTIVE: To study the role of the activating Fc gamma receptor types I and III (Fc gamma RI and Fc gamma RIII, respectively) and the inhibiting Fc gamma receptor II (Fc gamma RII) in inflammation and in various aspects of cartilage destruction during arthritis that is solely induced by immune

  3. Mutation analysis of peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1) and relationships of identified amino acid polymorphisms to Type II diabetes mellitus

    DEFF Research Database (Denmark)

    Ek, J; Andersen, G; Urhammer, S A

    2001-01-01

    This study aimed to investigate if variability in the peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1) gene is associated with Type II (non-insulin-dependent) diabetes mellitus.......This study aimed to investigate if variability in the peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1) gene is associated with Type II (non-insulin-dependent) diabetes mellitus....

  4. A highly phosphorylated subpopulation of insulin-like growth factor II/mannose 6-phosphate receptors is concentrated in a clathrin-enriched plasma membrane fraction

    International Nuclear Information System (INIS)

    Corvera, S.; Folander, K.; Clairmont, K.B.; Czech, M.P.

    1988-01-01

    Insulin-like growth factor II (IGF-II)/mannose 6-phosphate (Man-6-P) receptors immunoprecipitated from purified plasma membranes of 32 P-labeled rat adipocytes are markedly heterogenous in their phosphorylation state. Approximately 80% of the plasma membrane receptors are solubilized in 1% (vol/vol) Triton X-100 and are phosphorylated on serine residues at a stoichiometry of ∼ 0.1-0.2 mol of phosphate per mol of receptor. In contrast, 15-20% of the receptors are Triton X-100-insoluble and are phosphorylated on serine and threonine residues at ∼ 4 or 5 mol of phosphate per mol of receptor. This Triton X-100-insoluble membrane subfraction contains only 5% of the total plasma membrane protein and yet contains all of the clathrin heavy chain associated with plasma membrane. Based on the relative yields of protein in the detergent-insoluble material, IGF-II/Man-6-P receptors are concentrated ∼ 3-fold in this clathrin-enriched subfraction. Taken together, these results indicate that insulin decreases the phosphorylation state of a highly phosphorylated subpopulation of IGF-II/Man-6-P receptors on the plasma membrane. In addition, insulin action may prevent the concentration of these receptors in a clathrin-enriched membrane subfraction

  5. Electroacupuncture improves cerebral blood flow and attenuates moderate ischemic injury via Angiotensin II its receptors-mediated mechanism in rats.

    Science.gov (United States)

    Li, Jing; He, Jiaojun; Du, Yuanhao; Cui, Jingjun; Ma, Ying; Zhang, Xuezhu

    2014-11-11

    To investigate the effects and potential mechanism of electroacupuncture intervention on expressions of Angiotensin II and its receptors-mediated signaling pathway in experimentally induced cerebral ischemia. Totally 126 male Wistar rats were randomly divided into control group, model group and EA group. The latter two were further divided into ten subgroups (n = 6) following Middle Cerebral Artery Occlusion (MCAO). Changes in regional cerebral blood flow (rCBF) and expressions of Angiotensin II and its receptors (AT1R, AT2R), as well as effector proteins in phosphatidyl inositol signal pathway were monitored before and at different times after MCAO. MCAO-induced decline of ipsilateral rCBF was partially suppressed by electroacupuncture, and contralateral blood flow was also superior to that of model group. Angiotensin II level was remarkably elevated immediately after MCAO, while electroacupuncture group exhibited significantly lower levels at 1 to 3 h and the value was significantly increased thereafter. The enhanced expression of AT1R was partially inhibited by electroacupuncture, while increased AT2R level was further induced. Electroacupuncture stimulation attenuated and postponed the upregulated-expressions of Gq and CaM these upregulations. ELISA results showed sharply increased expressions of DAG and IP3, which were remarkably neutralized by electroacupuncture. MCAO induced significant increases in expression of Angiotensin II and its receptor-mediated signal pathway. These enhanced expressions were significantly attenuated by electroacupuncture intervention, followed by reduced vasoconstriction and improved blood supply in ischemic region, and ultimately conferred beneficial effects on cerebral ischemia.

  6. Altered expression patterns of group I and II metabotropic glutamate receptors in multiple sclerosis

    NARCIS (Netherlands)

    Geurts, J. J. G.; Wolswijk, G.; Bö, L.; van der Valk, P.; Polman, C. H.; Troost, D.; Aronica, E.

    2003-01-01

    Recent evidence supports a role for glutamate receptors in the pathophysiology of multiple sclerosis. In the present study, we have focused specifically on the expression of metabotropic glutamate receptors (mGluRs) in multiple sclerosis brain tissue. The expression of group I (mGluR1alpha and

  7. Intrapulmonary receptors in the Tegu lizard: II. Functional characteristics and localization;.

    Science.gov (United States)

    Scheid, P; Kuhlmann, W D; Fedde, M R

    1977-02-01

    Intrapulmonary receptors identified in the Tegu lizard by single-unit vagal recording (Fedde et al., 1977) were subjected to a number of stimuli and localized within the lung. Some carbon dioxide receptors could follow periodic changes in intrapulmonary CO2 concentrations as rapidly as 1.3 Hz; No oxygen sensitivity was observed with this receptor type, and halothane markedly depressed the discharge frequency. In response to intravenously injected acetazolamide they increased their discharge frequency and became almost totally insensitive to CO2, suggesting molecular per se is not the direct controller of receptor discharge; These receptors show many of the functional characteristics described for those in the avian lung. Afferent activity from both CO2 and mechanoreceptors could be elicited by electrically stimulating the lung surface. The CO2 receptors appeared to be organized in a receptive field covering more than 1 cm2 of lung surface, multiple receptors being innervated by a single afferent fiber. Activity in afferent fibers from mechanoreceptors could be evoked from only one distinct spot on the lung surface. Conduction velocities of afferent fibers from CO2 receptors ranged from 1 to 3 m-sec-1; from mechanoreceptors, from 1.9 to 5.2 m-sec-1.

  8. No effect of angiotensin II AT(2)-receptor antagonist PD 123319 on cerebral blood flow autoregulation

    DEFF Research Database (Denmark)

    Estrup, T M; Paulson, O B; Strandgaard, S

    2001-01-01

    Blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin AT1-receptor antagonists shift the limits of autoregulation of cerebral blood flow (CBF) towards lower blood pressure (BP). The role of AT2-receptors in the regulation of the cerebral cir...

  9. Effects of angiotensin II type 1 receptor blocker on bones in mice with type 1 diabetes induced by streptozotocin.

    Science.gov (United States)

    Zhang, Yan; Diao, Teng-Yue; Gu, Sa-Sa; Wu, Shu-Yan; Gebru, Yoseph A; Chen, Xi; Wang, Jing-Yu; Ran, Shu; Wong, Man-Sau

    2014-09-01

    This study was performed to address the pathological roles of the skeletal renin-angiotensin system (RAS) in type 1 diabetes-induced osteoporosis and the effects of the angiotensin II type 1 receptor blocker losartan on bones in diabetic mice. Bone histomorphology was detected by H&E staining, Safranin O staining and X-ray radiography. Micro-CT was performed for the analysis of bone parameters. Gene and protein expression were determined by RT-PCR and immunoblotting. Type 1 diabetic mice displayed osteopenia phenotype, and losartan treatment had no osteoprotective effects on diabetic mice as shown by the reduction of bone mineral density and microarchitectural parameters at the proximal metaphysis of the tibia. The mRNA expression of AGT, renin receptor and ACE, and protein expression of renin and AT1R were markedly up-regulated in the bones of vehicle-treated diabetic mice compared to those of non-diabetic mice. The treatment with losartan further significantly increased the expression of AGT, renin, angiotensin II and AT1R, and reduced the expression of AT2R receptor as compared to those of diabetic mice. Local bone RAS functionally played a role in the development of type 1 diabetic osteoporosis, and losartan had no bone-sparing function in diabetes mice because of enhance skeletal RAS activity. © The Author(s) 2013.

  10. Toll-like receptor 4 (TLR4) impairs nitric oxide contributing to Angiotensin II-induced cavernosal dysfunction.

    Science.gov (United States)

    Nunes, Kenia P; Bomfim, Gisele F; Toque, Haroldo A; Szasz, Theodora; Clinton Webb, R

    2017-12-15

    Angiotensin II (AngII), a corpus cavernosum (CC) constrictor peptide, modulates Toll like receptor (TLR) expression, a key element of the innate immune system, contributing to impaired vascular function in pathological conditions. However, it is unknown whether TLR4 is involved in AngII-induced erectile dysfunction. In this study, we investigated whether TLR4 plays a role in cavernosal dysfunction caused by AngII upregulation. Cavernosal smooth muscle cells (CSMC) from C57/BL6 mice were treated with AngII (0.1μM) or bacterial LPS (50ng/ml) for 12-24h and TLR4 expression was assessed. Mice were infused with AngII (90ng/min, 28days) and treated with anti-TLR4 antibody (0.1mg/daily, i.p.) for the last 14days of the treatment. CC tissue was used for functional studies and for Western blotting. Nitric Oxide Synthase (NOS) activity was measured by conversion of [ 3 H]-l-arginine to [ 3 H]-l-citrulline, systemic TNF-α levels by ELISA, and reactive oxygen species (ROS) by immunofluorescence. We report upregulation of TLR4 in CSMC following AngII or LPS stimulation. In AngII-infused mice, chronic treatment with anti-TLR4 antibody (28±2.1%) attenuates adrenergic CC contraction, which also ameliorates nitrergic (68.90±0.21 vs. 51.07±0.63, 8Hz, AngII-infused mice treated vs. non-treated). Decreased endothelial NOS expression, reduced NOS activity, and augmented levels of TNF-α, and ROS were found following AngII-infusion. These alterations were prevented, or at least decreased by anti-TLR4 antibody treatment. Inhibition of TLR4 ameliorates AngII-impaired cavernosal relaxation, decreases TNF-α levels, and restores NO bioavailability, demonstrating that TLR4 partly mediates AngII-induced cavernosal dysfunction. Copyright © 2017. Published by Elsevier Inc.

  11. Urotensin-II receptor is over-expressed in colon cancer cell lines and in colon carcinoma in humans.

    Science.gov (United States)

    Federico, Alessandro; Zappavigna, Silvia; Romano, Marco; Grieco, Paolo; Luce, Amalia; Marra, Monica; Gravina, Antonietta Gerarda; Stiuso, Paola; D'Armiento, Francesco Paolo; Vitale, Giovanni; Tuccillo, Concetta; Novellino, Ettore; Loguercio, Carmela; Caraglia, Michele

    2014-01-01

    Urotensin (U)-II receptor (UTR) has been previously reported to be over-expressed in a number of tumours. Whether UTR-related pathway plays a role in colon carcinogenesis is unknown. We evaluated UTR protein and mRNA expression in human epithelial colon cancer cell lines and in normal colon tissue, adenomatous polyps and colon cancer. U-II protein expression was assessed in cancer cell lines. Moreover, we evaluated the effects of U-II(4-11) (an UTR agonist), antagonists and knockdown of UTR protein expression through a specific shRNA, on proliferation, invasion and motility of human colon cancer cells. Cancer cell lines expressed U-II protein and UTR protein and mRNA. By immunohistochemistry, UTR was expressed in 5-30% of epithelial cells in 45 normal controls, in 30-48% in 21 adenomatous polyps and in 65-90% in 48 colon adenocarcinomas. UTR mRNA expression was increased by threefold in adenomatous polyps and eightfold in colon cancer, compared with normal colon. U-II(4-11) induced a 20-40% increase in cell growth while the blockade of the receptor with specific antagonists caused growth inhibition of 20-40%. Moreover, the knock down of UTR with a shRNA or the inhibition of UTR with the antagonist urantide induced an approximately 50% inhibition of both motility and invasion. UTR appears to be involved in the regulation of colon cancer cell invasion and motility. These data suggest that UTR-related pathway may play a role in colon carcinogenesis and that UTR may function as a target for therapeutic intervention in colon cancer. © 2013 Stichting European Society for Clinical Investigation Journal Foundation.

  12. NADPH oxidase 1 deficiency alters caveolin phosphorylation and angiotensin II-receptor localization in vascular smooth muscle.

    Science.gov (United States)

    Basset, Olivier; Deffert, Christine; Foti, Michelangelo; Bedard, Karen; Jaquet, Vincent; Ogier-Denis, Eric; Krause, Karl-Heinz

    2009-10-01

    The superoxide-generating NADPH oxidase NOX1 is thought to be involved in signaling by the angiotensin II-receptor AT1R. However, underlying signaling steps are poorly understood. In this study, we investigated the effect of AngII on aortic smooth muscle from wild-type and NOX1-deficient mice. NOX1-deficient cells showed decreased basal ROS generation and did not produce ROS in response to AngII. Unexpectedly, AngII-dependent Ca(2+) signaling was markedly decreased in NOX1-deficient cells. Immunostaining demonstrated that AT1R was localized on the plasma membrane in wild-type, but intracellularly in NOX1-deficient cells. Immunohistochemistry and immunoblotting showed a decreased expression of AT1R in the aorta of NOX1-deficient mice. To investigate the basis of the abnormal AT1R targeting, we studied caveolin expression and phosphorylation. The amounts of total caveolin and of caveolae were not different in NOX1-deficient mice, but a marked decrease occurred in the phosphorylated form of caveolin. Exogenous H(2)O(2) or transfection of a NOX1 plasmid restored AngII responses in NOX1-deficient cells. Based on these findings, we propose that NOX1-derived reactive oxygen species regulate cell-surface expression of AT1R through mechanisms including caveolin phosphorylation. The lack cell-surface AT1R expression in smooth muscle could be involved in the decreased blood pressure in NOX1-deficient mice.

  13. Effect of the AT1-receptor antagonists losartan, irbesartan, and telmisartan on angiotensin II-induced facilitation of sympathetic neurotransmission in the rat mesenteric artery

    NARCIS (Netherlands)

    Balt, J. C.; Mathy, M. J.; Nap, A.; Pfaffendorf, M.; van Zwieten, P. A.

    2001-01-01

    SUMMARY: The effect of the AT1-receptor antagonists losartan, irbesartan, and telmisartan on angiotensin II (Ang II)-induced facilitation of noradrenergic neurotransmission was investigated in the isolated rat mesenteric artery under isometric conditions. Electrical field stimulation (2, 4, and 8

  14. Angiotensin II Type 1 receptor (AT1) signaling in astrocytes regulates synaptic degeneration-induced leukocyte entry to the central nervous system

    DEFF Research Database (Denmark)

    Füchtbauer, L; Groth-Rasmussen, Maria; Holm, Thomas Hellesøe

    2011-01-01

    Astrocytes are the major cellular component of the blood-brain barrier glia limitans and act as regulators of leukocyte infiltration via chemokine expression. We have studied angiotensin-II receptor Type 1 (AT1) and related NF-κB signaling in astrocytes. Angiotensin II derives from cleavage of an...

  15. A different role of angiotensin II type 1a receptor in the development and hypertrophy of plantaris muscle in mice.

    Science.gov (United States)

    Zempo, Hirofumi; Suzuki, Jun-Ichi; Ogawa, Masahito; Watanabe, Ryo; Isobe, Mitsuaki

    2016-02-01

    The role of angiotensin II type 1 (AT1) receptors in muscle development and hypertrophy remains unclear. This study was designed to reveal the effects that a loss of AT1 receptors has on skeletal muscle development and hypertrophy in mice. Eight-week-old male AT1a receptor knockout (AT1a(-/-)) mice were used for this experiment. The plantaris muscle to body weight ratio, muscle fiber cross-sectional area, and number of muscle fibers of AT1a(-/-) mice was significantly greater than wild type (WT) mice in the non-intervention condition. Next, the functional overload (OL) model was used to induce plantaris muscle hypertrophy by surgically removing the two triceps muscles consisting of the calf, soleus, and gastrocnemius muscles in mice. After 14 days of OL intervention, the plantaris muscle weight, the amount of fiber, and the fiber area increased. However, the magnitude of the increment of plantaris weight was not different between the two strains. Agtr1a mRNA expression did not change after OL in WT muscle. Actually, the Agt mRNA expression level of WT-OL was lower than WT-Control (C) muscle. An atrophy-related gene, atrogin-1 mRNA expression levels of AT1a(-/-)-C, WT-OL, and AT1a(-/-)-OL muscle were lower than that of WT-C muscle. Our findings suggest that AT1 receptor contributes to plantaris muscle development via atrogin-1 in mice.

  16. Imaging the β-adrenergic receptor. II: [F-18]-fluoroalkyl derivatives of carazolol

    International Nuclear Information System (INIS)

    Kinsey, B.M.; Tewson, T.J.

    1990-01-01

    Carazolol is a ligand with one of the highest association constants known for the β-adrenergic receptor and presumably has one of the slowest rates of dissociation from the receptor. The authors have prepared a [F-18]-fluoroalkyl derivative of carazolol which the authors believe will be useful in the in vivo detection and measurement of the β-adrenergic receptor. The synthesis is based upon the formation of a hydrazole from cyclohexanedione and para-[2-hydroxyethyl]phenylhydrazine followed by Fischer indole synthesis, dehydrogenation and side chain addition to give the protected hydroxyethylcarazolol derivative 1

  17. Use of angiotensin II receptor blockers in children- a review of ...

    African Journals Online (AJOL)

    2015-05-19

    May 19, 2015 ... sex and height, whereas hypertension is defined as SBP and/or DBP persistently ... strated the efficacy of angiotensin receptor blockers in ... An open-label, multicenter, single-dose study was ..... sure among school children of.

  18. Angiotensin II type 2 receptor agonist Compound 21 attenuates pulmonary inflammation in a model of acute lung injury

    Directory of Open Access Journals (Sweden)

    Menk M

    2018-05-01

    Full Text Available Mario Menk, Jan Adriaan Graw, Clarissa von Haefen, Hendrik Steinkraus, Burkhard Lachmann, Claudia D Spies, David Schwaiberger Department of Anesthesiology and Operative Intensive Care Medicine, Charité – University Medicine Berlin, FreieUniversität Berlin, Humboldt-Universitätzu Berlin, and Berlin Institute of Health, Germany Purpose: Although the role of the angiotensin II type 2 (AT2 receptor in acute lung injury is not yet completely understood, a protective role of this receptor subtype has been suggested. We hypothesized that, in a rodent model of acute lung injury, stimulation of the AT2 receptor with the direct agonist Compound 21 (C21 might have a beneficial effect on pulmonary inflammation and might improve pulmonary gas exchange. Materials and methods: Male adult rats were divided into a treatment group that received pulmonary lavage followed by mechanical ventilation (LAV, n=9, a group receiving pulmonary lavage, mechanical ventilation, and direct stimulation of the AT2 receptor with C21 (LAV+C21, n=9, and a control group that received mechanical ventilation only (control, n=9. Arterial blood gas analysis was performed every 30 min throughout the 240-min observation period. Lung tissue and plasma samples were obtained at 240 min after the start of mechanical ventilation. Protein content and surface activity of bronchoalveolar lavage fluid were assessed and the wet/dry-weight ratio of lungs was determined. Transcriptional and translational regulation of pro- and antiinflammatory cytokines IL-1β, tumor necrosis factor-alpha, IL-6, IL-10, and IL-4 was determined in lungs and in plasma. Results: Pulmonary lavage led to a significant impairment of gas exchange, the formation of lung edema, and the induction of pulmonary inflammation. Protein content of lavage fluid was increased and contained washed-out surfactant. Direct AT2 receptor stimulation with C21 led to a significant inhibition of tumor necrosis factor-alpha and IL-6

  19. [Role of angiotensin II receptor type 2 in predicting biochemical recurrence in the treatment of prostate cancer].

    Science.gov (United States)

    Chibichyan, M B; Kogan, M I; Chernogubova, E A; Pavlenko, I A; Matishov, D G

    2016-12-01

    To identify markers for predicting aggressive forms of prostate cancer. The study retrospectively evaluated expression of angiotensin II type 2 receptors (AT2-R) in prostate needle biopsy tissue from patients with and without biochemical recurrence after combined hormone and radiation therapy. The study findings showed that low expression of AT2-R in prostate tissue was associated with a high risk of biochemical recurrence. The data on the nature of AT2-R expression in prostate tissue of prostate cancer patients may be considered as a tool for predicting biochemical recurrence after combined hormone and radiation therapy. The test has a sensitivity of 87.5% and specificity of 85.71%.

  20. Polymer-immobilized liquid membrane transport of palladium (II) from nitric acid media using some thia extractants as novel receptors

    International Nuclear Information System (INIS)

    Shukla, J.P.

    1996-01-01

    Carrier-facilitated co-transport of Pd (II) from dilute acidic nitrate solutions was examined across a polymer-immobilized liquid membrane (PILM) deploying S 6 -pentano-36 (S 6 -P-36), bis-(2-ethylhexyl) sulfoxide (BESO) and bis (2, 4, 4 trimethyl pentyl) monothio phosphinic acid (Cyanex 302) as the novel receptors. The study carried out to distinguish the driving force between H + and NO 3 - ion for the cation transport across PILM, indicated that NO 3 - ion not the H + ion seems to be the driving force for Pd (II) transport under the present conditions for both BESO-PILM and S 6 -P-36-PILM systems. Recovery of palladium from acidic process effluents generated in Purex reprocessing of spent fuels was successfully achieved. 39 refs., 8 figs., 7 tabs

  1. Two distinct calmodulin binding sites in the third intracellular loop and carboxyl tail of angiotensin II (AT(1A receptor.

    Directory of Open Access Journals (Sweden)

    Renwen Zhang

    Full Text Available In this study, we present data that support the presence of two distinct calmodulin binding sites within the angiotensin II receptor (AT(1A, at juxtamembrane regions of the N-terminus of the third intracellular loop (i3, amino acids 214-231 and carboxyl tail of the receptor (ct, 302-317. We used bioluminescence resonance energy transfer assays to document interactions of calmodulin with the AT(1A holo-receptor and GST-fusion protein pull-downs to demonstrate that i3 and ct interact with calmodulin in a Ca²⁺-dependent fashion. The former is a 1-12 motif and the latter belongs to 1-5-10 calmodulin binding motif. The apparent Kd of calmodulin for i3 is 177.0±9.1 nM, and for ct is 79.4±7.9 nM as assessed by dansyl-calmodulin fluorescence. Replacement of the tryptophan (W219 for alanine in i3, and phenylalanine (F309 or F313 for alanine in ct reduced their binding affinities for calmodulin, as predicted by computer docking simulations. Exogenously applied calmodulin attenuated interactions between G protein βγ subunits and i3 and ct, somewhat more so for ct than i3. Mutations W219A, F309A, and F313A did not alter Gβγ binding, but reduced the ability of calmodulin to compete with Gβγ, suggesting that calmodulin and Gβγ have overlapping, but not identical, binding requirements for i3 and ct. Calmodulin interference with the Gβγ binding to i3 and ct regions of the AT(1A receptor strongly suggests that calmodulin plays critical roles in regulating Gβγ-dependent signaling of the receptor.

  2. Two Distinct Calmodulin Binding Sites in the Third Intracellular Loop and Carboxyl Tail of Angiotensin II (AT1A) Receptor

    Science.gov (United States)

    Zhang, Renwen; Liu, Zhijie; Qu, Youxing; Xu, Ying; Yang, Qing

    2013-01-01

    In this study, we present data that support the presence of two distinct calmodulin binding sites within the angiotensin II receptor (AT1A), at juxtamembrane regions of the N-terminus of the third intracellular loop (i3, amino acids 214–231) and carboxyl tail of the receptor (ct, 302–317). We used bioluminescence resonance energy transfer assays to document interactions of calmodulin with the AT1A holo-receptor and GST-fusion protein pull-downs to demonstrate that i3 and ct interact with calmodulin in a Ca2+-dependent fashion. The former is a 1–12 motif and the latter belongs to 1-5-10 calmodulin binding motif. The apparent Kd of calmodulin for i3 is 177.0±9.1 nM, and for ct is 79.4±7.9 nM as assessed by dansyl-calmodulin fluorescence. Replacement of the tryptophan (W219) for alanine in i3, and phenylalanine (F309 or F313) for alanine in ct reduced their binding affinities for calmodulin, as predicted by computer docking simulations. Exogenously applied calmodulin attenuated interactions between G protein βγ subunits and i3 and ct, somewhat more so for ct than i3. Mutations W219A, F309A, and F313A did not alter Gβγ binding, but reduced the ability of calmodulin to compete with Gβγ, suggesting that calmodulin and Gβγ have overlapping, but not identical, binding requirements for i3 and ct. Calmodulin interference with the Gβγ binding to i3 and ct regions of the AT1A receptor strongly suggests that calmodulin plays critical roles in regulating Gβγ-dependent signaling of the receptor. PMID:23755207

  3. Endothelial Mineralocorticoid Receptor Mediates Parenchymal Arteriole and Posterior Cerebral Artery Remodeling During Angiotensin II-Induced Hypertension.

    Science.gov (United States)

    Diaz-Otero, Janice M; Fisher, Courtney; Downs, Kelsey; Moss, M Elizabeth; Jaffe, Iris Z; Jackson, William F; Dorrance, Anne M

    2017-12-01

    The brain is highly susceptible to injury caused by hypertension because the increased blood pressure causes artery remodeling that can limit cerebral perfusion. Mineralocorticoid receptor (MR) antagonism prevents hypertensive cerebral artery remodeling, but the vascular cell types involved have not been defined. In the periphery, the endothelial MR mediates hypertension-induced vascular injury, but cerebral and peripheral arteries are anatomically distinct; thus, these findings cannot be extrapolated to the brain. The parenchymal arterioles determine cerebrovascular resistance. Determining the effects of hypertension and MR signaling on these arterioles could lead to a better understanding of cerebral small vessel disease. We hypothesized that endothelial MR signaling mediates inward cerebral artery remodeling and reduced cerebral perfusion during angiotensin II (AngII) hypertension. The biomechanics of the parenchymal arterioles and posterior cerebral arteries were studied in male C57Bl/6 and endothelial cell-specific MR knockout mice and their appropriate controls using pressure myography. AngII increased plasma aldosterone and decreased cerebral perfusion in C57Bl/6 and MR-intact littermates. Endothelial cell MR deletion improved cerebral perfusion in AngII-treated mice. AngII hypertension resulted in inward hypotrophic remodeling; this was prevented by MR antagonism and endothelial MR deletion. Our studies suggest that endothelial cell MR mediates hypertensive remodeling in the cerebral microcirculation and large pial arteries. AngII-induced inward remodeling of cerebral arteries and arterioles was associated with a reduction in cerebral perfusion that could worsen the outcome of stroke or contribute to vascular dementia. © 2017 American Heart Association, Inc.

  4. Spectral methods for study of the G-protein-coupled receptor rhodopsin. II. Magnetic resonance methods

    Science.gov (United States)

    Struts, A. V.; Barmasov, A. V.; Brown, M. F.

    2016-02-01

    This article continues our review of spectroscopic studies of G-protein-coupled receptors. Magnetic resonance methods including electron paramagnetic resonance (EPR) and nuclear magnetic resonance (NMR) provide specific structural and dynamical data for the protein in conjunction with optical methods (vibrational, electronic spectroscopy) as discussed in the accompanying article. An additional advantage is the opportunity to explore the receptor proteins in the natural membrane lipid environment. Solid-state 2H and 13C NMR methods yield information about both the local structure and dynamics of the cofactor bound to the protein and its light-induced changes. Complementary site-directed spin-labeling studies monitor the structural alterations over larger distances and correspondingly longer time scales. A multiscale reaction mechanism describes how local changes of the retinal cofactor unlock the receptor to initiate large-scale conformational changes of rhodopsin. Activation of the G-protein-coupled receptor involves an ensemble of conformational substates within the rhodopsin manifold that characterize the dynamically active receptor.

  5. IN SILICO EVALUATION OF ANGIOTENSIN II RECEPTOR ANTAGONIST’S PLASMA PROTEIN BINDING USING COMPUTED MOLECULAR DESCRIPTORS

    Directory of Open Access Journals (Sweden)

    Jadranka Odović

    2014-03-01

    Full Text Available The discovery of new pharmacologically active substances and drugs modeling led to necessity of predicting drugs properties and its ADME data. Angiotensin II receptor antagonists are a group of pharmaceuticals which modulate the renin-angiotensin-aldosterone system and today represent the most commonly prescribed anti-hypertensive drugs. The aim of this study was to compare different molecular properties of seven angiotensin II receptor antagonists / blockers (ARBs, (eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan and their plasma protein binding (PPB data. Several ARBs molecular descriptors were calculated using software package Molinspiration Depiction Software as well as Virtual Computational Chemistry Laboratory (electronic descriptor – PSA, constitutional parameter – Mw, geometric descriptor – Vol, lipophilicity descriptors - logP values, aqueous solubility data – logS. The correlations between all collected descriptors and plasma protein binding data obtained from relevant literature were established. In the simple linear regression poor correlations were obtained in relationships between PPB data and all calculated molecular descriptors. In the next stage of the study multiple linear regression (MLR was used for correlation of PPB data with two different descriptors as independent variables. The best correlation (R2=0.70 with P<0.05 was established between PPB data and molecular weight with addition of volume values as independent variables. The possible application of computed molecular descriptors in drugs protein binding evaluation can be of great importance in drug research.

  6. REM sleep enhancement and behavioral cataplexy following orexin (hypocretin)-II receptor antisense perfusion in the pontine reticular formation.

    Science.gov (United States)

    Thakkar, M M; Ramesh, V; Cape, E G; Winston, S; Strecker, R E; McCarley, R W

    1999-01-01

    Orexin (hypocretin)-containing neurons of the hypothalamus project to brainstem sites that are involved in the neural control of REM sleep, including the locus coeruleus, the dorsal raphe nucleus, the cholinergic zone of the mesopontine tegmentum, and the pontine reticular formation (PRF). Orexin knockout mice exhibit narcolepsy/cataplexy, and a mutant and defective gene for the orexin type II receptor is present in dogs with an inherited form of narcolepsy/cataplexy. However, the physiological systems mediating these effects have not been described. We reasoned that, since the effector neurons for the majority of REM sleep signs, including muscle atonia, were located in the PRF, this region was likely implicated in the production of these orexin-related abnormalities. To test this possibility, we used microdialysis perfusion of orexin type II receptor antisense in the PRF of rats. Ten to 24 hours after antisense perfusion, REM sleep increased two- to three-fold during both the light period (quiescent phase) and the dark period (active phase), and infrared video showed episodes of behavioral cataplexy. Moreover, preliminary data indicated no REM-related effects following perfusion with nonsense DNA, or when perfusion sites were outside the PRF. More work is needed to provide precise localization of the most effective site of orexin-induced inhibition of REM sleep phenomena.

  7. Attenuation of myocardial fibrosis with curcumin is mediated by modulating expression of angiotensin II AT1/AT2 receptors and ACE2 in rats

    Directory of Open Access Journals (Sweden)

    Pang XF

    2015-11-01

    Full Text Available Xue-Fen Pang,1 Li-Hui Zhang,2 Feng Bai,1 Ning-Ping Wang,3 Ron E Garner,3 Robert J McKallip,4 Zhi-Qing Zhao1,3 1Department of Physiology, Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of China; 2Department of Cardiology, Shanxi Academy of Medical Sciences and Shanxi Dayi Hospital, Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of China; 3Department of Basic Biomedical Sciences, Mercer University School of Medicine, Savannah, GA, USA; 4Division of Basic Biomedical Sciences, Mercer University School of Medicine, Macon, GA, USA Abstract: Curcumin is known to improve cardiac function by balancing degradation and synthesis of collagens after myocardial infarction. This study tested the hypothesis that inhibition of myocardial fibrosis by curcumin is associated with modulating expression of angiotensin II (Ang II receptors and angiotensin-converting enzyme 2 (ACE2. Male Sprague Dawley rats were subjected to Ang II infusion (500 ng/kg/min using osmotic minipumps for 2 and 4 weeks, respectively, and curcumin (150 mg/kg/day was fed by gastric gavage during Ang II infusion. Compared to the animals with Ang II infusion, curcumin significantly decreased the mean arterial blood pressure during the course of the observation. The protein level of the Ang II type 1 (AT1 receptor was reduced, and the Ang II type 2 (AT2 receptor was up-regulated, evidenced by an increased ratio of the AT2 receptor over the AT1 receptor in the curcumin group (1.2±0.02% vs in the Ang II group (0.7±0.03%, P<0.05. These changes were coincident with less locally expressed AT1 receptor and enhanced AT2 receptor in the intracardiac vessels and intermyocardium. Along with these modulations, curcumin significantly decreased the populations of macrophages and alpha smooth muscle actin-expressing myofibroblasts, which were accompanied by reduced expression of transforming growth factor beta 1 and phosphorylated-Smad2/3. Collagen I synthesis was

  8. Immunohistochemical Localization of AT1a, AT1b, and AT2 Angiotensin II Receptor Subtypes in the Rat Adrenal, Pituitary, and Brain with a Perspective Commentary

    Directory of Open Access Journals (Sweden)

    Courtney Premer

    2013-01-01

    Full Text Available Angiotensin II increases blood pressure and stimulates thirst and sodium appetite in the brain. It also stimulates secretion of aldosterone from the adrenal zona glomerulosa and epinephrine from the adrenal medulla. The rat has 3 subtypes of angiotensin II receptors: AT1a, AT1b, and AT2. mRNAs for all three subtypes occur in the adrenal and brain. To immunohistochemically differentiate these receptor subtypes, rabbits were immunized with C-terminal fragments of these subtypes to generate receptor subtype-specific antibodies. Immunofluorescence revealed AT1a and AT2 receptors in adrenal zona glomerulosa and medulla. AT1b immunofluorescence was present in the zona glomerulosa, but not the medulla. Ultrastructural immunogold labeling for the AT1a receptor in glomerulosa and medullary cells localized it to plasma membrane, endocytic vesicles, multivesicular bodies, and the nucleus. AT1b and AT2, but not AT1a, immunofluorescence was observed in the anterior pituitary. Stellate cells were AT1b positive while ovoid cells were AT2 positive. In the brain, neurons were AT1a, AT1b, and AT2 positive, but glia was only AT1b positive. Highest levels of AT1a, AT1b, and AT2 receptor immunofluorescence were in the subfornical organ, median eminence, area postrema, paraventricular nucleus, and solitary tract nucleus. These studies complement those employing different techniques to characterize Ang II receptors.

  9. Dietary nitrate improves age-related hypertension and metabolic abnormalities in rats via modulation of angiotensin II receptor signaling and inhibition of superoxide generation

    DEFF Research Database (Denmark)

    Hezel, M.; Peleli, Maria; Liu, M.

    2016-01-01

    . Finally, nitrate treatment in aged rats normalized the gene expression profile of ANG II receptors (AT1A, AT2, AT1A/AT2 ratio) in the renal and cardiovascular systems without altering plasma levels of renin or ANG II. Our results show that boosting the nitrate-nitrite-NO pathway can partly compensate...... that increased angiotensin II (ANG II) signaling is also implicated in the pathogenesis of endothelial dysfunction and hypertension by accelerating formation of reactive oxygen species. This study was designed to test the hypothesis that dietary nitrate supplementation could reduce blood pressure and improve...... glucose tolerance in aged rats, via attenuation of NADPH oxidase activity and ANG II receptor signaling. Dietary nitrate supplementation for two weeks reduced blood pressure (10–15 mmHg) and improved glucose clearance in old, but not in young rats. These favorable effects were associated with increased...

  10. Expression of Angiotensin II Types 1 and 2 Receptors in Endometriotic Lesions.

    Science.gov (United States)

    Nakao, Takehiro; Chishima, Fumihisa; Sugitani, Masahiko; Tsujimura, Ryusuke; Hayashi, Chuyu; Yamamoto, Tatsuo

    2017-01-01

    The aim of this study was to evaluate the gene and protein expression of angiotensin type (AT) 1, AT2 receptors in endometriotic lesions and its relation to prostaglandin (PG) synthases. Endometriosis samples were obtained from 32 patients with endometriotic cysts. Endometrial tissues were obtained during operations for benign gynecological conditions. The expression of the AT1 and AT2 receptor mRNA and that of PG-endoperoxide synthase 2 and microsomal PGE2 synthase-1 (mPGES-1) was examined by quantitative RT-PCR. Immunohistochemical staining was performed for these receptors. AT1 and AT2 receptor proteins were mostly located in endometrial glandular epithelium and some stromal cells. Immunoreactivity of the receptor proteins was observed in both the eutopic endometrium and endometriotic lesions. The AT1/AT2 ratio in endometriotic cysts (median 7.29, range 1.88-187.60) was significantly increased compared with that in the eutopic endometrium in the proliferative-phase in controls (median 1.01, range 0.37-2.09, p < 0.001). There was a relationship between the AT1 mRNA expression and that of mPGES-1 mRNA in the endometriotic cysts (r = 0.394089, p < 0.05). There was a significant relationship between the mRNA expression of the AT2 receptor and that of mPGES-1 in eutopic endometrium of non-endometriotic control (r = 0.610714, p < 0.05). Renin-angiotensin system may play an important role in the pathophysiology of endometriosis. © 2016 S. Karger AG, Basel.

  11. Epac is required for exogenous and endogenous stimulation of adenosine A2B receptor for inhibition of angiotensin II-induced collagen synthesis and myofibroblast differentiation.

    Science.gov (United States)

    Phosri, Sarawuth; Bunrukchai, Kwanchai; Parichatikanond, Warisara; Sato, Vilasinee H; Mangmool, Supachoke

    2018-01-10

    Angiotensin II (Ang II) plays an important role on the pathogenesis of cardiac fibrosis. Prolong and overstimulation of angiotensin II type 1 receptor with Ang II-induced collagen synthesis and myofibroblast differentiation in cardiac fibroblasts, leading to cardiac fibrosis. Although adenosine and its analogues are known to have cardioprotective effects, the mechanistic by which adenosine A 2 receptors (A 2 Rs) inhibit Ang II-induced cardiac fibrosis is not clearly understood. In the present study, we examined the effects of exogenous adenosine and endogenous adenosine on Ang II-induced collagen and myofibroblast differentiation determined by α-smooth muscle action (α-SMA) overexpression and their underlying signal transduction. Elevation of endogenous adenosine levels resulted in the inhibition of Ang II-induced collagen type I and III and α-SMA synthesis in cardiac fibroblasts. Moreover, treatment with exogenous adenosine which selectively stimulated A 2 Rs also suppressed Ang II-induced collagen synthesis and α-SMA production. These antifibrotic effects of both endogenous and exogenous adenosines are mediated through the A 2B receptor (A 2B R) subtype. Stimulation of A 2B R exhibited antifibrotic effects via the cAMP-dependent and Epac-dependent pathways. Our results provide new mechanistic insights regarding the role for cAMP and Epac on A 2B R-mediated antifibrotic effects. Thus, A 2B R is one of the potential therapeutic targets against cardiac fibrosis.

  12. The Nuclear Receptor, Nor-1, Markedly Increases Type II Oxidative Muscle Fibers and Resistance to Fatigue

    OpenAIRE

    Pearen, Michael A.; Eriksson, Natalie A.; Fitzsimmons, Rebecca L.; Goode, Joel M.; Martel, Nick; Andrikopoulos, Sofianos; Muscat, George E. O.

    2012-01-01

    Nuclear hormone receptors (NR) have been implicated as regulators of lipid and carbohydrate metabolism. The orphan NR4A subgroup has emerged as regulators of metabolic function. Targeted silencing of neuron-derived orphan receptor 1 (Nor-1)/NR4A3 in skeletal muscle cells suggested that this NR was necessary for oxidative metabolism in vitro. To investigate the in vivo role of Nor-1, we have developed a mouse model with preferential expression of activated Nor-1 in skeletal muscle. In skeletal...

  13. Pharmacologic perspectives of functional selectivity by the angiotensin II type 1 receptor

    DEFF Research Database (Denmark)

    Aplin, Mark; Christensen, Gitte Lund; Hansen, Jakob Lerche

    2008-01-01

    and to sudden injury occurring in the circulatory system. Hence, current drugs that block all AT(1) receptor actions most likely leave room for improvement. Recent developments show that two major signaling pathways used by the AT(1) receptor may be dissected by pharmacologic means. Key pathologic responses...... protein actions and simultaneous activation of G protein-dependent or -independent signaling could therefore be desirable in certain situations. The previously unappreciated concept of "functional selectivity" makes this exact strategy feasible and may yield improved drugs for cardiovascular therapy....

  14. No effect of angiotensin II AT(2)-receptor antagonist PD 123319 on cerebral blood flow autoregulation

    DEFF Research Database (Denmark)

    Estrup, T M; Paulson, O B; Strandgaard, S

    2001-01-01

    Blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin AT1-receptor antagonists shift the limits of autoregulation of cerebral blood flow (CBF) towards lower blood pressure (BP). The role of AT2-receptors in the regulation of the cerebral...... group. CBF was measured by the intracarotid 133xenon injection method and BP was raised by noradrenaline infusion and lowered by controlled haemorrhage in separate groups of rats. The limits of autoregulation were determined by computed least-sum-of-squares analysis. PD 123319 did not influence baseline...

  15. Evaluation of transcobalamin II rs1801198 and transcobalamin II receptor rs2336573 gene polymorphisms in recurrent spontaneous abortion.

    Science.gov (United States)

    Hashemi, Mohammad; Mokhtari, Mojgan; Yazdani-Shahrbabaki, Vajiheh; Danesh, Hiva; Bizhani, Fatemeh; Taheri, Mohsen

    2018-03-14

    It has been proposed that transcobalamin 2 (TCN2) and the transcobalamin 2 receptor (TCN2R) are associated with idiopathic recurrent spontaneous abortion (RSA). The aim of the present study was to investigate the impact of TCN2 rs1801198 and TCN2R rs2336573 polymorphism on RSA in a sample of Iranian population. This case-control study was done on 92 RSA patients and 93 normal, fertile women. Genotyping of the TCN2 rs1801198 and TCN2R rs2336573 variants was done by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). The findings showed no significant association between the TCN2 rs1801198 and TCN2R rs2336573 polymorphisms and the risk/protection of RSA. Our results did not support an association between the TCN2 polymorphism and the risk of RSA in a sample of southeast Iranian population. Larger studies with different ethnicities are needed to evaluate the possible impact of TCN2 and TCN2R polymorphisms on the pathogenesis of RSA. Impact statement What is already known on this subject? Recurrent spontaneous abortion (RSA), a multifactorial condition, is one of the most common complications of pregnancy. It has been proposed that genetic polymorphisms play a role in the pathogenesis of RSA. Few studies have examined the association between TNC2 and TCN2R polymorphisms and the RSA risk and the findings were inconsistent. The aim of the current study was to determine the possible association between the TCN2 rs1801198 and TCN2R rs2336573 polymorphisms and the RSA in a sample of the southeast Iranian population. What do the results of the study add? The findings of the present case-control study did not support an association between the TCN2 rs1801198 and TCN2R rs2336573 polymorphisms and the risk of RSA in a sample of the Iranian population. What are the implications of these findings for clinical practice and future research? The findings of this study may provide a basis for future studies with larger sample sizes and different ethnicities

  16. New analogues of ACPD with selective activity for group II metabotropic glutamate receptors

    DEFF Research Database (Denmark)

    Bräuner-Osborne, Hans; Madsen, U; Mikiciuk-Olasik, E

    1997-01-01

    In this study we have determined the pharmacology of a series of 1-aminocyclopentane-1,3-dicarboxylic acid (1,3-ACPD) analogues at cloned metabotropic glutamic acid (mGlu) receptors. The new analogues comprise the four possible stereoisomers of 1-amino-1-carboxycyclopentane-3-acetic acid (1,3-hom...

  17. Increased angiotensin II type 1 receptor expression in temporal arteries from patients with giant cell arteritis

    DEFF Research Database (Denmark)

    Dimitrijevic, Ivan; Malmsjö, Malin; Andersson, Christina

    2009-01-01

    -AT(2) antibodies, was performed on formalin-fixed and paraffin-embedded temporal arteries. MAIN OUTCOME MEASURES: AT(1) and AT(2) receptor immunostaining intensity was quantified. RESULTS: Hematoxylin-eosin-stained sections of temporal arteries from patients with GCA showed intimal hyperplasia...

  18. Angiotensin II accelerates functional recovery in the rat sciatic nerve in vivo: role of the AT2 receptor and the transcription factor NF-kappaB.

    Science.gov (United States)

    Reinecke, Kirstin; Lucius, Ralph; Reinecke, Alexander; Rickert, Uta; Herdegen, Thomas; Unger, Thomas

    2003-11-01

    The AT2 receptor regulates several functions of nerve cells, e.g., ionic fluxes, cell differentiation, and axonal regeneration, but also modulates programmed cell death. We tested the hypothesis that angiotensin II (ANG II) via its AT2 receptor not only promotes regeneration but also functional recovery after sciatic nerve crush in adult rats. ANG II (10(-7), 10(-9), 10(-11) M) applied locally via osmotic minipumps promoted functional recovery with maximal effects after the lowest concentration. The toe spread distance as a parameter for re-innervation after 20 days was significantly (Pelectrical stimulation (return of sensorimotor function) was reduced to 14.6 days vs. 17.9 days in the control group (PSchwann cells. Histological criteria, morphometric analyses, and electron microscopy confirmed the functional data. These results are the first to present direct evidence for an involvement of the AT2 receptor and NF-kappaB in peripheral nerve regeneration.

  19. Gonadotropin-releasing hormone type II (GnRH-II) agonist regulates the invasiveness of endometrial cancer cells through the GnRH-I receptor and mitogen-activated protein kinase (MAPK)-dependent activation of matrix metalloproteinase (MMP)-2

    International Nuclear Information System (INIS)

    Wu, Hsien-Ming; Wang, Hsin-Shih; Huang, Hong-Yuan; Lai, Chyong-Huey; Lee, Chyi-Long; Soong, Yung-Kuei; Leung, Peter CK

    2013-01-01

    More than 25% of patients diagnosed with endometrial carcinoma have an invasive primary cancer accompanied by metastases. Gonadotropin-releasing hormone (GnRH) plays an important role in reproduction. In mammals, expression of GnRH-II is higher than GnRH-I in reproductive tissues. Here, we examined the effect of a GnRH-II agonist on the motility of endometrial cancer cells and its mechanism of action in endometrial cancer therapy. Immunoblotting and immunohistochemistry (IHC) were used to determine the expression of the GnRH-I receptor protein in human endometrial cancer. The activity of MMP-2 in the conditioned medium was determined by gelatin zymography. Cell motility was assessed by invasion and migration assay. GnRH-I receptor si-RNA was applied to knockdown GnRH-I receptor. The GnRH-I receptor was expressed in the endometrial cancer cells. The GnRH-II agonist promoted cell motility in a dose-dependent manner. The GnRH-II agonist induced the phosphorylation of ERK1/2 and JNK, and the phosphorylation was abolished by ERK1/2 inhibitor (U0126) and the JNK inhibitor (SP600125). Cell motility promoted by GnRH-II agonist was suppressed in cells that were pretreated with U0126 and SP600125. Moreover, U0126 and SP600125 abolished the GnRH-II agonist-induced activation of MMP-2. The inhibition of MMP-2 with MMP-2 inhibitor (OA-Hy) suppressed the increase in cell motility in response to the GnRH-II agonist. Enhanced cell motility mediated by GnRH-II agonist was also suppressed by the knockdown of the endogenous GnRH-I receptor using siRNA. Our study indicates that GnRH-II agonist promoted cell motility of endometrial cancer cells through the GnRH-I receptor via the phosphorylation of ERK1/2 and JNK, and the subsequent, MAPK-dependent activation of MMP-2. Our findings represent a new concept regarding the mechanism of GnRH-II-induced cell motility in endometrial cancer cells and suggest the possibility of exploring GnRH-II as a potential therapeutic target for the

  20. Serological cross-reaction between O-antigens of Shigella dysenteriae type 4 and an environmental Escherichia albertii isolate.

    Science.gov (United States)

    Rahman, Mohammed Ziaur; Akter, Selina; Azmuda, Nafisa; Sultana, Munawar; Weill, François-Xavier; Khan, Sirajul Islam; Grimont, Patrick A D; Birkeland, Nils-Kåre

    2013-11-01

    An environmental freshwater bacterial isolate, DM104, appearing as Shigella-like colonies on selective agar plates was found to show strong and specific serological cross-reactivity with Shigella dysenteriae type 4. Biochemical identification according to the analytical profile index, molecular serotyping by restriction of the amplified O-antigen gene cluster (rfb-RFLP), together with phylogenetic analysis of the 16S rRNA gene and multi-locus sequence analysis, identified the isolate as Escherichia albertii. rfb-RFLP of DM104, revealed a profile different from that of S. dysenteriae type 4. However, western blot analysis of extracted lipopolysaccharides demonstrated strong cross-reactivity with S. dysenteriae type 4 using specific monovalent antisera and a lipopolysaccharide gel banding profile similar to that of S. dysenteriae type 4. The observed O-antigen cross-reaction between an E. albertii isolate and S. dysenteriae extends our knowledge of the extent of O-antigen cross-reaction within the Escherichia/Shigella group of organisms, and offers the possibility of using DM104 and similar cross-reacting strains as shigellosis vaccine candidates.

  1. The expression of chemokine receptors CXCR3 and CXCR4 in predicting postoperative tumour progression in stages I-II colon cancer: a retrospective study.

    Science.gov (United States)

    Du, Changzheng; Yao, Yunfeng; Xue, Weicheng; Zhu, Wei-Guo; Peng, Yifan; Gu, Jin

    2014-01-01

    The prognostic significance of chemokine receptors in stage I/II colon cancer is unclear. We assessed the prognostic value of chemokine receptor CXCR3 and CXCR4 in stage I/II colon cancer. 145 patients with stage I/II colon cancer who underwent curative surgery alone from 2000 to 2007 were investigated. Chemokine receptor expression was assessed by immunohistochemistry. The associations between CXCR3, CXCR4 and clinicopathological variables were analysed using the χ2 test, and the relationships between chemokine receptors and a 5-year disease-free survival were analysed by univariate and multivariate analyses. The high-expression rates of CXCR3 and CXCR4 were 17.9% (26/145) and 38.6% (56/145), respectively. There were no significant associations between the expressions of CXCR3, CXCR4 and clinicopathological factors including gender, age, tumour location, histological differentiation, pathological stage, lymphovascular invasion and pretreatment serum carcinoembryonic antigen (CEA). The 5-year disease-free survival was not significantly different between low-expression groups and high-expression groups of CXCR3 and CXCR4. Multivariate analysis revealed that serum CEA and a number of retrieved lymph nodes, rather than chemokine receptors, were independent prognosticators. CXCR3 and CXCR4 are not independent prognosticators for stage I/II colon cancer after curative surgery.

  2. An Angiotensin II type 1 receptor activation switch patch revealed through Evolutionary Trace analysis

    DEFF Research Database (Denmark)

    Bonde, Marie Mi; Yao, Rong; Ma, Jian-Nong

    2010-01-01

    to be completely resolved. Evolutionary Trace (ET) analysis is a computational method, which identifies clusters of functionally important residues by integrating information on evolutionary important residue variations with receptor structure. Combined with known mutational data, ET predicted a patch of residues......) displayed phenotypes associated with changed activation state, such as increased agonist affinity or basal activity, promiscuous activation, or constitutive internalization highlighting the importance of testing different signaling pathways. We conclude that this evolutionary important patch mediates...

  3. LiCABEDS II. Modeling of ligand selectivity for G-protein-coupled cannabinoid receptors.

    Science.gov (United States)

    Ma, Chao; Wang, Lirong; Yang, Peng; Myint, Kyaw Z; Xie, Xiang-Qun

    2013-01-28

    The cannabinoid receptor subtype 2 (CB2) is a promising therapeutic target for blood cancer, pain relief, osteoporosis, and immune system disease. The recent withdrawal of Rimonabant, which targets another closely related cannabinoid receptor (CB1), accentuates the importance of selectivity for the development of CB2 ligands in order to minimize their effects on the CB1 receptor. In our previous study, LiCABEDS (Ligand Classifier of Adaptively Boosting Ensemble Decision Stumps) was reported as a generic ligand classification algorithm for the prediction of categorical molecular properties. Here, we report extension of the application of LiCABEDS to the modeling of cannabinoid ligand selectivity with molecular fingerprints as descriptors. The performance of LiCABEDS was systematically compared with another popular classification algorithm, support vector machine (SVM), according to prediction precision and recall rate. In addition, the examination of LiCABEDS models revealed the difference in structure diversity of CB1 and CB2 selective ligands. The structure determination from data mining could be useful for the design of novel cannabinoid lead compounds. More importantly, the potential of LiCABEDS was demonstrated through successful identification of newly synthesized CB2 selective compounds.

  4. Altered renal expression of angiotensin II receptors, renin receptor, and ACE-2 precede the development of renal fibrosis in aging rats.

    Science.gov (United States)

    Schulman, Ivonne Hernandez; Zhou, Ming-Sheng; Treuer, Adriana V; Chadipiralla, Kiranmai; Hare, Joshua M; Raij, Leopoldo

    2010-01-01

    The susceptibility to fibrosis and progression of renal disease is mitigated by inhibition of the renin-angiotensin system (RAS). We hypothesized that activation of the intrarenal RAS predisposes to renal fibrosis in aging. Intrarenal expression of angiotensin II type 1 (AT(1)R), type 2 (AT(2)R), and (pro)renin receptors, ACE and ACE-2, as well as pro- and antioxidant enzymes were measured in 3-month-old (young), 14-month-old (middle-aged), and 24-month-old (old) male Sprague-Dawley rats. Old rats manifested glomerulosclerosis and severe tubulointerstitial fibrosis with increased fibronectin and TGF-β expression (7-fold). AT(1)R /AT(2)R ratios were increased in middle-aged (cortical 1.6-fold, medullary 5-fold) and old rats (cortical 2-fold, medullary 4-fold). Similarly, (pro)renin receptor expression was increased in middle-aged (cortical 2-fold, medullary 3-fold) and old (cortical 5-fold, medullary 3-fold) rats. Cortical ACE was increased (+35%) in old rats, whereas ACE-2 was decreased (-50%) in middle-aged and old rats. NADPH oxidase activity was increased (2-fold), whereas antioxidant capacity and expression of the mitochondrial enzyme manganese superoxide dismutase (cortical -40%, medullary -53%) and medullary endothelial nitric oxide synthase (-48%) were decreased in old rats. Age-related intrarenal activation of the RAS preceded the development of severe renal fibrosis, suggesting that it contributes to the increased susceptibility to renal injury observed in the elderly. Copyright © 2010 S. Karger AG, Basel.

  5. Angiotensin II promotes development of the renal microcirculation through AT1 receptors

    DEFF Research Database (Denmark)

    Madsen, Kirsten; Marcussen, Niels; Pedersen, Michael

    2010-01-01

    Pharmacologic or genetic deletion of components of the renin-angiotensin system leads to postnatal kidney injury, but the roles of these components in kidney development are unknown. To test the hypothesis that angiotensin II supports angiogenesis during postnatal kidney development, we quantifie...

  6. Post-stroke angiotensin II type 2 receptor activation provides long-term neuroprotection in aged rats

    DEFF Research Database (Denmark)

    Bennion, Douglas M; Isenberg, Jacob D; Harmel, Allison T

    2017-01-01

    Activation of the angiotensin II type 2 receptor (AT2R) by administration of Compound 21 (C21), a selective AT2R agonist, induces neuroprotection in models of ischemic stroke in young adult animals. The mechanisms of this neuroprotective action are varied, and may include direct and indirect....... These findings demonstrate that the neuroprotection previously characterized only during earlier time points using stroke models in young animals is sustained long-term in aged rats, implying even greater clinical relevance for the study of AT2R agonists for the acute treatment of ischemic stroke in human....... Intraperitoneal injections of C21 (0.03mg/kg) after ischemic stroke induced by transient monofilament middle cerebral artery occlusion resulted in protective effects that were sustained for up to at least 3-weeks post-stroke. These included improved neurological function across multiple assessments...

  7. Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPARgamma-modulating activity

    Czech Academy of Sciences Publication Activity Database

    Benson, S. C.; Pershadsingh, H. A.; Ho, C. I.; Chittiboyina, A.; Desai, P.; Pravenec, Michal; Qi, N.; Wang, J.; Avery, M. A.; Kurtz, T. W.

    2004-01-01

    Roč. 43, č. 5 (2004), s. 993-1002 ISSN 0194-911X R&D Projects: GA ČR GA301/01/0278; GA MŠk LN00A079 Grant - others:NIH(US) 2R42AR44767-02A2; NIH(US) HL63709; NIH(US) TW01236 Institutional research plan: CEZ:AV0Z5011922 Keywords : receptors * insulin resistance * losartan Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 5.342, year: 2004

  8. Dopamine D2 Receptor Is Involved in Alleviation of Type II Collagen-Induced Arthritis in Mice.

    Science.gov (United States)

    Lu, Jian-Hua; Liu, Yi-Qian; Deng, Qiao-Wen; Peng, Yu-Ping; Qiu, Yi-Hua

    2015-01-01

    Human and murine lymphocytes express dopamine (DA) D2-like receptors including DRD2, DRD3, and DRD4. However, their roles in rheumatoid arthritis (RA) are less clear. Here we showed that lymphocyte DRD2 activation alleviates both imbalance of T-helper (Th)17/T-regulatory (Treg) cells and inflamed symptoms in a mouse arthritis model of RA. Collagen-induced arthritis (CIA) was prepared by intradermal injection of chicken collagen type II (CII) in tail base of DBA/1 mice or Drd2 (-/-) C57BL/6 mice. D2-like receptor agonist quinpirole downregulated expression of proinflammatory Th17-related cytokines interleukin- (IL-) 17 and IL-22 but further upregulated expression of anti-inflammatory Treg-related cytokines transforming growth factor- (TGF-) β and IL-10 in lymphocytes in vitro and in ankle joints in vivo in CIA mice. Quinpirole intraperitoneal administration reduced both clinical arthritis score and serum anti-CII IgG level in CIA mice. However, Drd2 (-/-) CIA mice manifested more severe limb inflammation and higher serum anti-CII IgG level and further upregulated IL-17 and IL-22 expression and downregulated TGF-β and IL-10 expression than wild-type CIA mice. In contrast, Drd1 (-/-) CIA mice did not alter limb inflammation or anti-CII IgG level compared with wild-type CIA mice. These results suggest that DRD2 activation is involved in alleviation of CIA symptoms by amelioration of Th17/Treg imbalance.

  9. Angiotensin II receptor blocker telmisartan enhances running endurance of skeletal muscle through activation of the PPAR-δ/AMPK pathway.

    Science.gov (United States)

    Feng, Xiaoli; Luo, Zhidan; Ma, Liqun; Ma, Shuangtao; Yang, Dachun; Zhao, Zhigang; Yan, Zhencheng; He, Hongbo; Cao, Tingbing; Liu, Daoyan; Zhu, Zhiming

    2011-07-01

    Clinical trials have shown that angiotensin II receptor blockers reduce the new onset of diabetes in hypertensives; however, the underlying mechanisms remain unknown. We investigated the effects of telmisartan on peroxisome proliferator activated receptor γ (PPAR-δ) and the adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathway in cultured myotubes, as well as on the running endurance of wild-type and PPAR-δ-deficient mice. Administration of telmisartan up-regulated levels of PPAR-δ and phospho-AMPKα in cultured myotubes. However, PPAR-δ gene deficiency completely abolished the telmisartan effect on phospho-AMPKαin vitro. Chronic administration of telmisartan remarkably prevented weight gain, enhanced running endurance and post-exercise oxygen consumption, and increased slow-twitch skeletal muscle fibres in wild-type mice, but these effects were absent in PPAR-δ-deficient mice. The mechanism is involved in PPAR-δ-mediated stimulation of the AMPK pathway. Compared to the control mice, phospho-AMPKα level in skeletal muscle was up-regulated in mice treated with telmisartan. In contrast, phospho-AMPKα expression in skeletal muscle was unchanged in PPAR-δ-deficient mice treated with telmisartan. These findings highlight the ability of telmisartan to improve skeletal muscle function, and they implicate PPAR-δ as a potential therapeutic target for the prevention of type 2 diabetes. © 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

  10. Selective Glucocorticoid Receptor (GR-II Antagonist Reduces Body Weight Gain in Mice

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    Tomoko Asagami

    2011-01-01

    Full Text Available Previous research has shown that mifepristone can prevent and reverse weight gain in animals and human subjects taking antipsychotic medications. This proof-of-concept study tested whether a more potent and selective glucocorticoid receptor antagonist could block dietary-induced weight gain and increase insulin sensitivity in mice. Ten-week-old, male, C57BL/6J mice were fed a diet containing 60% fat calories and water supplemented with 11% sucrose for 4 weeks. Groups (=8 received one of the following: CORT 108297 (80 mg/kg QD, CORT 108297 (40 mg/kg BID, mifepristone (30 mg/kg BID, rosiglitazone (10 mg/kg QD, or vehicle. Compared to mice receiving a high-fat, high-sugar diet plus vehicle, mice receiving a high-fat, high-sugar diet plus either mifepristone or CORT 108297 gained significantly less weight. At the end of the four week treatment period, mice receiving CORT 108297 40 mg/kg BID or CORT 108297 80 mg/kg QD also had significantly lower steady plasma glucose than mice receiving vehicle. However, steady state plasma glucose after treatment was not highly correlated with reduced weight gain, suggesting that the effect of the glucocorticoid receptor antagonist on insulin sensitivity may be independent of its mitigating effect on weight gain.

  11. receptores

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    Salete Regina Daronco Benetti

    2006-01-01

    Full Text Available Se trata de un estudio etnográfico, que tuvo lo objetivo de interpretar el sistema de conocimiento y del significado atribuidos a la sangre referente a la transfusión sanguínea por los donadores y receptores de un banco de sangre. Para la colecta de las informaciones se observaron los participantes y la entrevista etnográfica se realizó el análisis de dominio, taxonómicos y temáticos. Los dominios culturales fueron: la sangre es vida: fuente de vida y alimento valioso; creencias religiosas: fuentes simbólicas de apoyos; donación sanguínea: un gesto colaborador que exige cuidarse, gratifica y trae felicidad; donación sanguínea: fuente simbólica de inseguridad; estar enfermo es una condición para realizar transfusión sanguínea; transfusión sanguínea: esperanza de vida; Creencias populares: transfusión sanguínea como riesgo para la salud; donadores de sangre: personas benditas; donar y recibir sangre: como significado de felicidad. Temática: “líquido precioso que origina, sostiene, modifica la vida, provoca miedo e inseguridad”.

  12. Addition of a Nitric Oxide Donor to an Angiotensin II Type 1 Receptor Blocker May Cancel Its Blood Pressure-Lowering Effects.

    Science.gov (United States)

    Yahiro, Eiji; Miura, Shin-Ichiro; Suematsu, Yasunori; Matsuo, Yoshino; Arimura, Tadaaki; Kuwano, Takashi; Imaizumi, Satoshi; Iwata, Atsushi; Uehara, Yoshinari; Saku, Keijiro

    2015-01-01

    While physiological levels of nitric oxide (NO) protect the endothelium and have vasodilatory effects, excessive NO has adverse effects on the cardiovascular system. Recently, new NO-releasing pharmacodynamic hybrids of angiotensin II (Ang II) type 1 (AT1) receptor blockers (ARBs) have been developed.We analyzed whether olmesartan with NO-donor side chains (Olm-NO) was superior to olmesartan (Olm) for the control of blood pressure (BP). Although there was no significant difference in binding affinity to AT1 wild-type (WT) receptor between Olm and Olm-NO in a cell-based binding assay, the suppressive effect of Olm-NO on Ang II-induced inositol phosphate (IP) production was significantly weaker than that of Olm in AT1 WT receptor-expressing cells. While Olm had a strong inverse agonistic effect on IP production, Olm-NO did not. Next, we divided 18 C57BL mice into 3 groups: Ang II (infusion using an osmotic mini-pump) as a control group, Ang II (n = 6) + Olm, and Ang II (n = 6) + Olm-NO groups (n = 6). Olm-NO did not block Ang II-induced high BP after 10 days, whereas Olm significantly decreased BP. In addition, Olm, but not Olm-NO, significantly reduced the ratio of heart weight to body weight (HW/BW) with downregulation of the mRNA levels of atrial natriuretic peptide.An ARB with a NO-donor may cancel BP-lowering effects probably due to excessive NO and a weak blocking effect by Olm-NO toward AT1 receptor activation.

  13. Absence of transforming growth factor-beta type II receptor is associated with poorer prognosis in HER2-negative breast tumours

    DEFF Research Database (Denmark)

    Paiva, C E; Drigo, S A; Rosa, F E

    2010-01-01

    BACKGROUND: The clinical relevance of transforming growth factor-beta (TGF-beta)-signalling pathway in breast carcinomas (BCs) remained elusive. This study aimed to evaluate the prognostic value of TGF-beta1 and transforming growth factor-beta type II receptor (TGF-betaRII) expression levels in t...

  14. The herpesvirus 8-encoded chemokine vMIP-II, but not the poxvirus-encoded chemokine MC148, inhibits the CCR10 receptor

    DEFF Research Database (Denmark)

    Lüttichau, H R; Lewis, I C; Gerstoft, J

    2001-01-01

    The viral chemokine antagonist vMIP-II encoded by human herpesvirus 8 (HHV8) and MC148 encoded by the poxvirus - Molluscum contagiosum - were tested against the newly identified chemokine receptor CCR10. As the CCR10 ligand ESkine / CCL27 had the highest identity to MC148 and because both...

  15. Effects of angiotensin II receptor blockade on cerebral, cardiovascular, counter-regulatory, and symptomatic responses during hypoglycaemia in patients with type 1 diabetes

    DEFF Research Database (Denmark)

    Færch, Louise H; Thorsteinsson, Birger; Tarnow, Lise

    2015-01-01

    INTRODUCTION: High spontaneous activity of the renin-angiotensin system (RAS) results in more pronounced cognitive impairment and more prolonged QTc interval during hypoglycaemia in type 1 diabetes. We tested whether angiotensin II receptor blockade improves cerebral and cardiovascular function d...

  16. Angiotensin II reduces cardiac AdipoR1 expression through AT1 receptor/ROS/ERK1/2/c-Myc pathway.

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    Li Li

    Full Text Available Adiponectin, an abundant adipose tissue-derived protein, exerts protective effect against cardiovascular disease. Adiponectin receptors (AdipoR1 and AdipoR2 mediate the beneficial effects of adiponectin on the cardiovascular system. However, the alteration of AdipoRs in cardiac remodeling is not fully elucidated. Here, we investigated the effect of angiotensin II (AngII on cardiac AdipoRs expression and explored the possible molecular mechanism. AngII infusion into rats induced cardiac hypertrophy, reduced AdipoR1 but not AdipoR2 expression, and attenuated the phosphorylations of adenosine monophosphate-activated protein kinase and acetyl coenzyme A carboxylase, and those effects were all reversed by losartan, an AngII type 1 (AT1 receptor blocker. AngII reduced expression of AdipoR1 mRNA and protein in cultured neonatal rat cardiomyocytes, which was abolished by losartan, but not by PD123319, an AT2 receptor antagonist. The antioxidants including reactive oxygen species (ROS scavenger NAC, NADPH oxidase inhibitor apocynin, Nox2 inhibitor peptide gp91 ds-tat, and mitochondrial electron transport chain complex I inhibitor rotenone attenuated AngII-induced production of ROS and phosphorylation of extracellular signal-regulated kinase (ERK 1/2. AngII-reduced AdipoR1 expression was reversed by pretreatment with NAC, apocynin, gp91 ds-tat, rotenone, and an ERK1/2 inhibitor PD98059. Chromatin immunoprecipitation assay demonstrated that AngII provoked the recruitment of c-Myc onto the promoter region of AdipoR1, which was attenuated by PD98059. Moreover, AngII-induced DNA binding activity of c-Myc was inhibited by losartan, NAC, apocynin, gp91 ds-tat, rotenone, and PD98059. c-Myc small interfering RNA abolished the inhibitory effect of AngII on AdipoR1 expression. Our results suggest that AngII inhibits cardiac AdipoR1 expression in vivo and in vitro and AT1 receptor/ROS/ERK1/2/c-Myc pathway is required for the downregulation of AdipoR1 induced by AngII.

  17. Use of angiotensin II receptor blockers alone and in combination with other drugs: a large clinical experience trial

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    Matthew R Weir

    2001-03-01

    Full Text Available Angiotensin II (Ang II receptor blockers are the newest class of antihypertensive drugs to be developed. No large-scale clinical trials have been performed to evaluate their efficacy alone, or in combination with other drugs. A large-scale, eight week, open-label, non-placebo-controlled, single-arm trial evaluated the efficacy, tolerability and dose-response of candesartan cilexetil, 16—32 mg once-daily, either as monotherapy or as part of combination therapy, in a diverse hypertensive population in actual practice settings. 6465 patients with high blood pressure, of whom 52% were female and 16% African American, with a mean age of 58 years, were included. 5446 patients had essential hypertension and 1014 patients had isolated systolic hypertension. In order to be included in this study, patients had either untreated or uncontrolled hypertension (systolic blood pressure (SBP 140—179 mmHg and/or diastolic blood pressure (DBP 90—109 mmHg inclusive at baseline, despite a variety of other antihypertensive drugs. Of the 5156 patients with essential hypertension and at least one post baseline efficacy measurement, the mean pretreatment blood pressure (BP was 156/97 mmHg. Candesartan cilexetil monotherapy reduced mean SBP/DBP by 18.0/12.2 mmHg. Similarly, in the 964 patients with isolated systolic hypertension and at least one post baseline efficacy measurement, candesartan cilexetil monotherapy reduced SBP/DBP from 158/81 by 16.5/4.5 mmHg. Candesartan cilexetil was similarly effective when employed as add-on therapy. When added to baseline antihypertensive medication in 51% of the patients with essential hypertension not achieving BP control, additional reduction in BP was achieved regardless of the background therapy, including diuretics (17.8/11.7 mmHg calcium antagonists (16.6/11.2 mmHg, beta-blockers (16.5/10.4 mmHg, angiotensin-converting enzyme inhibitors (ACE-I (15.3/10.0 mmHg, and alpha blockers (16.4/10.4 mmHg. Likewise, when

  18. Inhibition of the 26S proteasome blocks progesterone receptor-dependent transcription through failed recruitment of RNA polymerase II.

    Science.gov (United States)

    Dennis, Andrew P; Lonard, David M; Nawaz, Zafar; O'Malley, Bert W

    2005-03-01

    In the present study, we investigated the involvement of protein degradation via the 26S proteasome during progesterone receptor (PR)-mediated transcription in T-47D cells containing a stably integrated MMTV-CAT reporter construct (CAT0 cells). Progesterone induced CAT and HSD11beta2 transcription while co-treatment with the proteasome inhibitor, MG132, blocked PR-induced transcription in a time-dependent fashion. MG132 treatment also inhibited transcription of beta-actin and cyclophilin, but not two proteasome subunit genes, PSMA1 and PSMC1, indicating that proteasome inhibition affects a subset of RNA polymerase II (RNAP(II))-regulated genes. Progesterone-mediated recruitment of RNAP(II) was blocked by MG132 treatment at time points later than 1 h that was not dependent on the continued presence of PR, associated cofactors, and components of the general transcription machinery, supporting the concept that proteasome-mediated degradation is needed for continued transcription. Surprisingly, progesterone-mediated acetylation of histone H4 was inhibited by MG132 with the concomitant recruitment of HDAC3, NCoR, and SMRT. We demonstrate that the steady-state protein levels of SMRT and NCoR are higher in the presence of MG132 in CAT0 cells, consistent with other reports that SMRT and NCoR are targets of the 26S proteasome. However, inhibition of histone deacetylation by trichostatin A (TSA) treatment or SMRT/NCoR knockdown by siRNA did not restore MG132-inhibited progesterone-dependent transcription. Therefore, events other than histone deacetylation and stability of SMRT and NCoR must also play a role in inhibition of PR-mediated transcription.

  19. Ruthenium(II) 2,2'-bibenzimidazole complex as a second-sphere receptor for anions interaction and colorimeter.

    Science.gov (United States)

    Cui, Ying; Niu, Yan-Li; Cao, Man-Li; Wang, Ke; Mo, Hao-Jun; Zhong, Yong-Rui; Ye, Bao-Hui

    2008-07-07

    A ruthenium(II) complex [Ru(bpy) 2(H 2bbim)](PF 6) 2 ( 1) as anions receptor has been exploited, where Ru(II)-bpy moiety acts as a chromophore and the H 2bbim ligand as an anion binding site. A systematic study suggests that 1 interacts with the Cl (-), Br (-), I (-), NO 3 (-), HSO 4 (-), and H 2PO 4 (-) anions via the formation of hydrogen bonds. Whereas 1 undergoes a stepwise process with the addition of F (-) and OAc (-) anions: formation of the monodeprotonated complex [Ru(bpy) 2(Hbbim)] with a low anion concentration, followed by the double-deprotonated complex [Ru(bpy) 2(bbim)], in the presence of a high anion concentration. These stepwise processes concomitant with the changes of vivid colors from yellow to orange brown and then to violet can be used for probing the F (-) and OAc (-) anions by naked eye. The deprotonation processes are not only determined by the basicity of the anion but also related to the strength of hydrogen bonding, as well as the stability of the formed compounds. Moreover, a double-deprotonated complex [Ru(bpy) 2(bbim)].CH 3OH.H 2O ( 3) has been synthesized, and the structural changes induced by the deprotonation has also been investigated. In addition, complexes [Ru(bpy) 2(Hbbim)] 2(HOAc) 3Cl 2.12H 2O ( 2), [Ru(bpy) 2(Hbbim)](HCCl 3CO 2)(CCl 3CO 2).2H 2O ( 4), and [Ru(bpy) 2(H 2bbim)](CF 3CO 2) 2.4H 2O ( 5) have been synthesized to observe the second sphere coordination between the Ru(II)-H 2bbim moiety and carboxylate groups via hydrogen bonds in the solid state.

  20. Gene expression profiling associated with angiotensin II type 2 receptor-induced apoptosis in human prostate cancer cells.

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    Nana Pei

    Full Text Available Increased expression of angiotensin II type 2 receptor (AT2R induces apoptosis in numerous tumor cell lines, with either Angiotensin II-dependent or Angiotensin II-independent regulation, but its molecular mechanism remains poorly understood. Here, we used PCR Array analysis to determine the gene and microRNA expression profiles in human prostate cancer cell lines transduced with AT2R recombinant adenovirus. Our results demonstrated that AT2R over expression leads to up-regulation of 6 apoptosis-related genes (TRAIL-R2, BAG3, BNIPI, HRK, Gadd45a, TP53BP2, 2 cytokine genes (IL6 and IL8 and 1 microRNA, and down-regulation of 1 apoptosis-related gene TNFSF10 and 2 cytokine genes (BMP6, BMP7 in transduced DU145 cells. HRK was identified as an up-regulated gene in AT2R-transduced PC-3 cells by real-time RT-PCR. Next, we utilized siRNAs to silence the up-regulated genes to further determine their roles on AT2R overexpression mediated apoptosis. The results showed downregulation of Gadd45a reduced the apoptotic effect by ∼30% in DU145 cells, downregulation of HRK reduced AT2R-mediated apoptosis by more than 50% in PC-3 cells, while downregulation of TRAIL-R2 enhanced AT2R-mediated apoptosis more than 4 times in DU145 cells. We also found that the effects on AT2R-mediated apoptosis caused by downregulation of Gadd45a, TRAIL-R2 and HRK were independent in activation of p38 MAPK, p44/42 MAPK and p53. Taken together, our results demonstrated that TRAIL-R2, Gadd45a and HRK may be novel target genes for further study of the mechanism of AT2R-mediated apoptosis in prostate cancer cells.

  1. C4d-negative antibody-mediated rejection with high anti-angiotensin II type I receptor antibodies in absence of donor-specific antibodies.

    Science.gov (United States)

    Fuss, Alexander; Hope, Christopher M; Deayton, Susan; Bennett, Greg Donald; Holdsworth, Rhonda; Carroll, Robert P; Coates, P Toby H

    2015-07-01

    Acute antibody-mediated rejection can occur in absence of circulating donor-specific antibodies. Agonistic antibodies targeting the anti-angiotensin II type 1 receptor (anti-AT1 R) are emerging as important non-human leucocyte antigen (HLA) antibodies. Elevated levels of anti-angiotensin II receptor antibodies were first observed in kidney transplant recipients with malignant hypertension and allograft rejection. They have now been studied in three separate kidney transplant populations and associate to frequency of rejection, severity of rejection and graft failure. We report 11 cases of biopsy-proven, Complement 4 fragment d (C4d)-negative, acute rejection occurring without circulating donor-specific anti-HLA antibodies. In eight cases, anti-angiotensin receptor antibodies were retrospectively examined. The remaining three subjects were identified from our centre's newly instituted routine anti-angiotensin receptor antibody screening. All subjects fulfilled Banff 2013 criteria for antibody-mediated rejection and all responded to anti-rejection therapy, which included plasma exchange and angiotensin receptor blocker therapy. These cases support the routine assessment of anti-AT1 R antibodies in kidney transplant recipients to identify subjects at risk. Further studies will need to determine optimal assessment protocol and the effectiveness of pre-emptive treatment with angiotensin receptor blockers. © 2015 Asian Pacific Society of Nephrology.

  2. Myostatin, follistatin and activin type II receptors are highly expressed in adenomyosis.

    Science.gov (United States)

    Carrarelli, Patrizia; Yen, Chih-Fen; Arcuri, Felice; Funghi, Lucia; Tosti, Claudia; Wang, Tzu-Hao; Huang, Joseph S; Petraglia, Felice

    2015-09-01

    To evaluate the expression pattern of activins and related growth factor messenger RNA (mRNA) levels in adenomyotic nodules and in their endometrium. Prospective study. University hospital. Symptomatic premenopausal women scheduled to undergo hysterectomy for adenomyosis. Samples from adenomyotic nodules and homologous endometria were collected. Endometrial tissue was also obtained from a control group. Quantitative real-time polymerase chain reaction (PCR) analysis and immunohistochemical localization of activin-related growth factors (activin A, activin B, and myostatin), binding protein (follistatin), antagonists (inhibin-α, cripto), and receptors (ActRIIa, ActRIIb) were performed. Myostatin mRNA levels in adenomyotic nodule were higher than in eutopic endometrium and myostatin, activin A, and follistatin concentrations were higher than in control endometrium. No difference was observed for inhibin-α, activin B, and cripto mRNA levels. Increased mRNA levels of ActRIIa and ActRIIb were observed in adenomyotic nodules compared with eutopic endometrium and control endometrium. Immunofluorescent staining for myostatin and follistatin confirmed higher protein expression in both glands and stroma of patients with adenomyosis than in controls. The present study showed for the first time that adenomyotic tissues express high levels of myostatin, follistatin, and activin A (growth factors involved in proliferation, apoptosis, and angiogenesis). Increased expression of their receptors supports the hypothesis of a possible local effect of these growth factors in adenomyosis. The augmented expression of ActRIIa, ActRIIb, and follistatin in the endometrium of these patients may play a role in adenomyosis-related infertility. Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  3. Keeping pace with ACE: are ACE inhibitors and angiotensin II type 1 receptor antagonists potential doping agents?

    Science.gov (United States)

    Wang, Pei; Fedoruk, Matthew N; Rupert, Jim L

    2008-01-01

    In the decade since the angiotensin-converting enzyme (ACE) gene was first proposed to be a 'human gene for physical performance', there have been numerous studies examining the effects of ACE genotype on physical performance phenotypes such as aerobic capacity, muscle function, trainability, and athletic status. While the results are variable and sometimes inconsistent, and corroborating phenotypic data limited, carriers of the ACE 'insertion' allele (the presence of an alu repeat element in intron 16 of the gene) have been reported to have higher maximum oxygen uptake (VO2max), greater response to training, and increased muscle efficiency when compared with individuals carrying the 'deletion' allele (absence of the alu repeat). Furthermore, the insertion allele has been reported to be over-represented in elite athletes from a variety of populations representing a number of endurance sports. The mechanism by which the ACE insertion genotype could potentiate physical performance is unknown. The presence of the ACE insertion allele has been associated with lower ACE activity (ACEplasma) in number of studies, suggesting that individuals with an innate tendency to have lower ACE levels respond better to training and are at an advantage in endurance sporting events. This could be due to lower levels of angiotensin II (the vasoconstrictor converted to active form by ACE), higher levels of bradykinin (a vasodilator degraded by ACE) or some combination of the two phenotypes. Observations that individuals carrying the ACE insertion allele (and presumably lower ACEplasma) have an enhanced response to training or are over-represented amongst elite athletes raises the intriguing question: would individuals with artificially lowered ACEplasma have similar training or performance potential? As there are a number of drugs (i.e. ACE inhibitors and angiotensin II type 1 receptor antagonists [angiotensin receptor blockers--ARBs]) that have the ability to either reduce ACEplasma

  4. Angiotensin II type 1 and 2 receptors and lymphatic vessels modulate lung remodeling and fibrosis in systemic sclerosis and idiopathic pulmonary fibrosis.

    Science.gov (United States)

    Parra, Edwin Roger; Ruppert, Aline Domingos Pinto; Capelozzi, Vera Luiza

    2014-01-01

    To validate the importance of the angiotensin II receptor isotypes and the lymphatic vessels in systemic sclerosis and idiopathic pulmonary fibrosis. We examined angiotensin II type 1 and 2 receptors and lymphatic vessels in the pulmonary tissues obtained from open lung biopsies of 30 patients with systemic sclerosis and 28 patients with idiopathic pulmonary fibrosis. Their histologic patterns included cellular and fibrotic non-specific interstitial pneumonia for systemic sclerosis and usual interstitial pneumonia for idiopathic pulmonary fibrosis. We used immunohistochemistry and histomorphometry to evaluate the number of cells in the alveolar septae and the vessels stained by these markers. Survival curves were also used. We found a significantly increased percentage of septal and vessel cells immunostained for the angiotensin type 1 and 2 receptors in the systemic sclerosis and idiopathic pulmonary fibrosis patients compared with the controls. A similar percentage of angiotensin 2 receptor positive vessel cells was observed in fibrotic non-specific interstitial pneumonia and usual interstitial pneumonia. A significantly increased percentage of lymphatic vessels was present in the usual interstitial pneumonia group compared with the non-specific interstitial pneumonia and control groups. A Cox regression analysis showed a high risk of death for the patients with usual interstitial pneumonia and a high percentage of vessel cells immunostained for the angiotensin 2 receptor in the lymphatic vessels. We concluded that angiotensin II receptor expression in the lung parenchyma can potentially control organ remodeling and fibrosis, which suggests that strategies aimed at preventing high angiotensin 2 receptor expression may be used as potential therapeutic target in patients with pulmonary systemic sclerosis and idiopathic pulmonary fibrosis.

  5. Decreased plasma levels of factor II + VII + X correlate with increased levels of soluble cytokine receptors in patients with malaria and meningococcal infections

    DEFF Research Database (Denmark)

    Bygbjerg, I C; Hansen, M B; Rønn, A M

    1997-01-01

    The levels of coagulation factors II + VII + X and of blood platelets (thrombocytes) as well as of cytokines and soluble cytokine receptors were studied in the patients with malaria or meningococcal infections. The coagulation factors were decreased particularly in the meningococcal patients, while...... thrombocytes were lowest in the Plasmodium falciparum malaria patients. There was no correlation between factors II + VII + X and thrombocytes, but plasma levels of coagulation factors II + VII + X were found to correlate inversely with levels of soluble interleukin-2 receptor (sIL-2R) and soluble tumour...... necrosis factor-I (sTNF-RI) in patients with malaria and meningococcal infections. Elevated sIL-2R and sTNF-RI levels and decreased coagulation factors reverted to normal within 3-5 days after initiation of therapy in P. falciparum patients followed consecutively. Estimation of coagulation factors may...

  6. Adição de Bloqueador do receptor de angiotensina II na insuficiência cardíaca descompensada Adición de bloqueante del receptor de angiotensina II en la insuficiencia cardiaca descompensada Angiotensin II receptor blocker add-on therapy for low cardiac output in decompensated heart failure

    Directory of Open Access Journals (Sweden)

    Marcelo E. Ochiai

    2010-02-01

    Full Text Available FUNDAMENTO: Durante a descompensação da insuficiência cardíaca, ocorre uma intensa ativação do sistema renina-angiotensina-aldosterona, entretanto, o uso de inibidor da enzima de conversão de angiotensina (IECA não pode bloqueá-lo completamente. De outro modo, a adição de bloqueador do receptor de angiotensina II (BRA pode ser útil quando ocorre a dependência de inotrópico. Avaliamos a eficiência da associação BRA-IECA para retirada da dobutamina na insuficiência cardíaca avançada e descompensada. OBJETIVO: Avaliar a eficácia da associação de bloqueador do receptor AT1 de angiotensina II ao inibidor de enzima de conversão, para a retirada da dobutamina em pacientes com dependência de suporte inotrópico decorrente da descompensação aguda da insuficiência cardíaca crônica. MÉTODOS: Em um estudo caso-controle (N = 24, selecionamos pacientes internados por descompensação da insuficiência cardíaca e com uso por mais de 15 dias de dobutamina, ou uma ou mais tentativas sem sucesso de retirada; dose otimizada de IECA; e FEVE FUNDAMENTO: Durante la descompensación de la insuficiencia cardiaca, ocurre una intensa activación del sistema renina-angiotensina-aldosterona, sin embargo, el empleo de inhibidor de la enzima de conversión de angiotensina (IECA no puede bloquearlo completamente. De otro modo, la adición de bloqueante del receptor de angiotensina II (BRA puede ser útil cuando ocurre la dependencia de inotrópico. Evaluamos la eficiencia de la asociación BRA-IECA para retirada de la dobutamina en la insuficiencia cardiaca avanzada y descompensada. OBJETIVO: Evaluar la eficacia de la asociación de bloqueante del receptor AT1 de angiotensina II al inhibidor de enzima de conversión, para la retirada de la dobutamina en pacientes con dependencia de soporte inotrópico que trascurre de la descompensación aguda de la insuficiencia cardiaca crónica. MÉTODOS: En un estudio caso-control (N = 24, seleccionamos a

  7. Angiotensin II receptor blocker ameliorates stress-induced adipose tissue inflammation and insulin resistance.

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    Motoharu Hayashi

    Full Text Available A strong causal link exists between psychological stress and insulin resistance as well with hypertension. Meanwhile, stress-related responses play critical roles in glucose metabolism in hypertensive patients. As clinical trials suggest that angiotensin-receptor blocker delays the onset of diabetes in hypertensive patients, we investigated the effects of irbesartan on stress-induced adipose tissue inflammation and insulin resistance. C57BL/6J mice were subjected to 2-week intermittent restraint stress and orally treated with vehicle, 3 and 10 mg/kg/day irbesartan. The plasma concentrations of lipid and proinflammatory cytokines [Monocyte Chemoattractant Protein-1 (MCP-1, tumor necrosis factor-α, and interleukin-6] were assessed with enzyme-linked immunosorbent assay. Monocyte/macrophage accumulation in inguinal white adipose tissue (WAT was observed with CD11b-positive cell counts and mRNA expressions of CD68 and F4/80 using immunohistochemistry and RT-PCR methods respectively. The mRNA levels of angiotensinogen, proinflammatory cytokines shown above, and adiponectin in WAT were also assessed with RT-PCR method. Glucose metabolism was assessed by glucose tolerance tests (GTTs and insulin tolerance tests, and mRNA expression of insulin receptor substrate-1 (IRS-1 and glucose transporter 4 (GLUT4 in WAT. Restraint stress increased monocyte accumulation, plasma free fatty acids, expression of angiotensinogen and proinflammatory cytokines including MCP-1, and reduced adiponectin. Irbesartan reduced stress-induced monocyte accumulation in WAT in a dose dependent manner. Irbesartan treatment also suppressed induction of adipose angiotensinogen and proinflammatory cytokines in WAT and blood, and reversed changes in adiponectin expression. Notably, irbesartan suppressed stress-induced reduction in adipose tissue weight and free fatty acid release, and improved insulin tolerance with restoration of IRS-1 and GLUT4 mRNA expressions in WAT. The results

  8. The Second Transmembrane Domain of the Human Type 1 Angiotensin II Receptor Participates in the Formation of the Ligand Binding Pocket and Undergoes Integral Pivoting Movement during the Process of Receptor Activation*

    Science.gov (United States)

    Domazet, Ivana; Holleran, Brian J.; Martin, Stéphane S.; Lavigne, Pierre; Leduc, Richard; Escher, Emanuel; Guillemette, Gaétan

    2009-01-01

    The octapeptide hormone angiotensin II (AngII) exerts a wide variety of cardiovascular effects through the activation of the angiotensin II type-1 (AT1) receptor, which belongs to the G protein-coupled receptor superfamily. Like other G protein-coupled receptors, the AT1 receptor possesses seven transmembrane domains that provide structural support for the formation of the ligand-binding pocket. In order to identify those residues in the second transmembrane domain (TMD2) that contribute to the formation of the binding pocket of the AT1 receptor, we used the substituted cysteine accessibility method. All of the residues within the Leu-70 to Trp-94 region were mutated one at a time to a cysteine, and, after expression in COS-7 cells, the mutant receptors were treated with the sulfhydryl-specific alkylating agent methanethiosulfonate-ethylammonium (MTSEA). MTSEA reacts selectively with water-accessible, free sulfhydryl groups of endogenous or introduced point mutation cysteines. If a cysteine is found in the binding pocket, the covalent modification will affect the binding kinetics of the ligand. MTSEA substantially decreased the binding affinity of D74C-AT1, L81C-AT1, A85C-AT1, T88C-AT1, and A89C-AT1 mutant receptors, which suggests that these residues orient themselves within the water-accessible binding pocket of the AT1 receptor. Interestingly, this pattern of acquired MTSEA sensitivity was altered for TMD2 reporter cysteines engineered in a constitutively active N111G-AT1 receptor background. Indeed, mutant D74C-N111G-AT1 became insensitive to MTSEA, whereas mutant L81C-N111G-AT1 lost some sensitivity and mutant V86C-N111G-AT1 became sensitive to MTSEA. Our results suggest that constitutive activation of the AT1 receptor causes TMD2 to pivot, bringing the top of TMD2 closer to the binding pocket and pushing the bottom of TMD2 away from the binding pocket. PMID:19276075

  9. The second transmembrane domain of the human type 1 angiotensin II receptor participates in the formation of the ligand binding pocket and undergoes integral pivoting movement during the process of receptor activation.

    Science.gov (United States)

    Domazet, Ivana; Holleran, Brian J; Martin, Stéphane S; Lavigne, Pierre; Leduc, Richard; Escher, Emanuel; Guillemette, Gaétan

    2009-05-01

    The octapeptide hormone angiotensin II (AngII) exerts a wide variety of cardiovascular effects through the activation of the angiotensin II type-1 (AT(1)) receptor, which belongs to the G protein-coupled receptor superfamily. Like other G protein-coupled receptors, the AT(1) receptor possesses seven transmembrane domains that provide structural support for the formation of the ligand-binding pocket. In order to identify those residues in the second transmembrane domain (TMD2) that contribute to the formation of the binding pocket of the AT(1) receptor, we used the substituted cysteine accessibility method. All of the residues within the Leu-70 to Trp-94 region were mutated one at a time to a cysteine, and, after expression in COS-7 cells, the mutant receptors were treated with the sulfhydryl-specific alkylating agent methanethiosulfonate-ethylammonium (MTSEA). MTSEA reacts selectively with water-accessible, free sulfhydryl groups of endogenous or introduced point mutation cysteines. If a cysteine is found in the binding pocket, the covalent modification will affect the binding kinetics of the ligand. MTSEA substantially decreased the binding affinity of D74C-AT(1), L81C-AT(1), A85C-AT(1), T88C-AT(1), and A89C-AT(1) mutant receptors, which suggests that these residues orient themselves within the water-accessible binding pocket of the AT(1) receptor. Interestingly, this pattern of acquired MTSEA sensitivity was altered for TMD2 reporter cysteines engineered in a constitutively active N111G-AT(1) receptor background. Indeed, mutant D74C-N111G-AT(1) became insensitive to MTSEA, whereas mutant L81C-N111G-AT(1) lost some sensitivity and mutant V86C-N111G-AT(1) became sensitive to MTSEA. Our results suggest that constitutive activation of the AT(1) receptor causes TMD2 to pivot, bringing the top of TMD2 closer to the binding pocket and pushing the bottom of TMD2 away from the binding pocket.

  10. Chimeric Feline Coronaviruses That Encode Type II Spike Protein on Type I Genetic Background Display Accelerated Viral Growth and Altered Receptor Usage▿

    Science.gov (United States)

    Tekes, Gergely; Hofmann-Lehmann, Regina; Bank-Wolf, Barbara; Maier, Reinhard; Thiel, Heinz-Jürgen; Thiel, Volker

    2010-01-01

    Persistent infection of domestic cats with feline coronaviruses (FCoVs) can lead to a highly lethal, immunopathological disease termed feline infectious peritonitis (FIP). Interestingly, there are two serotypes, type I and type II FCoVs, that can cause both persistent infection and FIP, even though their main determinant of host cell tropism, the spike (S) protein, is of different phylogeny and displays limited sequence identity. In cell culture, however, there are apparent differences. Type II FCoVs can be propagated to high titers by employing feline aminopeptidase N (fAPN) as a cellular receptor, whereas the propagation of type I FCoVs is usually difficult, and the involvement of fAPN as a receptor is controversial. In this study we have analyzed the phenotypes of recombinant FCoVs that are based on the genetic background of type I FCoV strain Black but encode the type II FCoV strain 79-1146 S protein. Our data demonstrate that recombinant FCoVs expressing a type II FCoV S protein acquire the ability to efficiently use fAPN for host cell entry and corroborate the notion that type I FCoVs use another main host cell receptor. We also observed that recombinant FCoVs display a large-plaque phenotype and, unexpectedly, accelerated growth kinetics indistinguishable from that of type II FCoV strain 79-1146. Thus, the main phenotypic differences for type I and type II FCoVs in cell culture, namely, the growth kinetics and the efficient usage of fAPN as a cellular receptor, can be attributed solely to the FCoV S protein. PMID:19906918

  11. Bg1II polymorphism of the epidermal growth factor receptor (EGF-R) gene

    Energy Technology Data Exchange (ETDEWEB)

    Biunno, I; Pozzi, M R; Radice, P; Mondini, P; Pierotti, M A; Porta, G D [Istituto Nazionale Tumori, Milan (Italy); Haley, J; Waterfield, M D [Ludwig Institute for Cancer Research, London (England)

    1988-08-11

    A 770 bp cDNA fragment was derived from the cytoplasmic portion of the EGF-R (ref. Libermann et al., 1985). Bg1II identifies 4 invariant bands of 7.0, 5.0, 3.5 and 1.2 kb and a two allele polymorphism with a band of either 10.6 kb (lane 1) or 9.4 kb (lane 3). An heterozygote individual is represented. The frequency was analyzed in 78 unrelated European Caucasians. Its chromosomal location was determined. Co-dominant segregation was demonstrated in three families of 12 individuals. A rare variant of 8.3 kb was seen in one chromosome out of the 144 examined. This allelic form has not yet been fully characterized.

  12. Effect angiotensin II receptor blockers on glomerular filtration rate in patients with incipient diabetic nephropathy

    International Nuclear Information System (INIS)

    Dragovic, T.; Ajdinovic, B.; Endocrinology Clinic

    2004-01-01

    Glomerular filtration rate (GFR) was calculated in patients with incipient diabetic nephropathy with an aim to evaluate the effect of angiotensin receptor blockator valsartan on GFR stabilisation to physiological levels. Investigation was done as a prospective, randomised, placebo controlled study, on 20 patients with diabetes mellitus, type I (age 25 years, disease lasting 14 years). In all patients was detected incipient diabetic nephropathy with daily urinary albumin excretion in range from 30 mg to 300 mg. Patients were randomised in two groups: 10 patients were treated with 80 mg /day valsartan, during 6 months, second group (10 patients) were on placebo at the same period. GFR, as a clearance of 51Cr-EDTA, was calculated at the start and at the end of the study. In the first patients group during investigation period, GFR was decreased from 150, 1 ml/min/1.73m 2 to physiological level of 127 ml/min/1,73m 2 (p 2 at the start, 139,9 ml/min/l.73m 2 at the end of the study).On the basis of these results it was concluded that 80 mg/day in 6 month valsartan therapy decreased GFR to physiological levels in patients with incipient diabetic nephropathy. (authors)

  13. Circulating angiotensin type II receptor: Possible marker for antibody mediated rejection after renal transplantation?

    Science.gov (United States)

    Kimball, Pamela M; Gupta, Gaurav; McDougan, Felecia

    2017-10-01

    Presence of antibody [Ab] against angiotensin receptor [AT1R] indicates heightened risk for antibody mediated rejection [AMR] after transplantation but is insufficient as a marker. We speculated AT1R might be released systemically because of AMR and might be a useful biomarker. AT1R was measured in blood from 73 Normals and 72 renal patients pre- and post-transplantation. Patients were stratified as AMR-free [Gp1], AMR1yr [Gp3]. AT1R was higher [13±26vs.367±537, p<0.01)] and more prevalent [20% vs. 92%, p<0.01] among renal patients than Normals. Pretransplant levels were similar [p=ns] between groups. One-year posttransplant levels approached [p<0.01] normalcy for Gps1+3 but spiked during AMR and remained elevated [155±58, p<0.01] for 50% Gp2 patients. One-year AT1R levels were higher among subsequent graft failures than surviving grafts [171±267vs. 38±50, p<0.01]. Pretransplant AT1R was abnormally elevated: possibly indicating ongoing tissue injury. Pretransplant AT1R didn't predict risk for AMR. However, AT1R spiked during early AMR and sustained elevations were associated with poorer outcomes. Copyright © 2017. Published by Elsevier Inc.

  14. Discovery of a Series of Imidazo[4,5-b]pyridines with Dual Activity at Angiotensin II Type 1 Receptor and Peroxisome Proliferator-Activated Receptor-[gamma

    Energy Technology Data Exchange (ETDEWEB)

    Casimiro-Garcia, Agustin; Filzen, Gary F.; Flynn, Declan; Bigge, Christopher F.; Chen, Jing; Davis, Jo Ann; Dudley, Danette A.; Edmunds, Jeremy J.; Esmaeil, Nadia; Geyer, Andrew; Heemstra, Ronald J.; Jalaie, Mehran; Ohren, Jeffrey F.; Ostroski, Robert; Ellis, Teresa; Schaum, Robert P.; Stoner, Chad (Pfizer)

    2013-03-07

    Mining of an in-house collection of angiotensin II type 1 receptor antagonists to identify compounds with activity at the peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}) revealed a new series of imidazo[4,5-b]pyridines 2 possessing activity at these two receptors. Early availability of the crystal structure of the lead compound 2a bound to the ligand binding domain of human PPAR{gamma} confirmed the mode of interaction of this scaffold to the nuclear receptor and assisted in the optimization of PPAR{gamma} activity. Among the new compounds, (S)-3-(5-(2-(1H-tetrazol-5-yl)phenyl)-2,3-dihydro-1H-inden-1-yl)-2-ethyl-5-isobutyl-7-methyl-3H-imidazo[4,5-b]pyridine (2l) was identified as a potent angiotensin II type I receptor blocker (IC{sub 50} = 1.6 nM) with partial PPAR{gamma} agonism (EC{sub 50} = 212 nM, 31% max) and oral bioavailability in rat. The dual pharmacology of 2l was demonstrated in animal models of hypertension (SHR) and insulin resistance (ZDF rat). In the SHR, 2l was highly efficacious in lowering blood pressure, while robust lowering of glucose and triglycerides was observed in the male ZDF rat.

  15. Dopamine D2 Receptor Is Involved in Alleviation of Type II Collagen-Induced Arthritis in Mice

    Directory of Open Access Journals (Sweden)

    Jian-Hua Lu

    2015-01-01

    Full Text Available Human and murine lymphocytes express dopamine (DA D2-like receptors including DRD2, DRD3, and DRD4. However, their roles in rheumatoid arthritis (RA are less clear. Here we showed that lymphocyte DRD2 activation alleviates both imbalance of T-helper (Th17/T-regulatory (Treg cells and inflamed symptoms in a mouse arthritis model of RA. Collagen-induced arthritis (CIA was prepared by intradermal injection of chicken collagen type II (CII in tail base of DBA/1 mice or Drd2−/− C57BL/6 mice. D2-like receptor agonist quinpirole downregulated expression of proinflammatory Th17-related cytokines interleukin- (IL- 17 and IL-22 but further upregulated expression of anti-inflammatory Treg-related cytokines transforming growth factor- (TGF- β and IL-10 in lymphocytes in vitro and in ankle joints in vivo in CIA mice. Quinpirole intraperitoneal administration reduced both clinical arthritis score and serum anti-CII IgG level in CIA mice. However, Drd2−/− CIA mice manifested more severe limb inflammation and higher serum anti-CII IgG level and further upregulated IL-17 and IL-22 expression and downregulated TGF-β and IL-10 expression than wild-type CIA mice. In contrast, Drd1−/− CIA mice did not alter limb inflammation or anti-CII IgG level compared with wild-type CIA mice. These results suggest that DRD2 activation is involved in alleviation of CIA symptoms by amelioration of Th17/Treg imbalance.

  16. Pitting type of pretibial edema in a patient with silent thyroiditis successfully treated by angiotensin ii receptor blockade.

    Science.gov (United States)

    Kazama, Itsuro; Mori, Yoko; Baba, Asuka; Nakajima, Toshiyuki

    2014-01-01

    Female, 56 FINAL DIAGNOSIS: Thyroiditis - silent Symptoms: Palpitations • pretibial pitting edema • short of breath • sweating - Clinical Procedure: - Specialty: Endocrinology and Metabolic. Unknown etiology. Hyper- or hypothyroidism sometimes causes pretibial myxedema characterized by non-pitting infiltration of a proteinaceous ground substance. However, in those patients, the "pitting" type of pretibial edema as a result of increased sodium and fluid retention or vascular hyper-permeability rarely occurs, except in cases complicated by heart failures due to severe cardiomyopathy or pulmonary hypertension. A 56-year-old woman developed bilateral pretibial pitting edema, followed by occasional sweating, palpitations, and shortness of breath, which persisted for more than 2 months. The diagnosis of hyperthyroidism due to silent thyroiditis was supported by elevated levels of free thyroxine (T4) and triiodothyronine (T3), with a marked decrease in thyroid-stimulating hormone (TSH), and the negative results for TSH receptor antibodies with typical findings of destructive thyrotoxicosis. Despite her "pitting" type of pretibial edema, a chest radio-graph demonstrated the absence of cardiomyopathy or congestive heart failure. Oral administration of angiotensin II receptor blocker (ARB) was initiated for her systolic hypertension, with a relatively higher elevation of plasma renin activity compared to that of the aldosterone level. Although the symptoms characteristic to hyperthyroidism, such as increased sweating, palpitations and shortness of breath, slowly improved with a spontaneous resolution of the disease, ARB quickly resolved the pretibial pitting edema shortly after the administration.. In this case, increased activity of the renin-angiotensin-aldosterone system stimulated by thyroid hormone was likely responsible for the patient's pitting type of edema. The pharmacological blockade of the renin-angiotensin-aldosterone system was thought to be effective for

  17. PI3K class II α regulates δ-opioid receptor export from the trans-Golgi network.

    Science.gov (United States)

    Shiwarski, Daniel J; Darr, Marlena; Telmer, Cheryl A; Bruchez, Marcel P; Puthenveedu, Manojkumar A

    2017-08-01

    The interplay between signaling and trafficking by G protein-coupled receptors (GPCRs) has focused mainly on endocytic trafficking. Whether and how surface delivery of newly synthesized GPCRs is regulated by extracellular signals is less understood. Here we define a signaling-regulated checkpoint at the trans -Golgi network (TGN) that controls the surface delivery of the delta opioid receptor (δR). In PC12 cells, inhibition of phosphoinositide-3 kinase (PI3K) activity blocked export of newly synthesized δR from the Golgi and delivery to the cell surface, similar to treatment with nerve growth factor (NGF). Depletion of class II phosphoinositide-3 kinase α (PI3K C2A), but not inhibition of class I PI3K, blocked δR export to comparable levels and attenuated δR-mediated cAMP inhibition. NGF treatment displaced PI3K C2A from the Golgi and optogenetic recruitment of the PI3K C2A kinase domain to the TGN-induced δR export downstream of NGF. Of importance, PI3K C2A expression promotes export of endogenous δR in primary trigeminal ganglion neurons. Taken together, our results identify PI3K C2A as being required and sufficient for δR export and surface delivery in neuronal cells and suggest that it could be a key modulator of a novel Golgi export checkpoint that coordinates GPCR delivery to the surface. © 2017 Shiwarski et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

  18. Novel and validated titrimetric method for determination of selected angiotensin-II-receptor antagonists in pharmaceutical preparations and its comparison with UV spectrophotometric determination

    Directory of Open Access Journals (Sweden)

    Shrikant H. Patil

    2012-12-01

    Full Text Available A novel and simple titrimetric method for determination of commonly used angiotensin-II-receptor antagonists (ARA-IIs is developed and validated. The direct acid base titration of four ARA-IIs, namely eprosartan mesylate, irbesartan, telmisartan and valsartan, was carried out in the mixture of ethanol:water (1:1 as solvent using standardized sodium hydroxide aqueous solution as titrant, either visually using phenolphthalein as an indicator or potentiometrically using combined pH electrode. The method was found to be accurate and precise, having relative standard deviation of less than 2% for all ARA-IIs studied. Also, it was shown that the method could be successfully applied to the assay of commercial pharmaceuticals containing the above-mentioned ARA-IIs. The validity of the method was tested by the recovery studies of standard addition to pharmaceuticals and the results were found to be satisfactory. Results obtained by this method were found to be in good agreement with those obtained by UV spectrophotometric method. For UV spectrophotometric analysis ethanol was used as a solvent and wavelength of 233 nm, 246 nm, 296 nm, and 250 nm was selected for determination of eprosartan mesylate, irbesartan, telmisartan, and valsartan respectively. The proposed titrimetric method is simple, rapid, convenient and sufficiently precise for quality control purposes. Keywords: Angiotensin-II-receptor antagonists, Titrimetric assay, UV spectrophotometry, Validation

  19. Combined blockade of angiotensin II and prorenin receptors ameliorates podocytic apoptosis induced by IgA-activated mesangial cells.

    Science.gov (United States)

    Leung, Joseph C K; Chan, Loretta Y Y; Saleem, M A; Mathieson, P W; Tang, Sydney C W; Lai, Kar Neng

    2015-07-01

    Glomerulo-podocytic communication plays an important role in the podocytic injury in IgA nephropathy (IgAN). In this study, we examine the role of podocytic angiotensin II receptor subtype 1 (AT1R) and prorenin receptor (PRR) in podocytic apoptosis in IgAN. Polymeric IgA (pIgA) was isolated from patients with IgAN and healthy controls. Conditioned media were prepared from growth arrested human mesangial cells (HMC) incubated with pIgA from patients with IgAN (IgA-HMC media) or healthy controls (Ctl-HMC media). A human podocyte cell line was used as a model to examine the regulation of the expression of AT1R, PRR, TNF-α and CTGF by IgA-HMC media. Podocytic nephrin expression, annexin V binding and caspase 3 activity were used as the functional readout of podocytic apoptosis. IgA-HMC media had no effect on AngII release by podocytes. IgA-HMC media significantly up-regulated the expression of AT1R and PRR, down-regulated nephrin expression and induced apoptosis in podocytes. Mono-blockade of AT1R, PRR, TNF-α or CTGF partially reduced podocytic apoptosis. IgA-HMC media activated NFκB, notch1 and HEY1 expression by podocytes and dual blockade of AT1R with PRR, or anti-TNF-α with anti-CTGF, effectively rescued the podocytic apoptosis induced by IgA-HMC media. Our data suggests that pIgA-activated HMC up-regulates the expression of AT1R and PRR expression by podocytes and the associated activation of NFκB and notch signalling pathways play an essential role in the podocytic apoptosis induced by glomerulo-podocytic communication in IgAN. Simultaneously targeting the AT1R and PRR could be a potential therapeutic option to reduce the podocytic injury in IgAN.

  20. Transforming growth factor beta receptor II polymorphisms are associated with Kawasaki disease

    Directory of Open Access Journals (Sweden)

    Yu Mi Choi

    2012-01-01

    Full Text Available Purpose : Transforming growth factor beta receptor 2 (TGFBR2 is a tumor suppressor gene that plays a role in the differentiation of striated cells and remodeling of coronary arteries. Single nucleotide polymorphisms (SNPs of this gene are associated with Marfan syndrome and sudden death in patients with coronary artery disease. Cardiovascular remodeling and T cell activation of TGFBR2 gene suggest that the TGFBR2 gene SNPs are related to the pathogenesis of Kawasaki disease (KD and coronary artery lesion (CAL. Methods : The subjects were 105 patients with KD and 500 healthy adults as controls. Mean age of KD group was 32 months age and 26.6% of those had CAL. We selected TGFBR2 gene SNPs from serum and performed direct sequencing. Results : The sequences of the eleven SNPs in the TGFBR2 gene were compared between the KD group and controls. Three SNPs (rs1495592, rs6550004, rs795430 were associated with development of KD (P=0.019, P=0.026, P=0.016, respectively. One SNP (rs1495592 was associated with CAL in KD group (P=0.022. Conclusion : Eleven SNPs in TGFBR2 gene were identified at that time the genome wide association. But, with the change of the data base, only six SNPs remained associated with the TGFBR2 gene. One of the six SNPs (rs6550004 was associated with development of KD. One SNP associated with CAL (rs1495592 was disassociated from the TGFBR2 gene. The other five SNPs were not functionally identified, but these SNPs are notable because the data base is changing. Further studies involving larger group of patients with KD are needed.

  1. Human fetal malformations associated with the use of an angiotensin II receptor antagonist: Case Report

    Directory of Open Access Journals (Sweden)

    Henri Augusto Korkes

    2014-09-01

    Full Text Available Introduction: The potential risks related to drug exposure during pregnancy represent a vast chapter in modern obstetrics and data regarding the safety of antihypertensive drugs during pregnancy are relatively scarce. Case report: A 37-year-old patient discovered her fifth pregnancy at our hospital after 26 weeks and 4 days of gestation. She reported a history of hypertension and was currently being treated with Losartan. Hospitalization was recommended for the patient and further evaluation of fetal vitality was performed. On the fourth day an ultrasound was performed, resulting in a severe oligohydramnios, fetal centralization and abnormal ductus venosus. After 36 hours, the newborn died. Pathologic evaluation: At autopsy, the skullcap had large fontanels and deficient ossification. The kidneys were slightly enlarged. A microscopic examination detected underdevelopment of the tubules and the presence of some dilated lumens. Immunohistochemical detection of epithelial membrane antigen was positive. Immunoreactivity of CD 15 was also assayed to characterize the proximal tubules, and lumen collapse was observed in some regions. Discussion: Angiotensin-converting enzyme inhibitors (ACEIs and angiotensin receptor antagonists (ARAs are among the most widely prescribed drugs for hypertension. They are often used by hypertensive women who are considering become pregnant. While their fetal toxicity in the second or third trimesters has been documented, their teratogenic effect during the first trimester has only recently been demonstrated. Conclusion: Constant awareness by physicians and patients should be encouraged, particularly in regard to the prescription of antihypertensive drugs in women of childbearing age who are or intend to become pregnant.

  2. A phase II study of preoperative capecitabine in women with operable hormone receptor positive breast cancer

    International Nuclear Information System (INIS)

    Tolaney, Sara M; Jeong, Joon; Guo, Hao; Brock, Jane; Morganstern, Daniel; Come, Steven E; Golshan, Mehra; Bellon, Jennifer; Winer, Eric P; Krop, Ian E

    2014-01-01

    Conventional preoperative chemotherapy regimens have only limited efficacy in hormone receptor positive (HR+) breast cancer and new approaches are needed. We hypothesized that capecitabine, which is effective in metastatic breast cancer, may be an active preoperative treatment for HR+ breast cancer. Women with HR+, HER2-negative operable breast cancer received capecitabine, 2000 mg/m 2 daily in divided doses for 14 days, followed by a 7-day rest period. Treatment was repeated every 21 days for a total of four cycles. The primary endpoint of the study was to determine the rate of pathological complete response (pCR). Because of slow accrual, the study was closed after 24 patients were enrolled. Three patients had a complete clinical response, and eight patients had a partial clinical response, for an overall clinical response rate of 45.8%. There were no cases of pCR. Of the 22 patients who had pathological response assessment by the Miller–Payne grading system, there were six grade 3 responses, and no grade 4 or 5 responses. Toxicity was manageable: the only grade 3 toxicities observed were one case each of diarrhea, palmar plantar erythrodysesthesia, hypokalemia, and mucositis. There was no association between baseline levels, or change in level from baseline to cycle 1, or from baseline to time of surgery, of thymidine phosphorylase (TYMP), thymidylate synthase (TYMS), dihydropyrimidine dehydrogenase (DPYD), or Ki67 and pathological, clinical, or radiographic response. Preoperative capecitabine is a well-tolerated regimen, but appears not lead to pCR when used as monotherapy in HR+ breast cancer

  3. G protein-independent effects of the Angiotensin II type I receptor

    DEFF Research Database (Denmark)

    Christensen, Gitte Lund

    2010-01-01

    Angiotensin II type 1 receptoren (AT1R) er en syv transmembranreceptor (7TMR) og et vigtigt terapeutisk target indenfor kardiovaskulær medicin. AT1R er gennem de seneste år blevet en model for det concept, at 7TMRer kan signalere via andre og mindre velbeskrevne signalveje end de G protein...... afhængige. Skæve agonister, som blokerer G protein signaleringen mens de samtidig aktiverer de G protein uafhængige signaleringsveje er blevet brugt til at beskrive de to hovedgrene i AT1R signaleringen i cellemodelsystemer. Vi påviser at denne farmakologiske differentiering af de to signalveje er relevant...... i primære kardiomyocytter og hele hjerter og endvidere at skæve agonister kan adskille skadelig hypertrofisk vækst fra ønskelig fornyelse af hjertemuskelceller. Deruover har fokus i denne PhD afhandling været på at beskrive de G protein uafhængige effekter af AT1R aktivering vha. den skæve agonist...

  4. Heterogeneous Downregulation of Angiotensin II AT1-A and AT1-B Receptors in Arterioles in STZ-Induced Diabetic Rat Kidneys

    Directory of Open Access Journals (Sweden)

    Zsolt Razga

    2014-01-01

    Full Text Available Introduction. The renin granulation of kidney arterioles is enhanced in diabetes despite the fact that the level of angiotensin II in the diabetic kidney is elevated. Therefore, the number of angiotensin II AT1-A and AT1-B receptors in afferent and efferent arteriole’s renin-positive and renin-negative smooth muscle cells (SMC was estimated. Method. Immunohistochemistry at the electron microscopic level was combined with 3D stereological sampling techniques. Results. In diabetes the enhanced downregulation of AT1-B receptors in the renin-positive than in the renin-negative SMCs in both arterioles was resulted: the significant difference in the number of AT1 (AT1-A + AT1-B receptors between the two types of SMCs in the normal rats was further increased in diabetes and in contrast with the significant difference observed between the afferent and efferent arterioles in the normal animals, there was no such difference in diabetes. Conclusions. The enhanced downregulation of the AT1-B receptors in the renin-negative SMCs in the efferent arterioles demonstrates that the regulation of the glomerular filtration rate by the pre- and postglomerular arterioles is changed in diabetes. The enhanced downregulation of the AT1-B receptors in the renin-positive SMCs in the arterioles may result in an enhanced level of renin granulation in the arterioles.

  5. Valsartan ameliorates ageing-induced aorta degeneration via angiotensin II type 1 receptor-mediated ERK activity

    Science.gov (United States)

    Shan, HaiYan; Zhang, Siyang; Li, Xuelian; yu, Kai; Zhao, Xin; Chen, Xinyue; Jin, Bo; Bai, XiaoJuan

    2014-01-01

    Angiotensin II (Ang II) plays important roles in ageing-related disorders through its type 1 receptor (AT1R). However, the role and underlying mechanisms of AT1R in ageing-related vascular degeneration are not well understood. In this study, 40 ageing rats were randomly divided into two groups: ageing group which received no treatment (ageing control), and valsartan group which took valsartan (selective AT1R blocker) daily for 6 months. 20 young rats were used as adult control. The aorta structure were analysed by histological staining and electron microscopy. Bcl-2/Bax expression in aorta was analysed by immunohistochemical staining, RT-PCR and Western blotting. The expressions of AT1R, AT2R and mitogen-activated protein kinases (MAPKs) were detected. Significant structural degeneration of aorta in the ageing rats was observed, and the degeneration was remarkably ameliorated by long-term administration of valsartan. With ageing, the expression of AT1R was elevated, the ratio of Bcl-2/Bax was decreased and meanwhile, an important subgroup of MAPKs, extracellular signal-regulated kinase (ERK) activity was elevated. However, these changes in ageing rats could be reversed to some extent by valsartan. In vitro experiments observed consistent results as in vivo study. Furthermore, ERK inhibitor could also acquire partial effects as valsartan without affecting AT1R expression. The results indicated that AT1R involved in the ageing-related degeneration of aorta and AT1R-mediated ERK activity was an important mechanism underlying the process. PMID:24548645

  6. Pneumonia prevention in intubated patients given sucralfate versus proton-pump inhibitors and/or histamine II receptor blockers.

    Science.gov (United States)

    Grindlinger, Gene A; Cairo, Sarah B; Duperre, Carole B

    2016-12-01

    Ventilator-associated pneumonia (VAP) is a common cause of infectious morbidity and mortality in the intensive care unit (ICU). The type of stress-ulcer prophylaxis (SUP) given to ventilated patients may, in part, be responsible. We observed an increase in VAP as ventilator bundle compliance increased and a decrease in VAP when bundle compliance decreased. We reasoned that SUP which raises gastric pH such as proton-pump inhibitors (PPIs) and histamine II (H2) receptor antagonists as opposed to SUP which does not raise pH such as sucralfate (S) may be responsible and also may alter the causative bacteria. This is a single-center retrospective cohort analysis of all intubated, adult surgical patients admitted to the surgical ICU between January and June during the 3-y period 2012-2014. Demographics, APACHE II, Injury Severity Score, VAP occurrence, culprit bacteria, ventilator days, and ICU days were recorded based on the type of SUP given. There were 45 instances of VAP in the 504 study patients, 33 in the PPI/H2 group, and 12 in the S group (P < 0.01). VAP per 1000 ventilator days were 10.2 for PPI/H2 and 3.7 for S (P < 0.01). Culprit bacteria were mostly Pseudomonas, gram-negative bacilli, and methicillin-resistant Staphylococcus aureus in PPI/H2 patients (n = 29) compared with oropharyngeal flora in S patients (n = 6; P < 0.001). There was a substantial difference in VAP occurrence and in the culprit bacteria between S and PPI/H2 treated patients due perhaps to gastric alkalization. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. Conditional expression of the dominant-negative TGF-β receptor type II elicits lingual epithelial hyperplasia in transgenic mice.

    Science.gov (United States)

    Li, Feng; Zhou, Mingliang

    2013-05-01

    The transforming growth factor-β (TGF-β) signaling pathway is generally believed to be a potent inhibitor of proliferation. However, many epithelia lacking the essential Tgfbr2 gene still maintain normal tissue homeostasis. Here, transgenic mice expressing rtTA from the human keratin 14 (K14) promoter were used to generate an inducible dominant-negative TGF-β receptor type II (Tgfbr2) mutant model, which allowed us to distinguish between the primary and secondary effects of TGF-β signaling disruption by Doxycycline treatment in K14+ epithelial stem cells. We showed that in mice lacking TGF-β signaling in K14+ cells, invasive carcinomas developed on the ventral surface of the tip of the tongue, while filiform papillae on the dorsal surface showed different pathological changes from the tip to the posterior of the tongue. In addition, acetylation levels of histone H4 and histone H3 rapidly increased, while pMAPK activity was enhanced and Jagged2 inactivated in lingual epithelia after disruption of TGF-β signaling. Our results contribute to the understanding of TGF-β signaling in regulating homeostasis and carcinogenesis in lingual epithelia. Copyright © 2013 Wiley Periodicals, Inc.

  8. Transdermal delivery of angiotensin II receptor blockers (ARBs), angiotensin-converting enzyme inhibitors (ACEIs) and others for management of hypertension.

    Science.gov (United States)

    Ahad, Abdul; Al-Mohizea, Abdullah Mohammed; Al-Jenoobi, Fahad Ibrahim; Aqil, Mohd

    2016-01-01

    Angiotensin II receptor blockers (ARBs), angiotensin-converting enzyme inhibitors (ACEIs) are some of the most commonly prescribed medications for hypertension. Most of all conventional dosage forms of ARBs and ACEIs undergo extensive first-pass metabolism, which significantly reduces bioavailability. Majority of ARBs and ACEIs are inherently short acting due to a rapid elimination half-life. In addition, oral dosage forms of ARBs and ACEIs have many high incidences of adverse effects due to variable absorption profiles, higher frequency of administration and poor patient compliance. Many attempts have been made globally at the laboratory level to investigate the skin permeation and to develop transdermal therapeutic systems of various ARBs, ACEIs and other anti-hypertensives, to circumvent the drawbacks associated with their conventional dosage form. This manuscript presents an outline of the transdermal research specifically in the area of ARBs, ACEIs and other anti-hypertensives reported in various pharmaceutical journals. The transdermal delivery has gained a significant importance for systemic treatment as it is able to avoid first-pass metabolism and major fluctuations of plasma levels typical of repeated oral administration. As we can experience from this review article that transdermal delivery of different ARBs and ACEIs improves bioavailability as well as patient compliance by many folds. In fact, the rationale development of some newer ARBs, ACEIs and other anti-hypertensives transdermal systems will provide new ways of treatment, circumventing current limitations for conventional dosage forms.

  9. Effects of angiotensin converting enzyme inhibitor and angiotensin II antagonist receptor on neointima hyperplasia after vascular balloon injury

    International Nuclear Information System (INIS)

    Wang Yeling; Zhao Lihua

    2004-01-01

    Objective: To study the effects of angiotensin converting enzyme inhibitor (captopril) and angiotensin II antagonist receptor (valsartan) on neointima hyperplasia after vascular balloon injury. Methods: Thirty-six rabbit models were randomly divided into three groups: injuried group, captopril group and valsartan group. Captopril (2 mg·kg -1 ·d -1 po) and valsartan (10 mg·kg -1 ·d -1 po) were given to twelve rabbits respectively from 1 day before the right carotidarteries were injuried by 2.0 mm ballon cathether to 14 days after injury in captopil group and valsartan group. The medicine was not administered in the injuried group. The tissue plasminogen activator (tPA), plaminogen activor inhibitor-1 (PAI-1) antigen level and plasma endothelin (ET) levels were measured before injury, and 7, 14 days after vascular injury. The pathomorphoiogical examination were carried out 14 days after angioplasty. Results: The levels of plasma PAI-1 and ET in captopril group and valsartan group were significantly lower than those in the injuried group (P<0.05). The intimal thickness and extent of lumen stenosis in captopril and valsartan groups were significantly lower than those in the injuried group (P<0.05). Conclusion: Captopril and valsartan can inhibit neointima hyperplasia after vascular ballon injury. (authors)

  10. Two selective HPTLC methods for determination of some angiotensin II receptor antagonists in tablets and biological fluids.

    Science.gov (United States)

    Salah, Gamal A; Abd El-Wadood, Hanaa M; Khairy, Mohamed; Khorshed, Ahmed A

    2017-07-01

    Two simple, selective, precise and highly sensitive high-performance thin-layer chromatography (HPTLC) methods have been developed and validated for analysis of five angiotensin II receptor antagonists, namely losartan, irbesartan valsartan, candesartan and olmesartan, which are widely used in clinical practice. HPTLC of the drugs was performed on pre-coated silica gel HPTLC plates 60 F 254 by development using a mobile phase composed of chloroform-acetone-glacial acetic acid (7.8:1.5:0.7m v/v/v), which was suitable for all of the studied drugs. The first method depended on utilizing reflectance/fluorescence mode for detection while the second method depended on using 2,3,5,6-tetrachloro-1,4-benzoquinone as spraying reagent for the first time to form orange spots scanned at 460 nm. A good linear relationship was obtained over the concentration ranges of 1.2-60 and 360-3000 ng/band while detection and quantification limits were in the ranges of 0.07-0.43, 45.2-140.49 and 0.21-1.29, 137.05-425.74 ng/band for reflectance/fluorescence and reflectance/absorbance methods respectively. The developed methods were applied successfully for their determination in tablets and spiked human plasma for reflectance/fluorescence method with good accuracy and precision, and so can be applied in the pharmacokinetic and bioavailability studies. Copyright © 2016 John Wiley & Sons, Ltd.

  11. Research resource: new and diverse substrates for the insulin receptor isoform a revealed by quantitative proteomics after stimulation with igf-ii or insulin

    DEFF Research Database (Denmark)

    Morcavallo, Alaide; Gaspari, Marco; Pandini, Giuseppe

    2011-01-01

    progression. We hypothesized that IGF-II binding to the IR-A elicits a unique signaling pathway. In order to obtain an unbiased evaluation of IR-A substrates differentially involved after IGF-II and insulin stimulation, we performed quantitative proteomics of IR-A substrates recruited to tyrosine......-phosphorylated protein complexes using stable isotope labeling with amino acids in cell culture in combination with antiphosphotyrosine antibody pull down and mass spectrometry. Using cells expressing only the human IR-A and lacking the IGF-I receptor, we identified 38 IR-A substrates. Only 10 were known IR mediators......, whereas 28 substrates were not previously related to IR signaling. Eleven substrates were recruited by stimulation with both ligands: two equally recruited by IGF-II and insulin, three more strongly recruited by IGF-II, and six more strongly recruited by insulin. Moreover, 14 substrates were recruited...

  12. Soluble TGF-β type II receptor gene therapy reduces TGF-β activity in irradiated lung tissue and protects lungs from radiation-induced injury

    International Nuclear Information System (INIS)

    Vujaskovic, Z.; Rabbani, Z.; Zhang, X.; Samulski, T.V.; Li, C.-Y.; Anscher, M.S.

    2003-01-01

    Full text: The objective was to determine whether administration of recombinant human adenoviral vector carrying soluble TGF-β1 type II receptor (TβR-II) gene reduces availability of active TGFβ1 and protects lung from radiation-induced injury. Female Fisher-344 rats were randomized into four groups to receive: 1) Control 2) Adenoviral green fluorescent protein vector (AdGFP) alone 3) Radiation (RT) + Adenoviral vector with TGF-β1 type II receptor gene (AdexTβR-II-Fc) 4) RT alone. Animals were irradiated to right hemithorax using a single dose of 30 Gy. The packaging and production of a recombinant adenovirus carrying the fused human TβR-II-IgG1 Fc gene was achieved by use of the AdEasy system. The treatment vector AdexTbR-II-Fc (1.5*1010 PFU) and control vector AdGFP (1*109 PFU) were injected i.v. 24 hrs after RT. Respiratory rate was measured as an index of pulmonary function weekly for 5 weeks post RT. Structural damage was scored histologically. Immunohistochemistry was performed to identify activated macrophages. ELISA was used to quantify active TGF-β1 in tissue homogenate. Western blot was used to determine TβR-II expression in plasma and lung tissue. Animals receiving treatment vector AdexTbR-II-Fc have elevated plasma levels of soluble TβR-II at 24 and 48 hours after injection. In the RT+AdexTbR-II-Fc group, there was a significant reduction in respiratory rate (p = 0.002) at four weeks after treatment compared to RT alone group. Histology revealed a significant reduction in lung structural damage in animals receiving gene therapy after RT vs RT alone (p=0.0013). There was also a decrease in the number of activated macrophage (p= 0.02) in RT+AdexTbR-II-Fc group vs RT alone. The tissue protein expression of active TGF-β1 was significantly reduced in rats receiving RT+AdexTbR-II-Fc treatment (p<0.05). This study shows the ability of adenovirus mediated soluble TβR-II gene therapy to reduce tissue levels of active TGF-β1 and ameliorate radiation

  13. Position paper of the EAACI: food allergy due to immunological cross-reactions with common inhalant allergens.

    Science.gov (United States)

    Werfel, T; Asero, R; Ballmer-Weber, B K; Beyer, K; Enrique, E; Knulst, A C; Mari, A; Muraro, A; Ollert, M; Poulsen, L K; Vieths, S; Worm, M; Hoffmann-Sommergruber, K

    2015-09-01

    In older children, adolescents, and adults, a substantial part of all IgE-mediated food allergies is caused by cross-reacting allergenic structures shared by inhalants and foods. IgE stimulated by a cross-reactive inhalant allergen can result in diverse patterns of allergic reactions to various foods. Local, mild, or severe systemic reactions may occur already after the first consumption of a food containing a cross-reactive allergen. In clinical practice, clinically relevant sensitizations are elucidated by skin prick testing or by the determination of specific IgE in vitro. Component-resolved diagnosis may help to reach a diagnosis and may predict the risk of a systemic reaction. Allergy needs to be confirmed in cases of unclear history by oral challenge tests. The therapeutic potential of allergen immunotherapy with inhalant allergens in pollen-related food allergy is not clear, and more placebo-controlled studies are needed. As we are facing an increasing incidence of pollen allergies, a shift in sensitization patterns and changes in nutritional habits, and the occurrence of new, so far unknown allergies due to cross-reactions are expected. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  14. Aqueous two-phase system patterning of detection antibody solutions for cross-reaction-free multiplex ELISA

    Science.gov (United States)

    Frampton, John P.; White, Joshua B.; Simon, Arlyne B.; Tsuei, Michael; Paczesny, Sophie; Takayama, Shuichi

    2014-05-01

    Accurate disease diagnosis, patient stratification and biomarker validation require the analysis of multiple biomarkers. This paper describes cross-reactivity-free multiplexing of enzyme-linked immunosorbent assays (ELISAs) using aqueous two-phase systems (ATPSs) to confine detection antibodies at specific locations in fully aqueous environments. Antibody cross-reactions are eliminated because the detection antibody solutions are co-localized only to corresponding surface-immobilized capture antibody spots. This multiplexing technique is validated using plasma samples from allogeneic bone marrow recipients. Patients with acute graft versus host disease (GVHD), a common and serious condition associated with allogeneic bone marrow transplantation, display higher mean concentrations for four multiplexed biomarkers (HGF, elafin, ST2 and TNFR1) relative to healthy donors and transplant patients without GVHD. The antibody co-localization capability of this technology is particularly useful when using inherently cross-reactive reagents such as polyclonal antibodies, although monoclonal antibody cross-reactivity can also be reduced. Because ATPS-ELISA adapts readily available antibody reagents, plate materials and detection instruments, it should be easily transferable into other research and clinical settings.

  15. A cleavable signal peptide enhances cell surface delivery and heterodimerization of Cerulean-tagged angiotensin II AT1 and bradykinin B2 receptor

    Energy Technology Data Exchange (ETDEWEB)

    Quitterer, Ursula, E-mail: ursula.quitterer@pharma.ethz.ch [Molecular Pharmacology Unit, Swiss Federal Institute of Technology and University of Zurich, Zurich (Switzerland); Pohl, Armin; Langer, Andreas; Koller, Samuel; AbdAlla, Said [Molecular Pharmacology Unit, Swiss Federal Institute of Technology and University of Zurich, Zurich (Switzerland)

    2011-06-10

    Highlights: {yields} A new FRET-based method detects AT1/B2 receptor heterodimerization. {yields} First time application of AT1-Cerulean as a FRET donor. {yields} Method relies on signal peptide-enhanced cell surface delivery of AT1-Cerulean. {yields} A high FRET efficiency revealed efficient heterodimerization of AT1/B2R proteins. {yields} AT1/B2R heterodimers were functionally coupled to desensitization mechanisms. -- Abstract: Heterodimerization of the angiotensin II AT1 receptor with the receptor for the vasodepressor bradykinin, B2R, is known to sensitize the AT1-stimulated response of hypertensive individuals in vivo. To analyze features of that prototypic receptor heterodimer in vitro, we established a new method that uses fluorescence resonance energy transfer (FRET) and applies for the first time AT1-Cerulean as a FRET donor. The Cerulean variant of the green fluorescent protein as donor fluorophore was fused to the C-terminus of AT1, and the enhanced yellow fluorescent protein (EYFP) as acceptor fluorophore was fused to B2R. In contrast to AT1-EGFP, the AT1-Cerulean fusion protein was retained intracellularly. To facilitate cell surface delivery of AT1-Cerulean, a cleavable signal sequence was fused to the receptor's amino terminus. The plasma membrane-localized AT1-Cerulean resembled the native AT1 receptor regarding ligand binding and receptor activation. A high FRET efficiency of 24.7% between membrane-localized AT1-Cerulean and B2R-EYFP was observed with intact, non-stimulated cells. Confocal FRET microscopy further revealed that the AT1/B2 receptor heterodimer was functionally coupled to receptor desensitization mechanisms because activation of the AT1-Cerulean/B2R-EYFP heterodimer with a single agonist triggered the co-internalization of AT1/B2R. Receptor co-internalization was sensitive to inhibition of G protein-coupled receptor kinases, GRKs, as evidenced by a GRK-specific peptide inhibitor. In agreement with efficient AT1/B2R

  16. A cleavable signal peptide enhances cell surface delivery and heterodimerization of Cerulean-tagged angiotensin II AT1 and bradykinin B2 receptor

    International Nuclear Information System (INIS)

    Quitterer, Ursula; Pohl, Armin; Langer, Andreas; Koller, Samuel; AbdAlla, Said

    2011-01-01

    Highlights: → A new FRET-based method detects AT1/B2 receptor heterodimerization. → First time application of AT1-Cerulean as a FRET donor. → Method relies on signal peptide-enhanced cell surface delivery of AT1-Cerulean. → A high FRET efficiency revealed efficient heterodimerization of AT1/B2R proteins. → AT1/B2R heterodimers were functionally coupled to desensitization mechanisms. -- Abstract: Heterodimerization of the angiotensin II AT1 receptor with the receptor for the vasodepressor bradykinin, B2R, is known to sensitize the AT1-stimulated response of hypertensive individuals in vivo. To analyze features of that prototypic receptor heterodimer in vitro, we established a new method that uses fluorescence resonance energy transfer (FRET) and applies for the first time AT1-Cerulean as a FRET donor. The Cerulean variant of the green fluorescent protein as donor fluorophore was fused to the C-terminus of AT1, and the enhanced yellow fluorescent protein (EYFP) as acceptor fluorophore was fused to B2R. In contrast to AT1-EGFP, the AT1-Cerulean fusion protein was retained intracellularly. To facilitate cell surface delivery of AT1-Cerulean, a cleavable signal sequence was fused to the receptor's amino terminus. The plasma membrane-localized AT1-Cerulean resembled the native AT1 receptor regarding ligand binding and receptor activation. A high FRET efficiency of 24.7% between membrane-localized AT1-Cerulean and B2R-EYFP was observed with intact, non-stimulated cells. Confocal FRET microscopy further revealed that the AT1/B2 receptor heterodimer was functionally coupled to receptor desensitization mechanisms because activation of the AT1-Cerulean/B2R-EYFP heterodimer with a single agonist triggered the co-internalization of AT1/B2R. Receptor co-internalization was sensitive to inhibition of G protein-coupled receptor kinases, GRKs, as evidenced by a GRK-specific peptide inhibitor. In agreement with efficient AT1/B2R heterodimerization, confocal FRET imaging of

  17. O polimorfismo A1166C do receptor tipo 1 da angiotensina II no infarto agudo do miocárdio The A1166C polymorphism of the angiotensin II type-1 receptor in acute myocardial infarction

    Directory of Open Access Journals (Sweden)

    Messias Antônio de Araújo

    2004-11-01

    Full Text Available RESUMO OBJETIVO:Avaliar a associação do polimorfismo A1166C do gene do receptor AT1 da angiotensina II (AT1R com o infarto agudo do miocárdio e a severidade da doença arterial coronariana. MÉTODOS: Estudo prospectivo, transversal de 110 pacientes com infarto agudo do miocárdio submetidos à angiografia coronariana com lesão significante (> 50% avaliada por três critérios de severidade: número de vasos lesados, morfologia da placa aterosclerótica e escore de risco coronariano. Sem lesões coronarianas 104 indivíduos controles. O polimorfismo A1166C do gene do AT1R foi determinado pela reação em cadeia da polimerase no DNA dos leucócitos do sangue periférico. Os fatores de risco coronariano clássicos foram analisados em todos os indivíduos. RESULTADOS: Na estratificação dos genótipos em relação aos fatores de risco apenas o tabagismo teve predominância nos heterozigotos AC (p = 0,02. A freqüência dos genótipos nos pacientes infartados foi de AA = 54,5%; AC = 35,5% e CC = 10%, sendo similar e não significativa em relação aos controles (p = 0,83. Não houve aumento do risco de infarto agudo do miocárdio nas comparações dos genótipos CC vs AA (OR = 1,35; IC-95% = 0,50 - 3,59, AC vs AA (OR = 1,03; IC-95% = 0,58 - 1,84 e AA+AC vs AA (OR = 1,33; IC-95% = 0,51 - 3,45. Nenhum dos critérios de severidade teve associação significativa com os genótipos. CONCLUSÃO: Os nossos resultados indicam não haver associação do polimorfismo A1166C do AT1R com o infarto agudo do miocárdio e nem com a severidade da doença arterial coronariana segundo nossos resultados.OBJECTIVE: To assess the association of the A1166C polymorphism of the angiotensin II type-1 receptor (AT1R gene with acute myocardial infarction and also with the severity of coronary artery disease. METHODS: A prospective, cross-sectional study was carried out with 110 patients with acute myocardial infarction, who, on coronary angiography, had significant

  18. Peptide receptor radionuclide therapy with {sup 177}Lu-DOTATATE: the IEO phase I-II study

    Energy Technology Data Exchange (ETDEWEB)

    Bodei, Lisa; Grana, Chiara M.; Baio, Silvia M.; Lombardo, Dario; Chinol, Marco; Paganelli, Giovanni [European Institute of Oncology, Division of Nuclear Medicine, Milan (Italy); Cremonesi, Marta; Ferrari, Mahila E. [European Institute of Oncology, Division of Medical Physics, Milan (Italy); Fazio, Nicola [European Institute of Oncology, Division of Medical Oncology, Milan (Italy); Iodice, Simona [European Institute of Oncology, Division of Epidemiology and Biostatistics, Milan (Italy); Bartolomei, Mirco [European Institute of Oncology, Division of Nuclear Medicine, Milan (Italy); M. Bufalini Hospital, Division of Nuclear Medicine, Cesena, FC (Italy); Sansovini, Maddalena [Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Unit of Radiometabolic Medicine, Meldola, FC (Italy)

    2011-12-15

    Peptide receptor radionuclide therapy (PRRT) is used in tumours expressing type 2 somatostatin receptors (sst{sub 2}), mainly neuroendocrine. The aim of this prospective phase I-II study was to evaluate the toxicity and efficacy of {sup 177}Lu-DOTATATE in multiple cycles. Fifty-one consecutive patients with unresectable/metastatic sst{sub 2}-positive tumours, divided into two groups, received escalating activities (3.7-5.18 GBq/cycle, group 1; 5.18-7.4 GBq/cycle, group 2) of {sup 177}Lu-DOTATATE. Cumulative activities ranged from 3.7 to 29.2 GBq (median 26.4 GBq in median 6 cycles, group 1, 21 patients) and 5.55 to 28.9 GBq (median 25.2 GBq in 4 cycles, group 2, 30 patients), based on dosimetry. No major acute or delayed renal or haematological toxicity occurred (one grade 3 leukopenia and thrombocytopenia). Cumulative renal absorbed doses were 8-37 Gy (9-41 Gy bioeffective doses). A median decrease of creatinine clearance of 21.7% 6 months after PRRT, 23.9% after 1 year and 27.6% after 2 years was observed. Higher losses (>20%) occurred in patients with risk factors for renal toxicity, particularly hypertension and diabetes. Cumulative bone marrow doses were <1.5 Gy. Blood elements showed a progressive mild drop during cycles and recovered during follow-up (median 30 months). Thirty-nine patients were progressive at enrolment. Partial and complete responses occurred in 15 of 46 (32.6%) assessable patients. The median time to progression was 36 months. Overall survival was 68% at 36 months. Non-responders and patients with extensive tumour involvement had lower survival. {sup 177}Lu-DOTATATE was well tolerated up to 29 GBq cumulative activity (up to 7.4 GBq/cycle). The maximum tolerated dose/cycle was not reached. However, considering the individual bone marrow function and the presence of risk factors for kidney toxicity, it seems safer to divide cumulative activities into lower activity cycles. (orig.)

  19. Differential effects of Rho-kinase inhibitor and angiotensin II type-1 receptor antagonist on the vascular function in hypertensive rats induced by chronic l-NAME treatment

    Directory of Open Access Journals (Sweden)

    Bainian Chen

    2012-10-01

    Full Text Available Little attention has been paid to the effect of Rho-kinase inhibitor on the vascular dysfunction of nitric oxide-deficient hypertension. We aimed to investigate whether the Rho-kinase inhibitor fasudil showed beneficial effect on the vascular dysfunction of the NG-nitro-l-arginine methyl ester (l-NAME treated rat, as well as to compare the differential effects of fasudil and angiotensin II receptor antagonist valsartan on vascular function. In the present study, both valsartan and fasudil exerted antihypertensive action on the l-NAME-treated rats, while only valsartan attenuated the cardiac hypertrophy. Treatment with valsartan showed improvement on vascular reactivity to norepinephrine, KCl and CaCl2, whereas fasudil therapy showed little effect on vasoconstriction. Endothelium-dependent vasodilation to acetylcholine was reduced in the NO-deficient group but was normalized by the fasudil therapy. The increased expression of RhoA and Rho-kinase (ROCK in the vasculature was corrected well to normal level by either valsartan or fasudil administration, which seemed to be at least partially responsible for the beneficial effect of the drug infusion. These findings suggest that the angiotensin II receptor antagonist interferes more with the contractile response than Rho-kinase inhibitor, whereas inhibition of Rho-kinase activity exhibits a better improvement on vasorelaxation than blockade of angiotensin II receptor.

  20. Dietary restriction but not angiotensin II type 1 receptor blockade improves DNA damage-related vasodilator dysfunction in rapidly aging Ercc1Δ/- mice.

    Science.gov (United States)

    Wu, Haiyan; van Thiel, Bibi S; Bautista-Niño, Paula K; Reiling, Erwin; Durik, Matej; Leijten, Frank P J; Ridwan, Yanto; Brandt, Renata M C; van Steeg, Harry; Dollé, Martijn E T; Vermeij, Wilbert P; Hoeijmakers, Jan H J; Essers, Jeroen; van der Pluijm, Ingrid; Danser, A H Jan; Roks, Anton J M

    2017-08-01

    DNA damage is an important contributor to endothelial dysfunction and age-related vascular disease. Recently, we demonstrated in a DNA repair-deficient, prematurely aging mouse model ( Ercc1 Δ/- mice) that dietary restriction (DR) strongly increases life- and health span, including ameliorating endothelial dysfunction, by preserving genomic integrity. In this mouse mutant displaying prominent accelerated, age-dependent endothelial dysfunction we investigated the signaling pathways involved in improved endothelium-mediated vasodilation by DR, and explore the potential role of the renin-angiotensin system (RAS). Ercc1 Δ/- mice showed increased blood pressure and decreased aortic relaxations to acetylcholine (ACh) in organ bath experiments. Nitric oxide (NO) signaling and phospho-Ser 1177 -eNOS were compromised in Ercc1 Δ / - DR improved relaxations by increasing prostaglandin-mediated responses. Increase of cyclo-oxygenase 2 and decrease of phosphodiesterase 4B were identified as potential mechanisms. DR also prevented loss of NO signaling in vascular smooth muscle cells and normalized angiotensin II (Ang II) vasoconstrictions, which were increased in Ercc1 Δ/- mice. Ercc1 Δ/ - mutants showed a loss of Ang II type 2 receptor-mediated counter-regulation of Ang II type 1 receptor-induced vasoconstrictions. Chronic losartan treatment effectively decreased blood pressure, but did not improve endothelium-dependent relaxations. This result might relate to the aging-associated loss of treatment efficacy of RAS blockade with respect to endothelial function improvement. In summary, DR effectively prevents endothelium-dependent vasodilator dysfunction by augmenting prostaglandin-mediated responses, whereas chronic Ang II type 1 receptor blockade is ineffective. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

  1. Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers reduced dementia risk in patients with diabetes mellitus and hypertension.

    Science.gov (United States)

    Kuan, Yi-Chun; Huang, Kuang-Wei; Yen, Der-Jen; Hu, Chaur-Jong; Lin, Cheng-Li; Kao, Chia-Hung

    2016-10-01

    The effects of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB) on dementia risk in patients with type 2 diabetes mellitus (DM) and hypertension remain unknown. We investigated the effects of ACEIs and ARBs on dementia risk in patients with type 2 DM and hypertension. We conducted a cohort study by using the Taiwan National Health Insurance Research Database. We included 2377 patients receiving ACEIs and 1780 patients receiving ARBs in the ACEI and ARB cohorts, respectively. We included a comparable number of patients not receiving ACEIs and ARBs as controls in the non-ACEI and non-ARB cohorts through propensity score matching. The effect of ACEIs and ARBs on dementia risk was estimated through multivariate Cox proportional hazard regression after adjustment for several confounding factors. During the 12-year follow-up period, compared with the non-ACEI cohort, all-cause dementia risk decreased by 26% in the ACEI cohort [hazard ratio (HR)=0.74, 95% confidence interval (CI)=0.56-0.96]. The all-cause dementia risk was nearly 40% lower in the ARB cohort than in the non-ARB cohort (HR=0.60, 95% CI=0.37-0.97). These drugs prevented the occurrence of vascular dementia (VD), however, this effect was nonsignificant for Alzheimer's dementia (AD). Treatment duration- and dosage-related protection effects on dementia occurrence were observed. ACEIs and ARBs may effectively prevent all-cause dementia, particularly VD, in patients with type 2 DM and hypertension. Moreover, compared with ACEIs, ARBs appear to be more advantageous in dementia prevention. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  2. Post-stroke angiotensin II type 2 receptor activation provides long-term neuroprotection in aged rats.

    Directory of Open Access Journals (Sweden)

    Douglas M Bennion

    Full Text Available Activation of the angiotensin II type 2 receptor (AT2R by administration of Compound 21 (C21, a selective AT2R agonist, induces neuroprotection in models of ischemic stroke in young adult animals. The mechanisms of this neuroprotective action are varied, and may include direct and indirect effects of AT2R activation. Our objectives were to assess the long-term protective effects of post-stroke C21 treatments in a clinically-relevant model of stroke in aged rats and to characterize the cellular localization of AT2Rs in the mouse brain of transgenic reporter mice following stroke. Intraperitoneal injections of C21 (0.03mg/kg after ischemic stroke induced by transient monofilament middle cerebral artery occlusion resulted in protective effects that were sustained for up to at least 3-weeks post-stroke. These included improved neurological function across multiple assessments and a significant reduction in infarct volume as assessed by magnetic resonance imaging. We also found AT2R expression to be on neurons, not astrocytes or microglia, in normal female and male mouse brains. Stroke did not induce altered cellular localization of AT2R when assessed at 7 and 14 days post-stroke. These findings demonstrate that the neuroprotection previously characterized only during earlier time points using stroke models in young animals is sustained long-term in aged rats, implying even greater clinical relevance for the study of AT2R agonists for the acute treatment of ischemic stroke in human disease. Further, it appears that this sustained neuroprotection is likely due to a mix of both direct and indirect effects stemming from selective activation of AT2Rs on neurons or other cells besides astrocytes and microglia.

  3. Post-stroke angiotensin II type 2 receptor activation provides long-term neuroprotection in aged rats.

    Science.gov (United States)

    Bennion, Douglas M; Isenberg, Jacob D; Harmel, Allison T; DeMars, Kelly; Dang, Alex N; Jones, Chad H; Pignataro, Megan E; Graham, Justin T; Steckelings, U Muscha; Alexander, Jon C; Febo, Marcelo; Krause, Eric G; de Kloet, Annette D; Candelario-Jalil, Eduardo; Sumners, Colin

    2017-01-01

    Activation of the angiotensin II type 2 receptor (AT2R) by administration of Compound 21 (C21), a selective AT2R agonist, induces neuroprotection in models of ischemic stroke in young adult animals. The mechanisms of this neuroprotective action are varied, and may include direct and indirect effects of AT2R activation. Our objectives were to assess the long-term protective effects of post-stroke C21 treatments in a clinically-relevant model of stroke in aged rats and to characterize the cellular localization of AT2Rs in the mouse brain of transgenic reporter mice following stroke. Intraperitoneal injections of C21 (0.03mg/kg) after ischemic stroke induced by transient monofilament middle cerebral artery occlusion resulted in protective effects that were sustained for up to at least 3-weeks post-stroke. These included improved neurological function across multiple assessments and a significant reduction in infarct volume as assessed by magnetic resonance imaging. We also found AT2R expression to be on neurons, not astrocytes or microglia, in normal female and male mouse brains. Stroke did not induce altered cellular localization of AT2R when assessed at 7 and 14 days post-stroke. These findings demonstrate that the neuroprotection previously characterized only during earlier time points using stroke models in young animals is sustained long-term in aged rats, implying even greater clinical relevance for the study of AT2R agonists for the acute treatment of ischemic stroke in human disease. Further, it appears that this sustained neuroprotection is likely due to a mix of both direct and indirect effects stemming from selective activation of AT2Rs on neurons or other cells besides astrocytes and microglia.

  4. Los niños del Cauca II. Receptor de la vitamina D con secuencia normal en un foco de pacientes con raquitismo dependiente de la vitamina D, tipo II

    Directory of Open Access Journals (Sweden)

    Luis Fernando García-Ramirez

    1993-12-01

    Full Text Available El Raquitismo Dependiente de Vitamina D, tipo II (RDVD II, es una enfermedad de herencia autosómica recesiva que se caracteriza por resistencia generalizada a la 1,25-dihidroxivitamina D, originada en alteraciones que comprometen la función del receptor para la vitamina D (RVD. El clonaje y caracterización del cDNA del RVD ha permitido el estudio de su secuencia en pacientes con RDVD II y el hallazgo de diversas mutaciones puntuales que explican el cuadro clínico. En este estudio, hemos utilizado las técnicas de PCR y clonación, para secuenciar el RVD de dos pacientes pertenecientes a un foco descrito previamente en el departamento del Cauca (Colombia, cuyas manifestaciones clínicas y de laboratorio son compatibles con RDVD II. La secuencia del RVD de nuestros pacientes fue normal, sugiriendo una alteración a nivel postranscripcional o postraduccional relacionada con la función del receptor, en lo que podría corresponder a una nueva variante de resistencia a la vitamina D.

  5. Leishmania, Babesia and Ehrlichia in urban pet dogs: co-infection or cross-reaction in serological methods?

    Directory of Open Access Journals (Sweden)

    Felipe da Silva Krawczak

    2015-02-01

    Full Text Available INTRODUCTION: The present study was designed to assess the occurrence of co-infection or cross-reaction in the serological techniques used for detecting the anti-Leishmania spp., -Babesia canis vogeli and -Ehrlichia canis antibodies in urban dogs from an area endemic to these parasites. METHODS: The serum samples from dogs were tested for the Babesia canis vogeli strain Belo Horizonte antigen and Ehrlichia canis strain São Paulo by immunofluorescence antibody test (IFAT and by anti-Leishmania immunoglobulin G (IgG antibody detection to assess Leishmania infection. We used the following four commercial kits for canine visceral leishmaniasis: ELISA, IFAT, Dual Path Platform (DPP (Bio Manguinhos(r/FIOCRUZ/MS and a rK39 RDT (Kalazar Detect Canine Rapid Test; Inbios. RESULTS : Of 96 serum samples submitted to serological assays, 4 (4.2% were positive for Leishmania as determined by ELISA; 12 (12.5%, by IFAT; 14 (14.6% by rK39 RDT; and 20 (20.8%, by DPP. Antibodies against Ehrlichia and Babesia were detected in 23/96 (23.9% and 30/96 (31.2% samples, respectively. No significant association was identified between the results of tests for detecting Babesia or Ehrlichia and those for detecting Leishmania (p-value>0.05. CONCLUSIONS: In the present study, we demonstrated co-infection with Ehrlichia or Babesia and Leishmania in dogs from Minas Gerais (Brazil; we also found that the serological tests that were used did not cross-react.

  6. The orphan germinant receptor protein GerXAO (but not GerX3b) is essential for L-alanine induced germination in Clostridium botulinum Group II.

    Science.gov (United States)

    Brunt, Jason; Carter, Andrew T; Pye, Hannah V; Peck, Michael W

    2018-05-04

    Clostridium botulinum is an anaerobic spore forming bacterium that produces the potent botulinum neurotoxin that causes a severe and fatal neuro-paralytic disease of humans and animals (botulism). C. botulinum Group II is a psychrotrophic saccharolytic bacterium that forms spores of moderate heat resistance and is a particular hazard in minimally heated chilled foods. Spore germination is a fundamental process that allows the spore to transition to a vegetative cell and typically involves a germinant receptor (GR) that responds to environmental signals. Analysis of C. botulinum Group II genomes shows they contain a single GR cluster (gerX3b), and an additional single gerA subunit (gerXAO). Spores of C. botulinum Group II strain Eklund 17B germinated in response to the addition of L-alanine, but did not germinate following the addition of exogenous Ca 2+ -DPA. Insertional inactivation experiments in this strain unexpectedly revealed that the orphan GR GerXAO is essential for L-alanine stimulated germination. GerX3bA and GerX3bC affected the germination rate but were unable to induce germination in the absence of GerXAO. No role could be identified for GerX3bB. This is the first study to identify the functional germination receptor of C. botulinum Group II.

  7. Natriuretic peptide receptor-C activation attenuates angiotensin II-induced enhanced oxidative stress and hyperproliferation of aortic vascular smooth muscle cells.

    Science.gov (United States)

    Madiraju, Padma; Hossain, Ekhtear; Anand-Srivastava, Madhu B

    2018-02-07

    We showed previously that natriuretic peptide receptor-C (NPR-C) agonist, C-ANP 4-23 , attenuated the enhanced expression of Giα proteins in vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHR) through the inhibition of enhanced oxidative stress. Since the enhanced levels of endogenous angiotensin II (Ang II) contribute to the overexpression of Giα proteins and augmented oxidative stress in VSMC from SHR, the present study was undertaken to investigate if C-ANP 4-23 could also attenuate angiotensin II (Ang II)-induced oxidative stress and associated signaling. Ang II treatment of aortic VSMC augmented the levels of superoxide anion (O 2 - ), NADPH oxidase activity, and the expression of NADPH oxidase subunits and C-ANP 4-23 treatment attenuated all these to control levels. In addition, Ang II-induced enhanced levels of thiobarbituric acid-reactive substances (TBARS) and protein carbonyl content were also attenuated toward control levels by C-ANP 4-23 treatment. On the other hand, Ang II inhibited the levels of nitric oxide (NO) and augmented the levels of peroxynitrite (OONO - ) in VSMC which were restored to control levels by C-ANP 4-23 treatment. Furthermore, C-ANP 4-23 treatment attenuated Ang II-induced enhanced expression of Giα proteins, phosphorylation of p38, JNK, and ERK 1,2 as well as hyperproliferation of VSMC as determined by DNA synthesis, and metabolic activity. These results indicate that C-ANP 4-23 , via the activation of NPR-C, attenuates Ang II-induced enhanced nitroxidative stress, overexpression of Giα proteins, increased activation of the p38/JNK/ERK 1,2 signaling pathways, and hyperproliferation of VSMC. It may be suggested that C-ANP 4-23 could be used as a therapeutic agent in the treatment of vascular remodeling associated with hypertension and atherosclerosis.

  8. High-Dose Estradiol-Replacement Therapy Enhances the Renal Vascular Response to Angiotensin II via an AT2-Receptor Dependent Mechanism

    Directory of Open Access Journals (Sweden)

    Tahereh Safari

    2015-01-01

    Full Text Available Physiological levels of estrogen appear to enhance angiotensin type 2 receptor- (AT2R- mediated vasodilatation. However, the effects of supraphysiological levels of estrogen, analogous to those achieved with high-dose estrogen replacement therapy in postmenopausal women, remain unknown. Therefore, we pretreated ovariectomized rats with a relatively high dose of estrogen (0.5 mg/kg/week for two weeks. Subsequently, renal hemodynamic responses to intravenous angiotensin II (Ang II, 30–300 ng/kg/min were tested under anesthesia, while renal perfusion pressure was held constant. The role of AT2R was examined by pretreating groups of rats with PD123319 or its vehicle. Renal blood flow (RBF decreased in a dose-related manner in response to Ang II. Responses to Ang II were enhanced by pretreatment with estradiol. For example, at 300 ng kg−1 min−1, Ang II reduced RBF by 45.7±1.9% in estradiol-treated rats but only by 27.3±5.1% in vehicle-treated rats. Pretreatment with PD123319 blunted the response of RBF to Ang II in estradiol-treated rats, so that reductions in RBF were similar to those in rats not treated with estradiol. We conclude that supraphysiological levels of estrogen promote AT2R-mediated renal vasoconstriction. This mechanism could potentially contribute to the increased risk of cardiovascular disease associated with hormone replacement therapy using high-dose estrogen.

  9. Excess of Aminopeptidase A in the Brain Elevates Blood Pressure via the Angiotensin II Type 1 and Bradykinin B2 Receptors without Dipsogenic Effect

    Directory of Open Access Journals (Sweden)

    Takuto Nakamura

    2017-01-01

    Full Text Available Aminopeptidase A (APA cleaves angiotensin (Ang II, kallidin, and other related peptides. In the brain, it activates the renin angiotensin system and causes hypertension. Limited data are available on the dipsogenic effect of APA and pressor effect of degraded peptides of APA such as bradykinin. Wistar-Kyoto rats received intracerebroventricular (icv APA in a conscious, unrestrained state after pretreatment with (i vehicle, (ii 80 μg of telmisartan, an Ang II type-1 (AT1 receptor blocker, (iii 800 nmol of amastatin, an aminopeptidase inhibitor, and (iv 1 nmol of HOE-140, a bradykinin B2 receptor blocker. Icv administration of 400 and 800 ng of APA increased blood pressure by 12.6 ± 3.0 and 19.0 ± 3.1 mmHg, respectively. APA did not evoke drinking behavior. Pressor response to APA was attenuated on pretreatment with telmisartan (vehicle: 22.1 ± 2.2 mmHg versus telmisartan: 10.4 ± 3.2 mmHg. Pressor response to APA was also attenuated with amastatin and HOE-140 (vehicle: 26.5 ± 1.1 mmHg, amastatin: 14.4 ± 4.2 mmHg, HOE-140: 16.4 ± 2.2 mmHg. In conclusion, APA increase in the brain evokes a pressor response via enzymatic activity without dipsogenic effect. AT1 receptors and B2 receptors in the brain may contribute to the APA-induced pressor response.

  10. High value of the radiobiological parameter Dq correlates to expression of the transforming growth factor beta type II receptor in a panel of small cell lung cancer cell lines

    DEFF Research Database (Denmark)

    Hougaard, S; Krarup, M; Nørgaard, P

    1998-01-01

    Our panel of SCLC cell lines have previously been examined for their radiobiological characteristics and sensitivity to treatment with TGF beta 1. In this study we examined the possible correlations between radiobiological parameters and the expression of the TGF beta type II receptor (TGF beta......-rII). We have, in other studies, shown that the presence of TGF beta-rII was mandatory for transmitting the growth inhibitory effect of TGF beta. The results showed a statistically significant difference in Dq, i.e. the shoulder width of the survival curve, between cell lines expressing TGF beta......-rII and cell lines which did not express the receptor (P = 0.01). Cell lines expressing TGF beta-rII had a high Dq-value. TGF beta-rII expression did not correlate with any other radiobiological parameters. We suggest that an intact growth inhibitory pathway mediated by the TGF beta-rII may have a significant...

  11. Angiotensin II Receptor Blockers

    Science.gov (United States)

    ... 2010. Mann JFE, et al. Renin-angiotensin system inhibition in the treatment of hypertension. http://www.uptodate. ... profit organization and proceeds from Web advertising help support our mission. Mayo Clinic does not endorse any ...

  12. Severe hepatic encephalopathy in a patient with liver cirrhosis after administration of angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker combination therapy: a case report

    Directory of Open Access Journals (Sweden)

    Podda Mauro

    2010-05-01

    Full Text Available Abstract Introduction A combination therapy of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers has been used to control proteinuria, following initial demonstration of its efficacy. However, recently concerns about the safety of this therapy have emerged, prompting several authors to urge for caution in its use. In the following case report, we describe the occurrence of a serious and unexpected adverse drug reaction after administration of a combination of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers to a patient with nephrotic syndrome and liver cirrhosis with severe portal hypertension. Case presentation We administered this combination therapy to a 40-year-old Caucasian man with liver cirrhosis in our Hepatology Clinic, given the concomitant presence of glomerulopathy associated with severe proteinuria. While the administration of one single drug appeared to be well-tolerated, our patient developed severe acute encephalopathy after the addition of the second one. Discontinuation of the therapy led to the disappearance of the side-effect. A tentative rechallenge with the same drug combination led to a second episode of acute severe encephalopathy. Conclusion We speculate that this adverse reaction may be directly related to the effect of angiotensin II on the excretion of blood ammonia. Therefore, we suggest that patients with liver cirrhosis and portal hypertension are at risk of developing clinically relevant encephalopathy when angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker combination therapy is administered, thus indicating the need for a careful clinical follow-up. In addition, the incidence of this serious side-effect should be rigorously evaluated in all patients with liver cirrhosis administered with this common treatment combination.

  13. Dual repressive effect of angiotensin II-type 1 receptor blocker telmisartan on angiotensin II-induced and estradiol-induced uterine leiomyoma cell proliferation.

    Science.gov (United States)

    Isobe, Aki; Takeda, Takashi; Sakata, Masahiro; Miyake, Asako; Yamamoto, Toshiya; Minekawa, Ryoko; Nishimoto, Fumihito; Oskamoto, Yoko; Walker, Cheryl Lyn; Kimura, Tadashi

    2008-02-01

    Although uterine leiomyomas or fibroids are the most common gynecological benign tumor and greatly affect reproductive health and well-being, the pathophysiology and epidemiology of uterine leiomyomas are poorly understood. Elevated blood pressure has an independent, positive association with risk for clinically detected uterine leiomyoma. Angiotensin II (Ang II) is a key biological peptide in the renin-angiotensin system that regulates blood pressure. In this study, we investigated the potential role of Ang II (1-1000 nM) in the proliferation of rat ELT-3 leiomyoma cells in vitro. RT-PCR and western blot analysis with cell proliferation and DNA transfection assays were performed to determine the mechanism of action of Ang II. Ang II induced ELT-3 leiomyoma cell proliferation (P estradiol-induced cell proliferation (P < 0.01). AT(1)R, but not AT(2)R, plays a role in Ang II-induced ELT-3 cell proliferation. These experimental findings in vitro highlight the potential role of Ang II in the proliferation of leiomyoma cells.

  14. Urocortin II: A member of the corticotropin-releasing factor (CRF) neuropeptide family that is selectively bound by type 2 CRF receptors

    Science.gov (United States)

    Reyes, T. M.; Lewis, K.; Perrin, M. H.; Kunitake, K. S.; Vaughan, J.; Arias, C. A.; Hogenesch, J. B.; Gulyas, J.; Rivier, J.; Vale, W. W.; Sawchenko, P. E.

    2001-01-01

    Here we describe the cloning and initial characterization of a previously unidentified CRF-related neuropeptide, urocortin II (Ucn II). Searches of the public human genome database identified a region with significant sequence homology to the CRF neuropeptide family. By using homologous primers deduced from the human sequence, a mouse cDNA was isolated from whole brain poly(A)+ RNA that encodes a predicted 38-aa peptide, structurally related to the other known mammalian family members, CRF and Ucn. Ucn II binds selectively to the type 2 CRF receptor (CRF-R2), with no appreciable activity on CRF-R1. Transcripts encoding Ucn II are expressed in discrete regions of the rodent central nervous system, including stress-related cell groups in the hypothalamus (paraventricular and arcuate nuclei) and brainstem (locus coeruleus). Central administration of 1–10 μg of peptide elicits activational responses (Fos induction) preferentially within a core circuitry subserving autonomic and neuroendocrine regulation, but whose overall pattern does not broadly mimic the CRF-R2 distribution. Behaviorally, central Ucn II attenuates nighttime feeding, with a time course distinct from that seen in response to CRF. In contrast to CRF, however, central Ucn II failed to increase gross motor activity. These findings identify Ucn II as a new member of the CRF family of neuropeptides, which is expressed centrally and binds selectively to CRF-R2. Initial functional studies are consistent with Ucn II involvement in central autonomic and appetitive control, but not in generalized behavioral activation. PMID:11226328

  15. Brucella abortus Inhibits Major Histocompatibility Complex Class II Expression and Antigen Processing through Interleukin-6 Secretion via Toll-Like Receptor 2▿

    Science.gov (United States)

    Barrionuevo, Paula; Cassataro, Juliana; Delpino, M. Victoria; Zwerdling, Astrid; Pasquevich, Karina A.; Samartino, Clara García; Wallach, Jorge C.; Fossati, Carlos A.; Giambartolomei, Guillermo H.

    2008-01-01

    The strategies that allow Brucella abortus to survive inside macrophages for prolonged periods and to avoid the immunological surveillance of major histocompatibility complex class II (MHC-II)-restricted gamma interferon (IFN-γ)-producing CD4+ T lymphocytes are poorly understood. We report here that infection of THP-1 cells with B. abortus inhibited expression of MHC-II molecules and antigen (Ag) processing. Heat-killed B. abortus (HKBA) also induced both these phenomena, indicating the independence of bacterial viability and involvement of a structural component of the bacterium. Accordingly, outer membrane protein 19 (Omp19), a prototypical B. abortus lipoprotein, inhibited both MHC-II expression and Ag processing to the same extent as HKBA. Moreover, a synthetic lipohexapeptide that mimics the structure of the protein lipid moiety also inhibited MHC-II expression, indicating that any Brucella lipoprotein could down-modulate MHC-II expression and Ag processing. Inhibition of MHC-II expression and Ag processing by either HKBA or lipidated Omp19 (L-Omp19) depended on Toll-like receptor 2 and was mediated by interleukin-6. HKBA or L-Omp19 also inhibited MHC-II expression and Ag processing of human monocytes. In addition, exposure to the synthetic lipohexapeptide inhibited Ag-specific T-cell proliferation and IFN-γ production of peripheral blood mononuclear cells from Brucella-infected patients. Together, these results indicate that there is a mechanism by which B. abortus may prevent recognition by T cells to evade host immunity and establish a chronic infection. PMID:17984211

  16. A Temporally Distinct Role for Group I and Group II Metabotropic Glutamate Receptors in Object Recognition Memory

    Science.gov (United States)

    Brown, Malcolm Watson; Warburton, Elizabeth Clea; Barker, Gareth Robert Isaac; Bashir, Zafar Iqbal

    2006-01-01

    Recognition memory, involving the ability to discriminate between a novel and familiar object, depends on the integrity of the perirhinal cortex (PRH). Glutamate, the main excitatory neurotransmitter in the cortex, is essential for many types of memory processes. Of the subtypes of glutamate receptor, metabotropic receptors (mGluRs) have received…

  17. Inhibición dual de la neprilisina y el receptor de angiotensina II: nueva estrategia prometedora en el tratamiento de la enfermedad cardiovascular

    Directory of Open Access Journals (Sweden)

    Fernando Manzur

    2013-12-01

    Full Text Available La inhibición de neprilisina y el bloqueo de los receptores de angiotensina II, ofrecen beneficios potenciales para el tratamiento de las enfermedades cardiovasculares. El compuesto LCZ696 es el primer fármaco en fase de estudio como inhibidor de la neprilisina y de los receptores de angiotensina. El aumento de la concentración de los péptidos natriuréticos a través de la inhibición de la neprilisina, representa un enfoque terapéutico que tiene el potencial de conferir protección cardiaca, renal y vascular. Sin embargo, diversos estudios demuestran que los beneficios clínicos de la inhibición de la neprilisina pueden ser mejor aprovechados si se inhibe simultáneamente el sistema renina-angiotensina. Esta revisión realizada en PubMed, tiene como objetivo presentar los avances prometedores en el mecanismo dual de inhibición de la neprilisina y el receptor de angiotensina II para el tratamiento de la hipertensión y la insuficiencia cardiaca.

  18. Stimulation of the Angiotensin II AT2 Receptor is Anti-inflammatory in Human Lipopolysaccharide-Activated Monocytic Cells

    DEFF Research Database (Denmark)

    Menk, Mario; Graw, Jan Adriaan; von Haefen, Clarissa

    2015-01-01

    and the translational level over course of time. Treatment with C21 attenuated the expression of TNFα, IL-6, and IL-10 after LPS challenge in both cell lines in a time- and dose-dependent manner. We conclude that selective AT2 receptor stimulation acts anti-inflammatory in human monocytes. Modulation of cytokine......Recently, AT2 receptors have been discovered on the surface of human immunocompetent cells such as monocytes. Data on regulative properties of this receptor on the cellular immune response are poor. We hypothesized that direct stimulation of the AT2 receptor mediates anti-inflammatory responses...... in these cells. Human monocytic THP-1 and U937 cells were stimulated with lipopolysaccharide (LPS) and the selective AT2 receptor agonist Compound 21 (C21). Expression of pro- and anti-inflammatory cytokines IL-6, IL-10, tumor necrosis factor-α (TNFα), and IL-1β were analyzed on both the transcriptional...

  19. A radioligand immunoassay for 1,25-dihydroxyvitamin D3 receptors using monoclonal antibody: detection of a phenotypic receptor variant in vitamin D-dependency rickets (type II) which does not bind hormone

    International Nuclear Information System (INIS)

    Pike, J.W.; Dokoh, Shigeharu; Liberman, U.A.; Eil, C.; Haussler, M.R.; Marx, S.J.

    1984-01-01

    Vitamin D-dependency rickets, type II (VDDRII), is a well recognized heritable disorder characterized by peripheral target organ resistance to 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ), the hormonally active form of the vitamin. Recently, cultured skin fibroblasts obtained from a number of patients with VDDRII have been utilized to characterize the underlying molecular defects associated with this malady. Recently monoclonal antibodies to the vitamin D receptor have been generated, and a radioligand immunoassay (RLIA) for the detection of this molecule has been developed which is independent of its hormone-binding capacity. This report describes the application of the immunoassay in the detection of receptor-like molecules in fibroblasts derived from patients with VDDRII. The results indicate that the molecule is generally present in all patients, and provides a mechanism for individual responsiveness to pharmacologic treatment with vitamin D 3 metabolites. 8 refs.; 3 figs.; 1 table

  20. Experience in using the covariances of some ENDF/B-V dosimetry cross sections: proposed improvements and addition of cross-reaction covariances

    International Nuclear Information System (INIS)

    Fu, C.Y.; Hetrick, D.M.

    1982-01-01

    Recent ratio data, with carefully evaluated covariances, were combined with eleven of the ENDF/B-V dosimetry cross sections using the generalized least-squares method. The purpose was to improve these evaluated cross sections and covariances, as well as to generate values for the cross-reaction covariances. The results represent improved cross sections as well as realistic and usable covariances. The latter are necessary for meaningful intergral-differential comparisons and for spectrum unfolding

  1. The ACE-2/Ang1-7/Mas cascade enhances bone structure and metabolism following angiotensin-II type 1 receptor blockade.

    Science.gov (United States)

    Abuohashish, Hatem M; Ahmed, Mohammed M; Sabry, Dina; Khattab, Mahmoud M; Al-Rejaie, Salim S

    2017-07-15

    The renin angiotensin system (RAS) regulates numerous systemic functions and is expressed locally in skeletal tissues. Angiotensin1-7 (Ang1-7) is a beneficial member of the RAS, and the therapeutic effects of a large number of angiotensin receptors blockers (ARBs) are mediated by an Ang1-7-dependent cascade. This study examines whether the reported osteo-preservative effects of losartan are mediated through the angiotensin converting enzyme2 (ACE-2)/Ang1-7/Mas pathway in ovariectomized (OVX) rats. Sham and OVX animals received losartan (10mg/kg/d p.o.) for 6 weeks. A specific Mas receptor blocker (A-779) was delivered via mini-osmotic pumps during the losartan treatment period. Serum and urine bone metabolism biomarker levels were measured. Bone trabecular and cortical morphometry were quantified in distal femurs, whereas mineral contents were estimated in ashed bones, serum and urine. Finally, the expression of RAS components, the receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG) was determined. Losartan significantly improved the elevated bone metabolism marker levels and altered trabecular and cortical structures in OVX animals, and restored normal urinary and skeletal mineral levels. Mas receptor inhibition significantly abolished all osteo-protective effects of losartan and enhanced the deleterious effects of OVX. Losartan enhanced OVX-induced up-regulation of ACE-1, AngII, angiotensin type 1 (AT 1 ) receptor and RANKL expression, and increased ACE-2, Ang1-7, Mas and OPG expression in OVX animals. However, A-779 significantly eradicated the effects of losartan on RAS components and RANKL/OPG expression. Thus, Ang1-7 are involved in the osteo-preservative effects of losartan via Mas receptor, which may add therapeutic value to this well-known antihypertensive agent. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. Administration of angiotensin II and a bradykinin B2 receptor blocker in midpregnancy impairs gestational outcome in guinea pigs.

    Science.gov (United States)

    Valdés, Gloria; Schneider, Daniela; Corthorn, Jenny; Ortíz, Rita; Acuña, Stephanie; Padilla, Oslando

    2014-06-04

    The opposing renin-angiotensin system (RAS) and kallikrein-kinin system (KKS) are upregulated in pregnancy and localize in the utero-placental unit. To test their participation as counter-regulators, circulating angiotensin II (AII) was exogenously elevated and the bradykinin B2 receptor (B2R) was antagonized in pregnant guinea-pigs. We hypothesized that disrupting the RAS/KKS balance during the period of maximal trophoblast invasion and placental development would provoke increased blood pressure, defective trophoblast invasion and a preeclampsia-like syndrome. Pregnant guinea-pigs received subcutaneous infusions of AII (200 μg/kg/day), the B2R antagonist Bradyzide (BDZ; 62.5 microg/kg/day), or both (AII + BDZ) from gestational day 20 to 34. Non-pregnant cycling animals were included in a control group (C NP) or received AII + BDZ (AII + BDZ NP) during 14 days. Systolic blood pressure was determined during cycle in C NP, and on the last day of infusion, and 6 and 26 days thereafter in the remaining groups. Twenty six days after the infusions blood and urine were extracted, fetuses, placentas and kidneys were weighed, and trophoblast invasion of spiral arteries was defined in the utero-placental units by immunocytochemistry. Systolic blood pressure transiently rose in a subgroup of the pregnant females while receiving AII + BDZ infusion, but not in AII + BDZ NP. Plasma creatinine was higher in AII- and BDZ-treated dams, but no proteinuria or hyperuricemia were observed. Kidney weight increased in AII + BDZ-treated pregnant and non-pregnant females. Aborted and dead fetuses were increased in dams that received AII and AII + BDZ. The fetal/placental weight ratio was reduced in litters of AII + BDZ-treated mothers. All groups that received interventions during pregnancy showed reduced replacement of endothelial cells by extravillous trophoblasts in lateral and myometrial spiral arteries. The acute effects on fetal viability, and the persistently impaired renal

  3. Gender Difference in Renal Blood Flow Response to Angiotensin II Administration after Ischemia/Reperfusion in Rats: The Role of AT2 Receptor.

    Science.gov (United States)

    Maleki, Maryam; Nematbakhsh, Mehdi

    2016-01-01

    Background. Renal ischemia/reperfusion (I/R) is one of the major causes of kidney failure, and it may interact with renin angiotensin system while angiotensin II (Ang II) type 2 receptor (AT2R) expression is gender dependent. We examined the role of AT2R blockade on vascular response to Ang II after I/R in rats. Methods. Male and female rats were subjected to 30 min renal ischemia followed by reperfusion. Two groups of rats received either vehicle or AT2R antagonist, PD123319. Mean arterial pressure (MAP), and renal blood flow (RBF) responses were assessed during graded Ang II (100, 300, and 1000 ng/kg/min, i.v.) infusion at controlled renal perfusion pressure (RPP). Results. Vehicle or antagonist did not alter MAP, RPP, and RBF levels significantly; however, 30 min after reperfusion, RBF decreased insignificantly in female treated with PD123319 (P = 0.07). Ang II reduced RBF and increased renal vascular resistance (RVR) in a dose-related fashion (P dose renal I/R injury appears to be sexually dimorphic. PD123319 infusion promotes these hemodynamic responses in female more than in male rats.

  4. Type I and II positive allosteric modulators differentially modulate agonist-induced up-regulation of α7 nicotinic acetylcholine receptors

    DEFF Research Database (Denmark)

    Thomsen, Morten Skøtt; Mikkelsen, Jens D

    2012-01-01

    Long-term treatment with nicotine or selective α7 nicotinic acetylcholine receptor (nAChR) agonists increases the number of α7 nAChRs and this up-regulation may be involved in the mechanism underlying the sustained procognitive effect of these compounds. Here, we investigate the influence of type I...... expressing human α7 nAChR, whereas the type I PAMs AVL-3288 or NS1738 do not. Contrarily, neither type I nor II PAMs affect 10 μM nicotine-induced receptor up-regulation, suggesting that nicotine and A-582941 induce up-regulation through different mechanisms. We further show in vivo that 3 mg/kg PNU-120596...... is involved in A-582941-induced up-regulation. Our results are the first to show an in vivo difference between type I and II α7 nAChR PAMs, and demonstrate an agonist-dependent effect of type II PAMs occurring on a much longer time scale than previously appreciated. Furthermore, our data suggest that nicotine...

  5. The carboxy-terminal tail or the intracellular loop 3 is required for β-arrestin-dependent internalization of a mammalian type II GnRH receptor.

    Science.gov (United States)

    Madziva, Michael T; Mkhize, Nonhlanhla N; Flanagan, Colleen A; Katz, Arieh A

    2015-08-15

    The type II GnRH receptor (GnRH-R2) in contrast to mammalian type I GnRH receptor (GnRH-R1) has a cytosolic carboxy-terminal tail. We investigated the role of β-arrestin 1 in GnRH-R2-mediated signalling and mapped the regions in GnRH-R2 required for recruitment of β-arrestin, employing internalization assays. We show that GnRH-R2 activation of ERK is dependent on β-arrestin and protein kinase C. Appending the tail of GnRH-R2 to GnRH-R1 enabled GRK- and β-arrestin-dependent internalization of the chimaeric receptor. Surprisingly, carboxy-terminally truncated GnRH-R2 retained β-arrestin and GRK-dependent internalization, suggesting that β-arrestin interacts with additional elements of GnRH-R2. Mutating serine and threonine or basic residues of intracellular loop 3 did not abolish β-arrestin 1-dependent internalization but a receptor lacking these basic residues and the carboxy-terminus showed no β-arrestin 1-dependent internalization. Our results suggest that basic residues at the amino-terminal end of intracellular loop 3 or the carboxy-terminal tail are required for β-arrestin dependent internalization. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  6. Dietary sodium deprivation evokes activation of brain regional neurons and down-regulation of angiotensin II type 1 receptor and angiotensin-convertion enzyme mRNA expression.

    Science.gov (United States)

    Lu, B; Yang, X J; Chen, K; Yang, D J; Yan, J Q

    2009-12-15

    Previous studies have indicated that the renin-angiotensin-aldosterone system (RAAS) is implicated in the induction of sodium appetite in rats and that different dietary sodium intakes influence the mRNA expression of central and peripheral RAAS components. To determine whether dietary sodium deprivation activates regional brain neurons related to sodium appetite, and changes their gene expression of RAAS components of rats, the present study examined the c-Fos expression after chronic exposure to low sodium diet, and determined the relationship between plasma and brain angiotensin I (ANG I), angiotensin II (ANG II) and aldosterone (ALD) levels and the sodium ingestive behavior variations, as well as the effects of prolonged dietary sodium deprivation on ANG II type 1 (AT1) and ANG II type 2 (AT2) receptors and angiotensin-convertion enzyme (ACE) mRNA levels in the involved brain regions using the method of real-time polymerase chain reaction (PCR). Results showed that the Fos immunoreactivity (Fos-ir) expression in forebrain areas such as subfornical organ (SFO), paraventricular hypothalamic nuclei (PVN), supraoptic nucleus (SON) and organum vasculosum laminae terminalis (OVLT) all increased significantly and that the levels of ANG I, ANG II and ALD also increased in plasma and forebrain in rats fed with low sodium diet. In contrast, AT1, ACE mRNA in PVN, SON and OVLT decreased significantly in dietary sodium depleted rats, while AT2 mRNA expression did not change in the examined areas. These results suggest that many brain areas are activated by increased levels of plasma and/or brain ANG II and ALD, which underlies the elevated preference for hypertonic salt solution after prolonged exposure to low sodium diet, and that the regional AT1 and ACE mRNA are down-regulated after dietary sodium deprivation, which may be mediated by increased ANG II in plasma and/or brain tissue.

  7. Comparative genomic analysis reveals independent expansion of a lineage-specific gene family in vertebrates: The class II cytokine receptors and their ligands in mammals and fish

    Directory of Open Access Journals (Sweden)

    Mogensen Knud

    2003-07-01

    Full Text Available Abstract Background The high degree of sequence conservation between coding regions in fish and mammals can be exploited to identify genes in mammalian genomes by comparison with the sequence of similar genes in fish. Conversely, experimentally characterized mammalian genes may be used to annotate fish genomes. However, gene families that escape this principle include the rapidly diverging cytokines that regulate the immune system, and their receptors. A classic example is the class II helical cytokines (HCII including type I, type II and lambda interferons, IL10 related cytokines (IL10, IL19, IL20, IL22, IL24 and IL26 and their receptors (HCRII. Despite the report of a near complete pufferfish (Takifugu rubripes genome sequence, these genes remain undescribed in fish. Results We have used an original strategy based both on conserved amino acid sequence and gene structure to identify HCII and HCRII in the genome of another pufferfish, Tetraodon nigroviridis that is amenable to laboratory experiments. The 15 genes that were identified are highly divergent and include a single interferon molecule, three IL10 related cytokines and their potential receptors together with two Tissue Factor (TF. Some of these genes form tandem clusters on the Tetraodon genome. Their expression pattern was determined in different tissues. Most importantly, Tetraodon interferon was identified and we show that the recombinant protein can induce antiviral MX gene expression in Tetraodon primary kidney cells. Similar results were obtained in Zebrafish which has 7 MX genes. Conclusion We propose a scheme for the evolution of HCII and their receptors during the radiation of bony vertebrates and suggest that the diversification that played an important role in the fine-tuning of the ancestral mechanism for host defense against infections probably followed different pathways in amniotes and fish.

  8. Expression and role of the angiotensin II AT2 receptor in human prostate tissue: in search of a new therapeutic option for prostate cancer.

    Science.gov (United States)

    Guimond, Marie-Odile; Battista, Marie-Claude; Nikjouitavabi, Fatemeh; Carmel, Maude; Barres, Véronique; Doueik, Alexandre A; Fazli, Ladan; Gleave, Martin; Sabbagh, Robert; Gallo-Payet, Nicole

    2013-07-01

    Evidence shows that angiotensin II type 1 receptor (AT1R) blockers may be associated with improved outcome in prostate cancer patients. It has been proposed that part of this effect could be due to angiotensin II type 2 receptor (AT2R) activation, the only active angiotensin II receptor in this situation. This study aimed to characterize the localization and expression of AT2R in prostate tissues and to assess its role on cell morphology and number in prostatic epithelial cells in primary culture. AT2R and its AT2R-interacting protein (ATIP) expression were assessed on non-tumoral and tumoral human prostate using tissue microarray immunohistochemistry, binding assay, and Western blotting. AT2R effect on cell number was measured in primary cultures of epithelial cells from non-tumoral human prostate. AT2R was localized at the level of the acinar epithelial layer and its expression decreased in cancers with a Gleason score 6 or higher. In contrast, ATIP expression increased with cancer progression. Treatment of primary cell cultures from non-tumoral prostate tissues with C21/M024, a selective AT2R agonist, alone or in co-incubation with losartan, an AT1R antagonist, significantly decreased cell number compared to untreated cells. AT2R and ATIP are present in non-tumoral human prostate tissues and differentially regulated according to Gleason score. The decrease in non-tumoral prostate cell number upon selective AT2R stimulation suggests that AT2R may have a protective role against prostate cancer development. Treatment with a selective AT2R agonist could represent a new approach for prostate cancer prevention or for patients on active surveillance. Copyright © 2013 Wiley Periodicals, Inc.

  9. MHC class II molecules deliver costimulatory signals in human T cells through a functional linkage with IL-2-receptors

    DEFF Research Database (Denmark)

    Odum, Niels; Kanner, S B; Ledbetter, J A

    1993-01-01

    MHC class II-positive T cells are found in tissues involved in autoimmune and infectious disorders. Because stimulation of class II molecules by mAb or bacterial superantigens induces protein tyrosine phosphorylation through activation of PTK3 in T cells, we hypothesized that class II signals play...... tyrosine phosphorylation of specific substrates including PLC-gamma 1. Combined stimulation of IL-2R and class II molecules had an additive effect on tyrosine phosphorylation. Pretreatment of T cells with a protein tyrosine kinase inhibitor, herbimycin A, inhibited IL-2 and class II-induced proliferation...... a regulatory function in T cell activation. Here, we show that cross-linking HLA-DR and -DP but not -DQ molecules by immobilized mAb enhanced proliferative T cell responses to IL-2. In contrast, class II stimulation had no effect on IL-4-induced proliferation. The costimulatory effect was most pronounced...

  10. Estrogen receptor binding radiopharmaceuticals: II. Tissue distribution of 17 α-methylestradiol in normal and tumor-bearing rats

    International Nuclear Information System (INIS)

    Feenstra, A.; Vaalburg, W.; Nolten, G.M.J.; Reiffers, S.; Talma, A.G.; Wiegman, T.; van der Molen, H.D.; Woldring, M.G.

    1983-01-01

    Tritiated 17α-methylestradiol was synthesized to investigate the potential of the carbon-11-labeled analog as an estrogen-receptor-binding radiopharmaceutical. In vitro, 17α-methylestradiol is bound with high affinity to the cytoplasmic estrogen receptor from rabbit uterus (K/sub d/ = 1.96 x 10 -10 M), and it sediments as an 8S hormone-receptor complex in sucrose gradients. The compound shows specific uptake in the uterus of the adult rat, within 1 h after injection. In female rats bearing DMBA-induced tumors, specific uterine and tumor uptakes were observed, although at 30 min the tumor uptake was only 23 to 30% of the uptake in the uterus. Tritiated 17α-methylestradiol with a specific activity of 6 Ci/mmole showed a similar tissue distribution. Our results indicate that a 17 α-methylestradiol is promising as an estrogen-receptor-binding radiopharmaceutical

  11. Imidazole derivatives as angiotensin II AT1 receptor blockers: Benchmarks, drug-like calculations and quantitative structure-activity relationships modeling

    Science.gov (United States)

    Alloui, Mebarka; Belaidi, Salah; Othmani, Hasna; Jaidane, Nejm-Eddine; Hochlaf, Majdi

    2018-03-01

    We performed benchmark studies on the molecular geometry, electron properties and vibrational analysis of imidazole using semi-empirical, density functional theory and post Hartree-Fock methods. These studies validated the use of AM1 for the treatment of larger systems. Then, we treated the structural, physical and chemical relationships for a series of imidazole derivatives acting as angiotensin II AT1 receptor blockers using AM1. QSAR studies were done for these imidazole derivatives using a combination of various physicochemical descriptors. A multiple linear regression procedure was used to design the relationships between molecular descriptor and the activity of imidazole derivatives. Results validate the derived QSAR model.

  12. In vitro receptor autoradiography reveals angiotensin IL (ANG II) binding associated with sensory and motor components of the vagus

    International Nuclear Information System (INIS)

    Diz, D.I.; Barnes, K.L.; Ferrario, C.M.

    1986-01-01

    Specific, high affinity Ang II binding in the dog's dorsal medulla is concentrated in the area postrema, nucleus tractus solitarii (nTS) and dorsal motor nucleus of the vagus (dmnX). More recently Ang II binding sites were observed where bundles of vagal afferent fibers enter the dorsal medulla 6 mm rostral to obex and in the nodose ganglia and peripheral vagal nerves. Since Ang II binding in the nTS and dmnX overlies the distribution of vagal afferent fibers and efferent neurons, the effects of nodose ganglionectomy and cervical vagotomy on Ang II binding in the dorsal medulla were studied in rats and dogs using autoradiography after incubation of 14 μm coronal sections with 0.4 nM 125 I-Ang II. Nonspecific binding was determined in the presence of 1 μm unlabeled Ang II. Two weeks after unilateral nodose ganglionectomy Ang II binding sites were absent ipsilaterally in the region where vagal afferent fibers enter the dorsal medulla. In the nTS and dmnX, binding near obex was reduced, while more rostrally these nuclei were almost completely devoid of Ang II binding on the denervated side. After cervical vagotomy, the loss of binding was restricted to the ipsilateral dmnX. These data are the first to reveal that Ang II binding in the dorsal medulla requires an intact vagal system

  13. An Angiotensin II Type 1 Receptor Blocker Prevents Renal Injury via Inhibition of the Notch Pathway in Ins2 Akita Diabetic Mice

    Directory of Open Access Journals (Sweden)

    Masaya Koshizaka

    2012-01-01

    Full Text Available Recently, it has been reported that the Notch pathway is involved in the pathogenesis of diabetic nephropathy. In this study, we investigated the activation of the Notch pathway in Ins2 Akita diabetic mouse (Akita mouse and the effects of telmisartan, an angiotensin II type1 receptor blocker, on the Notch pathway. The intracellular domain of Notch1 (ICN1 is proteolytically cleaved from the cell plasma membrane in the course of Notch activation. The expression of ICN1 and its ligand, Jagged1, were increased in the glomeruli of Akita mice, especially in the podocytes. Administration of telmisartan significantly ameliorated the expression of ICN1 and Jagged1. Telmisartan inhibited the angiotensin II-induced increased expression of transforming growth factor β and vascular endothelial growth factor A which could directly activate the Notch signaling pathway in cultured podocytes. Our results indicate that the telmisartan prevents diabetic nephropathy through the inhibition of the Notch pathway.

  14. Polymorphism AvaII of the LDL receptor (rs5925 is associated with carotid-intima media thickness in patients with diabetes mellitus type 2

    Directory of Open Access Journals (Sweden)

    Jovana Nikolajević-Starčević

    2014-08-01

    Full Text Available Introduction Increased serum level of low density lipoprotein (LDL cholesterol is a well established risk factor for atherosclerosis development and progression. Genetic variation in the LDL receptor gene could modulate serum LDL level and response to statin treatment thus affecting atherosclerosis development and progression. The present study was designed to investigate the association between polymorphism AvaII (rs5925 of the LDL receptor gene with serum lipid levels and carotid intima-media thickness (CIMT in patients with diabetes mellitus type 2 (DM2.Methods 595 patients with DM2 (399 on statin therapy and 196 without were enrolled in the study. The carotid intima-media thickness was assessed ultrasonographically. Biochemical analyses were performed using standard biochemical methods. AvaII (rs5925 genotypes were determined by real-time PCR. Results Genotype distribution and allele frequencies were not statistically significantly different between DM2 patients with regard to statin therapy. In DM2 patients using statins the highest serum levels of total and LDL cholesterol were observed in homozygous carriers of the A+ allele. After adjustment for well established cardiovascular risk factors homozygosity for the A+ allele (β=0.441 and p=0.04, statin treatment as well as serum levels of HDL, triglycerides, hsCRP and fibrinogen were independently associated with CIMT. Interactions of AvaII genotypes A-A+ and A+A+ with statin treatment were not statistically significant.Conclusion Homozigosity for the A+ allele of the AvaII polymorphism is associated with greater CIMT in DM2 patients.

  15. High-mobility group (HMG) protein HMG-1 and TATA-binding protein-associated factor TAF(II)30 affect estrogen receptor-mediated transcriptional activation.

    Science.gov (United States)

    Verrier, C S; Roodi, N; Yee, C J; Bailey, L R; Jensen, R A; Bustin, M; Parl, F F

    1997-07-01

    The estrogen receptor (ER) belongs to a family of ligand-inducible nuclear receptors that exert their effects by binding to cis-acting DNA elements in the regulatory region of target genes. The detailed mechanisms by which ER interacts with the estrogen response element (ERE) and affects transcription still remain to be elucidated. To study the ER-ERE interaction and transcription initiation, we employed purified recombinant ER expressed in both the baculovirus-Sf9 and his-tagged bacterial systems. The effect of high-mobility group (HMG) protein HMG-1 and purified recombinant TATA-binding protein-associated factor TAF(II)30 on ER-ERE binding and transcription initiation were assessed by electrophoretic mobility shift assay and in vitro transcription from an ERE-containing template (pERE2LovTATA), respectively. We find that purified, recombinant ER fails to bind to ERE in spite of high ligand-binding activity and electrophoretic and immunological properties identical to ER in MCF-7 breast cancer cells. HMG-1 interacts with ER and promotes ER-ERE binding in a concentration- and time-dependent manner. The effectiveness of HMG-1 to stimulate ER-ERE binding in the electrophoretic mobility shift assay depends on the sequence flanking the ERE consensus as well as the position of the latter in the oligonucleotide. We find that TAF(II)30 has no effect on ER-ERE binding either alone or in combination with ER and HMG-1. Although HMG-1 promotes ER-ERE binding, it fails to stimulate transcription initiation either in the presence or absence of hormone. In contrast, TAF(II)30, while not affecting ER-ERE binding, stimulates transcription initiation 20-fold in the presence of HMG-1. These results indicate that HMG-1 and TAF(II)30 act in sequence, the former acting to promote ER-ERE binding followed by the latter to stimulate transcription initiation.

  16. Angiotensin II Type 1 Receptor Mechanoactivation Involves RGS5 (Regulator of G Protein Signaling 5) in Skeletal Muscle Arteries: Impaired Trafficking of RGS5 in Hypertension.

    Science.gov (United States)

    Hong, Kwangseok; Li, Min; Nourian, Zahra; Meininger, Gerald A; Hill, Michael A

    2017-12-01

    Studies suggest that arteriolar pressure-induced vasoconstriction can be initiated by GPCRs (G protein-coupled receptors), including the AT 1 R (angiotensin II type 1 receptor). This raises the question, are such mechanisms regulated by negative feedback? The present studies examined whether RGS (regulators of G protein signaling) proteins in vascular smooth muscle cells are colocalized with the AT 1 R when activated by mechanical stress or angiotensin II and whether this modulates AT 1 R-mediated vasoconstriction. To determine whether activation of the AT 1 R recruits RGS5, an in situ proximity ligation assay was performed in primary cultures of cremaster muscle arteriolar vascular smooth muscle cells treated with angiotensin II or hypotonic solution in the absence or presence of candesartan (an AT 1 R blocker). Proximity ligation assay results revealed a concentration-dependent increase in trafficking/translocation of RGS5 toward the activated AT 1 R, which was attenuated by candesartan. In intact arterioles, knockdown of RGS5 enhanced constriction to angiotensin II and augmented myogenic responses to increased intraluminal pressure. Myogenic constriction was attenuated to a higher degree by candesartan in RGS5 siRNA-transfected arterioles, consistent with RGS5 contributing to downregulation of AT 1 R-mediated signaling. Further, translocation of RGS5 was impaired in vascular smooth muscle cells of spontaneously hypertensive rats. This is consistent with dysregulated (RGS5-mediated) AT 1 R signaling that could contribute to excessive vasoconstriction in hypertension. In intact vessels, candesartan reduced myogenic vasoconstriction to a greater extent in spontaneously hypertensive rats compared with controls. Collectively, these findings suggest that AT 1 R activation results in translocation of RGS5 toward the plasma membrane, limiting AT 1 R-mediated vasoconstriction through its role in G q/11 protein-dependent signaling. © 2017 American Heart Association, Inc.

  17. Sodium butyrate suppresses angiotensin II-induced hypertension by inhibition of renal (pro)renin receptor and intrarenal renin-angiotensin system.

    Science.gov (United States)

    Wang, Lei; Zhu, Qing; Lu, Aihua; Liu, Xiaofen; Zhang, Linlin; Xu, Chuanming; Liu, Xiyang; Li, Haobo; Yang, Tianxin

    2017-09-01

    Butyrate, a short-chain fatty acid, is the end product of the fermentation of complex carbohydrates by the gut microbiota. Recently, sodium butyrate (NaBu) has been found to play a protective role in a number of chronic diseases. However, it is still unclear whether NaBu has a therapeutic potential in hypertension. The present study was aimed to investigate the role of NaBu in angiotensin II (Ang II)-induced hypertension and to further explore the underlying mechanism. Ang II was infused into uninephrectomized Sprague-Dawley rats with or without intramedullary infusion of NaBu for 14 days. Mean arterial blood pressure was recorded by the telemetry system. Renal tissues, serum samples, and 24-h urine samples were collected to examine renal injury and the regulation of the (pro)renin receptor (PRR) and renin. Intramedullary infusion of NaBu in Sprague-Dawley rats lowered the Ang II-induced mean arterial pressure from 129 ± 6 mmHg to 108 ± 4 mmHg (P renal injury, including urinary albumin, glomerulosclerosis, and renal fibrosis, as well as the expression of inflammatory mediators tumor necrosis factor α, interleukin 6. The renal expression of PRR, angiotensinogen, angiotensin I-converting enzyme and the urinary excretion of soluble PRR, renin, and angiotensinogen were all increased by Ang II infusion but decreased by NaBu treatment. In cultured innermedullary collecting duct cells, NaBu treatment attenuated Ang II-induced expression of PRR and renin. These results demonstrate that NaBu exerts an antihypertensive action, likely by suppressing the PRR-mediated intrarenal renin-angiotensin system.

  18. Role of group II metabotropic glutamate receptors 2/3 and group I metabotropic glutamate receptor 5 in developing rat medial vestibular nuclei.

    Science.gov (United States)

    Grassi, Silvarosa; Frondaroli, Adele; Pettorossi, Vito Enrico

    2005-08-22

    In brainstem slices from developing rats, metabotropic glutamate receptors mGluR2/3 and mGluR5 play different inhibitory roles in synaptic transmission and plasticity of the medial vestibular nuclei. The mGluR2/3 block (LY341495) reduces the occurrence of long-term depression after vestibular afferent high frequency stimulation at P8-P10, and increases that of long-term potentiation, while the mGluR5 block prevents high frequency stimulation long-term depression. Later on, the receptor block does not influence high frequency stimulation effects. In addition, while mGluR2/3 agonist (APDC) always provokes a transient reduction of synaptic responses, that of mGluR5 (CHPG) induces long-term depression per se at P8-P10. These results show a key role of mGluR5 in inducing high frequency stimulation long-term depression in developing medial vestibular nuclei, while mGluR2/3 modulate synaptic transmission, probably through presynaptic control of glutamate release.

  19. Compensating for cross-reactions using avidity and computation in a suspension multiplex immunoassay for serotyping of Zika versus other flavivirus infections.

    Science.gov (United States)

    Rönnberg, Bengt; Gustafsson, Åke; Vapalahti, Olli; Emmerich, Petra; Lundkvist, Åke; Schmidt-Chanasit, Jonas; Blomberg, Jonas

    2017-10-01

    The recent spread of Zika virus (ZIKV) in the Americas and Asia necessitates an increased preparedness for improved maternal and perinatal health and blood safety. However, serological cross-reactions, especially to Dengue virus (DENV), complicate ZIKV antibody serodiagnosis. A novel "pan-Flavi" suspension multiplex immunoassay (PFSMIA) using 25 antigens, whole virus (WV), non-structural protein 1 (NS1), and envelope (E) proteins, from 7 zoonotic flaviviruses for specific detection of ZIKV and DENV IgM and IgG was developed. Patterns of antibody cross-reactivity, avidity, and kinetics were established in 104 sera from returning travelers with known ZIKV and DENV infections. PFSMIA gave IgM- and IgG-sensitivities for both viruses of 96-100%, compared to an immunofluorescence assay. Main IgM cross-reactions were to NS1, for IgG to the E and WV antigens. Infecting virus yielded reactivity to several antigens of the homologous virus, while cross-reactions tended to occur only to a single antigen from heterologous virus(es). A specificity-enhancing computer procedure took into account antibody isotype, number of antibody-reactive antigens per virus, avidity, average degree of cross-reactivity to heterologous flavivirus antigens, and reactivity changes in serial sera. It classified all 50 cases correctly. Applied to sera from 200 pregnant women and 173 blood donors from Sweden, one blood donor was found ZIKV NS1 IgM positive, and another as ZIKV NS1 IgG positive. These samples did not react with other ZIKV antigens and were thereby judged as false-positives. PFSMIA provided sensitive and specific ZIKV and DENV serology, warranting high-throughput serological surveillance and a minimized need for laborious and expensive virus neutralization assays.

  20. Effect of adding gefitinib to neoadjuvant chemotherapy in estrogen receptor negative early breast cancer in a randomized phase II trial

    DEFF Research Database (Denmark)

    Bernsdorf, M.; Ingvar, C.; Jorgensen, L.

    2011-01-01

    Gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, has shown both anti-proliferative and anti-tumoral activity in breast cancer. This study was designed to determine the effect of adding gefitinib to neoadjuvant epirubicin and cyclophosphamide (EC) on tumor response rates. ...

  1. Prevention of demoralization in prolonged bicultural conflict and interaction: the role of cultural receptors II - genesis of hybridization.

    Science.gov (United States)

    de Figueiredo, John M

    2013-08-01

    The objective of this article is to show that bicultural hybridization for the prevention of demoralization is anchored on the discovery of certain thematic areas (cultural receptors) in which social roles or cultural mandates are missing, unclear, ambiguous or congruent. The specific setting is the history of Goa, a former Portuguese territory on the western coast of India. Both published and unpublished sources of information were studied. Education, occupation and income, the three dimensions of social class, were less dominant than other aspects of the Hindu caste system, such as birth into a group viewed as a caste, observance of marriage circles, regulations of kinship and inheritance, and identification with a location. These other aspects were preserved as much as possible. The result was the conversion of the caste system into a system more akin to social class. Other examples of cultural receptors were found. A key step in the adaptation to acculturative stress is the discovery of cultural receptors in both cultures and the development of meaningful interconnections among those receptors. Psychotherapy attempts the restoration of morale. To be effective, therapists should consider the hierarchical organization of symbols and sentiments in the patient's culture.

  2. Effect of adding gefitinib to neoadjuvant chemotherapy in estrogen receptor negative early breast cancer in a randomized phase II trial

    DEFF Research Database (Denmark)

    Bernsdorf, Mogens; Ingvar, Christian; Jörgensen, Leif

    2011-01-01

    Gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, has shown both anti-proliferative and anti-tumoral activity in breast cancer. This study was designed to determine the effect of adding gefitinib to neoadjuvant epirubicin and cyclophosphamide (EC) on tumor response rates...

  3. Blockade of AT1 type receptors for angiotensin II prevents cardiac microvascular fibrosis induced by chronic stress in Sprague-Dawley rats.

    Science.gov (United States)

    Firoozmand, Lília Taddeo; Sanches, Andrea; Damaceno-Rodrigues, Nilsa Regina; Perez, Juliana Dinéia; Aragão, Danielle Sanches; Rosa, Rodolfo Mattar; Marcondes, Fernanda Klein; Casarini, Dulce Elena; Caldini, Elia Garcia; Cunha, Tatiana Sousa

    2018-04-20

    To test the effects of chronic-stress on the cardiovascular system, the model of chronic mild unpredictable stress (CMS) has been widely used. The CMS protocol consists of the random, intermittent, and unpredictable exposure of laboratory animals to a variety of stressors, during 3 consecutive weeks. In this study, we tested the hypothesis that exposure to the CMS protocol leads to left ventricle microcirculatory remodeling that can be attenuated by angiotensin II receptor blockade. Male Sprague-Dawley rats were randomly assigned into four groups: Control, Stress, Control + losartan, and Stress + losartan (N = 6, each group, losartan: 20 mg/kg/day). The rats were euthanized 15 days after CMS exposure, and blood samples and left ventricle were collected. Rats submitted to CMS presented increased glycemia, corticosterone, noradrenaline and adrenaline concentration, and losartan reduced the concentration of the circulating amines. Cardiac angiotensin II, measured by high-performance liquid chromatography (HPLC), was significantly increased in the CMS group, and losartan treatment reduced it, while angiotensin 1-7 was significantly higher in the CMS losartan-treated group as compared with CMS. Histological analysis, verified by transmission electron microscopy, showed that rats exposed to CMS presented increased perivascular collagen and losartan effectively prevented the development of this process. Hence, CMS induced a state of microvascular disease, with increased perivascular collagen deposition, that may be the trigger for further development of cardiovascular disease. In this case, CMS fibrosis is associated with increased production of catecholamines and with a disruption of renin-angiotensin system balance, which can be prevented by angiotensin II receptor blockade.

  4. Insight into the structural requirement of substituted quinazolinone biphenyl acylsulfonamides derivatives as Angiotensin II AT1 receptor antagonist: 2D and 3D QSAR approach

    Directory of Open Access Journals (Sweden)

    Mukesh C. Sharma

    2014-01-01

    Full Text Available A series of 19 molecules substituted quinazolinone biphenyl acylsulfonamides derivatives displaying variable inhibition of Angiotensin II receptor AT1 activity were selected to develop models for establishing 2D and 3D QSAR. The compounds in the selected series were characterized by spatial, molecular and electro topological descriptors using QSAR module of Molecular Design Suite (VLife MDS™ 3.5. The best 2D QSAR model was selected, having correlation coefficient r2 (0.8056 and cross validated squared correlation coefficient q2 (0.6742 with external predictive ability of pred_r2 0.7583 coefficient of correlation of predicted data set (pred_r2se 0.2165. The results obtained from QSAR studies could be used in designing better Ang II activity among the congeners in future. The optimum QSAR model showed that the parameters SsssCHE index, SddCE-index, T_2_Cl_4, and SssNHE-index contributed in the model. 3D QSAR analysis by kNN-molecular field analysis approach developed based on principles of the k-nearest neighbor method combined with Genetic algorithms, stepwise forward variable selection approach; a leave-one-out cross-validated correlation coefficient (q2 of 0.6516 and a non-cross-validated correlation coefficient (r2 of 0.8316 and pred_r2 0.6954 were obtained. Contour maps using this approach showed that steric, electrostatic, and hydrophobic field effects dominantly determine binding affinities. The information rendered by 3D QSAR models may lead to a better understanding of structural requirements of Angiotensin II receptor and can help in the design of novel potent antihypertensive molecules.

  5. Angiotensin II receptor one (AT1) mediates dextrose induced endoplasmic reticulum stress and superoxide production in human coronary artery endothelial cells.

    Science.gov (United States)

    Haas, Michael J; Onstead-Haas, Luisa; Lee, Tracey; Torfah, Maisoon; Mooradian, Arshag D

    2016-10-01

    Renin-angiotensin-aldosterone system (RAAS) has been implicated in diabetes-related vascular complications partly through oxidative stress. To determine the role of angiotensin II receptor subtype one (AT1) in dextrose induced endoplasmic reticulum (ER) stress, another cellular stress implicated in vascular disease. Human coronary artery endothelial cells with or without AT1 receptor knock down were treated with 27.5mM dextrose for 24h in the presence of various pharmacologic blockers of RAAS and ER stress and superoxide (SO) production were measured. Transfection of cells with AT1 antisense RNA knocked down cellular AT1 by approximately 80%. The ER stress was measured using the placental alkaline phosphatase (ES-TRAP) assay and western blot analysis of glucose regulated protein 78 (GRP78), c-jun-N-terminal kinase 1 (JNK1), phospho-JNK1, eukaryotic translation initiation factor 2α (eIF2α) and phospho-eIF2α measurements. Superoxide (SO) generation was measured using the superoxide-reactive probe 2-methyl-6-(4-methoxyphenyl)-3,7-dihydroimidazo[1,2-A]pyrazin-3-one hydrochloride (MCLA) chemiluminescence. In cells with AT1 knock down, dextrose induced ER stress was significantly blunted and treatment with 27.5mM dextrose resulted in significantly smaller increase in SO production compared to 27.5mM dextrose treated and sham transfected cells. Dextrose induced ER stress was reduced with pharmacologic blockers of AT1 (losartan and candesartan) and mineralocorticoid receptor blocker (spironolactone) but not with angiotensin converting enzyme inhibitors (captopril and lisinopril). The dextrose induced SO generation was inhibited by all pharmacologic blockers of RAAS tested. The results indicate that dextrose induced ER stress and SO production in endothelial cells are mediated at least partly through AT1 receptor activation. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  6. Casein Kinase 1α Mediates the Degradation of Receptors for Type I and Type II Interferons Caused by Hemagglutinin of Influenza A Virus.

    Science.gov (United States)

    Xia, Chuan; Wolf, Jennifer J; Vijayan, Madhuvanthi; Studstill, Caleb J; Ma, Wenjun; Hahm, Bumsuk

    2018-04-01

    Although influenza A virus (IAV) evades cellular defense systems to effectively propagate in the host, the viral immune-evasive mechanisms are incompletely understood. Our recent data showed that hemagglutinin (HA) of IAV induces degradation of type I IFN receptor 1 (IFNAR1). Here, we demonstrate that IAV HA induces degradation of type II IFN (IFN-γ) receptor 1 (IFNGR1), as well as IFNAR1, via casein kinase 1α (CK1α), resulting in the impairment of cellular responsiveness to both type I and II IFNs. IAV infection or transient HA expression induced degradation of both IFNGR1 and IFNAR1, whereas HA gene-deficient IAV failed to downregulate the receptors. IAV HA caused the phosphorylation and ubiquitination of IFNGR1, leading to the lysosome-dependent degradation of IFNGR1. Influenza viral HA strongly decreased cellular sensitivity to type II IFNs, as it suppressed the activation of STAT1 and the induction of IFN-γ-stimulated genes in response to exogenously supplied recombinant IFN-γ. Importantly, CK1α, but not p38 MAP kinase or protein kinase D2, was proven to be critical for HA-induced degradation of both IFNGR1 and IFNAR1. Pharmacologic inhibition of CK1α or small interfering RNA (siRNA)-based knockdown of CK1α repressed the degradation processes of both IFNGR1 and IFNAR1 triggered by IAV infection. Further, CK1α was shown to be pivotal for proficient replication of IAV. Collectively, the results suggest that IAV HA induces degradation of IFN receptors via CK1α, creating conditions favorable for viral propagation. Therefore, the study uncovers a new immune-evasive pathway of influenza virus. IMPORTANCE Influenza A virus (IAV) remains a grave threat to humans, causing seasonal and pandemic influenza. Upon infection, innate and adaptive immunity, such as the interferon (IFN) response, is induced to protect hosts against IAV infection. However, IAV seems to be equipped with tactics to evade the IFN-mediated antiviral responses, although the detailed

  7. Angiotensin 1-7 receptor and angiotensin ii receptor 2 blockades prevent the increased serum and kidney nitric oxide levels in response to angiotensin ii administration: Gender-related difference

    Directory of Open Access Journals (Sweden)

    Tahereh Safari

    2013-01-01

    Conclusions: The renal vasculature of male rats may provide more response to Ang II administration-induced NO, which is dependent on masR and AT2R. During dual masR + AT2R blockades, the kidney NO formation wasreduced in a non-gender related manner.

  8. Probing Receptor Specificity by Sampling the Conformational Space of the Insulin-like Growth Factor II C-domain

    Czech Academy of Sciences Publication Activity Database

    Hexnerová, Rozálie; Křížková, Květoslava; Fábry, Milan; Sieglová, Irena; Kedrová, Kateřina; Collinsová, Michaela; Ullrichová, P.; Srb, Pavel; Williams, C.; Crump, M. P.; Tošner, Z.; Jiráček, Jiří; Veverka, Václav; Žáková, Lenka

    2016-01-01

    Roč. 291, č. 40 (2016), s. 21234-21245 ISSN 0021-9258 R&D Projects: GA ČR GA15-19018S; GA MŠk(CZ) LK11205; GA MŠk(CZ) LO1304 Institutional support: RVO:61388963 ; RVO:68378050 Keywords : insulin * IGF-2 * receptor Subject RIV: CE - Biochemistry Impact factor: 4.125, year: 2016 http://www.jbc.org/content/291/40/21234.full

  9. Insulin and Insulin-like Growth Factor II Differentially Regulate Endocytic Sorting and Stability of Insulin Receptor Isoform A

    Czech Academy of Sciences Publication Activity Database

    Morcavallo, A.; Genua, M.; Palummo, A.; Kletvíková, Emília; Jiráček, Jiří; Brzozowski, A. M.; Lozzo, R. V.; Belfiore, A.; Morrione, A.

    2012-01-01

    Roč. 287, č. 14 (2012), s. 11422-11436 ISSN 0021-9258 Institutional research plan: CEZ:AV0Z40550506 Keywords : insulin * IGF -II * mitogenic response * IR-A Subject RIV: CE - Biochemistry Impact factor: 4.651, year: 2012

  10. Cloning and primary immunological study of TGF-β1 and its receptors TβR I /TβR II in tilapia(Oreochromis niloticus).

    Science.gov (United States)

    Zhan, Xu-liang; Ma, Tai-yang; Wu, Jin-ying; Yi, Li-yuan; Wang, Jing-yuan; Gao, Xiao-ke; Li, Wen-sheng

    2015-07-01

    The transforming growth factor β (TGF-β) superfamily plays critical roles in tumor suppression, cell proliferation and differentiation, tissue morphogenesis, lineage determination, cell migration and apoptosis. Recently, TGF-β1, one important member of TGF-β superfamily, is suggested as an immune regulator in the teleost. In this study, we cloned the cDNAs of TGF-β1 and its receptors, TβR I and TβR II (including three isoforms) from tilapia (Genbank accession numbers: KP754231- KP754235). A tissue distribution profile analysis indicated that TGF-β1 was highly expressed in the head kidney, gill, spleen, kidney and PBLs (peripheral blood leukocytes); TβR I only showed considerable expression in the liver; and TβR II-2 was highly expressed in the kidney, gill, liver, head kidney and heart. We determined that the mRNA expressions of TGF-β and TβR I /TβR II-2 were significantly increased in tilapia head kidney and spleen leukocytes by the stimulation of Lipopolysaccharide (LPS) or Poly I: C. We also examined their expressions in the spleen and head kidney of tilapia after IP injection of streptococcus agalactiae. The results showed that the mRNA expressions of these three genes all increased in the head kidney as early as 6 h post infection, and in the spleen 3 d post infection. In addition, the protein level of TGF-β1 was also up-regulated in the head kidney and the spleen after infection. Taken together, our data indicate that the TGF-β1-TβR I /TβR II-2 system functions potentially in tilapia immune system. Copyright © 2015 Elsevier Ltd. All rights reserved.

  11. Immediate and Catastrophic Antibody-Mediated Rejection in a Lung Transplant Recipient With Anti-Angiotensin II Receptor Type 1 and Anti-Endothelin-1 Receptor Type A Antibodies.

    Science.gov (United States)

    Cozzi, E; Calabrese, F; Schiavon, M; Feltracco, P; Seveso, M; Carollo, C; Loy, M; Cardillo, M; Rea, F

    2017-02-01

    Preexisting donor-specific anti-HLA antibodies (DSAs) have been associated with reduced survival of lung allografts. However, antibodies with specificities other than HLA may have a detrimental role on the lung transplant outcome. A young man with cystic fibrosis underwent lung transplantation with organs from a suitable deceased donor. At the time of transplantation, there were no anti-HLA DSAs. During surgery, the patient developed a severe and intractable pulmonary hypertension associated with right ventriular dysfunction, which required arteriovenous extracorporeal membrane oxygenation. After a brief period of clinical improvement, a rapid deterioration in hemodynamics led to the patient's death on postoperative day 5. Postmortem studies showed that lung specimens taken at the end of surgery were compatible with antibody-mediated rejection (AMR), while terminal samples evidenced diffuse capillaritis, blood extravasation, edema, and microthrombi, with foci of acute cellular rejection (A3). Immunological investigations demonstrated the presence of preexisting antibodies against the endothelin-1 receptor type A (ET A R) and the angiotensin II receptor type 1 (AT 1 R), two of the most potent vasoconstrictors reported to date, whose levels slightly rose after transplantation. These data suggest that preexisting anti-ET A R and anti-AT 1 R antibodies may have contributed to the onset of AMR and to the catastrophic clinical course of this patient. © Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.

  12. In vivo imaging of oxidative stress in the kidney of diabetic mice and its normalization by angiotensin II type 1 receptor blocker

    International Nuclear Information System (INIS)

    Sonta, Toshiyo; Inoguchi, Toyoshi; Matsumoto, Shingo; Yasukawa, Keiji; Inuo, Mieko; Tsubouchi, Hirotaka; Sonoda, Noriyuki; Kobayashi, Kunihisa; Utsumi, Hideo; Nawata, Hajime

    2005-01-01

    This study was undertaken to evaluate oxidative stress in the kidney of diabetic mice by electron spin resonance (ESR) imaging technique. Oxidative stress in the kidney was evaluated as organ-specific reducing activity with the signal decay rates of carbamoyl-PROXYL probe using ESR imaging. The signal decay rates were significantly faster in corresponding image pixels of the kidneys of streptozotocin-induced diabetic mice than in those of controls. This technique further demonstrated that administration of angiotensin II type 1 receptor blocker (ARB), olmesartan (5 mg/kg), completely restored the signal decay rates in the diabetic kidneys to control values. In conclusion, this study provided for the first time the in vivo evidence for increased oxidative stress in the kidneys of diabetic mice and its normalization by ARB as evaluated by ESR imaging. This technique would be useful as a means of further elucidating the role of oxidative stress in diabetic nephropathy

  13. Brain penetration of telmisartan, a unique centrally acting angiotensin II type 1 receptor blocker, studied by PET in conscious rhesus macaques

    International Nuclear Information System (INIS)

    Noda, Akihiro; Fushiki, Hiroshi; Murakami, Yoshihiro; Sasaki, Hiroshi; Miyoshi, Sosuke; Kakuta, Hirotoshi; Nishimura, Shintaro

    2012-01-01

    Introduction: Telmisartan is a widely used, long-acting antihypertensive agent. Known to be a selective angiotensin II type 1 (AT 1 ) receptor (AT 1 R) blocker (ARB), telmisartan acts as a partial agonist of peroxisome proliferator-activated receptor-gamma (PPAR-γ) and inhibits centrally mediated effects of angiotensin II in rats following peripheral administration, although the brain penetration of telmisartan remains unclear. We investigated the brain concentration and localization of telmisartan using 11 C-labeled telmisartan and positron emission tomography (PET) in conscious rhesus macaques. Methods: Three male rhesus macaques were bolus intravenously administered [ 11 C]telmisartan either alone or as a mixture with unlabeled telmisartan (1 mg/kg). Dynamic PET images were acquired for 95 min following administration. Blood samples were collected for the analysis of plasma concentration and metabolites, and brain and plasma concentrations were calculated from detected radioactivity using the specific activity of the administered drug preparation, in which whole blood radioactivity was used for the correction of intravascular blood radioactivity in brain. Results: Telmisartan penetrated into the brain little but enough to block AT 1 R and showed a consistently increasing brain/plasma ratio within the PET scanning period, suggesting slow clearance of the compound from the brain compared to the plasma clearance. Brain/plasma ratios at 30, 60, and 90 min were 0.06, 0.13, and 0.18, respectively. No marked localization according to the AT 1 R distribution was noted over the entire brain, even on tracer alone dosing. Conclusions: Telmisartan penetrated into the brain enough to block AT 1 R and showed a slow clearance from the brain in conscious rhesus macaques, supporting the long-acting and central responses of telmisartan as a unique property among ARBs.

  14. The Inhibitory Core of the Myostatin Prodomain: Its Interaction with Both Type I and II Membrane Receptors, and Potential to Treat Muscle Atrophy.

    Science.gov (United States)

    Ohsawa, Yutaka; Takayama, Kentaro; Nishimatsu, Shin-ichiro; Okada, Tadashi; Fujino, Masahiro; Fukai, Yuta; Murakami, Tatsufumi; Hagiwara, Hiroki; Itoh, Fumiko; Tsuchida, Kunihiro; Hayashi, Yoshio; Sunada, Yoshihide

    2015-01-01

    Myostatin, a muscle-specific transforming growth factor-β (TGF-β), negatively regulates skeletal muscle mass. The N-terminal prodomain of myostatin noncovalently binds to and suppresses the C-terminal mature domain (ligand) as an inactive circulating complex. However, which region of the myostatin prodomain is required to inhibit the biological activity of myostatin has remained unknown. We identified a 29-amino acid region that inhibited myostatin-induced transcriptional activity by 79% compared with the full-length prodomain. This inhibitory core resides near the N-terminus of the prodomain and includes an α-helix that is evolutionarily conserved among other TGF-β family members, but suppresses activation of myostatin and growth and differentiation factor 11 (GDF11) that share identical membrane receptors. Interestingly, the inhibitory core co-localized and co-immunoprecipitated with not only the ligand, but also its type I and type II membrane receptors. Deletion of the inhibitory core in the full-length prodomain removed all capacity for suppression of myostatin. A synthetic peptide corresponding to the inhibitory core (p29) ameliorates impaired myoblast differentiation induced by myostatin and GDF11, but not activin or TGF-β1. Moreover, intramuscular injection of p29 alleviated muscle atrophy and decreased the absolute force in caveolin 3-deficient limb-girdle muscular dystrophy 1C model mice. The injection suppressed activation of myostatin signaling and restored the decreased numbers of muscle precursor cells caused by caveolin 3 deficiency. Our findings indicate a novel concept for this newly identified inhibitory core of the prodomain of myostatin: that it not only suppresses the ligand, but also prevents two distinct membrane receptors from binding to the ligand. This study provides a strong rationale for the use of p29 in the amelioration of skeletal muscle atrophy in various clinical settings.

  15. Replicative homeostasis II: Influence of polymerase fidelity on RNA virus quasispecies biology: Implications for immune recognition, viral autoimmunity and other "virus receptor" diseases

    Directory of Open Access Journals (Sweden)

    Sallie Richard

    2005-08-01

    Full Text Available Abstract Much of the worlds' population is in active or imminent danger from established infectious pathogens, while sporadic and pandemic infections by these and emerging agents threaten everyone. RNA polymerases (RNApol generate enormous genetic and consequent antigenic heterogeneity permitting both viruses and cellular pathogens to evade host defences. Thus, RNApol causes more morbidity and premature mortality than any other molecule. The extraordinary genetic heterogeneity defining viral quasispecies results from RNApol infidelity causing rapid cumulative genomic RNA mutation a process that, if uncontrolled, would cause catastrophic loss of sequence integrity and inexorable quasispecies extinction. Selective replication and replicative homeostasis, an epicyclical regulatory mechanism dynamically linking RNApol fidelity and processivity with quasispecies phenotypic diversity, modulating polymerase fidelity and, hence, controlling quasispecies behaviour, prevents this happening and also mediates immune escape. Perhaps more importantly, ineluctable generation of broad phenotypic diversity after viral RNA is translated to protein quasispecies suggests a mechanism of disease that specifically targets, and functionally disrupts, the host cell surface molecules – including hormone, lipid, cell signalling or neurotransmitter receptors – that viruses co-opt for cell entry. This mechanism – "Viral Receptor Disease (VRD" – may explain so-called "viral autoimmunity", some classical autoimmune disorders and other diseases, including type II diabetes mellitus, and some forms of obesity. Viral receptor disease is a unifying hypothesis that may also explain some diseases with well-established, but multi-factorial and apparently unrelated aetiologies – like coronary artery and other vascular diseases – in addition to diseases like schizophrenia that are poorly understood and lack plausible, coherent, pathogenic explanations.

  16. LCZ696, Angiotensin II Receptor-Neprilysin Inhibitor, Ameliorates High-Salt-Induced Hypertension and Cardiovascular Injury More Than Valsartan Alone.

    Science.gov (United States)

    Kusaka, Hiroaki; Sueta, Daisuke; Koibuchi, Nobutaka; Hasegawa, Yu; Nakagawa, Takashi; Lin, BoWen; Ogawa, Hisao; Kim-Mitsuyama, Shokei

    2015-12-01

    LCZ696, an angiotensin receptor-neprilysin inhibitor, has recently been demonstrated to exert more beneficial effects on hypertensive or heart failure patients than conventional renin-angiotensin system blockers. However, the mechanism underlying the benefit of LCZ696 remains to be understood. The present study was undertaken to examine the effect of LCZ696 compared with valsartan on hypertension and cardiovascular injury. (i) Using telemetry, we compared the hypotensive effect of LCZ696 and valsartan in spontaneously hypertensive rats (SHR) that were fed a high-salt diet followed by a low-salt diet. (ii) We also examined the comparative effect of LCZ696 and valsartan on salt loaded SHRcp, a model of metabolic syndrome. (i) LCZ696 exerted a greater blood pressure (BP) lowering effect than valsartan in SHR regardless of high-salt or low-salt intake. Additive BP reduction by LCZ696 was associated with a significant increase in urinary sodium excretion and sympathetic activity suppression. (ii) LCZ696 significantly ameliorated cardiac hypertrophy and inflammation, coronary arterial remodeling, and vascular endothelial dysfunction in high-salt loaded SHRcp compared with valsartan. LCZ696 caused greater BP reduction than valsartan in SHR regardless of the degree of salt intake, which was associated with a significant enhancement in urinary sodium excretion and sympathetic activity suppression. Furthermore, an additive BP lowering effect of LCZ696 led to greater cardiovascular protection in hypertensive rats. © American Journal of Hypertension, Ltd 2015. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  17. The discovery of new potent non-peptide Angiotensin II AT1 receptor blockers: A concise synthesis, molecular docking studies and biological evaluation of N-substituted 5-butylimidazole derivatives

    Czech Academy of Sciences Publication Activity Database

    Agelis, G.; Resvani, A.; Durdagi, S.; Spyridaki, K.; Tůmová, Tereza; Slaninová, Jiřina; Giannopoulos, P.; Vlahakos, D.; Liapakis, G.; Mavromoustakos, T.; Matsoukas, J.

    2012-01-01

    Roč. 55, Sep (2012), s. 358-374 ISSN 0223-5234 Institutional research plan: CEZ:AV0Z40550506 Keywords : synthesis * angiotensin II receptor blockers * N-substituted 5-butylimidazole derivatives * antihypertensive activity * molecular docking Subject RIV: CC - Organic Chemistry Impact factor: 3.499, year: 2012

  18. Tarantula huwentoxin-IV inhibits neuronal sodium channels by binding to receptor site 4 and trapping the domain ii voltage sensor in the closed configuration.

    Science.gov (United States)

    Xiao, Yucheng; Bingham, Jon-Paul; Zhu, Weiguo; Moczydlowski, Edward; Liang, Songping; Cummins, Theodore R

    2008-10-03

    Peptide toxins with high affinity, divergent pharmacological functions, and isoform-specific selectivity are powerful tools for investigating the structure-function relationships of voltage-gated sodium channels (VGSCs). Although a number of interesting inhibitors have been reported from tarantula venoms, little is known about the mechanism for their interaction with VGSCs. We show that huwentoxin-IV (HWTX-IV), a 35-residue peptide from tarantula Ornithoctonus huwena venom, preferentially inhibits neuronal VGSC subtypes rNav1.2, rNav1.3, and hNav1.7 compared with muscle subtypes rNav1.4 and hNav1.5. Of the five VGSCs examined, hNav1.7 was most sensitive to HWTX-IV (IC(50) approximately 26 nM). Following application of 1 microm HWTX-IV, hNav1.7 currents could only be elicited with extreme depolarizations (>+100 mV). Recovery of hNav1.7 channels from HWTX-IV inhibition could be induced by extreme depolarizations or moderate depolarizations lasting several minutes. Site-directed mutagenesis analysis indicated that the toxin docked at neurotoxin receptor site 4 located at the extracellular S3-S4 linker of domain II. Mutations E818Q and D816N in hNav1.7 decreased toxin affinity for hNav1.7 by approximately 300-fold, whereas the reverse mutations in rNav1.4 (N655D/Q657E) and the corresponding mutations in hNav1.5 (R812D/S814E) greatly increased the sensitivity of the muscle VGSCs to HWTX-IV. Our data identify a novel mechanism for sodium channel inhibition by tarantula toxins involving binding to neurotoxin receptor site 4. In contrast to scorpion beta-toxins that trap the IIS4 voltage sensor in an outward configuration, we propose that HWTX-IV traps the voltage sensor of domain II in the inward, closed configuration.

  19. Effect of Angiotensin II Type I Receptor Blockade with Valsartan on Carotid Artery Atherosclerosis: A Double Blind Randomized Clinical Trial Comparing Valsartan and Placebo (EFFERVESCENT).

    Science.gov (United States)

    Ramadan, Ronnie; Dhawan, Saurabh S; Binongo, José Nilo G; Alkhoder, Ayman; Jones, Dean P; Oshinski, John N; Quyyumi, Arshed A

    2016-04-01

    Progression of atherosclerosis is associated with a greater risk for adverse outcomes. Angiotensin II plays a key role in the pathogenesis and progression of atherosclerosis. We aimed to investigate the effects of angiotensin II type-1 receptor blockade with Valsartan on carotid wall atherosclerosis, with the hypothesis that Valsartan will reduce progression of atherosclerosis. Subjects (n = 120) with carotid intima-media thickness >0.65 mm by ultrasound were randomized (2:1) in a double-blind manner to receive either Valsartan or placebo for 2 years. Bilateral T2-weighted black-blood carotid magnetic resonance imaging was performed at baseline, 12 and 24 months. Changes in the carotid bulb vessel wall area and wall thickness were primary endpoints. Secondary endpoints included changes in carotid plaque thickness, plasma levels of aminothiols, C-reactive protein, fibrinogen, and endothelium-dependent and -independent vascular function. Over 2 years, the carotid bulb vessel wall area decreased with Valsartan (-6.7, 95% CI [-11.6, -1.9] mm(2)) but not with placebo (3.4, 95% CI [-2.8, 9.6] mm(2)), P = .01 between groups. Similarly, mean wall thickness decreased with Valsartan (-0.18, 95% CI [-0.30, -0.06] mm), but not with placebo (0.08, 95% CI [-0.07, 0.23] mm), P = .009 between groups. Furthermore, plaque thickness decreased with Valsartan (-0.35, 95% CI [-0.63, -0.08] mm) but was unchanged with placebo (+0.28, 95% CI [-0.11, 0.69] mm), P = .01 between groups. These findings were unaffected by statin therapy or changes in blood pressure. Notably, there were significant improvements in the aminothiol cysteineglutathione disulfide, and trends to improvements in fibrinogen levels and endothelium-independent vascular function. In subjects with carotid wall thickening, angiotensin II type-1 receptor blockade was associated with regression in carotid atherosclerosis. Whether these effects translate into improved outcomes in subjects with subclinical atherosclerosis

  20. Differential Regulation of Smad3 and of the Type II Transforming Growth Factor-β Receptor in Mitosis: Implications for Signaling

    Science.gov (United States)

    Hirschhorn, Tal; Barizilay, Lior; Smorodinsky, Nechama I.; Ehrlich, Marcelo

    2012-01-01

    The response to transforming growth factor-β (TGF-β) depends on cellular context. This context is changed in mitosis through selective inhibition of vesicle trafficking, reduction in cell volume and the activation of mitotic kinases. We hypothesized that these alterations in cell context may induce a differential regulation of Smads and TGF-β receptors. We tested this hypothesis in mesenchymal-like ovarian cancer cells, arrested (or not) in mitosis with 2-methoxyestradiol (2ME2). In mitosis, without TGF-β stimulation, Smad3 was phosphorylated at the C-terminus and linker regions and localized to the mitotic spindle. Phosphorylated Smad3 interacted with the negative regulators of Smad signaling, Smurf2 and Ski, and failed to induce a transcriptional response. Moreover, in cells arrested in mitosis, Smad3 levels were progressively reduced. These phosphorylations and reduction in the levels of Smad3 depended on ERK activation and Mps1 kinase activity, and were abrogated by increasing the volume of cells arrested in mitosis with hypotonic medium. Furthermore, an Mps1-dependent phosphorylation of GFP-Smad3 was also observed upon its over-expression in interphase cells, suggesting a mechanism of negative regulation which counters increases in Smad3 concentration. Arrest in mitosis also induced a block in the clathrin-mediated endocytosis of the type II TGF-β receptor (TβRII). Moreover, following the stimulation of mitotic cells with TGF-β, the proteasome-mediated attenuation of TGF-β receptor activity, the degradation and clearance of TβRII from the plasma membrane, and the clearance of the TGF-β ligand from the medium were compromised, and the C-terminus phosphorylation of Smad3 was prolonged. We propose that the reduction in Smad3 levels, its linker phosphorylation, and its association with negative regulators (observed in mitosis prior to ligand stimulation) represent a signal attenuating mechanism. This mechanism is balanced by the retention of active TGF

  1. A PROSPECTIVE STUDY OF EFFECT OF TELMISARTAN (ANGIOTENSIN II RECEPTOR BLOCKER ON METABOLIC PARAMETERS IN HYPERTENSIVE PATIENTS WITH METABOLIC SYNDROME

    Directory of Open Access Journals (Sweden)

    Somesekhar

    2016-04-01

    Full Text Available BACKGROUND The metabolic syndrome is currently a major worldwide epidemic. It strongly associates with obesity, insulin resistance, type 2 diabetes, and cardiovascular diseases, which are major pathologies contributing to mortality and morbidity worldwide. The effect of PPAR-y on metabolic syndrome is significant it is critical regulator of adipogenesis the gain in PPAR-y is resulted in obesity but loss of PPAR–y by mutation is associated with loss of weight and insulin resistance. Telmisartan is an orally active, long-acting, non-peptide angiotensin type 1 (ATI receptor blocker. In addition to this, it has been identified as partial agonist/selective modulator of the nuclear hormone receptor PPAR-y. MATERIAL AND METHOD This is a prospective, randomised and open labelled 16 weeks study conducted in the Dept. of General Medicine, Konaseema Institute of Medical Science, Amalapuram. Present study is designed to study the effect of telmisartan on various metabolic parameters in hypertensive patients who fulfilled the criteria of metabolic syndrome. RESULT There was statistically significant change in all parameters most important was lipid profile; LDL concentration was decreased from 139.2 mg/dL to 120.2 mg/dL. Baseline triglyceride concentration was 161.0 mg/dL which was changed 152.8 mg/dL Total cholesterol was decreased from 203.2 to 193.8 mg/dL. CONCLUSION In our study, we have also found that use of telmisartan is associated with decrease in lipid concentration in addition to its effect on blood pressure regulation. But a long term study with high dose required of this drug is required because safety profile of this drug is better than thiazolidinedione. Financial part of this study is our limitation.

  2. Regulation of Akt and Wnt signaling by the group II metabotropic glutamate receptor antagonist LY341495 and agonist LY379268.

    Science.gov (United States)

    Sutton, Laurie P; Rushlow, Walter J

    2011-06-01

    Metabotropic glutamate receptors 2/3 (mGlu(2/3)) have been implicated in schizophrenia and as a novel treatment target for schizophrenia. The current study examined whether mGlu(2/3) regulates Akt (protein kinase B) and Wnt (Wingless/Int-1) signaling, two cascades associated with schizophrenia and modified by antipsychotics. Western blotting revealed increases in phosphorylated Akt (pAkt) and phosphorylated glycogen synthase kinase-3 (pGSK-3) following acute and repeated treatment of LY379268 (mGlu(2/3) agonist), whereas increases in dishevelled-2 (Dvl-2), dishevelled-3 (Dvl-3), GSK-3 and β-catenin were only observed following repeated treatment. LY341495 (mGlu(2/3) antagonist) induced the opposite response compared with LY379268. Co-immunoprecipitation experiments showed an association between the mGlu(2/3) complex and Dvl-2 providing a possible mechanism to explain how the mGlu(2/3) can mediate changes in Wnt signaling. However, there was no association between the mGlu(2/3) complex and Akt suggesting that changes in Akt signaling following LY341495 and LY379268 treatments may not be directly mediated by the mGlu(2/3) . Finally, an increase in locomotor activity induced by LY341495 treatment correlated with increased pAkt and pGSK-3 levels and was attenuated by the administration of the GSK-3 inhibitor, SB216763. Overall, the results suggest that mGlu(2/3) regulates Akt and Wnt signaling and LY379268 treatment has overlapping effects with D(2) dopamine receptor antagonists (antipsychotic drugs). © 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.

  3. Characterization of the growth of murine fibroblasts that express human insulin receptors. II. Interaction of insulin with other growth factors

    International Nuclear Information System (INIS)

    Randazzo, P.A.; Jarett, L.

    1990-01-01

    The effects of insulin-like growth factor-1 (IGF-1), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), and insulin on DNA synthesis were studied in murine fibroblasts transfected with an expression vector containing human insulin receptor cDNA (NIH 3T3/HIR) and the parental NIH 3T3 cells. In NIH 3T3/HIR cells, individual growth factors in serum-free medium stimulated DNA synthesis with the following relative efficacies: insulin greater than or equal to 10% fetal calf serum greater than PDGF greater than IGF-1 much greater than EGF. In comparison, the relative efficacies of these factors in stimulating DNA synthesis by NIH 3T3 cells were 10% fetal calf serum greater than PDGF greater than EGF much greater than IGF-1 = insulin. In NIH 3T3/HIR cells, EGF was synergistic with 1-10 ng/ml insulin but not with 100 ng/ml insulin or more. Synergy of PDGF or IGF-1 with insulin was not detected. In the parental NIH 3T3 cells, insulin and IGF-1 were found to be synergistic with EGF (1 ng/ml), PDGF (100 ng/ml), and PDGF plus EGF. In NIH 3T3/HIR cells, the lack of interaction of insulin with other growth factors was also observed when the percentage of cells synthesizing DNA was examined. Despite insulin's inducing only 60% of NIH 3T3/HIR cells to incorporate thymidine, addition of PDGF, EGF, or PDGF plus EGF had no further effect. In contrast, combinations of growth factors resulted in 95% of the parental NIH 3T3 cells synthesizing DNA. The independence of insulin-stimulated DNA synthesis from other mitogens in the NIH 3T3/HIR cells is atypical for progression factor-stimulated DNA synthesis and is thought to be partly the result of insulin receptor expression in an inappropriate context or quantity

  4. Toll-like receptor 4 upregulation by angiotensin II contributes to hypertension and vascular dysfunction through reactive oxygen species production.

    Directory of Open Access Journals (Sweden)

    Priscila R De Batista

    Full Text Available Hypertension is considered as a low-grade inflammatory disease, with adaptive immunity being an important mediator of this pathology. TLR4 may have a role in the development of several cardiovascular diseases; however, little is known about its participation in hypertension. We aimed to investigate whether TLR4 activation due to increased activity of the renin-angiotensin system (RAS contributes to hypertension and its associated endothelial dysfunction. For this, we used aortic segments from Wistar rats treated with a non-specific IgG (1 µg/day and SHRs treated with losartan (15 mg/kg·day, the non-specific IgG or the neutralizing antibody anti-TLR4 (1 µg/day, as well as cultured vascular smooth muscle cells (VSMC from Wistar and SHRs. TLR4 mRNA levels were greater in the VSMC and aortas from SHRs compared with Wistar rats; losartan treatment reduced those levels in the SHRs. Treatment of the SHRs with the anti-TLR4 antibody: 1 reduced the increased blood pressure, heart rate and phenylephrine-induced contraction while it improved the impaired acetylcholine-induced relaxation; 2 increased the potentiation of phenylephrine contraction after endothelium removal; and 3 abolished the inhibitory effects of tiron, apocynin and catalase on the phenylephrine-induced response as well as its enhancing effect of acetylcholine-induced relaxation. In SHR VSMCs, angiotensin II increased TLR4 mRNA levels, and losartan reduced that increase. CLI-095, a TLR4 inhibitor, mitigated the increases in NAD(PH oxidase activity, superoxide anion production, migration and proliferation that were induced by angiotensin II. In conclusion, TLR4 pathway activation due to increased RAS activity is involved in hypertension, and by inducing oxidative stress, this pathway contributes to the endothelial dysfunction associated with this pathology. These results suggest that TLR4 and innate immunity may play a role in hypertension and its associated end-organ damage.

  5. Analysis of Gln223Agr Polymorphism of Leptin Receptor Gene in Type II Diabetic Mellitus Subjects among Malaysians

    Directory of Open Access Journals (Sweden)

    Chong Pei Pei

    2013-09-01

    Full Text Available Leptin is known as the adipose peptide hormone. It plays an important role in the regulation of body fat and inhibits food intake by its action. Moreover, it is believed that leptin level deductions might be the cause of obesity and may play an important role in the development of Type 2 Diabetes Mellitus (T2DM, as well as in cardiovascular diseases (CVD. The Leptin Receptor (LEPR gene and its polymorphisms have not been extensively studied in relation to the T2DM and its complications in various populations. In this study, we have determined the association of Gln223Agr loci of LEPR gene in three ethnic groups of Malaysia, namely: Malays, Chinese and Indians. A total of 284 T2DM subjects and 281 healthy individuals were recruited based on International Diabetes Federation (IDF criteria. Genomic DNA was extracted from the buccal specimens of the subjects. The commercial polymerase chain reaction (PCR method was carried out by proper restriction enzyme MSP I to both amplify and digest the Gln223Agr polymorphism. The p-value among the three studied races was 0.057, 0.011 and 0.095, respectively. The values such as age, WHR, FPG, HbA1C, LDL, HDL, Chol and Family History were significantly different among the subjects with Gln223Agr polymorphism of LEPR (p < 0.05.

  6. Effectiveness of angiotensin II receptor antagonists in a cohort of Dutch patients with type 2 diabetes mellitus (ZODIAC-14).

    Science.gov (United States)

    van Hateren, Kornelis J J; Landman, Gijs W D; Groenier, Klaas H; Bilo, Henk J G; Kleefstra, Nanne

    2015-04-01

    There is limited evidence with respect to the between-group effects of various angiotensin receptor blockers (ARBs) on blood pressure and albuminuria in patients with type 2 diabetes mellitus. Therefore, we aimed to investigate the effects of differing ARBs on systolic blood pressure (SBP) and the albumin-creatinine ratio after 1 year in a large cohort of patients with type 2 diabetes mellitus. In 2007, 24 940 primary care patients with type 2 diabetes mellitus participated in the Zwolle Outpatient Diabetes project Integrating Available Care (ZODIAC) study, a prospective observational cohort study. Patients were included in the current study if they were prescribed an ARB in 2007 and if 1-year follow-up data were available. The final study population comprised 3610 patients. Multivariate mixed-model analyses were performed to estimate effects of the various ARBs on SBP and albuminuria. Stratified subgroup analyses were performed according to baseline hypertension and albuminuria. SBP decreased in all groups, the largest decrease being observed in the group receiving telmisartan. No significant or relevant changes over time were observed among groups for SBP and albuminuria. In the subgroup (n=1225) of normotensive patients, telmisartan was associated with a larger decrease in SBP after 1 year compared to other ARBs, without different effects on the albumin-creatinine ratio. We observed no differences in effects on SBP and the albumin-creatinine ratio among differing ARBs in patients with type 2 diabetes mellitus. Copyright © 2015 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.

  7. Analysis of Gln223Agr polymorphism of Leptin Receptor Gene in type II diabetic mellitus subjects among Malaysians.

    Science.gov (United States)

    Etemad, Ali; Ramachandran, Vasudevan; Pishva, Seyyed Reza; Heidari, Farzad; Aziz, Ahmad Fazli Abdul; Yusof, Ahmad Khairuddin Mohamed; Pei, Chong Pei; Ismail, Patimah

    2013-09-18

    Leptin is known as the adipose peptide hormone. It plays an important role in the regulation of body fat and inhibits food intake by its action. Moreover, it is believed that leptin level deductions might be the cause of obesity and may play an important role in the development of Type 2 Diabetes Mellitus (T2DM), as well as in cardiovascular diseases (CVD). The Leptin Receptor (LEPR) gene and its polymorphisms have not been extensively studied in relation to the T2DM and its complications in various populations. In this study, we have determined the association of Gln223Agr loci of LEPR gene in three ethnic groups of Malaysia, namely: Malays, Chinese and Indians. A total of 284 T2DM subjects and 281 healthy individuals were recruited based on International Diabetes Federation (IDF) criteria. Genomic DNA was extracted from the buccal specimens of the subjects. The commercial polymerase chain reaction (PCR) method was carried out by proper restriction enzyme MSP I to both amplify and digest the Gln223Agr polymorphism. The p-value among the three studied races was 0.057, 0.011 and 0.095, respectively. The values such as age, WHR, FPG, HbA1C, LDL, HDL, Chol and Family History were significantly different among the subjects with Gln223Agr polymorphism of LEPR (p < 0.05).

  8. IGF-II-mediated downregulation of peroxisome proliferator-activated receptor-γ coactivator-1α in myoblast cells involves PI3K/Akt/FoxO1 signaling pathway.

    Science.gov (United States)

    Mu, Xiaoyu; Qi, Weihong; Liu, Yunzhang; Zhou, Jianfeng; Li, Yun; Rong, Xiaozhi; Lu, Ling

    2017-08-01

    Insulin-like growth factor II (IGF-II) can stimulate myogenesis and is critically involved in skeletal muscle differentiation. The presence of negative regulators of this process, however, is not well explored. Here, we showed that in myoblast cells, IGF-II negatively regulated peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) mRNA expression, while constitutive expression of PGC-1α induced myoblast differentiation. These results suggest that the negative regulation of PGC-1α by IGF-II may act as a negative feedback mechanism in IGF-II-induced myogenic differentiation. Reporter assays demonstrated that IGF-II suppresses the basal PGC-1α promoter activity. Blocking the IGF-II signaling pathway increased the endogenous PGC-1α levels. In addition, pharmacological inhibition of PI3 kinase activity prevented the downregulation of PGC-1α but the activation of mTOR was not required for this process. Importantly, further analysis showed that forkhead transcription factor FoxO1 contributes to mediating the effects of IGF-II on PGC-1 promoter activity. These findings indicate that IGF-II reduces PGC-1α expression in skeletal muscle cells through a mechanism involving PI3K-Akt-FoxO1 but not p38 MAPK or Erk1/2 MAPK pathways.

  9. Olfactory Receptor Database: a sensory chemoreceptor resource

    OpenAIRE

    Skoufos, Emmanouil; Marenco, Luis; Nadkarni, Prakash M.; Miller, Perry L.; Shepherd, Gordon M.

    2000-01-01

    The Olfactory Receptor Database (ORDB) is a WWW-accessible database that has been expanded from an olfactory receptor resource to a chemoreceptor resource. It stores data on six classes of G-protein-coupled sensory chemoreceptors: (i) olfactory receptor-like proteins, (ii) vomeronasal receptors, (iii) insect olfactory receptors, (iv) worm chemoreceptors, (v) taste papilla receptors and (vi) fungal pheromone receptors. A complementary database of the ligands of these receptors (OdorDB) has bee...

  10. Phosphatidylinositol 5-phosphate 4-kinase type II beta is required for vitamin D receptor-dependent E-cadherin expression in SW480 cells

    International Nuclear Information System (INIS)

    Kouchi, Zen; Fujiwara, Yuki; Yamaguchi, Hideki; Nakamura, Yoshikazu; Fukami, Kiyoko

    2011-01-01

    Highlights: → We analyzed Phosphatidylinositol 5-phosphate kinase IIβ (PIPKIIβ) function in cancer. → PIPKIIβ is required for vitamin D receptor-mediated E-cadherin upregulation in SW480. → PIPKIIβ suppresses cellular motility through E-cadherin induction in SW480 cells. → Nuclear PIP 2 but not plasma membrane-localized PIP 2 mediates E-cadherin upregulation. -- Abstract: Numerous epidemiological data indicate that vitamin D receptor (VDR) signaling induced by its ligand or active metabolite 1α,25-dihydroxyvitamin D 3 (1α,25(OH) 2 D 3 ) has anti-cancer activity in several colon cancers. 1α,25(OH) 2 D 3 induces the epithelial differentiation of SW480 colon cancer cells expressing VDR (SW480-ADH) by upregulating E-cadherin expression; however, its precise mechanism remains unknown. We found that phosphatidylinositol-5-phosphate 4-kinase type II beta (PIPKIIβ) but not PIPKIIα is required for VDR-mediated E-cadherin induction in SW480-ADH cells. The syntenin-2 postsynaptic density protein/disc large/zona occludens (PDZ) domain and pleckstrin homology domain of phospholipase C-delta1 (PLCδ1 PHD) possess high affinity for phosphatidylinositol-4,5-bisphosphate (PI(4,5)P 2 ) mainly localized to the nucleus and plasma membrane, respectively. The expression of syntenin-2 PDZ but not PLCδ1 PHD inhibited 1α,25(OH) 2 D 3 -induced E-cadherin upregulation, suggesting that nuclear PI(4,5)P 2 production mediates E-cadherin expression through PIPKIIβ in a VDR-dependent manner. PIPKIIβ is also involved in the suppression of the cell motility induced by 1α,25(OH) 2 D 3 . These results indicate that PIPKIIβ-mediated PI(4,5)P 2 signaling is important for E-cadherin upregulation and inhibition of cellular motility induced by VDR activation.

  11. Secondary metabolites of Cynodon dactylon as an antagonist to angiotensin II type1 receptor: Novel in silico drug targeting approach for diabetic retinopathy

    Science.gov (United States)

    Jananie, R. K.; Priya, V.; Vijayalakshmi, K.

    2012-01-01

    Objectives: To study the ability of the secondary metabolites of Cynodon dactylon to serve as an antagonist to angiotensin II type 1 receptor (AT1); activation of this receptor plays a vital role in diabetic retinopathy (DR). Materials and Methods: In silico methods are mainly harnessed to reduce time, cost and risk associated with drug discovery. Twenty-four compounds were identified as the secondary metabolites of hydroalcoholic extract of C. dactylon using the GCMS technique. These were considered as the ligands or inhibitors that would serve as an antagonist to the AT1. The ACD/Chemsketch tool was used to generate 3D structures of the ligands. A molecular file format converter tool was used to convert the generated data to the PDB format (Protein Data Bank) and was used for docking studies. The AT1 structure was retrieved from the Swissprot data base and PDB and visualized using the Rasmol tool. Domain analysis was carried from the Pfam data base; following this, the active site of the target protein was identified using a Q-site finder tool. The ability of the ligands to bind with the active site of AT1 was studied using the Autodocking tool. The docking results were analyzed using the WebLab viewer tool. Results: Sixteen ligands showed effective binding with the target protein; diazoprogesteron, didodecyl phthalate, and 9,12-octadecadienoyl chloride (z,z) may be considered as compounds that could be used to bind with the active site sequence of AT1. Conclusions: The present study shows that the metabolites of C. dactylon could serve as a natural antagonist to AT1 that could be used to treat diabetic retinopathy. PMID:22368412

  12. Urotensin II receptor (UTR) exists in hyaline chondrocytes: a study of peripheral distribution of UTR in the African clawed frog, Xenopus laevis.

    Science.gov (United States)

    Konno, Norifumi; Fujii, Yuya; Imae, Haruka; Kaiya, Hiroyuki; Mukuda, Takao; Miyazato, Mikiya; Matsuda, Kouhei; Uchiyama, Minoru

    2013-05-01

    Urotensin II (UII) and UII-related peptide (URP) exhibit diverse physiological actions including vasoconstriction, locomotor activity, osmoregulation, and immune response through UII receptor (UTR), which is expressed in the central nervous system and peripheral tissues of fish and mammals. In amphibians, only UII has been identified. As the first step toward elucidating the actions of UII and URP in amphibians, we cloned and characterized URP and UTR from the African clawed frog Xenopus laevis. Functional analysis showed that treatment of UII or URP with Chinese hamster ovary cells transfected with the cloned receptor increased the intracellular calcium concentration in a concentration-dependent manner, whereas the administration of the UTR antagonist urantide inhibited UII- or URP-induced Ca(2+) mobilization. An immunohistochemical study showed that UTR was expressed in the splenocytes and leukocytes isolated from peripheral blood, suggesting that UII and URP are involved in the regulation of the immune system. UTR was also localized in the apical membrane of the distal tubule of the kidney and in the transitional epithelial cells of the urinary bladder. This result supports the view that the UII/URP-UTR system plays an important role in osmoregulation of amphibians. Interestingly, immunopositive labeling for UTR was first detected in the chondrocytes of various hyaline cartilages (the lung septa, interphalangeal joint and sternum). The expression of UTR was also observed in the costal cartilage, tracheal cartilages, and xiphoid process of the rat. These novel findings probably suggest that UII and URP mediate the formation of the cartilaginous matrix. Copyright © 2013 Elsevier Inc. All rights reserved.

  13. A phase II trial of abiraterone acetate plus prednisone in patients with triple-negative androgen receptor positive locally advanced or metastatic breast cancer (UCBG 12-1).

    Science.gov (United States)

    Bonnefoi, H; Grellety, T; Tredan, O; Saghatchian, M; Dalenc, F; Mailliez, A; L'Haridon, T; Cottu, P; Abadie-Lacourtoisie, S; You, B; Mousseau, M; Dauba, J; Del Piano, F; Desmoulins, I; Coussy, F; Madranges, N; Grenier, J; Bidard, F C; Proudhon, C; MacGrogan, G; Orsini, C; Pulido, M; Gonçalves, A

    2016-05-01

    Several expression array studies identified molecular apocrine breast cancer (BC) as a subtype that expresses androgen receptor (AR) but not estrogen receptor α. We carried out a multicentre single-arm phase II trial in women with AR-positive, estrogen, progesterone receptor and HER2-negative (triple-negative) metastatic or inoperable locally advanced BC to assess the efficacy and safety of abiraterone acetate (AA) plus prednisone. Patients with a metastatic or locally advanced, centrally reviewed, triple-negative and AR-positive (≥10% by immunohistochemistry, IHC) BC were eligible. Any number of previous lines of chemotherapy was allowed. AA (1000 mg) was administered once a day with prednisone (5 mg) twice a day until disease progression or intolerance. The primary end point was clinical benefit rate (CBR) at 6 months defined as the proportion of patients presenting a complete response (CR), partial response (PR) or stable disease (SD) ≥6 months. Secondary end points were objective response rate (ORR), progression-free survival (PFS) and safety. One hundred and forty-six patients from 27 centres consented for IHC central review. Of the 138 patients with sufficient tissue available, 53 (37.6%) were AR-positive and triple-negative, and 34 of them were included from July 2013 to December 2014. Thirty patients were eligible and evaluable for the primary end point. The 6-month CBR was 20.0% [95% confidence interval (CI) 7.7%-38.6%], including 1 CR and 5 SD ≥6 months, 5 of them still being under treatment at the time of analysis (6.4+, 9.2+, 14.5+, 17.6+, 23.4+ months). The ORR was 6.7% (95% CI 0.8%-22.1%). The median PFS was 2.8 months (95% CI 1.7%-5.4%). Fatigue, hypertension, hypokalaemia and nausea were the most common drug-related adverse events; the majority of them being grade 1 or 2. AA plus prednisone treatment is beneficial for some patients with molecular apocrine tumours and five patients are still on treatment. NCT01842321. © The Author 2016

  14. Receptor-targeted metalloradiopharmaceuticals. Final technical report

    International Nuclear Information System (INIS)

    Green, Mark A.

    2000-01-01

    Copper (II) and platinum (II) coordination complexes were prepared and characterized. These complexes were designed to afford structural homology with steroidal and non-steroidal estrogens for possible use as receptor-targeted radiopharmaceuticals. While weak affinity for the estrogen receptor was detectable, none would appear to have sufficient receptor-affinity for estrogen-receptor-targeted imaging or therapy

  15. A Phase II Safety and Efficacy Study of the Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor Pazopanib in Patients With Metastatic Urothelial Cancer

    Science.gov (United States)

    Pili, Roberto; Qin, Rui; Flynn, P.J.; Picus, Joel; Millward, Michael; Ho, Wing Ming; Pitot, Henry; Tan, Winston; Miles, Kiersten M.; Erlichman, Charles; Vaishampayan, Ulka

    2013-01-01

    Vascular endothelial growth factor (VEGF) is expressed in human bladder tumors. A phase II study was conducted to assess the VEGF inhibitor pazopanib in patients with metastatic, urothelial carcinoma. Nineteen patients with one prior systemic therapy were enrolled. No objective responses were observed and median progression-free survival was 1.9 months. The role of anti-VEGF therapies in urothelial carcinoma remains to be determined. Background Vascular endothelial growth factor (VEGF) is produced by bladder cancer cell lines in vitro and expressed in human bladder tumor tissues. Pazopanib is a vascular endothelial receptor tyrosine kinase inhibitor with anti-angiogenesis and anti-tumor activity in several preclinical models. A 2-stage phase II study was conducted to assess the activity and toxicity profile of pazopanib in patients with metastatic, urothelial carcinoma. Methods Patients with one prior systemic therapy for metastatic urothelial carcinoma were eligible. Patients received pazopanib at a dose of 800 mg orally for a 4-week cycle. Results Nineteen patients were enrolled. No grade 4 or 5 events were experienced. Nine patients experienced 11 grade 3 adverse events. Most common toxicities were anemia, thrombocytopenia, leucopenia, and fatigue. For stage I, none of the first 16 evaluable patients were deemed a success (complete response or partial response) by the Response Evaluation Criteria In Solid Tumors criteria during the first four 4-week cycles of treatment. Median progression-free survival was 1.9 months. This met the futility stopping rule of interim analysis, and therefore the trial was recommended to be permanently closed. Conclusions Pazopanib did not show significant activity in patients with urothelial carcinoma. The role of anti-VEGF therapies in urothelial carcinoma may need further evaluation in rational combination strategies. PMID:23891158

  16. Angiotensin II type 1a receptors in subfornical organ contribute towards chronic intermittent hypoxia-associated sustained increase in mean arterial pressure.

    Science.gov (United States)

    Saxena, Ashwini; Little, Joel T; Nedungadi, T Prashant; Cunningham, J Thomas

    2015-03-01

    Sleep apnea is associated with hypertension. The mechanisms contributing to a sustained increase in mean arterial pressure (MAP) even during normoxic awake-state remain unknown. Rats exposed to chronic intermittent hypoxia for 7 days, a model of the hypoxemia associated with sleep apnea, exhibit sustained increases in MAP even during the normoxic dark phase. Activation of the renin-angiotensin system (RAS) has been implicated in chronic intermittent hypoxia (CIH) hypertension. Since the subfornical organ (SFO) serves as a primary target for the central actions of circulating ANG II, we tested the effects of ANG II type 1a receptor (AT1aR) knockdown in the SFO on the sustained increase in MAP in this CIH model. Adeno-associated virus carrying green fluorescent protein (GFP) and small-hairpin RNA against either AT1aR or a scrambled control sequence (SCM) was stereotaxically injected in the SFO of rats. After recovery, MAP, heart rate, respiratory rate, and activity were continuously recorded using radiotelemetry. In the normoxic groups, the recorded variables did not deviate from the baseline values. Both CIH groups exhibited significant increases in MAP during CIH exposures (P < 0.05). During the normoxic dark phase in the CIH groups, only the SCM-injected group exhibited a sustained increase in MAP (P < 0.05). The AT1aR-CIH group showed significant decreases in FosB/ΔFosB staining in the median preoptic nucleus and the paraventricular nuclei of the hypothalamus compared with the SCM-CIH group. Our data indicate that AT1aRs in the SFO are critical for the sustained elevation in MAP and increased FosB/ΔFosB expression in forebrain autonomic nuclei associated with CIH. Copyright © 2015 the American Physiological Society.

  17. Exercício de força ativa a via AKT/mTor pelo receptor de angiotensina II tipo I no músculo cardíaco de ratos Activation of AKT-mTor signaling pathways by angiotensin II receptor type 1 after a session of strength exercise in cardiac muscle of rats

    Directory of Open Access Journals (Sweden)

    Stéphano Freitas Soares Melo

    2011-09-01

    Full Text Available O receptor de angiotensina II tipo I (AT1 tem uma importante participação no desenvolvimento da hipertrofia cardíaca. Em um trabalho publicado anteriormente, por nosso grupo, demonstramos que o bloqueio do receptor AT1 durante o treinamento de força inibiu a hipertrofia cardíaca em ratos. Por isso, o objetivo deste trabalho foi estudar a participação do receptor AT1 na ativação de vias de sinalização intracelular relacionadas com o aumento da síntese de proteína em ratos submetidos a uma sessão de exercício de força. Para isso, realizamos um experimento com seis grupos de animais (n = 6; cada: controle (Con, exercitado e sacrificado cinco minutos após o exercício (Exe 5, exercitado e sacrificado 30 minutos após o exercício (Exe 30, controle tratado com losartan (Con Los, tratado com losartan, exercitado e sacrificado cinco minutos após o exercício (Exe 5 Los, tratado com losartan, exercitado e sacrificado 30 minutos após o exercício (Exe 30 Los. Os resultados mostram que no grupo Exe 5 e Exe 30 ocorreu um aumento de 63% (P The angiotensin II type I (AT1 receptor has an important participation in the development of cardiac hypertrophy. Previously, we have shown that AT1 receptor participates in the cardiac hypertrophy induced by resistance training in rats. Here, we studied the involvement of AT1 receptor in the activation of intracellular signaling pathways related to the concentric HC in rats submitted to a session of strength exercise. Male Wistar rats were divided into 6 groups (n= 6 each: control (Con; exercised and killed 5 minutes after exercise (Exe 5; exercised and killed 30 minutes after exercise (Exe 30; control treated with Losartan (Con Los; treated with Losartan, exercised and killed 5 minutes after the exercise (Exe Los 5; treated with Losartan, exercised and killed 30 minutes after training (Exe Los 30. The results show that phosphorylation activity of AKT in group Exe 5 and Exe 30 increased 63% (P < 0

  18. Improving the prognosis of diabetic patients: evaluating the role of intensive versus moderate blood pressure control with selective angiotensin II receptor blocker (ARB therapy

    Directory of Open Access Journals (Sweden)

    Martin P Bedigian

    2000-06-01

    Full Text Available The ABCD (Appropriate Blood Pressure Control in Diabetes and ABCD-2V (Part 2 with Valsartan are prospective, randomised clinical trials which will provide important data on the impact of intensive vs. moderate blood pressure (BP control on microvascular and macrovascular complications in normotensive and hypertensive patients with type 2 diabetes mellitus (DM. The ABCD trial was a five-year study that compared the effects of intensive vs. moderate BP control on the endpoints of nephropathy, retinopathy, neuropathy, and cardiovascular disease events using a calcium channel blocker (CCB and an angiotensin-converting enzyme (ACE inhibitor as the primary antihypertensive agents. The recently published results of the hypertensive cohort of ABCD are reviewed herein. The follow-up study, ABCD-2V, is ongoing and was designed to compare intensive vs. moderate BP control on the same endpoints as the ABCD study, using the highly selective angiotensin II receptor blocker (ARB valsartan as the primary antihypertensive agent. First results of ABCD-2V are expected in 2004. The baseline characteristics for the patients enrolled thus far in the hypertensive cohort of ABCD-2V are reviewed. These studies will provide insight into the role of intensive vs. moderate BP control in the management of normotensive and hypertensive patients with type 2 DM.

  19. Phase II randomized trial of neoadjuvant metformin plus letrozole versus placebo plus letrozole for estrogen receptor positive postmenopausal breast cancer (METEOR)

    International Nuclear Information System (INIS)

    Kim, Jisun; Kim, Lee Su; Han, Sehwan; Nam, Seok Jin; Kang, Han-Sung; Kim, Seung Il; Yoo, Young Bum; Jeong, Joon; Kim, Tae Hyun; Kang, Taewoo; Kim, Sung-Won; Lim, Woosung; Jung, Yongsik; Lee, Jeong Eon; Kim, Ku Sang; Yu, Jong-Han; Chae, Byung Joo; Jung, So-Youn; Kang, Eunyoung; Choi, Su Yun; Moon, Hyeong-Gon; Noh, Dong-Young; Kim, Eun-Kyu; Han, Wonshik; Kim, Min-Kyoon; Paik, Nam-Sun; Jeong, Sang-Seol; Yoon, Jung-han; Park, Chan Heun; Ahn, Sei Hyun

    2014-01-01

    Neoadjuvant endocrine therapy with an aromatase inhibitor has shown efficacy comparable to that of neoadjuvant chemotherapy in patients with postmenopausal breast cancer. Preclinical and clinical studies have shown that the antidiabetic drug metformin has anti-tumor activity. This prospective, multicenter, phase II randomized, placebo controlled trial was designed to evaluate the direct anti-tumor effect of metformin in non-diabetic postmenopausal women with estrogen-receptor (ER) positive breast cancer. Patients meeting the inclusion criteria and providing written informed consent will be randomized to 24 weeks of neoadjuvant treatment with letrozole (2.5 mg/day) and either metformin (2000 mg/day) or placebo. Target accrual number is 104 patients per arm. The primary endpoint will be clinical response rate, as measured by calipers. Secondary endpoints include pathologic complete response rate, breast conserving rate, change in Ki67 expression, breast density change, and toxicity profile. Molecular assays will be performed using samples obtained before treatment, at week 4, and postoperatively. This study will provide direct evidence of the anti-tumor effect of metformin in non-diabetic, postmenopausal patients with ER-positive breast cancer. ClinicalTrials.gov Identifier http://clinicaltrial.gov/ct2/show/NCT01589367?term

  20. Beyond the androgen receptor II: New approaches to understanding and treating metastatic prostate cancer; Report from the 2017 Coffey-Holden Prostate Cancer Academy Meeting.

    Science.gov (United States)

    Miyahira, Andrea K; Cheng, Heather H; Abida, Wassim; Ellis, Leigh; Harshman, Lauren C; Spratt, Daniel E; Simons, Jonathan W; Pienta, Kenneth J; Soule, Howard R

    2017-11-01

    The 2017 Coffey-Holden Prostate Cancer Academy (CHPCA) Meeting, "Beyond the Androgen Receptor II: New Approaches to Understanding and Treating Metastatic Prostate Cancer," was held in Carlsbad, California from June 14-17, 2017. The CHPCA is an annual scientific conference hosted by the Prostate Cancer Foundation (PCF) that is uniquely designed to produce extensive and constructive discussions on the most urgent and impactful topics concerning research into the biology and treatment of metastatic prostate cancer. The 2017 CHPCA Meeting was the 5th meeting in this annual series and was attended by 71 investigators focused on prostate cancer and a variety of other fields including breast and ovarian cancer. The discussions at the meeting were concentrated on topics areas including: mechanisms and therapeutic approaches for molecular subclasses of castrate resistant prostate cancer (CRPC), the epigenetic landscape of prostate cancer, the role of DNA repair gene mutations, advancing the use of germline genetics in clinical practice, radionuclides for imaging and therapy, advances in molecular imaging, and therapeutic strategies for successful use of immunotherapy in advanced prostate cancer. This article reviews the presentations and discussions from the 2017 CHPCA Meeting in order to disseminate this knowledge and accelerate new biological understandings and advances in the treatment of patients with metastatic prostate cancer. © 2017 Wiley Periodicals, Inc.

  1. Effect of angiotensin II type I receptor A1166C polymorphism on benazepril action in hypertensive patients: a family-based association test study.

    Science.gov (United States)

    Zhang, Ning; Cui, Huadong; Yang, Lili

    2012-10-01

    Few studies have examined the effect of the angiotensin II type I receptor (AT1R) A1166C polymorphism on the antihypertensive effect of the angiotensin-converting-enzyme inhibitor benazepril in patients with hypertension, and no such studies have performed analysis using the Family-Based Association Test (FBAT), The aim of our study was to examine the association between AT1R A1166C gene polymorphism and the antihypertensive effect of benazepril using the FBAT. A total of 864 patients (aged, 26-62 years) with essential hypertension were identified in an epidemiological survey and enrolled in this study. Blood pressure (BP) was measured before and after 16 days of treatment with benazepril (10 mg/day). The association between the A1166C gene polymorphism and the antihypertensive effect of benazepril was assessed by FBAT. The frequencies of alleles A and C were 95.1% and 4.9%, respectively. FBAT analysis revealed that the C allele was significantly associated with high baseline diastolic BP (Z = 2.041, p = 0.041), decreased systolic BP after treatment (Z = 2.549, p = 0.011), and decreased diastolic BP after treatment (Z = 2.320, p = 0.020). Our results, determined using the FBAT, are the first evidence that the AT1R A1166C polymorphism may increase the antihypertensive effect of benazepril in patients with hypertension.

  2. Dynamic 123I-BMIPP single-photon emission computed tomography in patients with congestive heart failure: effect of angiotensin II type-1 receptor blockade.

    Science.gov (United States)

    Takeishi, Yasuchika; Minamihaba, Osamu; Yamauchi, Sou; Arimoto, Takanori; Hirono, Osamu; Takahashi, Hiroki; Akiyama, Hideyuki; Miyamoto, Takuya; Nitobe, Joji; Nozaki, Naoki; Tachibana, Hidetada; Okuyama, Masaki; Fukui, Akio; Kubota, Isao; Okada, Akio; Takahashi, Kazuei

    2004-04-01

    Heart failure is a major and growing public health problem with a high mortality rate. Although recent studies have demonstrated that a variety of metabolic and/or neurohumoral factors are involved in the progression of this syndrome, the precise mechanisms responsible for this complex condition are poorly understood. To examine 123I-beta-methyl-iodophenylpentadecanoic acid (BMIPP) kinetics in the early phase soon after tracer injection in patients with congestive heart failure (CHF), we performed dynamic single-photon emission computed tomography (SPECT). Twenty-six patients with CHF and eight control subjects were examined. The consecutive 15 images of 2-min dynamic SPECT were acquired for 30 min after injection. In the early phase after injection (0-4 min), a significant amount of radioactivity existed in the blood pool. After 6 min, the myocardial 123I-BMIPP image was clear and thus the washout rate of 123I-BMIPP from 6 to 30 min was calculated. The washout rate of 123I-BMIPP from the myocardium was faster in patients with CHF than in the controls (8 +/- 4 vs. -5 +/- 3%, p acid metabolism may represent a new mechanism for beneficial effects of angiotensin II receptor blockade on cardiac function and survival in patients with heart failure. 123I-BMIPP washout in the early phase obtained from dynamic SPECT may be a new marker for evaluating the severity of heart failure and the effects of medical treatment.

  3. Inhibitory Effect of the Punica granatum Fruit Extract on Angiotensin-II Type I Receptor and Thromboxane B2 in Endothelial Cells Induced by Plasma from Preeclamptic Patients.

    Science.gov (United States)

    Kusumawati, Widya; Keman, Kusnarman; Soeharto, Setyawati

    2016-01-01

    This study aims to evaluate whether the Punica granatum fruit extract modulates the Angiotensin-II Type I receptor (AT1-R) and thromboxane B2 level in endothelial cells induced by plasma from preeclamptic patients. Endothelial cells were obtained from human umbilical vascular endothelial cells. At confluence, endothelial cells were divided into five groups, which included endothelial cells exposed to 2% plasma from normal pregnancy (NP), endothelial cells exposed to 2% plasma from preeclamptic patients (PP), and endothelial cells exposed to PP in the presence of ethanolic extract of Punica granatum (PP + PG) at the following three doses: 14; 28; and 56 ppm. The expression of AT1-R was observed by immunohistochemistry technique, and thromboxane B2 level was done by immunoassay technique. Plasma from PP significantly increased AT1-R expression and thromboxane B2 levels compared to cells treated by normal pregnancy plasma. The increasing of AT1-R expression significantly (P Punica granatum extract. Moreover, the increasing of thromboxane B2 levels significantly (P Punica granatum extract. We further concluded that Punica granatum fruit protects and inhibits the sensitivity of endothelial cells to plasma from preeclamptic patients due to inhibition of AT1-R expression (56 ppm) and reduced thromboxane B2 levels (14 ppm).

  4. Central Infusion of Angiotensin II Type 2 Receptor Agonist Compound 21 Attenuates DOCA/NaCl-Induced Hypertension in Female Rats

    Directory of Open Access Journals (Sweden)

    Shu-Yan Dai

    2016-01-01

    Full Text Available The present study investigated whether central activation of angiotensin II type 2 receptor (AT2-R attenuates deoxycorticosterone acetate (DOCA/NaCl-induced hypertension in intact and ovariectomized (OVX female rats and whether female sex hormone status has influence on the effects of AT2-R activation. DOCA/NaCl elicited a greater increase in blood pressure in OVX females than that in intact females. Central infusion of compound 21, a specific AT2-R agonist, abolished DOCA/NaCl pressor effect in intact females, whereas same treatment in OVX females produced an inhibitory effect. Real-time RT-PCR analysis revealed that DOCA/NaCl enhanced the mRNA expression of hypertensive components including AT1-R, ACE-1, and TNF-α in the paraventricular nucleus of hypothalamus in both intact and OVX females. However, the mRNA expressions of antihypertensive components such as AT2-R, ACE-2, and IL-10 were increased only in intact females. Central AT2-R agonist reversed the changes in the hypertensive components in all females, while this agonist further upregulated the expression of ACE2 and IL-10 in intact females, but only IL-10 in OVX females. These results indicate that brain AT2-R activation plays an inhibitory role in the development of DOCA/NaCl-induced hypertension in females. This beneficial effect of AT2-R activation involves regulation of renin-angiotensin system and proinflammatory cytokines.

  5. Prognostic Impact of Erythropoietin Expression and Erythropoietin Receptor Expression on Locoregional Control and Survival of Patients Irradiated for Stage II/III Non-Small-Cell Lung Cancer

    International Nuclear Information System (INIS)

    Rades, Dirk; Setter, Cornelia; Dahl, Olav; Schild, Steven E.; Noack, Frank

    2011-01-01

    Purpose: Prognostic factors can guide the physician in selecting the optimal treatment for an individual patient. This study investigates the prognostic value of erythropoietin (EPO) and EPO receptor (EPO-R) expression of tumor cells for locoregional control and survival in non-small-cell lung cancer (NSCLC) patients. Methods and Materials: Fourteen factors were investigated in 62 patients irradiated for stage II/III NSCLC, as follows: age, gender, Karnofsky performance score (KPS), histology, grading, TNM/American Joint Committee on Cancer (AJCC) stage, surgery, chemotherapy, pack years (average number of packages of cigarettes smoked per day multiplied by the number of years smoked), smoking during radiotherapy, hemoglobin levels during radiotherapy, EPO expression, and EPO-R expression. Additionally, patients with tumors expressing both EPO and EPO-R were compared to those expressing either EPO or EPO-R and to those expressing neither EPO nor EPO-R. Results: On univariate analysis, improved locoregional control was associated with AJCC stage II cancer (p 70 (p = 0.08), an N stage of 0 to 1 (p = 0.07), and no EPO-R expression (p = 0.10). On multivariate analysis, AJCC stage II and no EPO expression remained significant. No smoking during radiotherapy was almost significant. On univariate analysis, improved survival was associated with N stage 0 to 1 (p = 0.009), surgery (p = 0.039), hemoglobin levels of ≥12 g/d (p = 0.016), and no EPO expression (p = 0.001). On multivariate analysis, N stage 0 to 1 and no EPO expression maintained significance. Hemoglobin levels of ≥12 g/d were almost significant. On subgroup analyses, patients with tumors expressing both EPO and EPO-R had worse outcomes than those expressing either EPO or EPO-R and those expressing neither EPO nor RPO-R. Conclusions: EPO expression of tumor cells was an independent prognostic factor for locoregional control and survival in patients irradiated for NSCLC. EPO-R expression showed a trend

  6. Calcium/calmodulin-dependent kinase II and nitric oxide synthase 1-dependent modulation of ryanodine receptors during β-adrenergic stimulation is restricted to the dyadic cleft.

    Science.gov (United States)

    Dries, Eef; Santiago, Demetrio J; Johnson, Daniel M; Gilbert, Guillaume; Holemans, Patricia; Korte, Sanne M; Roderick, H Llewelyn; Sipido, Karin R

    2016-10-15

    The dyadic cleft, where coupled ryanodine receptors (RyRs) reside, is thought to serve as a microdomain for local signalling, as supported by distinct modulation of coupled RyRs dependent on Ca 2+ /calmodulin-dependent kinase II (CaMKII) activation during high-frequency stimulation. Sympathetic stimulation through β-adrenergic receptors activates an integrated signalling cascade, enhancing Ca 2+ cycling and is at least partially mediated through CaMKII. Here we report that CaMKII activation during β-adrenergic signalling is restricted to the dyadic cleft, where it enhances activity of coupled RyRs thereby contributing to the increase in diastolic events. Nitric oxide synthase 1 equally participates in the local modulation of coupled RyRs. In contrast, the increase in the Ca 2+ content of the sarcoplasmic reticulum and related increase in the amplitude of the Ca 2+ transient are primarily protein kinase A-dependent. The present data extend the concept of microdomain signalling in the dyadic cleft and give perspectives for selective modulation of RyR subpopulations and diastolic events. In cardiac myocytes, β-adrenergic stimulation enhances Ca 2+ cycling through an integrated signalling cascade modulating L-type Ca 2+ channels (LTCCs), phospholamban and ryanodine receptors (RyRs). Ca 2+ /calmodulin-dependent kinase II (CaMKII) and nitric oxide synthase 1 (NOS1) are proposed as prime mediators for increasing RyR open probability. We investigate whether this pathway is confined to the high Ca 2+ microdomain of the dyadic cleft and thus to coupled RyRs. Pig ventricular myocytes are studied under whole-cell voltage-clamp and confocal line-scan imaging with Fluo-4 as a [Ca 2+ ] i indicator. Following conditioning depolarizing pulses, spontaneous RyR activity is recorded as Ca 2+ sparks, which are assigned to coupled and non-coupled RyR clusters. Isoproterenol (ISO) (10 nm) increases Ca 2+ spark frequency in both populations of RyRs. However, CaMKII inhibition reduces

  7. Effect of Angiotensin II Type I Receptor Blockade with Valsartan on Carotid Artery Atherosclerosis: A Double Blind Randomized Clinical Trial Comparing Valsartan and Placebo (EFFERVESCENT)

    Science.gov (United States)

    Ramadan, Ronnie; Dhawan, Saurabh S.; Binongo, José Nilo G.; Alkhoder, Ayman; Jones, Dean P.; Oshinski, John N.; Quyyumi, Arshed A.

    2016-01-01

    Background Progression of atherosclerosis is associated with a greater risk for adverse outcomes. Angiotensin II plays a key role in the pathogenesis and progression of atherosclerosis. We aimed to investigate the effects of Angiotensin II type-1 receptor (AT1R) blockade with Valsartan on carotid wall atherosclerosis, with the hypothesis that Valsartan will reduce progression of atherosclerosis. Methods Subjects (n= 120) with carotid intima-media thickness >0.65mm by ultrasound were randomized (2:1) in a double-blind manner to receive either Valsartan or placebo for 2 years. Bilateral T2-weighted black-blood carotid magnetic resonance imaging was performed at baseline, 12 and 24 months. Changes in the carotid bulb vessel wall area (VWA) and wall thickness (WT) were primary endpoints. Secondary endpoints included changes in carotid plaque thickness, plasma levels of aminothiols, C-reactive protein, fibrinogen, and endothelium-dependent and -independent vascular function. Results Over 2 years, the carotid bulb VWA decreased with Valsartan (−6.7, 95% CI: (−11.6,−1.9) mm2) but not with placebo (3.4, 95% CI: (−2.8,9.6) mm2)), p=0.01 between groups. Similarly, mean WT decreased with Valsartan (−0.18, 95% CI: (−0.30,−0.06) mm), but not with placebo (0.08, 95% CI: (−0.07,0.23) mm),), p=0.009 between groups. Furthermore, plaque thickness decreased with Valsartan (−0.35, 95% CI: (−0.63,−0.08) mm) but was unchanged with placebo (+0.28, 95% CI: (−0.11,0.69) mm), p=0.01 between groups. These findings were unaffected by statin therapy or changes in blood pressure. Notably, there were significant improvements in the aminothiol cysteineglutathione disulfide, and trends to improvements in fibrinogen levels and endothelium–independent vascular function. Conclusions In subjects with carotid wall thickening, AT1R blockade was associated with regression in carotid atherosclerosis. Whether these effects translate into improved outcomes in subjects with

  8. Phase II study of paclitaxel given once per week along with trastuzumab and pertuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer.

    Science.gov (United States)

    Dang, Chau; Iyengar, Neil; Datko, Farrah; D'Andrea, Gabriella; Theodoulou, Maria; Dickler, Maura; Goldfarb, Shari; Lake, Diana; Fasano, Julie; Fornier, Monica; Gilewski, Theresa; Modi, Shanu; Gajria, Devika; Moynahan, Mary Ellen; Hamilton, Nicola; Patil, Sujata; Jochelson, Maxine; Norton, Larry; Baselga, Jose; Hudis, Clifford

    2015-02-10

    The CLEOPATRA (Clinical Evaluation of Trastuzumab and Pertuzumab) study demonstrated superior progression-free survival (PFS) and overall survival when pertuzumab was added to trastuzumab and docetaxel. Paclitaxel given once per week is effective and less toxic than docetaxel. We performed a phase II study to evaluate the efficacy and safety of pertuzumab and trastuzumab with paclitaxel given once per week. Patients with metastatic human epidermal growth factor receptor 2-positive breast cancer with zero to one prior therapy were enrolled. Treatment consisted of paclitaxel 80 mg/m(2) once per week plus trastuzumab (8 mg/kg loading dose → 6 mg/kg) once every 3 weeks plus pertuzumab (840 mg loading dose → 420 mg) once every 3 weeks, all given intravenously. The primary end point was 6-month PFS assessed by Kaplan-Meier methods. From January 2011 to December 2013, we enrolled 69 patients: 51 (74%) and 18 (26%) treated in first- and second-line metastatic settings, respectively. At a median follow-up of 21 months (range, 3 to 38 months), 6-month PFS was 86% (95% CI, 75% to 92%). The median PFS was 19.5 months (95% CI, 14 to 26 months) overall. PFS was 24.2 months (95% CI, 14 months to not reached [NR]) and 16.4 months (95% CI, 8.5 months to NR) for those without and with prior treatment, respectively. At 1 year, Kaplan-Meier PFS was 70% (95% CI, 56% to 79%) overall, 71% (95% CI, 55% to 82%) for those without prior therapy, and 66% (95% CI, 40% to 83%) for those with prior therapy. Treatment was well-tolerated; there was no febrile neutropenia or symptomatic left ventricular systolic dysfunction. Paclitaxel given once per week with trastuzumab and pertuzumab is highly active and well tolerated and seems to be an effective alternative to docetaxel-based combination therapy. © 2014 by American Society of Clinical Oncology.

  9. Comparative effect of angiotensin II type I receptor blockers and calcium channel blockers on laboratory parameters in hypertensive patients with type 2 diabetes

    Directory of Open Access Journals (Sweden)

    Nishida Yayoi

    2012-05-01

    Full Text Available Abstract Background Both angiotensin II type I receptor blockers (ARBs and calcium channel blockers (CCBs are widely used antihypertensive drugs. Many clinical studies have demonstrated and compared the organ-protection effects and adverse events of these drugs. However, few large-scale studies have focused on the effect of these drugs as monotherapy on laboratory parameters. We evaluated and compared the effects of ARB and CCB monotherapy on clinical laboratory parameters in patients with concomitant hypertension and type 2 diabetes mellitus. Methods We used data from the Clinical Data Warehouse of Nihon University School of Medicine obtained between Nov 1, 2004 and July 31, 2011, to identify cohorts of new ARB users (n = 601 and propensity-score matched new CCB users (n = 601, with concomitant mild to moderate hypertension and type 2 diabetes mellitus. We used a multivariate-adjusted regression model to adjust for differences between ARB and CCB users, and compared laboratory parameters including serum levels of triglyceride (TG, total cholesterol (TC, non-fasting blood glucose, hemoglobin A1c (HbA1c, sodium, potassium, creatinine, alanine aminotransferase (ALT, aspartate aminotransferase (AST, gamma-glutamyltransferase (GGT, hemoglobin and hematocrit, and white blood cell (WBC, red blood cell (RBC and platelet (PLT counts up to 12 months after the start of ARB or CCB monotherapy. Results We found a significant reduction of serum TC, HbA1c, hemoglobin and hematocrit and RBC count and a significant increase of serum potassium in ARB users, and a reduction of serum TC and hemoglobin in CCB users, from the baseline period to the exposure period. The reductions of RBC count, hemoglobin and hematocrit in ARB users were significantly greater than those in CCB users. The increase of serum potassium in ARB users was significantly greater than that in CCB users. Conclusions Our study suggested that hematological adverse effects and

  10. Weight loss has an additive effect on the proteinuria reduction of angiotensin II receptor blockers in hypertensive patients with chronic kidney disease

    Directory of Open Access Journals (Sweden)

    Shin Young Ahn

    2018-03-01

    Full Text Available Background : Weight reduction is a lifestyle intervention that has been introduced for prevention and management of chronic kidney disease (CKD. We investigate the additive anti-proteinuric effect of weight reduction on the usage of angiotensin II receptor blockers (ARBs and its potential mechanisms in hypertensive CKD patients. Methods : This study is a subanalysis of data from an open-label, randomized, controlled clinical trial. Among the 235 participants, 227 were assigned to subgroups according to changes in body weight. Results : Fifty-eight participants (25.6% were assigned to group 1 (≥ 1.5% decrease in body weight after 16 weeks, 32 participants (14.1% were assigned to group 2 (1.5-0.1% decrease in body weight, and 136 participants (59.9% were assigned to group 3 (≥ 0.0% increase in body weight. Characteristics at enrollment were not different among the three groups, but mean differences in weight and percent changes in urinary sodium excretion over the period were statistically different (P < 0.001 and P = 0.017. Over the study period, unintentional weight loss independently increased the probability of reduced albuminuria (group 1, relative risk 6.234, 95% confidence interval 1.913-20.315, P = 0.002. Among urinary cytokines, only podocalyxin level decreased significantly in participants who lost weight (P = 0.013. Conclusion : We observed that weight loss had an additive effect on the anti-proteinuric effects of ARBs in nondiabetic hypertensive CKD patients, although it was minimal. An additive effect was shown in both obese and non-obese participants, and its possible mechanism is related to reduction of podocyte damage.

  11. Cyclic GMP-dependent protein kinase II is necessary for macrophage M1 polarization and phagocytosis via toll-like receptor 2.

    Science.gov (United States)

    Liao, Wei-Ting; You, Huey-Ling; Li, Changgui; Chang, Jan-Gowth; Chang, Shun-Jen; Chen, Chung-Jen

    2015-05-01

    Cyclic GMP-dependent protein kinase II (cGKII; PRKG2) phosphorylates a variety of biological targets and has been identified as a gout-susceptible gene. However, the regulatory role of cGKII in triggering gout disease has yet to be clarified. Thus, we plan to explore the specific function of cGKII in macrophages related to gout disease. By using cGKII gene knockdown method, we detected macrophage M1/M2 polarization, phagocytosis, and their responses to stimulation by monosodium urate (MSU). cGKII was highly expressed in M1 phenotype, but not in M2, and cGKII knockdown significantly inhibited macrophage M1 polarization by decreasing M1 chemokine markers (CXCL10 and CCL2) and downregulating phagocytosis function. We further identified that cGKII-associated phagocytosis was mediated by upregulating toll-like receptor 2 (TLR2) expression, but not by TLR4. Mimicking gout condition by MSU treatments, we found that MSU alone induced cGKII and TLR2 expression with increased M1 polarization markers and phagocytosis activity. It means that cGKII knockdown significantly inhibited this MSU-induced cGKII-TLR2-phagocytosis axis. Our study showed that cGKII plays a key role in M1 polarization, especially in TLR2-mediated phagocytosis under MSU exposure. The findings provide evidence for the possible role of cGKII as an inflammation exciter in gout disease. Gout-susceptible gene cGKII is necessary for macrophage M1 polarization. cGKII regulates M1 phagocytosis function via TLR2. Monosodium urate treatments increase cGKII expression and related function. This study reveals the role of cGKII in enhancing gouty inflammatory responses.

  12. Chicken type II collagen induced immune tolerance of mesenteric lymph node lymphocytes by enhancing beta2-adrenergic receptor desensitization in rats with collagen-induced arthritis.

    Science.gov (United States)

    Zhao, Wei; Tong, Tong; Wang, Ling; Li, Pei-Pei; Chang, Yan; Zhang, Ling-Ling; Wei, Wei

    2011-01-01

    Chicken type II collagen (CCII) is a protein extracted from the cartilage of chicken breast and exhibits intriguing possibilities for the treatment of autoimmune diseases by inducing oral tolerance. In this study, we investigated the effects of CCII on inflammatory and immune responses to the mesenteric lymph node lymphocytes (MLNLs) and the mechanisms by which CCII regulates beta2-adrenergic receptor (beta2-AR) signal transduction in collagen-induced arthritis (CIA) rats. The onset of secondary arthritis in rats appeared around day 14 after injection of CCII emulsion. Remarkable secondary inflammatory response and lymphocytes proliferation were observed in CIA rats. The administration of CCII (10, 20, 40μgkg(-1)day(-1), days 15-22) could significantly reduce synovial hyperplasia, lymphatic follicle hyperplasia, inflammatory cells infiltration of MLNLs in CIA rats. CCII (10, 20, 40μgkg(-1)day(-1), days 15-22) restored the previously decreased level of cAMP of MLNLs of CIA rats. Meanwhile, CCII increased total protein expressions of beta2-AR, GRK2 and decreased that of beta-arrestin1, 2 of MLNLs in CIA rats but had an slight effect on GRK3. CCII further increased plasmatic protein expressions of GRK2, G(α)s and decreased that of beta-arrestin1, 2, beta2-AR, and increased membrane protein expressions of beta2-AR, GRK2, G(α)s and decreased that of beta-arrestin1, 2 of MLNLs in CIA rats. These results demonstrate that the mechanisms of CCII on beta2-AR desensitization and beta2-AR-AC-cAMP transmembrane signal transduction of MLNLs play crucial roles in pathogenesis of this disease. Copyright © 2010 Elsevier B.V. All rights reserved.

  13. The inhibitory effect of angiotensin II type 1 receptor blocker combined with radiation on the proliferation and invasion ability of human nasopharyngeal carcinoma cells

    International Nuclear Information System (INIS)

    Wang Qiong; Zhao Wei; Li Guiling; Zhang Sheng; Wu Gang

    2008-01-01

    Objective: To investigate the effect of valsartan, an angiotensin II type 1 receptor (AT1 R) blocker, on radiosensitivity, invasive potential and proliferation activity of nasopharyngeal carcinoma cells(CNE-2) in vitro. Methods: Radiosensitization of valsartan on CNE-2 cells in vitro was investigated by colony forming assay. Effect of AT1R blocker combined with radiation on invasive potential of CNE-2 cells was evaluated using 24-well Matrigel invasion chambers (Transwell). Apoptosis-inducing effect of valsartan combined with radiation on apoptosis of CNE-2 was identified by flow cytometry (FCM). Results: When valsartan was given at 10 -9 , 10 -8 and 10 -7 mol/L combined with radiation, sensitivity enhancement ratios (SER) were 1.10, 1.20 and 1.36, and the invasive inhibition rates were 8.11%, 16.49% and 16.77%, respectively. The SER of valsartan on CNE-2 distinctly increased when the exposure time was increased. After 24 h exposure to 10 -8 mol/L valsartan combined with radiation, the apoptosis rate was 1.89% ± 0.09%, which was higher than 1.62% ± 0.06% in radiation alone group (t=4.79, P<0.05). Conclusions: AT1R blocker valsartan combined with radiation can significantly inhibit the proliferation activity of nasopharyngeal carcinoma cells in vitro in a dose- and time-dependent manner. Valsartan combined with radiation can potently inhibit the invasive potential of CNE-2, which may be involved in the mechanism of valsartan treatment in vivo. (authors)

  14. Valsartan regulates the interaction of angiotensin II type 1 receptor and endothelial nitric oxide synthase via Src/PI3K/Akt signalling.

    Science.gov (United States)

    Su, Kuo-Hui; Tsai, Jin-Yi; Kou, Yu Ru; Chiang, An-Na; Hsiao, Sheng-Huang; Wu, Yuh-Lin; Hou, Hsin-Han; Pan, Ching-Chian; Shyue, Song-Kun; Lee, Tzong-Shyuan

    2009-06-01

    Valsartan, a selective angiotensin II type 1 receptor (AT1R) blocker, has beneficial effects in the cardiovascular system in part by its increase of nitric oxide (NO) bioavailability, yet the mechanisms are unclear. We investigated the molecular mechanisms underlying this effect in endothelial cells (ECs). NO production was examined by Griess reagent assay, DAF-2 DA fluorescence staining and cGMP ELISA kits. Protein interaction was determined by western blotting and immunoprecipitation. Treating bovine or human aortic ECs with valsartan increased NO production, as evidenced by elevated level of stable NO metabolites and intracellular cGMP. Valsartan increased the phosphorylation but not the protein level of endothelial NO synthase (eNOS). Inhibition of phosphoinositide-3 kinase (PI3K)/Akt and Src pathways by specific inhibitors suppressed valsartan-induced NO release. In addition, valsartan increased the tyrosine residue phosphorylation of AT1R, which was attenuated by inhibition of Src but not PI3K activities. Valsartan also suppressed the interaction of eNOS and AT1R, which was blocked by Src or PI3K inhibition. Valsartan-induced NO production in ECs is mediated through Src/PI3K/Akt-dependent phosphorylation of eNOS. Valsartan-induced AT1R phosphorylation depends on Src but not PI3K, whereas valsartan-induced suppression of AT1R-eNOS interaction depends on Src/PI3K/Akt signalling. These results indicate a novel vasoprotective mechanism of valsartan in upregulating NO production in ECs.

  15. Type I and type II interferons upregulate functional type I interleukin-1 receptor in a human fibroblast cell line TIG-1.

    Science.gov (United States)

    Takii, T; Niki, N; Yang, D; Kimura, H; Ito, A; Hayashi, H; Onozaki, K

    1995-12-01

    The regulation of type I interleukin-1 receptor (IL-1R) expression by type I, interferon (IFN)-alpha A/D, and type II IFN, IFN-gamma, in a human fibroblast cell line TIG-1 was investigated. After 2 h stimulation with human IFN-alpha A/D or IFN-gamma, the levels of type I IL-1R mRNA increased. We previously reported that IL-1 upregulates transcription and cell surface molecules of type I IL-1R in TIG-1 cells through induction of prostaglandin (PG) E2 and cAMP accumulation. However, indomethacin was unable to inhibit the effect of IFNs, indicating that IFNs augment IL-1R expression through a pathway distinct from that of IL-1. The augmentation was also observed in other fibroblast cell lines. Nuclear run-on assays and studies of the stability of mRNA suggested that the increase in IL-1R mRNA was a result of the enhanced transcription of IL-1R gene. Binding studies using 125I-IL-1 alpha revealed that the number of cell surface IL-1R increased with no change in binding affinity by treatment with these IFNs. Pretreatment of the cells with IFNs enhanced IL-1-induced IL-6 production, indicating that IFNs upregulate functional IL-1R. IL-1 and IFNs are produced by the same cell types, as well as by the adjacent different cell types, and are concomitantly present in lesions of immune and inflammatory reactions. These results therefore suggest that IFNs exhibit synergistic effects with IL-1 through upregulation of IL-1R. Augmented production of IL-6 may also contribute to the reactions.

  16. Effect of angiotensin II receptor blocker, olmesartan, on turnover of bone metabolism in bedridden elderly hypertensive women with disuse syndrome.

    Science.gov (United States)

    Aoki, Motokuni; Kawahata, Hirohisa; Sotobayashi, Daisuke; Yu, Hisahiro; Moriguchi, Atsushi; Nakagami, Hironori; Ogihara, Toshio; Morishita, Ryuichi

    2015-08-01

    Although recent studies suggest that several antihypertensive drugs could reduce the risk of bone fracture, it is still unclear how these drugs act on bone remodeling, especially in elderly women with severe osteoporosis with disuse syndrome. In the present study, we investigated the effects of a calcium channel blocker (CCB) and an angiotensin II receptor blocker (ARB) on bone metabolism in elderly bedridden women with hypertension and disuse syndrome. Elderly bedridden women (aged >75 years) receiving antihypertensive therapy treated with CCB were recruited in the present study. The participants were divided into two groups--CCB group and ARB group--and followed up to 12 months. Markers of bone resorption were markedly increased, suggesting accelerated bone resorption in the participants of the present study. In the follow-up period, the patients treated with a CCB showed a significant decrease in bone mineral density in a time-dependent manner, accompanied by a significant increase in bone resorption markers, whereas treatment with olmesartan inhibited bone loss, associated with attenuation of increased bone resorption markers. Bone mineral density of femoral neck in the CCB group was significantly lower than that in the ARB group at 6 months. The present study showed inhibitory effects of an ARB on bone resorption in hypertensive patients with accelerated bone resorption, such as elderly bedridden women, and indicated an important role of the renin-angiotensin system in bone metabolism. In elderly hypertensive patients, ARB might be expected to have additional beneficial potential to maintain bone health in bedridden patients. © 2014 Japan Geriatrics Society.

  17. Functional transforming growth factor-β receptor type II expression by CD4+ T cells in Peyer's patches is essential for oral tolerance induction.

    Directory of Open Access Journals (Sweden)

    Rebekah S Gilbert

    Full Text Available Our previous studies have shown that Peyer's patches (PPs play a key role in the induction of oral tolerance. Therefore, we hypothesized that PPs are an important site for Transforming Growth Factor (TGF-β signaling and sought to prove that this tissue is of importance in oral tolerance induction. We found that expression of TGF-β type II receptor (TGFβRII by CD4(+ T cells increases and persists in the PPs of normal C57BL/6 mice after either high- or low-dose feeding of OVA when compared to mesenteric lymph nodes (MLNs and spleen. Approximately one-third of these TGFβRII(+ CD4(+ T cells express the transcription factor Foxp3. Interestingly, the number of TGFβRII(+ CD4(+ T cells in PPs decreased when OVA-fed mice were orally challenged with OVA plus native cholera toxin (CT. In contrast, numbers of TGFβRII(+ CD4(+ T cells were increased in the intestinal lamina propria (iLP of these challenged mice. Further, these PP CD4(+ TGFβRII(+ T cells upregulated Foxp3 within 2 hours after OVA plus CT challenge. Mice fed PBS and challenged with OVA plus CT did not reveal any changes in TGFβRII expression by CD4(+ T cells. In order to test the functional property of TGFβRII in the induction of oral tolerance, CD4dnTGFβRII transgenic mice, in which TGFβRII signaling is abrogated from all CD4(+ T cells, were employed. Importantly, these mice could not develop oral tolerance to OVA. Our studies show a critical, dose-independent, role for TGFβRII expression and function by CD4(+ T cells in the gut-associated lymphoid tissues, further underlining the vital role of PPs in oral tolerance.

  18. Angiotensin II type 2 receptor stimulation improves fatty acid ovarian uptake and hyperandrogenemia in an obese rat model of polycystic ovary syndrome.

    Science.gov (United States)

    Leblanc, Samuel; Battista, Marie-Claude; Noll, Christophe; Hallberg, Anders; Gallo-Payet, Nicole; Carpentier, André C; Vine, Donna F; Baillargeon, Jean-Patrice

    2014-09-01

    Polycystic ovary syndrome (PCOS) is mainly defined by hyperandrogenism but is also characterized by insulin resistance (IR). Studies showed that overexposure of nonadipose tissues to nonesterified fatty acids (NEFA) may explain both IR and hyperandrogenism. Recent studies indicate that treatment with an angiotensin II type 2 receptor (AT2R)-selective agonist improves diet-induced IR. We thus hypothesized that PCOS hyperandrogenism is triggered by ovarian NEFA overexposure and is improved after treatment with an AT2R agonist. Experiments were conducted in 12-week-old female JCR:LA-cp/cp rats, which are characterized by visceral obesity, IR, hyperandrogenism, and polycystic ovaries. Control JCR:LA +/? rats have a normal phenotype. Rats were treated for 8 days with saline or the selective AT2R agonist C21/M24 and then assessed for: 1) fasting testosterone, NEFA, and insulin levels; and 2) an iv 14(R,S)-[(18)F]fluoro-6-thia-heptadecanoic acid test to determine NEFA ovarian tissue uptake (Km). Compared with controls, saline-treated PCOS/cp rats displayed higher insulin (100 vs 5.6 μU/mL), testosterone (0.12 vs 0.04 nmol/L), NEFA (0.98 vs 0.48 mmol/L), and Km (20.7 vs 12.9 nmol/g·min) (all P < .0001). In PCOS/cp rats, C21/M24 did not significantly improve insulin or NEFA but normalized testosterone (P = .004) and Km (P = .009), which were strongly correlated together in all PCOS/cp rats (ρ = 0.74, P = .009). In conclusion, in an obese PCOS rat model, ovarian NEFA uptake and testosterone levels are strongly associated and are both significantly reduced after short-term C21/M24 therapy. These findings provide new information on the role of NEFA in PCOS hyperandrogenemia and suggest a potential role for AT2R agonists in the treatment of PCOS.

  19. Distribution and levels of [125I]IGF-I, [125I]IGF-II and [125I]insulin receptor binding sites in the hippocampus of aged memory-unimpaired and -impaired rats

    International Nuclear Information System (INIS)

    Quirion, R.; Rowe, W.; Kar, S.; Dore, S.

    1997-01-01

    The insulin-like growth factors (IGF-I and IGF-II) and insulin are localized within distinct brain regions and their respective functions are mediated by specific membrane receptors. High densities of binding sites for these growth factors are discretely and differentially distributed throughout the brain, with prominent levels localized to the hippocampal formation. IGFs and insulin, in addition to their growth promoting actions, are considered to play important roles in the development and maintenance of normal cell functions throughout life. We compared the anatomical distribution and levels of IGF and insulin receptors in young (five month) and aged (25 month) memory-impaired and memory-unimpaired male Long-Evans rats as determined in the Morris water maze task in order to determine if alterations in IGF and insulin activity may be related to the emergence of cognitive deficits in the aged memory-impaired rat. In the hippocampus, [ 125 I]IGF-I receptors are concentrated primarily in the dentate gyrus (DG) and the CA3 sub-field while high amounts of [ 125 I]IGF-II binding sites are localized to the pyramidal cell layer, and the granular cell layer of the DG. [ 125 I]insulin binding sites are mostly found in the molecular layer of the DG and the CA1 sub-field. No significant differences were found in [ 125 I]IGF-I, [ 125 I]IGF-II or [ 125 I]insulin binding levels in any regions or laminae of the hippocampus of young vs aged rats, and deficits in cognitive performance did not relate to altered levels of these receptors in aged memory-impaired vs aged memory-unimpaired rats. Other regions, including various cortical areas, were also examined and failed to reveal any significant differences between the three groups studied.It thus appears that IGF-I, IGF-II and insulin receptor sites are not markedly altered during the normal ageing process in the Long-Evans rat, in spite of significant learning deficits in a sub-group (memory-impaired) of aged animals. Hence

  20. Blood pressure, magnesium and other mineral balance in two rat models of salt-sensitive, induced hypertension: effects of a non-peptide angiotensin II receptor type 1 antagonist.

    Science.gov (United States)

    Rondón, Lusliany Josefina; Marcano, Eunice; Rodríguez, Fátima; del Castillo, Jesús Rafael

    2014-01-01

    The renin-angiotensin system is critically involved in regulating arterial blood pressure (BP). Inappropriate angiotensin type-1 receptor activation by angiotensin-II (Ang-II) is related to increased arterial BP. Mg has a role in BP; it can affect cardiac electrical activity, myocardial contractility, and vascular tone. To evaluate the relationship between high BP induced by a high sodium (Na) diet and Mg, and other mineral balances, two experimental rat models of salt-sensitive, induced-hypertension were used: Ang-II infused and Dahl salt-sensitive (SS) rats. We found that: 1) Ang-II infusion progressively increased BP, which was accompanied by hypomagnesuria and signs of secondary hyperaldosteronism; 2) an additive effect between Ang-II and a high Na load may have an effect on strontium (Sr), zinc (Zn) and copper (Cu) balances; 3) Dahl SS rats fed a high Na diet had a slow pressor response, accompanied by altered Mg, Na, potassium (K), and phosphate (P) balances; and 4) losartan prevented BP increases induced by Ang II-NaCl, but did not modify mineral balances. In Dahl SS rats, losartan attenuated high BP and ameliorated magnesemia, Na and K balances. Mg metabolism maybe considered a possible defect in this strain of rat that may contribute to hypertension.

  1. Growth suppression by transforming growth factor beta 1 of human small-cell lung cancer cell lines is associated with expression of the type II receptor

    DEFF Research Database (Denmark)

    Nørgaard, P; Damstrup, L; Rygaard, K

    1994-01-01

    was observed in two cell lines expressing only type III receptor and in TGF-beta-r negative cell lines. In two cell lines expressing all three receptor types, growth suppression was accompanied by morphological changes. To evaluate the possible involvement of the retinoblastoma protein (pRb) in mediating...

  2. Discovery of novel, potent and low-toxicity angiotensin II receptor type 1 (AT1) blockers: Design, synthesis and biological evaluation of 6-substituted aminocarbonyl benzimidazoles with a chiral center.

    Science.gov (United States)

    Han, Xiao-Feng; He, Xing; Wang, Miao; Xu, Di; Hao, Li-Ping; Liang, Ai-Hua; Zhang, Jun; Zhou, Zhi-Ming

    2015-10-20

    Novel angiotensin II receptor type 1 (AT1) blockers bearing 6-substituted carbamoyl benzimidazoles with a chiral center were designed and synthesized as the first step to develop new antihypertensive agents and understand their pharmacodynamic and pharmacokinetic properties. The newly synthesized compounds were tested for their potential ability to displace [(125)I] Sar(1) Ile(8)-Ang II, which was specifically bound to human AT1 receptor. Radioligand binding assays revealed nanomolar affinity in several compounds under study. The IC50 values of nine ligands were higher than those of Losartan. The screening of decreased blood pressure in spontaneous hypertensive rats displayed that compound 8S (IC₅₀ = 5.0 nM) was equipotent with Losartan, whereas compounds 13R (IC₅₀ = 7.3 nM), 14R (IC₅₀ = 6.3 nM), and 14S (IC₅₀ = 3.5 nM) were slightly ahead of Losartan, and the most significant activity was demonstrated by compound 8R (IC₅₀ = 1.1 nM). Candidate 8R was identified for its excellent efficacy in antihypertension and fairly low toxicity based on plasma analyses, toxicology studies, and chronic oral tests. Finally, compound 8R exhibited strong and multiple interactions with target active sites of the theoretical AT1 receptor model in docking study. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  3. Receptor type I and type II binding regions and the peptidyl-prolyl isomerase site of cyclophilin B are required for enhancement of T-lymphocyte adhesion to fibronectin.

    Science.gov (United States)

    Carpentier, Mathieu; Allain, Fabrice; Slomianny, Marie-Christine; Durieux, Sandrine; Vanpouille, Christophe; Haendler, Bernard; Spik, Geneviève

    2002-04-23

    Cyclophilin B (CyPB), a cyclosporin A (CsA) binding protein, interacts with two types of binding sites at the surface of T-lymphocytes. The type I sites correspond to functional receptors involved in endocytosis and the type II sites to sulfated glycosaminoglycans (GAGs). Mutational analysis of CyPB has revealed that W128, which is part of the CsA-binding pocket, is implicated in the binding to the functional type I receptors and that two amino acid clusters located in the N-terminus ensure the binding to GAGs. The peptidyl-prolyl isomerase activity of CyPB is not required for receptor binding. We have recently demonstrated that CyPB enhances adhesion of peripheral blood T-lymphocytes to fibronectin, a component of the extracellular matrix. We intended to identify additional amino acids involved in the binding of CyPB to its functional type I receptor and to determine regions responsible for the stimulation of peripheral blood T-lymphocyte adhesion. We determined that residues R76, G77, K132, D155, and D158 of the calcineurin (CN) interacting region were implicated in the recognition of type I receptor but not of GAGs. We also found that two different changes in the N-terminal extension that abated binding to GAGs prevented adhesion of peripheral blood T-lymphocytes to coated CyPB, whereas abbrogation of the PPIase activity had no effect. On the other hand, the adhesion of peripheral blood T-lymphocytes to coated fibronectin was not stimulated by CyPB mutants devoid of either type I receptor or GAGs binding activity or by mutants of the PPIase site. Altogether, the results demonstrate that different regions of CyPB are involved in peripheral blood T-lymphocyte activation and imply a novel important physiological function for peptidyl-prolyl isomerase activity.

  4. Angiotensin-Converting Inhibitors and Angiotensin II Receptor Blockers and Longitudinal Change in Percent Emphysema on Computed Tomography. The Multi-Ethnic Study of Atherosclerosis Lung Study

    Science.gov (United States)

    Parikh, Megha A.; Aaron, Carrie P.; Hoffman, Eric A.; Schwartz, Joseph E.; Madrigano, Jaime; Austin, John H. M.; Lovasi, Gina; Watson, Karol; Stukovsky, Karen Hinckley

    2017-01-01

    Rationale: Although emphysema on computed tomography (CT) is associated with increased morbidity and mortality in patients with and without spirometrically defined chronic obstructive pulmonary disease, no available medications target emphysema outside of alpha-1 antitrypsin deficiency. Transforming growth factor-β and endothelial dysfunction are implicated in emphysema pathogenesis, and angiotensin II receptor blockers (ARBs) inhibit transforming growth factor-β, improve endothelial function, and restore airspace architecture in murine models. Evidence in humans is, however, lacking. Objectives: To determine whether angiotensin-converting enzyme (ACE) inhibitor and ARB dose is associated with slowed progression of percent emphysema by CT. Methods: The Multi-Ethnic Study of Atherosclerosis researchers recruited participants ages 45–84 years from the general population from 2000 to 2002. Medication use was assessed by medication inventory. Percent emphysema was defined as the percentage of lung regions less than −950 Hounsfield units on CTs. Mixed-effects regression models were used to adjust for confounders. Results: Among 4,472 participants, 12% used an ACE inhibitor and 6% used an ARB at baseline. The median percent emphysema was 3.0% at baseline, and the rate of progression was 0.64 percentage points over a median of 9.3 years. Higher doses of ACE or ARB were independently associated with a slower change in percent emphysema (P = 0.03). Over 10 years, in contrast to a predicted mean increase in percent emphysema of 0.66 percentage points in those who did not take ARBs or ACE inhibitors, the predicted mean increase in participants who used maximum doses of ARBs or ACE inhibitors was 0.06 percentage points (P = 0.01). The findings were of greatest magnitude among former smokers (P emphysema. There was no evidence that ACE inhibitor or ARB dose was associated with decline in lung function. Conclusions: In a large population-based study, ACE

  5. Translational Breast Cancer Research Consortium (TBCRC) 022: A Phase II Trial of Neratinib for Patients With Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer and Brain Metastases.

    Science.gov (United States)

    Freedman, Rachel A; Gelman, Rebecca S; Wefel, Jeffrey S; Melisko, Michelle E; Hess, Kenneth R; Connolly, Roisin M; Van Poznak, Catherine H; Niravath, Polly A; Puhalla, Shannon L; Ibrahim, Nuhad; Blackwell, Kimberly L; Moy, Beverly; Herold, Christina; Liu, Minetta C; Lowe, Alarice; Agar, Nathalie Y R; Ryabin, Nicole; Farooq, Sarah; Lawler, Elizabeth; Rimawi, Mothaffar F; Krop, Ian E; Wolff, Antonio C; Winer, Eric P; Lin, Nancy U

    2016-03-20

    Evidence-based treatments for metastatic, human epidermal growth factor receptor 2 (HER2)-positive breast cancer in the CNS are limited. Neratinib is an irreversible inhibitor of erbB1, HER2, and erbB4, with promising activity in HER2-positive breast cancer; however, its activity in the CNS is unknown. We evaluated the efficacy of treatment with neratinib in patients with HER2-positive breast cancer brain metastases in a multicenter, phase II open-label trial. Eligible patients were those with HER2-positive brain metastases (≥ 1 cm in longest dimension) who experienced progression in the CNS after one or more line of CNS-directed therapy, such as whole-brain radiotherapy, stereotactic radiosurgery, and/or surgical resection. Patients received neratinib 240 mg orally once per day, and tumors were assessed every two cycles. The primary endpoint was composite CNS objective response rate (ORR), requiring all of the following: ≥ 50% reduction in volumetric sum of target CNS lesions and no progression of non-target lesions, new lesions, escalating corticosteroids, progressive neurologic signs/symptoms, or non-CNS progression--the threshold for success was five of 40 responders. Forty patients were enrolled between February 2012 and June 2013; 78% of patients had previous whole-brain radiotherapy. Three women achieved a partial response (CNS objective response rate, 8%; 95% CI, 2% to 22%). The median number of cycles received was two (range, one to seven cycles), with a median progression-free survival of 1.9 months. Five women received six or more cycles. The most common grade ≥ 3 event was diarrhea (occurring in 21% of patients taking prespecified loperamide prophylaxis and 28% of those without prophylaxis). Patients in the study experienced a decreased quality of life over time. Although neratinib had low activity and did not meet our threshold for success, 12.5% of patients received six or more cycles. Studies combining neratinib with chemotherapy in patients

  6. Effect of urine urea nitrogen and protein intake adjusted by using the estimated urine creatinine excretion rate on the antiproteinuric effect of angiotensin II type I receptor blockers.

    Science.gov (United States)

    Chin, Ho Jun; Kim, Dong Ki; Park, Jung Hwan; Shin, Sung Joon; Lee, Sang Ho; Choi, Bum Soon; Kim, Suhnggwon; Lim, Chun Soo

    2015-01-01

    The aim of this study was to determine the role of protein intake on proteinuria in chronic kidney disease (CKD), as it is presently not conclusive. This is a subanalysis of data from an open-label, case-controlled, randomized clinical trial on education about low-salt diets (NCT01552954). We estimated the urine excretion rate of parameters in a day, adjusted by using the equation for estimating urine creatinine excretion, and analyzed the effect of urine urea nitrogen (UUN), as well as estimating protein intake on the level of albuminuria in hypertensive patients with chronic kidney disease. Among 174 participants from whom complete 24-h urine specimens were collected, the estimates from the Tanaka equation resulted in the highest accuracy for the urinary excretion rate of creatinine, sodium, albumin, and UUN. Among 227 participants, the baseline value of estimated urine albumin excretion (eUalb) was positively correlated with the estimated UUN (eUUN) or protein intake according to eUUN (P = 0.012 and P = 0.038, respectively). We were able to calculate the ratios of eUalb and eUUN in 221 participants and grouped them according to the ratio of eUUN during 16-wk trial period. The proportion of patients that achieved a decrement of eUalb ≥25% during 16 wk with an angiotensin II type I receptor blocker (ARB) medication was 80% (24 of 30) in group 1, with eUUN ratio ≤-25%; 82.2% (111 of 135) in group 2, with eUUN ratio between -25% and 25%; and 66.1% (37 and 56) in group 3, with eUUN ratio ≥25% (P = 0.048). The probability of a decrease in albuminuria with ARB treatment was lower in patients with an increase of eUUN or protein intake during the 16 wk of ARB treatment, as observed in multiple logistic regression analysis as well. The estimated urine urea excretion rate showed a positive association with the level of albuminuria in hypertensive patients with chronic kidney disease. The increase of eUUN excretion ameliorated the antiproteinuric effect of ARB

  7. Systemic administration of kainic acid induces selective time dependent decrease in [125I]insulin-like growth factor I, [125I]insulin-like growth factor II and [125I]insulin receptor binding sites in adult rat hippocampal formation

    International Nuclear Information System (INIS)

    Quirion, R.; Chabot, J.-G.; Dore, S.; Seto, D.; Kar, S.

    1997-01-01

    Administration of kainic acid evokes acute seizure in hippocampal pathways that results in a complex sequence of functional and structural alterations resembling human temporal lobe epilepsy. The structural alterations induced by kainic acid include selective loss of neurones in CA1-CA3 subfields and the hilar region of the dentate gyrus followed by sprouting and permanent reorganization of the synaptic connections of the mossy fibre pathways. Although the neuronal degeneration and process of reactive synaptogenesis have been extensively studied, at present little is known about means to prevent pathological conditions leading to kainate-induced cell death. In the present study, to address the role of insulin-like growth factors I and II, and insulin in neuronal survival as well as synaptic reorganization following kainate-induced seizure, the time course alterations of the corresponding receptors were evaluated. Additionally, using histological preparations, the temporal profile of neuronal degeneration and hypertrophy of resident astroglial cells were also studied. [ 125 I]Insulin-like growth factor I binding was found to be decreased transiently in almost all regions of the hippocampal formation at 12 h following treatment with kainic acid. The dentate hilar region however, exhibited protracted decreases in [ 125 I]insulin-like growth factor I receptor sites throughout (i.e. 30 days) the study. [ 125 I]Insulin-like growth factor II receptor binding sites in the hippocampal formation were found to be differentially altered following systemic administration of kainic acid. A significant decrease in [ 125 I]insulin-like growth factor II receptor sites was observed in CA1 subfield and the pyramidal cell layer of the Ammon's horn at all time points studied whereas the hilar region and the stratum radiatum did not exhibit alteration at any time. A kainate-induced decrease in [ 125 I]insulin receptor binding was noted at all time points in the molecular layer of the

  8. Regulation of insulin-like growth factor (IGF) I receptor expression during muscle cell differentiation. Potential autocrine role of IGF-II.

    OpenAIRE

    Rosenthal, S M; Brunetti, A; Brown, E J; Mamula, P W; Goldfine, I D

    1991-01-01

    Muscle is an important target tissue for insulin-like growth factor (IGF) action. The presence of specific, high affinity IGF receptors, as well as the expression of IGF peptides and binding proteins by muscle suggest that a significant component of IGF action in this tissue is mediated through autocrine and/or paracrine mechanisms. To explore autocrine/paracrine action of IGFs in muscle, we studied the regulation of the IGF-I receptor and the expression of IGF peptides during differentiation...

  9. Image-derived and arterial blood sampled input functions for quantitative PET imaging of the angiotensin II subtype 1 receptor in the kidney

    Energy Technology Data Exchange (ETDEWEB)

    Feng, Tao; Tsui, Benjamin M. W.; Li, Xin; Vranesic, Melin; Lodge, Martin A.; Gulaldi, Nedim C. M.; Szabo, Zsolt, E-mail: zszabo@jhmi.edu [Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins School of Medicine, Baltimore, Maryland 21287 (United States)

    2015-11-15

    Purpose: The radioligand {sup 11}C-KR31173 has been introduced for positron emission tomography (PET) imaging of the angiotensin II subtype 1 receptor in the kidney in vivo. To study the biokinetics of {sup 11}C-KR31173 with a compartmental model, the input function is needed. Collection and analysis of arterial blood samples are the established approach to obtain the input function but they are not feasible in patients with renal diseases. The goal of this study was to develop a quantitative technique that can provide an accurate image-derived input function (ID-IF) to replace the conventional invasive arterial sampling and test the method in pigs with the goal of translation into human studies. Methods: The experimental animals were injected with [{sup 11}C]KR31173 and scanned up to 90 min with dynamic PET. Arterial blood samples were collected for the artery derived input function (AD-IF) and used as a gold standard for ID-IF. Before PET, magnetic resonance angiography of the kidneys was obtained to provide the anatomical information required for derivation of the recovery coefficients in the abdominal aorta, a requirement for partial volume correction of the ID-IF. Different image reconstruction methods, filtered back projection (FBP) and ordered subset expectation maximization (OS-EM), were investigated for the best trade-off between bias and variance of the ID-IF. The effects of kidney uptakes on the quantitative accuracy of ID-IF were also studied. Biological variables such as red blood cell binding and radioligand metabolism were also taken into consideration. A single blood sample was used for calibration in the later phase of the input function. Results: In the first 2 min after injection, the OS-EM based ID-IF was found to be biased, and the bias was found to be induced by the kidney uptake. No such bias was found with the FBP based image reconstruction method. However, the OS-EM based image reconstruction was found to reduce variance in the subsequent

  10. Insulin receptors

    International Nuclear Information System (INIS)

    Kahn, C.R.; Harrison, L.C.

    1988-01-01

    This book contains the proceedings on insulin receptors. Part A: Methods for the study of structure and function. Topics covered include: Method for purification and labeling of insulin receptors, the insulin receptor kinase, and insulin receptors on special tissues

  11. Association of estrogen receptor α PvuII and XbaI polymorphisms with prostate cancer susceptibility and risk stratification: a meta-analysis from case-control studies

    Directory of Open Access Journals (Sweden)

    Zhao YN

    2017-06-01

    Full Text Available Yining Zhao,1,* Xi Zheng,2,* Lijie Zhang,3 Qiang Hu,3 Yitian Guo,3 Hua Jiang,3 Shennan Shi,4 Xiang Zhang1 1Department of Urology, Qilu Hospital of Shandong University, Jinan, 2Department of Urology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, 3Department of Urology, Affiliated Zhongda Hospital, Medical School, Southeast University, Nanjing, 4Department of General Surgery, Qilu Hospital of Shandong University, Jinan, People’s Republic of China *These authors contributed equally to this work Background: Studies on the association between two single nucleotide polymorphisms (SNPs in estrogen receptor α (ERα, PvuII (rs2234693 T>C and XbaI (rs9340799 A>G, and the prostate cancer risk are inconsistent. Therefore, we performed a meta-analysis to derive a more accurate estimation of this relationship. Methods: A literature search of PubMed, Embase, Web of Science databases until October 1, 2016, was conducted. Crude odds ratios (ORs with 95% confidence intervals (CIs were calculated to assess the strength of this association. Results: Eighteen case-control studies, with a total of 3,317 prostate cancer patients and 8,324 controls, were included. Results showed that both PvuII and XbaI polymorphisms were significantly associated with a higher prostate cancer risk in overall populations. To derive a more accurate estimation, subgroup analysis stratified by ethnicity revealed that this relationship existed only in Caucasians, but not in Asians. Furthermore, PvuII polymorphism was significantly associated with high Gleason grade (Gleason score ≥7 cancers. Conclusion: The current meta-analysis demonstrates that ERα PvuII and XbaI polymorphisms are associated with a higher prostate cancer risk in Caucasians, but not in Asians, and PvuII polymorphism is significantly associated with high Gleason grade tumors, indicating the probability of inherited susceptibility to prostate cancer arising from different genomic ERα SNPs

  12. Selective agonists at group II metabotropic glutamate receptors: synthesis, stereochemistry, and molecular pharmacology of (S)- and (R)-2-amino-4-(4-hydroxy[1,2,5]thiadiazol-3-yl)butyric acid

    DEFF Research Database (Denmark)

    Clausen, Rasmus P; Bräuner-Osborne, Hans; Greenwood, Jeremy R

    2002-01-01

    Homologation of analogues of the central excitatory neurotransmitter glutamic acid (Glu), in which the distal carboxy group has been bioisosterically replaced by acidic heterocyclic units, has previously provided subtype selective ligands for metabotropic Glu receptors (mGluRs). The (S......)-form of the 1,2,5-thiadiazol-3-ol Glu analogue, 2-amino-3-(4-hydroxy[1,2,5]thiadiazol-3-yl)propionic acid (TDPA, 6), is an 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor agonist, which in addition stereospecifically activates group I mGluRs. We have now synthesized the (S)- and (R......)-forms of 2-amino-4-(4-hydroxy[1,2,5]thiadiazol-3-yl)butyric acid (homo-TDPA, 7) and shown that whereas neither enantiomer interacts with AMPA receptors, (S)- and (R)-7 appear to be selective and equipotent agonists at group II mGluRs as represented by the mGluR2 subtype. The activities of (S)- and (R)-7...

  13. Constitutive homo- and hetero-oligomerization of TbetaRII-B, an alternatively spliced variant of the mouse TGF-beta type II receptor

    DEFF Research Database (Denmark)

    Krishnaveni, Manda S; Hansen, Jakob Lerche; Seeger, Werner

    2006-01-01

    , but the oligomerization pattern and dynamics of TbetaRII splice variants in live cells has not been demonstrated thus far. Using co-immunoprecipitation and bioluminescence resonance energy transfer (BRET), we demonstrate that the mouse TbetaRII receptor splice variant TbetaRII-B is capable of forming ligand...

  14. Rational design, efficient syntheses and biological evaluation of N,N '-symmetrically bis-substituted butylimidazole analogs as a new class of potent Angiotensin II receptor blockers

    Czech Academy of Sciences Publication Activity Database

    Agelis, G.; Resvani, A.; Koukoulitsa, C.; Tůmová, Tereza; Slaninová, Jiřina; Kalavrizioti, D.; Spyridaki, K.; Afantitis, A.; Melagraki, G.; Siafaka, A.; Gkini, E.; Megariotis, G.; Grdadolnik, S. G.; Papadopoulos, M. G.; Vlahakos, D.; Maragoudakis, M.; Liapakis, G.; Mavromoustakos, T.; Matsoukas, J.

    2013-01-01

    Roč. 62, Apr (2013), s. 352-370 ISSN 0223-5234 Institutional support: RVO:61388963 Keywords : AT1 receptor blockers * N,N '-Bis-alkylated butylimidazole analogs * synthesis * Wittig reaction * hydroxymethylation * structure elucidation Subject RIV: CC - Organic Chemistry Impact factor: 3.432, year: 2013

  15. Angiotensin II and CRF receptors in the central nucleus of the amygdala mediate hemodynamic response variability to cocaine in conscious rats.

    Science.gov (United States)

    Watanabe, Mari A; Kucenas, Sarah; Bowman, Tamara A; Ruhlman, Melissa; Knuepfer, Mark M

    2010-01-14

    Stress or cocaine evokes either a large increase in systemic vascular resistance (SVR) or a smaller increase in SVR accompanied by an increase in cardiac output (designated vascular and mixed responders, respectively) in Sprague-Dawley rats. We hypothesized that the central nucleus of the amygdala (CeA) mediates this variability. Conscious, freely-moving rats, instrumented for measurement of arterial pressure and cardiac output and for drug delivery into the CeA, were given cocaine (5 mg/kg, iv, 4-6 times) and characterized as vascular (n=15) or mixed responders (n=10). Subsequently, we administered cocaine after bilateral microinjections (100 nl) of saline or selective agents in the CeA. Muscimol (80 pmol), a GABA(A) agonist, or losartan (43.4 pmol), an AT(1) receptor antagonist, attenuated the cocaine-induced increase in SVR in vascular responders, selectively, such that vascular responders were no longer different from mixed responders. The corticotropin releasing factor (CRF) antagonist, alpha-helical CRF(9-41) (15.7 pmol), abolished the difference between cardiac output and SVR in mixed and vascular responders. We conclude that greater increases in SVR observed in vascular responders are dependent on AT(1) receptor activation and, to a lesser extent on CRF receptors. Therefore, AT(1) and CRF receptors in the CeA contribute to hemodynamic response variability to intravenous cocaine.

  16. QSAR Classification of ToxCast and Tox21 Chemicals on the Basis of Estrogen Receptor Assays (FutureToxII)

    Science.gov (United States)

    The ToxCast and Tox21 programs have tested ~8,200 chemicals in a broad screening panel of in vitro high-throughput screening (HTS) assays for estrogen receptor (ER) agonist and antagonist activity. The present work uses this large in vitro data set to develop in silico QSAR model...

  17. A phase II study of combined ridaforolimus and dalotuzumab compared with exemestane in patients with estrogen receptor-positive breast cancer

    DEFF Research Database (Denmark)

    Baselga, José; Morales, Serafin M.; Awada, Ahmad

    2017-01-01

    Purpose: Combining the mTOR inhibitor ridaforolimus and the anti-IGFR antibody dalotuzumab demonstrated antitumor activity, including partial responses, in estrogen receptor (ER)-positive advanced breast cancer, especially in high proliferation tumors (Ki67 > 15%). Methods: This randomized...

  18. CD54/intercellular adhesion molecule 1 and major histocompatibility complex II signaling induces B cells to express interleukin 2 receptors and complements help provided through CD40 ligation

    DEFF Research Database (Denmark)

    Poudrier, J; Owens, T

    1994-01-01

    We have examined signaling roles for CD54 intercellular adhesion molecule 1 and major histocompatibility complex (MHC) II as contact ligands during T help for B cell activation. We used a T helper 1 (Th1)-dependent helper system that was previously shown to be contact as well as interleukin 2 (IL-2......) dependent to demonstrate the relative roles of CD54, MHC II, and CD40 signaling in the events leading to the induction of B cell proliferation and responsiveness to IL-2. Paraformaldehyde-fixed activated Th1-induced expression of IL-2R alpha, IL-2R beta, and B7, and upregulated MHC II and CD54 on B cells...... resulted in the upregulated expression of MHC II and of CD54 and B7, respectively, analogous to the effect of fixed activated Th1 cells. B7 expression was further enhanced by co-cross-linking CD54 and MHC II. Cross-linking of CD40 achieved comparable effects. Strikingly, cross-linking ligation of CD54...

  19. Increased perfusion pressure enhances the expression of endothelin (ETB) and angiotensin II (AT1, AT2) receptors in rat mesenteric artery smooth muscle cells

    DEFF Research Database (Denmark)

    Lindstedt, Isak; Xu, Cang-Bao; Zhang, Yaping

    2009-01-01

    and luminally perfused in a perfusion chamber. After either exposure to no ("organ culture" (0 mmHg)), normal (85/75 mmHg) or high pressure (160/150 mmHg) at constant flow for 1-17 h, the vessel segments were snap frozen and real-time polymerase chain reaction was performed to quantify the ET- and AT-receptor m...

  20. The effects of repeated delivery of angiotensin II AT1 receptor antisense on distinct vasoactive systems in Ren-2 transgenic rats: young vs. adult animals

    Czech Academy of Sciences Publication Activity Database

    Vaněčková, Ivana; Dobešová, Zdenka; Kuneš, Jaroslav; Zicha, Josef

    2012-01-01

    Roč. 35, č. 7 (2012), s. 761-768 ISSN 0916-9636 R&D Projects: GA AV ČR(CZ) IAA500110902; GA ČR(CZ) GAP304/12/0259 Institutional support: RVO:67985823 Keywords : AT(1) receptor * BP regulation * gene therapy * oligodeoxynucleotides * vasodilator and vasoconstrictor systems Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery Impact factor: 2.791, year: 2012

  1. Additive effects of cilnidipine, an L-/N-type calcium channel blocker, and an angiotensin II receptor blocker on reducing cardiorenal damage in Otsuka Long-Evans Tokushima Fatty rats with type 2 diabetes mellitus

    Directory of Open Access Journals (Sweden)

    Mori Y

    2014-06-01

    Full Text Available Yutaka Mori,1,2 Shizuka Aritomi,3 Kazumi Niinuma,3 Tarou Nakamura,3 Kenichi Matsuura,1 Junichi Yokoyama,1 Kazunori Utsunomiya1 1Division of Diabetes and Endocrinology, Department of Internal Medicine, The Jikei University School of Medicine, Minato-ku, Japan; 2Department of Clinical Research, National Hospital Organization, Utsunomiya National Hospital, Utsunomiya, Japan; 3Research Center, Ajinomoto Pharmaceuticals Co, Ltd, Kanagawa, Japan Abstract: Cilnidipine (Cil, which is an L-/N-type calcium channel blocker (CCB, has been known to provide renal protection by decreasing the activity of the sympathetic nervous system (SNS and the renin–angiotensin system. In this study, we compared the effects of the combination of Cil and amlodipine (Aml, which is an L-type CCB, with an angiotensin (Ang II receptor blocker on diabetic cardiorenal damage in spontaneously type 2 diabetic rats. Seventeen-week-old Otsuka Long-Evans Tokushima Fatty rats were randomly assigned to receive Cil, Aml, valsartan (Val, Cil + Val, Aml + Val, or a vehicle (eight rats per group for 22 weeks. Antihypertensive potencies were nearly equal among the CCB monotherapy groups and the combination therapy groups. The lowering of blood pressure by either treatment did not significantly affect the glycemic variables. However, exacerbations of renal and heart failure were significantly suppressed in rats administered Cil or Val, and additional suppression was observed in those administered Cil + Val. Although Val increased the renin–Ang system, Aml + Val treatment resulted in additional increases in these parameters, while Cil + Val did not show such effects. Furthermore, Cil increased the ratio of Ang-(1–7 to Ang-I, despite the fact that Val and Aml + Val decreased the Ang-(1–7 levels. These actions of Cil + Val might be due to their synergistic inhibitory effect on the activity of the SNS, and on aldosterone secretion through N-type calcium channel antagonism and Ang II

  2. A Bis-Triazacyclononane Tris-Pyridyl N9 -Azacryptand "Beer Can" Receptor for Complexation of Alkali Metal and Lead(II) Cations.

    Science.gov (United States)

    Brown, Asha; Bunchuay, Thanthapatra; Crane, Christopher G; White, Nicholas G; Thompson, Amber L; Beer, Paul D

    2018-04-18

    A new bis-triazacyclononane tris-pyridyl N 9 -azacryptand ligand is prepared via a convenient one-pot [2+3] condensation reaction between triazacyclononane and 2,6-bis(bromomethyl) pyridine in the presence of M 2 CO 3 (M=Li, Na, K). The proton, lithium, sodium, potassium and lead(II) complexes of the ligand are characterised in the solid state. Preliminary solution-phase competition experiments indicate that the cryptand ligand preferentially binds lead(II) in the presence of sodium, calcium, potassium and zinc cations in methanol solution. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  3. Angiotensin II AT1 receptor blockade decreases vasopressin-induced water reabsorption and AQP2 levels in NaCl-restricted rats

    DEFF Research Database (Denmark)

    Kwon, Tae-Hwan; Nielsen, Jakob; Knepper, M.A.

    2005-01-01

    Vasopressin and ANG II, which are known to play a major role in renal water and sodium reabsorption, are mainly coupled to the cAMP/PKA and phosphoinositide pathways, respectively. There is evidence for cross talk between these intracellular signaling pathways. We therefore hypothesized that vaso......Vasopressin and ANG II, which are known to play a major role in renal water and sodium reabsorption, are mainly coupled to the cAMP/PKA and phosphoinositide pathways, respectively. There is evidence for cross talk between these intracellular signaling pathways. We therefore hypothesized...

  4. Part I. Naltrexone-derived conjugate addition ligands for opioid receptors. Part II. Chemical and enantioselective aspects of the metabolism of verapamil

    International Nuclear Information System (INIS)

    Olsen, L.D.

    1987-01-01

    Selective chemoaffinity ligands to aid in identification and purification of opioid receptor subtypes were prepared from 6α- and 6β-naltrexol, obtained stereoselectively from the μ-receptor antagonist naltrexone. The targets were the 6α- and 6β-methacrylate ethers and 6α- and 6β-methacrylate esters prepared from reaction of 6α- and 6β-naltrexol with methyl α-(bromomethyl)acrylate or methacryloyl chloride. Of three methacrylate derivatives, the 6α-ether was the most potent in an opioid receptor binding assay with [ 3 H]-naltrexone. In the presence of sodium ion, preincubation of the 6α-ether resulted in recovery of about 60% of original [ 3 H]-naltrexone binding suggesting some irreversible effects. The methacrylate esters precipitated withdrawal in morphine dependent monkeys. The enantiomers of verapamil, a calcium channel antagonist, have different pharmacological and pharmacokinetic properties. The oxidative metabolism of verapamil was studied in rat and human liver microsomes and in man after a single oral dose

  5. Part I. Naltrexone-derived conjugate addition ligands for opioid receptors. Part II. Chemical and enantioselective aspects of the metabolism of verapamil

    Energy Technology Data Exchange (ETDEWEB)

    Olsen, L.D.

    1987-01-01

    Selective chemoaffinity ligands to aid in identification and purification of opioid receptor subtypes were prepared from 6..cap alpha..- and 6..beta..-naltrexol, obtained stereoselectively from the ..mu..-receptor antagonist naltrexone. The targets were the 6..cap alpha..- and 6..beta..-methacrylate ethers and 6..cap alpha..- and 6..beta..-methacrylate esters prepared from reaction of 6..cap alpha..- and 6..beta..-naltrexol with methyl ..cap alpha..-(bromomethyl)acrylate or methacryloyl chloride. Of three methacrylate derivatives, the 6..cap alpha..-ether was the most potent in an opioid receptor binding assay with (/sup 3/H)-naltrexone. In the presence of sodium ion, preincubation of the 6..cap alpha..-ether resulted in recovery of about 60% of original (/sup 3/H)-naltrexone binding suggesting some irreversible effects. The methacrylate esters precipitated withdrawal in morphine dependent monkeys. The enantiomers of verapamil, a calcium channel antagonist, have different pharmacological and pharmacokinetic properties. The oxidative metabolism of verapamil was studied in rat and human liver microsomes and in man after a single oral dose.

  6. Bis(morpholine) hydrogen bond pincer - a novel series of heteroleptic Cu(II) coordination compounds as receptors for electron rich guests

    NARCIS (Netherlands)

    Stilinovic, Vladimir; Uzarevic, Krunoslav; Cvrtila, Ivica; Kaitner, Branko

    2012-01-01

    Crystallisation from morpholine (morph) solutions of copper(II) salts with monovalent anions (A) and 1,3-diketones (Hdkt) yielded nine heteroleptic coordination compounds [Cu(dkt)(morph)(2)A]. The coordination polyhedron of the copper ion in these compounds is a square pyramid with a monovalent

  7. Effect of iron deficiency on the expression of insulin-like growth factor-II and its receptor in neuronal and glial cells.

    Science.gov (United States)

    Morales González, E; Contreras, I; Estrada, J A

    2014-09-01

    Many studies have demonstrated that iron deficiency modifies the normal function of the central nervous system and alters cognitive abilities. When cellular damage occurs in the central nervous system, neuroprotective mechanisms, such as the production of neurotrophic factors, are essential in order for nervous tissue to function correctly. Insulin-like growth factor II (IGF- II) is a neurotrophic factor that was recently shown to be involved in the normal functioning of cognitive processes in animal models. However, the impact of iron deficiency on the expression and function of this molecule has not yet been clarified. Mixed primary cell cultures from the central nervous system were collected to simulate iron deficiency using deferoxamine. The expression of IGF-I, IGF-II, IGF-IR, and IGF-IIR was determined with the western blot test. We observed increased expression of IGF-II, along with a corresponding decrease in the expression of IGF-IIR, in iron-deficient mixed primary cell cultures. We did not observe alterations in the expression of these proteins in isolated microglia or neuronal cultures under the same conditions. We did not detect differences in the expression of IGF-I and IGF-IR in iron-deficient cultures. In vitro iron deficiency increases the expression of IGF-II in mixed glial cell cultures, which may have a beneficial effect on brain tissue homeostasis in a situation in which iron availability is decreased. Copyright © 2013 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.

  8. Key Role of Toll-Like Receptor 2 in the Inflammatory Response and Major Histocompatibility Complex Class II Downregulation in Brucella abortus-Infected Alveolar Macrophages

    Science.gov (United States)

    Ferrero, Mariana C.; Hielpos, M. Soledad; Carvalho, Natalia B.; Barrionuevo, Paula; Corsetti, Patricia P.; Giambartolomei, Guillermo H.; Oliveira, Sergio C.

    2014-01-01

    Alveolar macrophages (AM) seem to constitute the main cellular target of inhaled brucellae. Here, we show that Brucella abortus invades and replicates in murine AM without inducing cytotoxicity. B. abortus infection induced a statistically significant increase of tumor necrosis factor alpha (TNF-α), CXCL1 or keratinocyte chemoattractant (KC), interleukin-1β (IL-1β), IL-6, and IL-12 in AM from C57BL/6 mice and BALB/c mice, but these responses were generally weaker and/or delayed compared to those elicited in peritoneal macrophages. Studies using knockout mice for TLR2, TLR4, and TLR9 revealed that TNF-α and KC responses were mediated by TLR2 recognition. Brucella infection reduced in a multiplicity of infection-dependent manner the expression of major histocompatibility complex class II (MHC-II) molecules induced by gamma interferon (IFN-γ) in AM. The same phenomenon was induced by incubation with heat-killed B. abortus (HKBA) or the lipidated form of the 19-kDa outer membrane protein of Brucella (L-Omp19), and it was shown to be mediated by TLR2 recognition. In contrast, no significant downregulation of MHC-II was induced by either unlipidated Omp19 or Brucella LPS. In a functional assay, treatment of AM with either L-Omp19 or HKBA reduced the MHC-II-restricted presentation of OVA peptides to specific T cells. One week after intratracheal infection, viable B. abortus was detected in AM from both wild-type and TLR2 KO mice, but CFU counts were higher in the latter. These results suggest that B. abortus survives in AM after inhalatory infection in spite of a certain degree of immune control exerted by the TLR2-mediated inflammatory response. Both the modest nature of the latter and the modulation of MHC-II expression by the bacterium may contribute to such survival. PMID:24478078

  9. cobalt (ii), nickel (ii)

    African Journals Online (AJOL)

    DR. AMINU

    Department of Chemistry Bayero University, P. M. B. 3011, Kano, Nigeria. E-mail: hnuhu2000@yahoo.com. ABSTRACT. The manganese (II), cobalt (II), nickel (II) and .... water and common organic solvents, but are readily soluble in acetone. The molar conductance measurement [Table 3] of the complex compounds in.

  10. Quantitative receptor radioautography in the study of receptor-receptor interactions in the nucleus tractus solitarii

    Directory of Open Access Journals (Sweden)

    Fior-Chadi D.R.

    1998-01-01

    Full Text Available The nucleus tractus solitarii (NTS in the dorsomedial medulla comprises a wide range of neuropeptides and biogenic amines. Several of them are related to mechanisms of central blood pressure control. Angiotensin II (Ang II, neuropeptide Y (NPY and noradrenaline (NA are found in the NTS cells, as well as their receptors. Based on this observation we have evaluated the modulatory effect of these peptide receptors on a2-adrenoceptors in the NTS. Using quantitative receptor radioautography, we observed that NPY and Ang II receptors decreased the affinity of a2-adrenoceptors for their agonists in the NTS of the rat. Cardiovascular experiments agreed with the in vitro data. Coinjection of a threshold dose of Ang II or of the NPY agonists together with an ED50 dose of adrenergic agonists such as NA, adrenaline and clonidine counteracted the depressor effect produced by the a2-agonist in the NTS. The results provide evidence for the existence of an antagonistic interaction between Ang II at1 receptors and NPY receptor subtypes with the a2-adrenoceptors in the NTS. This receptor interaction may reduce the transduction over the a2-adrenoceptors which can be important in central cardiovascular regulation and in the development of hypertension

  11. Neuroprotective effects of metabotropic glutamate receptor group II and III activators against MPP(+)-induced cell death in human neuroblastoma SH-SY5Y cells: the impact of cell differentiation state.

    Science.gov (United States)

    Jantas, D; Greda, A; Golda, S; Korostynski, M; Grygier, B; Roman, A; Pilc, A; Lason, W

    2014-08-01

    Recent studies have documented that metabotropic glutamate receptors from group II and III (mGluR II/III) are a potential target in the symptomatic treatment of Parkinson's disease (PD), however, the neuroprotective effects of particular mGluR II/III subtypes in relation to PD pathology are recognized only partially. In the present study, we investigated the effect of various mGluR II/III activators in the in vitro model of PD using human neuroblastoma SH-SY5Y cell line and mitochondrial neurotoxin MPP(+). We demonstrated that all tested mGluR ligands: mGluR II agonist - LY354740, mGluR III agonist - ACPT-I, mGluR4 PAM - VU0361737, mGluR8 agonist - (S)-3,4-DCPG, mGluR8 PAM - AZ12216052 and mGluR7 allosteric agonist - AMN082 were protective against MPP(+)-evoked cell damage in undifferentiated (UN-) SH-SY5Y cells with the highest neuroprotection mediated by mGluR8-specific agents. However, in retinoic acid- differentiated (RA-) SH-SY5Y cells we found protection mediated only by mGluR8 activators. We also demonstrated the cell proliferation stimulating effect for mGluR4 and mGluR8 PAMs. Next, we showed that the protection mediated by mGluR II/III activators in UN-SH-SY5Y was not accompanied by the modulation of caspase-3 activity, however, a decrease in the number of apoptotic nuclei was found. Finally, we showed that the inhibitor of necroptosis, necrostatin-1 blocked the mGluR III-mediated protection. Altogether our comparative in vitro data add a further proof to neuroprotective effects of mGluR agonists or PAMs and point to mGluR8 as a promising target for neuroprotective interventions in PD. The results also suggest the participation of necroptosis-related molecular pathways in neuroprotective effects of mGluR III activation. Copyright © 2014 Elsevier Ltd. All rights reserved.

  12. Sorafenib suppresses TGF-β responses by inducing caveolae/lipid raft-mediated internalization/degradation of cell-surface type II TGF-β receptors: Implications in development of effective adjunctive therapy for hepatocellular carcinoma.

    Science.gov (United States)

    Chung, Chih-Ling; Wang, Shih-Wei; Sun, Wei-Chih; Shu, Chih-Wen; Kao, Yu-Chen; Shiao, Meng-Shin; Chen, Chun-Lin

    2018-04-18

    Sorafenib is the only FDA approved drug for the treatment of advanced hepatocellular carcinoma (HCC) and other malignancies. Studies indicate that TGF-β signalling is associated with tumour progression in HCC. Autocrine and paracrine TGF-β promotes tumour growth and malignancy by inducing epithelial-mesenchymal transition (EMT). Sorafenib is believed to antagonize tumour progression by inhibiting TGF-β-induced EMT. It improves survival of patients but HCC later develops resistance and relapses. The underlying mechanism of resistance is unknown. Understanding of the molecular mechanism of sorafenib inhibition of TGF-β-induced signalling or responses in HCC may lead to development of adjunctive effective therapy for HCC. In this study, we demonstrate that sorafenib suppresses TGF-β responsiveness in hepatoma cells, hepatocytes, and animal liver, mainly by downregulating cell-surface type II TGF-β receptors (TβRII) localized in caveolae/lipid rafts and non-lipid raft microdomains via caveolae/lipid rafts-mediated internalization and degradation. Furthermore, sorafenib-induced downregulation and degradation of cell-surface TβRII is prevented by simultaneous treatment with a caveolae disruptor or lysosomal inhibitors. On the other hand, sorafenib only downregulates cell-surface TβRII localized in caveolae/lipid rafts but not localized in non-lipid raft microdomains in hepatic stellate cells. These results suggest that sorafenib inhibits TGF-β signalling mainly by inducing caveolae/lipid raft-mediated internalization and degradation of cell-surface TβR-II in target cells. They may also imply that treatment with agents which promote formation of caveolae/lipid rafts, TGF-β receptor kinase inhibitors (e.g., LY2157299) or TGF-β peptide antagonists (by liver-targeting delivery) may be considered as effective adjunct therapy with sorafenib for HCC. Copyright © 2018 Elsevier Inc. All rights reserved.

  13. Tritiated-nicotine- and 125I-alpha-bungarotoxin-labeled nicotinic receptors in the interpeduncular nucleus of rats. II. Effects of habenular destruction

    International Nuclear Information System (INIS)

    Clarke, P.B.; Hamill, G.S.; Nadi, N.S.; Jacobowitz, D.M.; Pert, A.

    1986-01-01

    The cholinergic innervation of the interpeduncular nucleus (IPN) is wholly extrinsic and is greatly attenuated by bilateral habenular destruction. We describe changes in the labeling of putative nicotinic receptors within this nucleus at 3, 5, or 11 days after bilateral habenular lesions. Adjacent tissue sections of the rat IPN were utilized for 3 H-nicotine and 125 I-alpha-bungarotoxin ( 125 I-BTX) receptor autoradiography. Compared to sham-operated controls, habenular destruction significantly reduced autoradiographic 3 H-nicotine labeling in rostral (-25%), intermediate (-13%), and lateral subnuclei (-36%). Labeling in the central subnucleus was unchanged. Loss of labeling was maximal at the shortest survival time (3 days) and did not change thereafter. In order to establish whether this loss was due to a reduction in the number or the affinity of 3 H-nicotine-binding sites, a membrane assay was performed on microdissected IPN tissue from rats that had received surgery 3 days previously. Bilateral habenular lesions produced a 35% reduction of high-affinity 3 H-nicotine-binding sites, with no change in binding affinity. Bilateral habenular lesions reduced 125 I-BTX labeling in the intermediate subnuclei, and a slight increase occurred in the rostral subnucleus. In the lateral subnuclei, 125 I-BTX labeling was significantly reduced (27%) at 3 days but not at later survival times. In view of the known synaptic morphology of the habenulointerpeduncular tract, it is concluded that a subpopulation of 3 H-nicotine binding sites within the IPN is located on afferent axons and/or terminals. This subpopulation, located within rostral, intermediate, and lateral subnuclei, may correspond to presynaptic nicotinic cholinergic receptors. Sites that bind 125 I-BTX may include a presynaptic subpopulation located in the lateral and possibly the intermediate subnuclei

  14. Reduced type II interleukin-4 receptor signalling drives initiation, but not progression, of colorectal carcinogenesis: evidence from transgenic mouse models and human case?control epidemiological observations

    OpenAIRE

    Ingram, Nicola; Northwood, Emma L.; Perry, Sarah L.; Marston, Gemma; Snowden, Helen; Taylor, John C.; Scott, Nigel; Bishop, D. Timothy; Coletta, P. Louise; Hull, Mark A.

    2013-01-01

    We investigated the role of interleukin (IL)-4 receptor (IL-4R) signalling during mouse carcinogen-induced colorectal carcinogenesis and in a case-control genetic epidemiological study of IL-4Rα single nucleotide polymorphisms (SNPs). Azoxymethane-induced aberrant crypt focus (ACF; 6 weeks) and tumours (32 weeks) were analysed in wild-type (WT) BALB/c mice, as well as in IL-4Rα (-) (/-) , IL-13 (-/-) and 'double-knockout' (DKO) animals. Colorectal cancer (CRC) cases (1502) and controls (584) ...

  15. The Selective Angiotensin II Type 2 Receptor Agonist, Compound 21, Attenuates the Progression of Lung Fibrosis and Pulmonary Hypertension in an Experimental Model of Bleomycin-Induced Lung Injury.

    Science.gov (United States)

    Rathinasabapathy, Anandharajan; Horowitz, Alana; Horton, Kelsey; Kumar, Ashok; Gladson, Santhi; Unger, Thomas; Martinez, Diana; Bedse, Gaurav; West, James; Raizada, Mohan K; Steckelings, Ulrike M; Sumners, Colin; Katovich, Michael J; Shenoy, Vinayak

    2018-01-01

    Idiopathic Pulmonary Fibrosis (IPF) is a chronic lung disease characterized by scar formation and respiratory insufficiency, which progressively leads to death. Pulmonary hypertension (PH) is a common complication of IPF that negatively impacts clinical outcomes, and has been classified as Group III PH. Despite scientific advances, the dismal prognosis of IPF and associated PH remains unchanged, necessitating the search for novel therapeutic strategies. Accumulating evidence suggests that stimulation of the angiotensin II type 2 (AT 2 ) receptor confers protection against a host of diseases. In this study, we investigated the therapeutic potential of Compound 21 (C21), a selective AT 2 receptor agonist in the bleomycin model of lung injury. A single intra-tracheal administration of bleomycin (2.5 mg/kg) to 8-week old male Sprague Dawley rats resulted in lung fibrosis and PH. Two experimental protocols were followed: C21 was administered (0.03 mg/kg/day, ip) either immediately (prevention protocol, BCP) or after 3 days (treatment protocol, BCT) of bleomycin-instillation. Echocardiography, hemodynamic, and Fulton's index assessments were performed after 2 weeks of bleomycin-instillation. Lung tissue was processed for gene expression, hydroxyproline content (a marker of collagen deposition), and histological analysis. C21 treatment prevented as well as attenuated the progression of lung fibrosis, and accompanying PH. The beneficial effects of C21 were associated with decreased infiltration of macrophages in the lungs, reduced lung inflammation and diminished pulmonary collagen accumulation. Further, C21 treatment also improved pulmonary pressure, reduced muscularization of the pulmonary vessels and normalized cardiac function in both the experimental protocols. However, there were no major differences in any of the outcomes measured from the two experimental protocols. Collectively, our findings indicate that stimulation of the AT 2 receptor by C21 attenuates

  16. The Selective Angiotensin II Type 2 Receptor Agonist, Compound 21, Attenuates the Progression of Lung Fibrosis and Pulmonary Hypertension in an Experimental Model of Bleomycin-Induced Lung Injury

    Directory of Open Access Journals (Sweden)

    Anandharajan Rathinasabapathy

    2018-03-01

    Full Text Available Idiopathic Pulmonary Fibrosis (IPF is a chronic lung disease characterized by scar formation and respiratory insufficiency, which progressively leads to death. Pulmonary hypertension (PH is a common complication of IPF that negatively impacts clinical outcomes, and has been classified as Group III PH. Despite scientific advances, the dismal prognosis of IPF and associated PH remains unchanged, necessitating the search for novel therapeutic strategies. Accumulating evidence suggests that stimulation of the angiotensin II type 2 (AT2 receptor confers protection against a host of diseases. In this study, we investigated the therapeutic potential of Compound 21 (C21, a selective AT2 receptor agonist in the bleomycin model of lung injury. A single intra-tracheal administration of bleomycin (2.5 mg/kg to 8-week old male Sprague Dawley rats resulted in lung fibrosis and PH. Two experimental protocols were followed: C21 was administered (0.03 mg/kg/day, ip either immediately (prevention protocol, BCP or after 3 days (treatment protocol, BCT of bleomycin-instillation. Echocardiography, hemodynamic, and Fulton's index assessments were performed after 2 weeks of bleomycin-instillation. Lung tissue was processed for gene expression, hydroxyproline content (a marker of collagen deposition, and histological analysis. C21 treatment prevented as well as attenuated the progression of lung fibrosis, and accompanying PH. The beneficial effects of C21 were associated with decreased infiltration of macrophages in the lungs, reduced lung inflammation and diminished pulmonary collagen accumulation. Further, C21 treatment also improved pulmonary pressure, reduced muscularization of the pulmonary vessels and normalized cardiac function in both the experimental protocols. However, there were no major differences in any of the outcomes measured from the two experimental protocols. Collectively, our findings indicate that stimulation of the AT2 receptor by C21 attenuates

  17. A Single Base Pair Mutation Encoding a Premature Stop Codon in the MIS type II receptor is Responsible for Canine Persistent Müllerian Duct Syndrome

    Science.gov (United States)

    Wu, Xiufeng; Wan, Shengqin; Pujar, Shashikant; Haskins, Mark E.; Schlafer, Donald H.; Lee, Mary M.; Meyers-Wallen, Vicki N.

    2008-01-01

    Müllerian Inhibiting Substance (MIS), a secreted glycoprotein in the Transforming Growth Factor-beta (TGF-beta) family of growth factors, mediates regression of the Müllerian ducts during embryonic sex differentiation in males. In Persistent Müllerian Duct Syndrome (PMDS), rather than undergoing involution, the Müllerian ducts persist in males, giving rise to the uterus, Fallopian tubes, and upper vagina. Genetic defects in MIS or its receptor (MISRII) have been identified in patients with PMDS. The phenotype in the canine model of PMDS derived from the miniature schnauzer breed is strikingly similar to that of human patients. In this model, PMDS is inherited as a sex-limited autosomal recessive trait. Previous studies indicated that a defect in the MIS receptor or its downstream signaling pathway was likely to be causative of the canine syndrome. In this study the canine PMDS phenotype and clinical sequelae are described in detail. Affected and unaffected members of this pedigree are genotyped, identifying a single base pair substitution in MISRII that introduces a stop codon in exon 3. The homozygous mutation terminates translation at 80 amino acids, eliminating much of the extracellular domain and the entire transmembrane and intracellular signaling domains. Findings in this model may enable insights to be garnered from correlation of detailed clinical descriptions with molecular defects, which are not otherwise possible in the human syndrome. PMID:18723470

  18. Evaluation of folate receptor 1 (FOLR1) mRNA expression, its specific promoter methylation and global DNA hypomethylation in type I and type II ovarian cancers

    International Nuclear Information System (INIS)

    Notaro, Sara; Reimer, Daniel; Fiegl, Heidi; Schmid, Gabriel; Wiedemair, Annamarie; Rössler, Julia; Marth, Christian; Zeimet, Alain Gustave

    2016-01-01

    In this retrospective study we evaluated the respective correlations and clinical relevance of FOLR1 mRNA expression, FOLR1 promoter specific methylation and global DNA hypomethylation in type I and type II ovarian cancer. Two hundred fifty four ovarian cancers, 13 borderline tumours and 60 samples of healthy fallopian epithelium and normal ovarian epithelium were retrospectively analysed for FOLR1 expression with RT-PCR. FOLR1 DNA promoter methylation and global DNA hypomethylation (measured by means of LINE1 DNA hypomethylation) were evaluated with MethyLight technique. No correlation between FOLR1 mRNA expression and its specific promoter DNA methylation was found neither in type I nor in type II cancers, however, high FOLR1 mRNA expression was found to be correlated with global DNA hypomethylation in type II cancers (p = 0.033). Strong FOLR1 mRNA expression was revealed for Grades 2-3, FIGO stages III-IV, residual disease > 0, and serous histotype. High FOLR1 expression was found to predict increased platinum sensitivity in type I cancers (odds ratio = 3.288; 1.256-10.75; p = 0.020). One-year survival analysis showed in type I cancers an independent better outcome for strong expression of FOLR1 in FIGO stage III and IV. For the entire follow up period no significant independent outcome for FOLR1 expression was revealed. In type I cancers LINE 1 DNA hypomethylation was found to exhibit a worse PFS and OS which were confirmed to be independent in multivariate COX regression model for both PFS (p = 0.026) and OS (p = 0.012). No correlations were found between FOLR1 expression and its specific promoter methylation, however, high FOLR1 mRNA expression was associated with DNA hypomethylation in type II cancers. FOLR1 mRNA expression did not prove to predict clinical outcome in type II cancers, although strong FOLR1 expression generally denotes ovarian cancers with highly aggressive phenotype. In type I cancers, however, strong FOLR1 expression has been found to be a

  19. Anti-Fibrotic Effect of Losartan, an Angiotensin II Receptor Blocker, Is Mediated through Inhibition of ER Stress via Up-Regulation of SIRT1, Followed by Induction of HO-1 and Thioredoxin

    Directory of Open Access Journals (Sweden)

    Hyosang Kim

    2017-01-01

    Full Text Available Endoplasmic reticulum (ER stress is increasingly identified as modulator of fibrosis. Losartan, an angiotensin II receptor blocker, has been widely used as the first choice of treatment in chronic renal diseases. We postulated that anti-fibrotic effect of losartan is mediated through inhibition of ER stress via SIRT1 (silent mating type information regulation 2 homolog 1 hemeoxygenase-1 (HO-1/thioredoxin pathway. Renal tubular cells, tunicamycin (TM-induced ER stress, and unilateral ureteral obstruction (UUO mouse model were used. Expression of ER stress was assessed by Western blot analysis and immunohistochemical stain. ER stress was induced by chemical ER stress inducer, tunicamycin, and non-chemical inducers such as TGF-β, angiotensin II, high glucose, and albumin. Losartan suppressed the TM-induced ER stress, as shown by inhibition of TM-induced expression of GRP78 (glucose related protein 78 and p-eIF2α (phosphospecific-eukaryotic translation initiation factor-2α, through up-regulation of SIRT1 via HO-1 and thioredoxin. Losartan also suppressed the ER stress by non-chemical inducers. In both animal models, losartan reduced the tubular expression of GRP78, which were abolished by pretreatment with sirtinol (SIRT1 inhibitor. Sirtinol also blocked the inhibitory effect of losartan on the UUO-induced renal fibrosis. These findings provide new insights into renoprotective effects of losartan and suggest that SIRT1, HO-1, and thioredoxin may be potential pharmacological targets in kidney diseases under excessive ER stress condition.

  20. Monocyte galactose/N-acetylgalactosamine-specific C-type lectin receptor stimulant immunotherapy of an experimental glioma. Part II: combination with external radiation improves survival

    Directory of Open Access Journals (Sweden)

    Kushchayev SV

    2012-09-01

    Full Text Available Sergiy V Kushchayev,1 Tejas Sankar,1 Laura L Eggink,5,6 Yevgeniya S Kushchayeva,5 Philip C Wiener,1,5 J Kenneth Hoober,5,6 Jennifer Eschbacher,3 Ruolan Liu,2 Fu-Dong Shi,2 Mohammed G Abdelwahab,4 Adrienne C Scheck,4 Mark C Preul11Neurosurgery Research Laboratory, 2Neuroimmunology Laboratory, 3Department of Pathology, 4Neurooncology Research, Barrow Neurological Institute, St Joseph's Hospital and Medical Center, Phoenix, 5School of Life Sciences, Arizona State University, Tempe, 6Susavion Biosciences, Inc, Tempe, AZ, USABackground: A peptide mimetic of a ligand for the galactose/N-acetylgalactosamine-specific C-type lectin receptors (GCLR exhibited monocyte-stimulating activity, but did not extend survival when applied alone against a syngeneic murine malignant glioma. In this study, the combined effect of GCLRP with radiation was investigated.Methods: C57BL/6 mice underwent stereotactic intracranial implantation of GL261 glioma cells. Animals were grouped based on randomized tumor size by magnetic resonance imaging on day seven. One group that received cranial radiation (4 Gy on days seven and nine only were compared with animals treated with radiation and GCLRP (4 Gy on days seven and nine combined with subcutaneous injection of 1 nmol/g on alternative days beginning on day seven. Magnetic resonance imaging was used to assess tumor growth and correlated with survival rate. Blood and brain tissues were analyzed with regard to tumor and contralateral hemisphere using fluorescence-activated cell sorting analysis, histology, and enzyme-linked immunosorbent assay.Results: GCLRP activated peripheral monocytes and was associated with increased blood precursors of dendritic cells. Mean survival increased (P < 0.001 and tumor size was smaller (P < 0.02 in the GCLRP + radiation group compared to the radiation-only group. Accumulation of dendritic cells in both the tumoral hemisphere (P < 0.005 and contralateral tumor-free hemisphere (P< 0.01 was

  1. Seizures induced in immature rats by homocysteic acid and the associated brain damage are prevented by group II metabotropic glutamate receptor agonist (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate.

    Science.gov (United States)

    Folbergrová, Jaroslava; Druga, Rastislav; Otáhal, Jakub; Haugvicová, Renata; Mares, Pavel; Kubová, Hana

    2005-04-01

    The present study has examined the anticonvulsant and neuroprotective effect of group II metabotropic glutamate receptor (mGluR) agonist (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (2R,4R-APDC) in the model of seizures induced in immature 12-day-old rats by bilateral intracerebroventricular infusion of dl-homocysteic acid (DL-HCA, 600 nmol/side). For biochemical analyses, rat pups were sacrificed during generalized clonic-tonic seizures, approximately 45-50 min after infusion. Comparable time intervals were used for sacrificing the pups which had received 2R,4R-APDC. Low doses of 2R,4R-APDC (0.05 nmol/side) provided a pronounced anticonvulsant effect which was abolished by pretreatment with a selective group II mGluR antagonist LY341495. Generalized clonic-tonic seizures were completely suppressed and cortical energy metabolite changes which normally accompany these seizures were either normalized (decrease of glucose and glycogen) or markedly reduced (an accumulation of lactate). EEG recordings support the marked anticonvulsant effect of 2R,4R-APDC, nevertheless, this was only partial. In spite of the absence of obvious motor phenomena, isolated spikes or even short periods of partial ictal activity could be observed. Isolated spikes could also be seen in some animals after application of 2R,4R-APDC alone, reflecting most likely subclinical proconvulsant activity of this agonist. The neuroprotective effect of 2R,4R-APDC was evaluated after 24 h and 6 days of survival following DL-HCA-induced seizures. Massive neuronal degeneration, as revealed by Fluoro-Jade B staining, was observed in a number of brain regions following infusion of DL-HCA alone (seizure group), whereas 2R,4R-APDC pretreatment provided substantial neuroprotection. The present findings support the possibility that group II mGluRs are a promising target for a novel approach to treating epilepsy.

  2. Activation of Group II Metabotropic Glutamate Receptors Increases Proliferation but does not Influence Neuronal Differentiation of a Human Neural Stem Cell Line

    DEFF Research Database (Denmark)

    Dindler, Anne; Blaabjerg, Morten; Kamand, Morad

    2018-01-01

    of pharmacological activation and inhibition of mGluR2/3 on proliferation, differentiation and viability of a human neural stem cell line. Immunofluorescence staining revealed the presence of mGluR2/3 receptors on both proliferating and differentiating stem cells, including cells differentiated into β-tubulin III....... Western blot analysis revealed that the active, dimeric form of mGluR2/3 was mainly present on the proliferating cells, which may explain our findings. The present study emphasises the importance of glutamate and mGluRs on regulation of human neural stem cells and suggests a significant role of mGluR2....../3 during cell proliferation. This article is protected by copyright. All rights reserved....

  3. PvuII and XbaI polymorphisms of estrogen receptor-α and the results of estroprogestagen therapy in girls with functional hypothalamic amenorrhea - preliminary study.

    Science.gov (United States)

    Sowińska-Przepiera, Elżbieta; Syrenicz, Anhelli; Friebe, Zbigniew; Jarząbek-Bielecka, Grażyna; Chełstowski, Kornel

    2012-11-09

    The aim of this study was the long-term prospective evaluation of the effects of estroprogestagen (EP) therapy on the bone mineral density (BMD) of girls with functional hypothalamic amenorrhea (FHA) carrying various PvuII and XbaI polymorphisms of ER-α. Prospective observation included 84 FHA girls and 50 controls. The FHA patients were subjected to 4-year sequential therapy with 17β estradiol (2 mg from the 2(nd) to 25(th) day of the menstrual cycle) and dydrogesterone (10 mg from the 16(th) to the 25(th) day). Hormonal parameters, serum concentration of the bone fraction of alkaline phosphatase (BALP), urine concentration of cross-linked n-telopeptide of type I collagen (Ntx) and BMD were determined before and after the treatment. Six-month treatment resulted in a marked increase in estradiol (p = 0.001), testosterone and prolactin levels (p = 0.01 both) and a significant decrease in BALP and Ntx (p = 0.001 both). Patients with the PP polymorphism had significantly lower baseline BMD compared to carriers of other polymorphic variants of PvuII (p = 0.003). A significant increase in BMD was observed throughout the entire therapy period, with no significant differences in the yearly dynamics of BMD changes observed amongst various polymorphic variants and haplotypes of ER-α. The EP therapy is effective in the treatment of BMD disorders associated with FHA, and treatment results do not depend on PvuII and XbaI polymorphisms of ER-α.

  4. PvuII and XbaI polymorphisms of estrogen receptor-α and the results of estroprogestagen therapy in girls with functional hypothalamic amenorrhea – preliminary study

    Science.gov (United States)

    Syrenicz, Anhelli; Friebe, Zbigniew; Jarząbek-Bielecka, Grażyna; Chełstowski, Kornel

    2012-01-01

    Introduction The aim of this study was the long-term prospective evaluation of the effects of estroprogestagen (EP) therapy on the bone mineral density (BMD) of girls with functional hypothalamic amenorrhea (FHA) carrying various PvuII and XbaI polymorphisms of ER-α. Material and methods Prospective observation included 84 FHA girls and 50 controls. The FHA patients were subjected to 4-year sequential therapy with 17β estradiol (2 mg from the 2nd to 25th day of the menstrual cycle) and dydrogesterone (10 mg from the 16th to the 25th day). Hormonal parameters, serum concentration of the bone fraction of alkaline phosphatase (BALP), urine concentration of cross-linked n-telopeptide of type I collagen (Ntx) and BMD were determined before and after the treatment. Results Six-month treatment resulted in a marked increase in estradiol (p = 0.001), testosterone and prolactin levels (p = 0.01 both) and a significant decrease in BALP and Ntx (p = 0.001 both). Patients with the PP polymorphism had significantly lower baseline BMD compared to carriers of other polymorphic variants of PvuII (p = 0.003). A significant increase in BMD was observed throughout the entire therapy period, with no significant differences in the yearly dynamics of BMD changes observed amongst various polymorphic variants and haplotypes of ER-α. Conclusions The EP therapy is effective in the treatment of BMD disorders associated with FHA, and treatment results do not depend on PvuII and XbaI polymorphisms of ER-α. PMID:23185193

  5. Antigen presentation by hapten-specific B lymphocytes. II. Specificity and properties of antigen-presenting B lymphocytes, and function of immunoglobulin receptors

    International Nuclear Information System (INIS)

    Abbas, A.K.; Haber, S.; Rock, K.L.

    1985-01-01

    Studies were designed to examine the ability of hapten-binding murine B lymphocytes to present hapten-protein conjugates to protein antigen-specific, Ia-restricted T cell hybridomas. BALB/c B cells specific for TNP or FITC presented hapten-modified proteins (TNP-G1 phi, TNP-OVA, or FITC-OVA) to the relevant T cell hybridomas at concentrations below 0.1 microgram/ml. Effective presentation of the same antigens by B lymphocyte-depleted splenocytes, and of unmodified proteins by either hapten-binding B cells or Ig spleen cells, required about 10(3)-to 10(4)-fold higher concentrations of antigen. The use of two different haptens and two carrier proteins showed that this extremely efficient presentation of antigen was highly specific, with hapten specificity being a property of the B cells and carrier specificity of the responding T cells. The presentation of hapten-proteins by hapten-binding B lymphocytes was radiosensitive and was not affected by the depletion of plastic-adherent cells, suggesting that conventional APCs (macrophages or dendritic cells) are not required in this phenomenon. Antigen-pulsing and antibody-blocking experiments showed that this hapten-specific antigen presentation required initial binding of antigen to surface Ig receptors. Moreover, linked recognition of hapten and carrier determinants was required, but these recognition events could be temporally separated. Finally, an antigen-processing step was found to be necessary, and this step was disrupted by ionizing radiation. These data suggest a role for B cell surface Ig in providing a specific high-affinity receptor to allow efficient uptake or focusing of antigen for its subsequent processing and presentation to T lymphocytes

  6. Somatostatin receptor scintigraphy in advanced renal cell carcinoma. Results of a phase II-trial of somatostatine analogue therapy in patients with advanced RCC

    International Nuclear Information System (INIS)

    Freudenberg, L.S.; Goerges, R.; Stergar, H.; Bockisch, A.; Gauler, T.; Bauer, S.; Antoch, G.; Schuette, J.

    2008-01-01

    Aims: objective of this prospective study was to evaluate the role of somatostatin receptor scintigraphy (SRS) in advanced renal cell carcinoma (RCC) with respect to potential therapy with somatostatin analogue (SST-A) and to assess the response rate under therapy with SST-A. Patients, methods: 16 patients with documented progression of histologically confirmed advanced RCC were included. Planar whole-body SRS was performed 4, 24 and 48h post i.v. injection of 175-200 MBq 111 In-pentetreoide. 5 and 25 h p.i. SPECT of thorax and abdomen were performed. Documentation of somatostatin receptor expression via SRS in > 50% of known tumour lesions was the criteria for treatment start with SST-A (Sandostatin LAR registered -Depot 30mg i.m. every four weeks). Results: in 9/16 of the patients SRS showed at least one metastasis with moderate (n = 5) or intense (n = 4) tracer uptake. Lesion-based SRS evaluation showed only 12.1% (20/165) of all metastases. Most false-negative lesions were located in the lungs. In too patients, the majority of the known metastases was SRS positive and these patients received SST-A therapy. The first radiographic evaluation after a two-month interval showed progressive disease in both patients. Conclusions: we conclude that SRS is of limited value in staging of advanced RCC. In our patients SST-A did not result in a growth control of RCC. Consequently, the use of SST-A in advanced RCC seems to be no relevant therapeutic option. (orig.)

  7. Somatostatin receptors

    DEFF Research Database (Denmark)

    Møller, Lars Neisig; Stidsen, Carsten Enggaard; Hartmann, Bolette

    2003-01-01

    functional units, receptors co-operate. The total receptor apparatus of individual cell types is composed of different-ligand receptors (e.g. SRIF and non-SRIF receptors) and co-expressed receptor subtypes (e.g. sst(2) and sst(5) receptors) in characteristic proportions. In other words, levels of individual......-peptides, receptor agonists and antagonists. Relatively long half lives, as compared to those of the endogenous ligands, have been paramount from the outset. Motivated by theoretical puzzles or the shortcomings of present-day diagnostics and therapy, investigators have also aimed to produce subtype...

  8. Characterization of the human Activin-A receptor type II-like kinase 1 (ACVRL1 promoter and its regulation by Sp1

    Directory of Open Access Journals (Sweden)

    Botella Luisa M

    2010-06-01

    Full Text Available Abstract Background Activin receptor-like kinase 1 (ALK1 is a Transforming Growth Factor-β (TGF-β receptor type I, mainly expressed in endothelial cells that plays a pivotal role in vascular remodelling and angiogenesis. Mutations in the ALK1 gene (ACVRL1 give rise to Hereditary Haemorrhagic Telangiectasia, a dominant autosomal vascular dysplasia caused by a haploinsufficiency mechanism. In spite of its patho-physiological relevance, little is known about the transcriptional regulation of ACVRL1. Here, we have studied the different origins of ACVRL1 transcription, we have analyzed in silico its 5'-proximal promoter sequence and we have characterized the role of Sp1 in the transcriptional regulation of ACVRL1. Results We have performed a 5'Rapid Amplification of cDNA Ends (5'RACE of ACVRL1 transcripts, finding two new transcriptional origins, upstream of the one previously described, that give rise to a new exon undiscovered to date. The 5'-proximal promoter region of ACVRL1 (-1,035/+210 was analyzed in silico, finding that it lacks TATA/CAAT boxes, but contains a remarkably high number of GC-rich Sp1 consensus sites. In cells lacking Sp1, ACVRL1 promoter reporters did not present any significant transcriptional activity, whereas increasing concentrations of Sp1 triggered a dose-dependent stimulation of its transcription. Moreover, silencing Sp1 in HEK293T cells resulted in a marked decrease of ACVRL1 transcriptional activity. Chromatin immunoprecipitation assays demonstrated multiple Sp1 binding sites along the proximal promoter region of ACVRL1 in endothelial cells. Furthermore, demethylation of CpG islands, led to an increase in ACVRL1 transcription, whereas in vitro hypermethylation resulted in the abolishment of Sp1-dependent transcriptional activation of ACVRL1. Conclusions Our results describe two new transcriptional start sites in ACVRL1 gene, and indicate that Sp1 is a key regulator of ACVRL1 transcription, providing new insights into

  9. Angiotensin II type 1 receptor blockade partially attenuates hypoxia-induced pulmonary hypertension in newborn piglets: relationship with the nitrergic system

    Energy Technology Data Exchange (ETDEWEB)

    Camelo, J.S. Jr. [Departamento de Puericultura e Pediatria, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP (Brazil); Martins, A.R. [Departamento de Farmacologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP (Brazil); Instituto de Ciências Biológicas, Universidade Federal do Triângulo Mineiro, Uberaba, MG (Brazil); Rosa, E. [Departamento de Farmacologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP (Brazil); Ramos, S.G. [Departamento de Patologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SPBrasil (Brazil); Hehre, D.; Bancalari, E.; Suguihara, C. [Department of Pediatrics, Division of Neonatology, Neonatal Developmental Biology Laboratory, University of Miami Miller School of Medicine, Miami, FL (United States)

    2012-02-10

    The objective of this study was to observe possible interactions between the renin-angiotensin and nitrergic systems in chronic hypoxia-induced pulmonary hypertension in newborn piglets. Thirteen chronically instrumented newborn piglets (6.3 ± 0.9 days; 2369 ± 491 g) were randomly assigned to receive saline (placebo, P) or the AT{sub 1} receptor (AT{sub 1}-R) blocker L-158,809 (L) during 6 days of hypoxia (FiO{sub 2} = 0.12). During hypoxia, pulmonary arterial pressure (Ppa; P < 0.0001), pulmonary vascular resistance (PVR; P < 0.02) and the pulmonary to systemic vascular resistance ratio (PVR/SVR; P < 0.05) were significantly attenuated in the L (N = 7) group compared to the P group (N = 6). Western blot analysis of lung proteins showed a significant decrease of endothelial NOS (eNOS) in both P and L animals, and of AT{sub 1}-R in P animals during hypoxia compared to normoxic animals (C group, N = 5; P < 0.01 for all groups). AT{sub 1}-R tended to decrease in L animals. Inducible NOS (iNOS) did not differ among P, L, and C animals and iNOS immunohistochemical staining in macrophages was significantly more intense in L than in P animals (P < 0.01). The vascular endothelium showed moderate or strong eNOS and AT{sub 1}-R staining. Macrophages and pneumocytes showed moderate or strong iNOS and AT{sub 1}-R staining, but C animals showed weak iNOS and AT{sub 1}-R staining. Macrophages of L and P animals showed moderate and weak AT{sub 2}-R staining, respectively, but the endothelium of all groups only showed weak staining. In conclusion, pulmonary hypertension induced by chronic hypoxia in newborn piglets is partially attenuated by AT{sub 1}-R blockade. We suggest that AT{sub 1}-R blockade might act through AT{sub 2}-R and/or Mas receptors and the nitrergic system in the lungs of hypoxemic newborn piglets.

  10. Experimental pain ratings and reactivity of cortisol and soluble tumor necrosis factor-α receptor II following a trial of hypnosis: Results of a randomized controlled pilot study

    Science.gov (United States)

    Goodin, Burel R.; Quinn, Noel B.; Kronfli, Tarek; King, Christopher D.; Page, Gayle G.; Haythornthwaite, Jennifer A.; Edwards, Robert R.; Stapleton, Laura M.; McGuire, Lynanne

    2011-01-01

    Objective Current evidence supports the efficacy of hypnosis for reducing the pain associated with experimental stimulation and various acute and chronic conditions; however, the mechanisms explaining how hypnosis exerts its effects remain less clear. The hypothalamic-pituitary-adrenal (HPA) axis and pro-inflammatory cytokines represent potential targets for investigation given their purported roles in the perpetuation of painful conditions; yet, no clinical trials have thus far examined the influence of hypnosis on these mechanisms. Design Healthy participants, highly susceptible to the effects of hypnosis, were randomized to either a hypnosis intervention or a no-intervention control. Using a cold pressor task, assessments of pain intensity and pain unpleasantness were collected prior to the intervention (Pre) and following the intervention (Post) along with pain-provoked changes in salivary cortisol and the soluble receptor of tumor necrosis factor-α (sTNFαRII). Results Compared to the no-intervention control, data analyses revealed that hypnosis significantly reduced pain intensity and pain unpleasantness. Hypnosis was not significantly associated with suppression of cortisol or sTNFαRII reactivity to acute pain from Pre to Post; however, the effect sizes for these associations were medium-sized. Conclusions Overall, the findings from this randomized controlled pilot study support the importance of a future large-scale study on the effects of hypnosis for modulating pain-related changes of the HPA axis and pro-inflammatory cytokines. PMID:22233394

  11. TNF-alpha, produced by feline infectious peritonitis virus (FIPV)-infected macrophages, upregulates expression of type II FIPV receptor feline aminopeptidase N in feline macrophages.

    Science.gov (United States)

    Takano, Tomomi; Hohdatsu, Tsutomu; Toda, Ayako; Tanabe, Maki; Koyama, Hiroyuki

    2007-07-20

    The pathogenicity of feline infectious peritonitis virus (FIPV) is known to depend on macrophage tropism, and this macrophage infection is enhanced by mediation via anti-S antibody (antibody-dependent enhancement, ADE). In this study, we found that TNF-alpha production was increased with viral replication in macrophages inoculated with a mixture of FIPV and anti-S antibody, and demonstrated that this culture supernatant had feline PBMC apoptosis-inducing activity. We also demonstrated that the expression level of the FIPV virus receptor, feline aminopeptidase N (fAPN), was increased in macrophages of FIP cats. For upregulation of TNF-alpha and fAPN in macrophages, viral replication in macrophages is necessary, and their expressions were increased by ADE of FIPV infection. It was demonstrated that a heat-resistant fAPN-inducing factor was present in the culture supernatant of FIPV-infected macrophages, and this factor was TNF-alpha: fAPN expression was upregulated in recombinant feline TNF-alpha-treated macrophages, and FIPV infectivity was increased in these macrophages. These findings suggested that FIPV replication in macrophages increases TNF-alpha production in macrophages, and the produced TNF-alpha acts and upregulates fAPN expression, increasing FIPV sensitivity.

  12. Comparative effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on the risk of pneumonia and severe exacerbations in patients with COPD

    Directory of Open Access Journals (Sweden)

    Lai CC

    2018-03-01

    Full Text Available Chih-Cheng Lai,1 Ya-Hui Wang,2 Cheng-Yi Wang,3 Hao-Chien Wang,4 Chong-Jen Yu,4 Likwang Chen5 On behalf of the Taiwan Clinical Trial Consortium for Respiratory Diseases (TCORE 1Department of Intensive Care Medicine, Chi Mei Medical Center, Liouying, Taiwan; 2Medical Research Center, Cardinal Tien Hospital and School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan; 3Department of Internal Medicine, Cardinal Tien Hospital and School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan; 4Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan; 5Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan Objectives: This study aimed to compare the effects of angiotensin-converting-enzyme inhibitors (ACEis and angiotensin receptor blockers (ARBs on the risk of pneumonia and severe exacerbations in patients with COPD.Patients and methods: All patients with COPD who used ACEis and ARBs for >90 days between 2000 and 2005 were recruited. Pairwise matching (1:1 of the ACEi and ARB groups resulted in two similar subgroups, with 6,226 patients in each. The primary outcomes were pneumonia and COPD exacerbations, and the secondary outcome was death.Results: During the follow-up period, the incidence of pneumonia was 7.20 per 100 person-years in the ACEi group and 5.89 per 100 person-years in the ARB group. The ACEi group had a higher risk of pneumonia (adjusted hazard ratio [aHR], 1.22; 95% CI, 1.15–1.29 than the ARB group. The incidence of severe exacerbations was 0.65 per person-year for the patients receiving ACEis and 0.52 per person-year for those receiving ARBs. The patients receiving ACEis had a higher risk of severe exacerbations (aHR, 1.19; 95% CI, 1.16–1.21 than those receiving ARBs. Similar trends were noted in terms of severe exacerbations requiring

  13. Monitoring of chemotherapy successfulness of Platina/Taxol chemotherapy protocol by using determination of serum urokinase plasminogen activator (uPA and soluble urokinase plasminogen activator receptor (suPAR in patients with ovarian carcinoma FIGO II

    Directory of Open Access Journals (Sweden)

    Dženita Ljuca

    2007-05-01

    Full Text Available In about 70% of cases, ovarian carcinoma has been diagnosed at an advanced stage. Invasion and metastasis of solid tumors request protease activity resulting in basal membrane destruction and surrounding matrix. In that process, urokinase plasminogen activator (uPA and its receptor, urokinase plasminogen activator receptor (suPAR play a key role, that via plasmin activation lead to basal membrane and matrix degradation in surrounding of the tumor, enable to its invasion and metastasis. Determination of serum concentration of those tumor markers can be useful in preoperative as well as in postoperative period. Their serum concentrations in ovarian cancer patients may help in good monitoring of remission or progression during chemotherapy treatment. In late 1950s and eariy 1960s, when it was found out that malignant ovarian tumors were chemosensitive, their chemotherapy treatment has begun. In the beginning it was used only mono-therapy, and by discovering new cytostatics it was replaced by poly-chemotherapy. Now days, in the therapy of advanced stages of ovarian carcinoma combination of cisplatine or carboplatine with paclitaxel is considering as standard treatment. Aim of this study was to determine serum uPA, suPAR and CEA in FIGO II and III patients with different histo-logical type (serous, mucinous, clear cell tumor before and after PT chemotherapy protocol during following three cycles. In this prospective study we have analyzed 17 patients with ovarian carcinoma, those have been after surgery treated by chemotherapy. Serum levels of uPA and suPAR have been determined by ELISA-test (Imubind uPA, Imubind uPAR, American Diagnostica, and CEA by OPUS Imunoassay method. Results of this study have shown that uPA, suPAR and CEA met criteria for prognostic markers for monitoring of successful-ness of platina/taxol chemotherapy protocol for serous, mucinous and clear cell tumor FIGO II and III stage of ovarian carcinoma. In case of PT chemotherapy

  14. Customized chemotherapy based on epidermal growth factor receptor mutation status for elderly patients with advanced non-small-cell lung cancer: a phase II trial

    International Nuclear Information System (INIS)

    Fujita, Shiro; Mio, Tadashi; Katakami, Nobuyuki; Masago, Katsuhiro; Yoshioka, Hiroshige; Tomii, Keisuke; Kaneda, Toshihiko; Hirabayashi, Masataka; Kunimasa, Kei; Morizane, Toshio

    2012-01-01

    Elderly patients are more vulnerable to toxicity from chemotherapy. Activating epidermal growth factor receptor (EGFR) mutations in non-small-cell lung cancer (NSCLC) are associated with enhanced response to EGFR tyrosine-kinase inhibitors. We studied patients with advanced NSCLC for whom treatment was customized based on EGFR mutation status. We screened 57 chemotherapy-naïve patients with histologically or cytologically confirmed NSCLC, stage IIIB or IV, aged 70 years or older, and with an Eastern Cooperative Oncology Group performance status 0 or 1, for EGFR exon 19 codon 746–750 deletion and exon 21 L858R mutation. Twenty-two patients with EGFR mutations received gefitinib; 32 patients without mutations received vinorelbine or gemcitabine. The primary endpoint was the response rate. The response rate was 45.5% (95% confidence interval [CI]: 24.4%, 67.8%) in patients with EGFR mutations and 18.8% (95% CI: 7.2%, 36.4%) in patients without EGFR mutations. The median overall survival was 27.9 months (95%CI: 24.4 months, undeterminable months) in patients with EGFR mutations and 14.9 months (95%CI: 11.0 months, 22.4 months) in patients without EGFR mutations. In the gefitinib group, grade 3/4 hepatic dysfunction and dermatitis occurred in 23% and 5% of patients, respectively. In patients treated with vinorelbine or gemcitabine, the most common grade 3 or 4 adverse events were neutropenia (47%; four had febrile neutropenia), anemia (13%), and anorexia (9%). No treatment-related deaths occurred. Treatment customization based on EGFR mutation status deserves consideration, particularly for elderly patients who often cannot receive second-line chemotherapy due to poor organ function or comorbidities. This trial is registered at University hospital Medical Information Network-clinical trial registration (http://www.umin.ac.jp/ctr/index/htm) with the registration identification number C000000436

  15. Insulin receptors mediate growth effects in cultured fetal neurons. II. Activation of a protein kinase that phosphorylates ribosomal protein S6

    International Nuclear Information System (INIS)

    Heidenreich, K.A.; Toledo, S.P.

    1989-01-01

    As an initial attempt to identify early steps in insulin action that may be involved in the growth responses of neurons to insulin, we investigated whether insulin receptor activation increases the phosphorylation of ribosomal protein S6 in cultured fetal neurons and whether activation of a protein kinase is involved in this process. When neurons were incubated for 2 h with 32Pi, the addition of insulin (100 ng/ml) for the final 30 min increased the incorporation of 32Pi into a 32K microsomal protein. The incorporation of 32Pi into the majority of other neuronal proteins was unaltered by the 30-min exposure to insulin. Cytosolic extracts from insulin-treated neurons incubated in the presence of exogenous rat liver 40S ribosomes and [gamma-32P]ATP displayed a 3- to 8-fold increase in the phosphorylation of ribosomal protein S6 compared to extracts from untreated cells. Inclusion of cycloheximide during exposure of the neurons to insulin did not inhibit the increased cytosolic kinase activity. Activation of S6 kinase activity by insulin was dose dependent (seen at insulin concentration as low as 0.1 ng/ml) and reached a maximum after 20 min of incubation. Addition of phosphatidylserine, diolein, and Ca2+ to the in vitro kinase reaction had no effect on the phosphorylation of ribosomal protein S6. Likewise, treatment of neurons with (Bu)2cAMP did not alter the phosphorylation of ribosomal protein S6 by neuronal cytosolic extracts. We conclude that insulin activates a cytosolic protein kinase that phosphorylates ribosomal S6 in neurons and is distinct from protein kinase-C and cAMP-dependent protein kinase. Stimulation of this kinase may play a role in insulin signal transduction in neurons

  16. Neratinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor: results of a phase II trial in patients with advanced non-small-cell lung cancer.

    Science.gov (United States)

    Sequist, Lecia V; Besse, Benjamin; Lynch, Thomas J; Miller, Vincent A; Wong, Kwok K; Gitlitz, Barbara; Eaton, Keith; Zacharchuk, Charles; Freyman, Amy; Powell, Christine; Ananthakrishnan, Revathi; Quinn, Susan; Soria, Jean-Charles

    2010-06-20

    Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have had a significant impact on non-small-cell lung cancer (NSCLC) outcomes, particularly for patients with EGFR mutations. Resistance emerges after 9 to 12 months, primarily mediated by the T790M resistance mutation. We studied neratinib, an irreversible pan-ErbB TKI that may overcome T790M. Patients with advanced NSCLC underwent EGFR sequencing of available tumor tissue at enrollment. Those with > or = 12 weeks of prior TKI therapy were placed in arm A if they were EGFR mutation positive or arm B if they were wild-type. Arm C included TKI-naïve patients with adenocarcinoma and light smoking histories (neratinib, initially at 320 mg but subsequently reduced to 240 mg because of excessive diarrhea. The primary end point was objective response rate (RR). One-hundred sixty-seven patients were treated: 91 in arm A, 48 in arm B, and 28 in arm C. Diarrhea was the most common toxicity; grade 3 incidence was 50% at 320 mg but improved to 25% after dose reduction. The RR was 3% in arm A and zero in arms B and C. No patients with known T790M responded. Notably, three of four patients with an exon 18 G719X EGFR mutation had a partial response and the fourth had stable disease lasting 40 weeks. Neratinib had low activity in patients with prior benefit from TKIs and in TKI-naïve patients, potentially because of insufficient bioavailability from diarrhea-imposed dose limitation. Responses were seen in patients with the rare G719X EGFR mutation, highlighting the importance of obtaining comprehensive genetic information on trials of targeted agents.

  17. Downregulation of TGF-beta receptor types II and III in oral squamous cell carcinoma and oral carcinoma-associated fibroblasts

    International Nuclear Information System (INIS)

    Meng, Wenxia; Xia, Qingjie; Wu, Lanyan; Chen, Sixiu; He, Xin; Zhang, Lin; Gao, Qinghong; Zhou, Hongmei

    2011-01-01

    The purpose of this study was to assess the expression levels for TβRI, TβRII, and TβRIII in epithelial layers of oral premalignant lesions (oral leukoplakia, OLK) and oral squamous cell carcinoma (OSCC), as well as in oral carcinoma-associated fibroblasts (CAFs), with the final goal of exploring the roles of various types of TβRs in carcinogenesis of oral mucosa. Normal oral tissues, OLK, and OSCC were obtained from 138 previously untreated patients. Seven primary human oral CAF lines and six primary normal fibroblast (NF) lines were established successfully via cell culture. The three receptors were detected using immunohistochemical (IHC), quantitative RT-PCR, and Western blot approaches. IHC signals for TβRII and TβRIII in the epithelial layer decreased in tissue samples with increasing disease aggressiveness (P < 0.05); no expression differences were observed for TβRI, in OLK and OSCC (P > 0.05); and TβRII and TβRIII were significantly downregulated in CAFs compared with NFs, at the mRNA and protein levels (P < 0.05). Exogenous expression of TGF-β1 led to a remarkable decrease in the expression of TβRII and TβRIII in CAFs (P < 0.05). This study provides the first evidence that the loss of TβRII and TβRIII expression in oral epithelium and stroma is a common event in OSCC. The restoration of the expression of TβRII and TβRIII in oral cancerous tissues may represent a novel strategy for the treatment of oral carcinoma

  18. GABA receptors in the region of the dorsomedial hypothalamus of rats regulate anxiety in the elevated plus-maze test. II. Physiological measures.

    Science.gov (United States)

    Shekhar, A; Sims, L S; Bowsher, R R

    1993-11-05

    In the previous report, we had shown that blockade and enhancement of GABAA receptors in the DMH of rats increased or decreased the level of anxiety, respectively, as measured by the elevated plus-maze test. The present study was conducted to assess the effects of enhancing GABAA neurotransmission in the DMH of rats on the physiological concomitants of anxiety such as increases in heart rate (HR), blood pressure (BP) and plasma norepinephrine (NE) levels while the animals were placed on the elevated plus-maze. Male Sprague-Dawley rats were equipped with arterial and venous catheters and stereotaxically implanted with microinjection cannulae in the cardiostimulatory region of the DMH where injection of bicuculline methiodide (BMI) elicited increases in heart rate under anesthesia. After recovery, rats were injected with either saline or the GABAA agonist muscimol and their HR, BP and plasma NE responses were measured when confined in the open or the closed arm of the elevated plus-maze. Injection of muscimol into the DMH reduced the increases seen in HR, BP and plasma NE when the rats were confined to either the closed or the open arms in addition to decreasing 'anxiety' in the plus-maze. Injection of muscimol into the areas of the hypothalamus surrounding the DMH did not significantly affect the changes in HR, BP and plasma NE in the plus-maze. Blocking the changes in HR and BP elicited by microinjecting GABAergic drugs into the DMH of rats, with systemic injections of a combination of atropine and the beta-blocker atenolol, did not block the behavioral effects of the GABAergic drugs in the plus-maze test.

  19. Complete reversal of muscle wasting in experimental cancer cachexia: Additive effects of activin type II receptor inhibition and β-2 agonist.

    Science.gov (United States)

    Toledo, Míriam; Busquets, Sílvia; Penna, Fabio; Zhou, Xiaolan; Marmonti, Enrica; Betancourt, Angelica; Massa, David; López-Soriano, Francisco J; Han, H Q; Argilés, Josep M

    2016-04-15

    Formoterol is a highly potent β2-adrenoceptor-selective agonist, which is a muscle growth promoter in many animal species. Myostatin/activin inhibition reverses skeletal muscle loss and prolongs survival of tumor-bearing animals. The aim of this investigation was to evaluate the effects of a combination of the soluble myostatin receptor ActRIIB (sActRIIB) and the β2-agonist formoterol in the cachectic Lewis lung carcinoma model. The combination of formoterol and sActRIIB was extremely effective in reversing muscle wasting associated with experimental cancer cachexia in mice. Muscle weights from tumor-bearing animals were completely recovered following treatment and this was also reflected in the measured grip strength. This combination increased food intake in both control and tumor-bearing animals. The double treatment also prolonged survival significantly without affecting the weight and growth of the primary tumor. In addition, it significantly reduced the number of metastasis. Concerning the mechanisms for the preservation of muscle mass during cachexia, the effects of formoterol and sActRIIB seemed to be additive, since formoterol reduced the rate of protein degradation (as measured in vitro as tyrosine release, using incubated isolated individual muscles) while sActRIIB only affected protein synthesis (as measured in vivo using tritiated phenylalanine). Formoterol also increased the rate of protein synthesis and this seemed to be favored by the presence of sActRIIB. Combining formoterol and sActRIIB seemed to be a very promising treatment for experimental cancer cachexia. Further studies in human patients are necessary and may lead to a highly effective treatment option for muscle wasting associated with cancer. © 2015 UICC.

  20. Low density lipoprotein receptor gene Ava II polymorphism and serum lipid levels in the Guangxi Bai Ku Yao and Han populations

    Directory of Open Access Journals (Sweden)

    Wu Dong-Feng

    2011-02-01

    Full Text Available Abstract Background Several common genetic polymorphisms in the low density lipoprotein receptor (LDL-R gene have associated with modifications of serum total cholesterol (TC and low density lipoprotein cholesterol (LDL-C levels, but the results are not consistent in different populations. Bai Ku Yao is a special subgroup of the Yao minority in China. The present study was undertaken to detect the association of LDL-R gene Ava Ⅱ polymorphism and serum lipid levels in the Guangxi Bai Ku Yao and Han populations. Methods A total of 1024 subjects of Bai Ku Yao and 792 participants of Han Chinese were randomly selected from our previous stratified randomized cluster samples. Genotyping of the LDL-R gene Ava Ⅱ polymorphism was performed by polymerase chain reaction and restriction fragment length polymorphism combined with gel electrophoresis, and then confirmed by direct sequencing. Results The levels of serum TC, high density lipoprotein cholesterol (HDL-C, LDL-C, apolipoprotein (Apo A1 and the ratio of ApoA1 to ApoB were lower in Bai Ku Yao than in Han (P - and A+ alleles was 65.5% and 34.5% in Bai Ku Yao, and 80.7% and 19.3% in Han (P -A-, A-A+ and A+A+ genotypes was 42.6%, 45.9% and 11.5% in Bai Ku Yao, and 64.9%, 31.6% and 3.5% in Han (P P 3.20 mmol/L subgroups in Bai Ku Yao (P P P P +A+ genotype had higher serum LDL-C, TC, HDL-C or ApoA1 levels than the subjects with A-A+ and A-A- genotypes. Spearman rank correlation analysis revealed that the levels of LDL-C in Bai Ku Yao and HDL-C in Han were correlated with genotypes (P P Conclusions The association of LDL-R gene Ava Ⅱ polymorphism and serum lipid levels is different between the Bai Ku Yao and Han populations. The discrepancy might partly result from different LDL-R gene Ava Ⅱ polymorphism or LDL-R gene-enviromental interactions.

  1. Effects of stimulation of soluble guanylate cyclase on diabetic nephropathy in diabetic eNOS knockout mice on top of angiotensin II receptor blockade.

    Directory of Open Access Journals (Sweden)

    Ina M Ott

    Full Text Available The prevalence of diabetes mellitus and its complications, such as diabetic nephropathy (DN, is rising worldwide and prevention and treatment are therefore becoming increasingly important. Therapy of DN is particularly important for patients who do not adequately respond to angiotensin receptor blocker (ARB treatment. Novel approaches include the stimulation of soluble guanylate cyclase (sGC as it is reported to have beneficial effects on cardiac and renal damage. We aimed to investigate the effects of the sGC stimulator riociguat and ARB telmisartan on kidney function and structure in a hypertensive model of diabetic nephropathy. Seventy-six diabetic male eNOS knockout C57BL/6J mice were randomly divided after having received streptozotocin: telmisartan (1 mg/kg/d, riociguat (3 mg/kg/d, riociguat+telmisartan (3+1 mg/kg/d, and vehicle. Fourteen mice were used as non-diabetic controls. Treatment duration was 11 weeks. Glucose concentrations were increased and similar in all diabetic groups. Telmisartan insignificantly reduced blood pressure by 5.9 mmHg compared with diabetic controls (111.2±2.3 mmHg vs. 117.1±2.2 mmHg; p = 0.071. Treatment with riociguat both alone and in combination with telmisartan led to a significant reduction of blood pressure towards diabetic vehicle (105.2±2.5 mmHg and 105.0±3.2 mmHg, respectively, vs. 117.1±2.2 mmHg. Combined treatment also significantly decreased albuminuria compared with diabetic controls (47.3±9.6 µg/24 h vs. 170.8±34.2 µg/24 h; p = 0.002 reaching levels similar to those of non-diabetic controls (34.4±10.6 µg/24 h, whereas the reduction by single treatment with either telmisartan (97.8±26.4 µg/24 h or riociguat (97.1±15.7 µg/24 h was not statistically significant. The combination treatment led to a significant (p<0.01 decrease of tissue immunoreactivity of malondialdehyde, as consequence of reduced oxidative stress. In conclusion, stimulation of sGC significantly reduced urinary

  2. Exposure to 3,3',5-triiodothyronine affects histone and RNA polymerase II modifications, but not DNA methylation status, in the regulatory region of the Xenopus laevis thyroid hormone receptor βΑ gene.

    Science.gov (United States)

    Kasai, Kentaro; Nishiyama, Norihito; Izumi, Yushi; Otsuka, Shunsuke; Ishihara, Akinori; Yamauchi, Kiyoshi

    2015-11-06

    Thyroid hormones (THs) play a critical role in amphibian metamorphosis, during which the TH receptor (TR) gene, thrb, is upregulated in a tissue-specific manner. The Xenopus laevis thrb gene has 3 TH response elements (TREs) in the 5' flanking regulatory region and 1 TRE in the exon b region, around which CpG sites are highly distributed. To clarify whether exposure to 3,3',5-triiodothyronine (T3) affects histone and RNA polymerase II (RNAPII) modifications and the level of DNA methylation in the 5' regulatory region, we conducted reverse transcription-quantitative polymerase chain reaction, bisulfite sequencing and chromatin immunoprecipitation assay using X. laevis cultured cells and premetamorphic tadpoles treated with or without 2 nM T3. Exposure to T3 increased the amount of the thrb transcript, in parallel with enhanced histone H4 acetylation and RNAPII recruitment, and probably phosphorylation of RNAPII at serine 5, in the 5' regulatory and exon b regions. However, the 5' regulatory region remained hypermethylated even with exposure to T3, and there was no significant difference in the methylation status between DNAs from T3-untreated and -treated cultured cells or tadpole tissues. Our results demonstrate that exposure to T3 induced euchromatin-associated epigenetic marks by enhancing histone acetylation and RNAPII recruitment, but not by decreasing the level of DNA methylation, in the 5' regulatory region of the X. laevis thrb gene. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. Association of Angiotensin-Converting Enzyme Intron 16 Insertion/Deletion and Angiotensin II Type 1 Receptor A1166C Gene Polymorphisms with Preeclampsia in South East of Iran

    Directory of Open Access Journals (Sweden)

    Saeedeh Salimi

    2011-01-01

    Full Text Available Some evidence suggests that a variety of genetic factors contributed in pathogenesis of the preeclampsia. The aim of this study was to assess the association between the angiotensin-converting enzyme (ACE I/D and angiotensin II type1 receptor A1166C polymorphisms with preeclampsia. This study was performed in 125 preeclamptic pregnant women and 132 controls. The I/D Polymorphism of the ACE gene was assessed by polymerase chain reaction and the A1166C Polymorphism of the AT1R gene was determined by restriction fragment length polymorphism. The genotype and allele frequencies of I/D polymorphism differed between two groups. The risk of preeclampsia was 3.2-fold in pregnant women with D allele (OR, 3.2 [95% CI, 1.1 to 3.8]; P=0.01. The distribution of the AT1R gene A1166C polymorphism was similar in affected and control groups. Our results supported that presence of the I/D polymorphism of ACE gene is a marker for the increased risk of preeclampsia.

  4. Occurrence and fate of the angiotensin II receptor antagonist transformation product valsartan acid in the water cycle--a comparative study with selected β-blockers and the persistent anthropogenic wastewater indicators carbamazepine and acesulfame.

    Science.gov (United States)

    Nödler, Karsten; Hillebrand, Olav; Idzik, Krzysztof; Strathmann, Martin; Schiperski, Ferry; Zirlewagen, Johannes; Licha, Tobias

    2013-11-01

    The substantial transformation of the angiotensin II receptor antagonist valsartan to the transformation product 2'-(2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-carboxylic acid (referred to as valsartan acid) during the activated sludge process was demonstrated in the literature and confirmed in the here presented study. However, there was a severe lack of knowledge regarding the occurrence and fate of this compound in surface water and its behavior during drinking water treatment. In this work a comparative study on the occurrence and persistency of valsartan acid, three frequently used β-blockers (metoprolol, atenolol, and sotalol), atenolol acid (one significant transformation product of atenolol and metoprolol), and the two widely distributed persistent anthropogenic wastewater indicators carbamazepine and acesulfame in raw sewage, treated wastewater, surface water, groundwater, and tap water is presented. Median concentrations of valsartan acid in the analyzed matrices were 101, 1,310, 69, waters valsartan acid was found just as relevant as the analyzed β-blockers and the anticonvulsant carbamazepine. Regarding its persistency in surface waters it was comparable to carbamazepine and acesulfame. Furthermore, removal of valsartan acid during bank filtration was poor, which demonstrated the relevance of this compound for drinking water suppliers. Regarding drinking water treatment (Muelheim Process) the compound was resistant to ozonation but effectively eliminated (≥90%) by subsequent activated carbon filtration. However, without applying activated carbon filtration the compound may enter the drinking water distribution system as it was demonstrated for Berlin tap water. Copyright © 2013 Elsevier Ltd. All rights reserved.

  5. Discovery of a Significant Acetone•Hydroperoxy Adduct Chaperone Effect and Its Impact on the Determination of Room Temperature Rate Constants for Acetonylperoxy/Hydroperoxy Self-Reactions and Cross Reaction Via Infrared Kinetic Spectroscopy.

    Science.gov (United States)

    Grieman, F. J.; Hui, A. O.; Okumura, M.; Sander, S. P.

    2017-12-01

    In order to model the upper troposphere/lower stratosphere in regions containing acetone properly, the kinetics of the acetonylperoxy/hydroperoxy self-reactions and cross reaction have been studied over a wide temperature range using Infrared Kinetic Spectroscopy. We report here the determination of different rate constants for the acetonylperoxy chemistry that we obtained at 298 K compared to currently accepted values. A considerable increase in the observed HO2 self-reaction rate constant due to rate enhancement via the chaperone effect from the reaction between HO2 and the (CH3)2CO•HO2 hydrogen-bonded adduct, even at room temperature, was discovered that was previously ignored. Correct determination of the acetonylperoxy and hydroperoxy kinetics must include this dependence of the HO2 self-reaction rate on acetone concentration. Via excimer laser flash photolysis to create the radical reactants, HO2 absorption was monitored in the infrared by diode laser wavelength modulation detection simultaneously with CH3C(O)CH2O2absorption monitored in the ultraviolet at 300 nm as a function of time. Resulting decay curves were fit concurrently first over a short time scale to obtain the rate constants minimizing subsequent product reactions. Modeling/fitting with a complete reaction scheme was then performed to refine the rate constants and test their veracity. Experiments were carried out over a variety of concentrations of acetone and methanol. Although no effect due to methanol concentration was found at room temperature, the rate constant for the hydroperoxy self-reaction was found to increase linearly with acetone concentration which is interpreted as the adduct being formed and resulting in a chaperone mechanism that enhances the self-reaction rate: (CH3)2CO·HO2 + HO2 → H2O2 + O2 + (CH3)2CO Including this effect, the resulting room temperature rate constants for the cross reaction and the acetonylperoxy self-reaction were found to be 2-3 times smaller than

  6. Metformin and insulin receptors

    International Nuclear Information System (INIS)

    Vigneri, R.; Gullo, D.; Pezzino, V.

    1984-01-01

    The authors evaluated the effect of metformin (N,N-dimethylbiguanide), a biguanide known to be less toxic than phenformin, on insulin binding to its receptors, both in vitro and in vivo. Specific 125 I-insulin binding to cultured IM-9 human lymphocytes and MCF-7 human breast cancer cells was determined after preincubation with metformin. Specific 125 I-insulin binding to circulating monocytes was also evaluated in six controls, eight obese subjects, and six obese type II diabetic patients before and after a short-term treatment with metformin. Plasma insulin levels and blood glucose were also measured on both occasions. Metformin significantly increased insulin binding in vitro to both IM-9 lymphocytes and MCF-7 cells; the maximum increment was 47.1% and 38.0%, respectively. Metformin treatment significantly increased insulin binding in vivo to monocytes of obese subjects and diabetic patients. Scatchard analysis indicated that the increased binding was mainly due to an increase in receptor capacity. Insulin binding to monocytes of normal controls was unchanged after metformin as were insulin levels in all groups; blood glucose was significantly reduced after metformin only in diabetic patients. These data indicate that metformin increases insulin binding to its receptors in vitro and in vivo. The effect in vivo is observed in obese subjects and in obese type II diabetic patients, paralleling the clinical effectiveness of this antidiabetic agent, and is not due to receptor regulation by circulating insulin, since no variation in insulin levels was recorded

  7. TEMPO/viologen electrochemical heterojunction for diffusion-controlled redox mediation: a highly rectifying bilayer-sandwiched device based on cross-reaction at the interface between dissimilar redox polymers.

    Science.gov (United States)

    Tokue, Hiroshi; Oyaizu, Kenichi; Sukegawa, Takashi; Nishide, Hiroyuki

    2014-03-26

    A couple of totally reversible redox-active molecules, which are different in redox potentials, 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) and viologen (V(2+)), were employed to give rise to a rectified redox conduction effect. Single-layer and bilayer devices were fabricated using polymers containing these sites as pendant groups per repeating unit. The devices were obtained by sandwiching the redox polymer layer(s) with indium tin oxide (ITO)/glass and Pt foil electrodes. Electrochemical measurements of the single-layer device composed of polynorbornene-bearing TEMPO (PTNB) exhibited a diffusion-limited current-voltage response based on the TEMPO(+)/TEMPO exchange reaction, which was almost equivalent to a redox gradient through the PTNB layer depending upon the thickness. The bilayer device gave rise to the current rectification because of the thermodynamically favored cross-reaction between TEMPO(+) and V(+) at the polymer/polymer interface. A current-voltage response obtained for the bilayer device demonstrated a two-step diffusion-limited current behavior as a result of the concurrent V(2+)/V(+) and V(+)/V(0) exchange reactions according to the voltage and suggested that the charge transport process through the device was most likely to be rate-determined by a redox gradient in the polymer layer. Current collection experiments revealed a charge transport balance throughout the device, as a result of the electrochemical stability and robustness of the polymers in both redox states.

  8. Receptor assay

    Energy Technology Data Exchange (ETDEWEB)

    Kato, K; Ibayashi, H [Kyushu Univ., Fukuoka (Japan). Faculty of Medicine

    1975-05-01

    This paper summarized present status and problems of analysis of hormone receptor and a few considerations on clinical significance of receptor abnormalities. It was pointed that in future clinical field quantitative and qualitative analysis of receptor did not remain only in the etiological discussion, but that it was an epoch-making field of investigation which contained the possiblity of artificial change of sensitivity of living body on drugs and the development connected directly with treatment of various diseases.

  9. New polymorphisms of the angiotensin II type 1 receptor gene and their associations with myocardial infarction and blood pressure: the ECTIM study. Etude Cas-Témoin de l'Infarctus du Myocarde.

    Science.gov (United States)

    Poirier, O; Georges, J L; Ricard, S; Arveiler, D; Ruidavets, J B; Luc, G; Evans, A; Cambien, F; Tiret, L

    1998-10-01

    In an earlier report, we suggested that a polymorphism located in the 3' untranslated region of the angiotensin II type 1 receptor gene (AT1R+1166 A/C) might interact with the angiotensin I converting enzyme (ACE) insertion/deletion (I/D) polymorphism to increase the risk of myocardial infarction. Since the AT1R+1166 A/C polymorphism does not appear to be functional, we postulated that it might be in linkage disequilibrium with an unidentified functional variant which would affect the regulation of the gene in response to angiotensin II. The present study was conducted to identify new polymorphisms of the AT1R gene that might be responsible for this interaction. The first four exons, which are untranslated, and 2.2 kb in the 5' flanking region of the AT1R gene were explored by polymerase chain reaction/single-strand conformation polymorphism. Seven polymorphisms were detected in the 5' region at positions -1424, -810, -713, -521, -214, -213 and -153 upstream from the start of transcription. The genotypes of the -810, -713, -214, -213 and -153 polymorphisms were completely concordant. One substitution was detected at the 55th nucleotide of exon 4. These polymorphisms, together with the +1166 A/C polymorphism and a previously described T/C substitution at the 573th nucleotide of exon 5, were genotyped in the Etude Cas-Témoin de l'Infarctus du Myocarde (ECTIM) study, a multicentre study comparing 651 patients who had survived a myocardial infarction and 728 controls from Belfast (United Kingdom) and Lille, Strasbourg and Toulouse (France). The newly identified polymorphisms were not in linkage disequilibrium with the +1166 A/C polymorphism and therefore could not explain the interaction observed with ACE I/D. None of the polymorphisms was associated with blood pressure levels in control subjects. In the four populations, the A allele of the -810 polymorphism was associated with a lower risk of myocardial infarction (population-adjusted odds ratio of 0.80, confidence

  10. Nature and regulation of the receptors for insulin-like growth factors

    International Nuclear Information System (INIS)

    Rechler, M.M.; Nissley, S.P.

    1985-01-01

    Two subtypes of IGF receptors have been identified. Type I IGF receptors have a Mr greater than 300,000 and are composed of disulfide-linked 130,000-dalton (alpha) and approximately 90,000-dalton (beta) subunits. Type I receptors preferentially bind IGF-I but also bind IGF-II and, more weakly, insulin. Type II IGF receptors consist of a 250,000-dalton protein that contains internal disulfide bonds but is not linked to other membrane components. Type II receptors bind IGF-II with higher affinity than IGF-I. They do not interact with even very high concentrations of insulin. Type I IGF receptors and insulin receptors are homologous structures. Type II IGF receptors do not appear to be homologous to type I receptors. Type II receptors do not appear to be downregulated. Insulin acutely upregulates type II IGF receptors in intact rat adipose cells by effecting a redistribution of receptors cycling between a large intracellular pool and the plasma membrane. Insulin and the IGFs elicit the same biological responses, either by cross-reacting with one of the receptors for the heterologous ligand or by concurrent activation of convergent effector pathways by binding to the homologous receptor. Which mechanism is utilized appears to depend more on the tissue than on the biological response. Insulin desensitizes rat hepatoma cells to the actions of insulin and IGFs, mediated by both insulin and IGF receptors, by mechanisms distal to hormone binding and possibly common to IGF and insulin effector pathways

  11. Sympatho-inhibitory properties of various AT1 receptor antagonists

    NARCIS (Netherlands)

    Balt, Jippe C.; Mathy, Marie-Jeanne; Pfaffendorf, Martin; van Zwieten, Peter A.

    2002-01-01

    It is well known that angiotensin II (Ang II) can facilitate the effects of sympathetic neurotransmission. In the present study, using various experimental models, we investigated the inhibitory effects of several Ang II subtype 1 receptor (AT1) antagonists on this Ang II-induced facilitation. We

  12. TNF Receptor Type II as an Emerging Drug Target for the Treatment of Cancer, Autoimmune Diseases, and Graft-Versus-Host Disease: Current Perspectives and In Silico Search for Small Molecule Binders

    Directory of Open Access Journals (Sweden)

    Faraz Shaikh

    2018-06-01

    Full Text Available There is now compelling evidence that TNF receptor type II (TNFR2 is predominantly expressed on CD4+Foxp3+ regulatory T cells (Tregs and myeloid-derived suppressor cells (MDSCs, and plays a major role in the expansion and function of Tregs and MDSCs. Consequently, targeting of TNFR2 by either antagonists or agonists may represent a novel strategy in the treatment of cancer and autoimmune diseases, by downregulating or upregulating suppressor cell activity. The advance in the understanding of complex structure of TNFR2 and its binding with TNF at molecular levels offers opportunity for structure-guided drug discovery. This article reviews the current evidences regarding the decisive role of TNFR2 in immunosuppressive function of Tregs and MDSCs, and the current effort to develop novel TNFR2-targeting therapeutic agents in the treatment of cancer, autoimmune diseases, and graft-versus-host disease. To shed light on the potential TNFR2-targeting small molecules, we for the first time performed virtual screening of 400,000 natural compounds against the two TNF-binding sites, regions 3 and 4, of TNFR2. Our result showed that the top hits at region 4 had slightly higher docking energies than those at region 3. Nevertheless, free energy calculation from the TNF–TNFR2 molecular dynamics simulation revealed that the binding strength of TNF in region 3 is only one-tenth of that in region 4. This suggests that region 3 is a potentially more viable binding site to be targeted by small molecules than region 4. Therefore, the effectiveness in targeting region 3 of TNFR2 deserves further investigation.

  13. Phase II Study of Paclitaxel Given Once per Week Along With Trastuzumab and Pertuzumab in Patients With Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer

    Science.gov (United States)

    Dang, Chau; Iyengar, Neil; Datko, Farrah; D'Andrea, Gabriella; Theodoulou, Maria; Dickler, Maura; Goldfarb, Shari; Lake, Diana; Fasano, Julie; Fornier, Monica; Gilewski, Theresa; Modi, Shanu; Gajria, Devika; Moynahan, Mary Ellen; Hamilton, Nicola; Patil, Sujata; Jochelson, Maxine; Norton, Larry; Baselga, Jose; Hudis, Clifford

    2015-01-01

    Purpose The CLEOPATRA (Clinical Evaluation of Trastuzumab and Pertuzumab) study demonstrated superior progression-free survival (PFS) and overall survival when pertuzumab was added to trastuzumab and docetaxel. Paclitaxel given once per week is effective and less toxic than docetaxel. We performed a phase II study to evaluate the efficacy and safety of pertuzumab and trastuzumab with paclitaxel given once per week. Patients and Methods Patients with metastatic human epidermal growth factor receptor 2–positive breast cancer with zero to one prior therapy were enrolled. Treatment consisted of paclitaxel 80 mg/m2 once per week plus trastuzumab (8 mg/kg loading dose → 6 mg/kg) once every 3 weeks plus pertuzumab (840 mg loading dose → 420 mg) once every 3 weeks, all given intravenously. The primary end point was 6-month PFS assessed by Kaplan-Meier methods. Results From January 2011 to December 2013, we enrolled 69 patients: 51 (74%) and 18 (26%) treated in first- and second-line metastatic settings, respectively. At a median follow-up of 21 months (range, 3 to 38 months), 6-month PFS was 86% (95% CI, 75% to 92%). The median PFS was 19.5 months (95% CI, 14 to 26 months) overall. PFS was 24.2 months (95% CI, 14 months to not reached [NR]) and 16.4 months (95% CI, 8.5 months to NR) for those without and with prior treatment, respectively. At 1 year, Kaplan-Meier PFS was 70% (95% CI, 56% to 79%) overall, 71% (95% CI, 55% to 82%) for those without prior therapy, and 66% (95% CI, 40% to 83%) for those with prior therapy. Treatment was well-tolerated; there was no febrile neutropenia or symptomatic left ventricular systolic dysfunction. Conclusion Paclitaxel given once per week with trastuzumab and pertuzumab is highly active and well tolerated and seems to be an effective alternative to docetaxel-based combination therapy. PMID:25547504

  14. Acute Systemic Infection with Dengue Virus Leads to Vascular Leakage and Death through Tumor Necrosis Factor-α and Tie2/Angiopoietin Signaling in Mice Lacking Type I and II Interferon Receptors.

    Science.gov (United States)

    Phanthanawiboon, Supranee; Limkittikul, Kriengsak; Sakai, Yusuke; Takakura, Nobuyuki; Saijo, Masayuki; Kurosu, Takeshi

    2016-01-01

    Severe dengue is caused by host responses to viral infection, but the pathogenesis remains unknown. This is, in part, due to the lack of suitable animal models. Here, we report a non-mouse-adapted low-passage DENV-3 clinical isolate, DV3P12/08, derived from recently infected patients. DV3P12/08 caused a lethal systemic infection in type I and II IFN receptor KO mice (IFN-α/β/γR KO mice), which have the C57/BL6 background. Infection with DV3P12/08 induced a cytokine storm, resulting in severe vascular leakage (mainly in the liver, kidney and intestine) and organ damage, leading to extensive hemorrhage and rapid death. DV3P12/08 infection triggered the release of large amounts of TNF-α, IL-6, and MCP-1. Treatment with a neutralizing anti-TNF-α antibody (Ab) extended survival and reduced liver damage without affecting virus production. Anti-IL-6 neutralizing Ab partly prolonged mouse survival. The anti-TNF-α Ab suppressed IL-6, MCP-1, and IFN-γ levels, suggesting that the severe response to infection was triggered by TNF-α. High levels of TNF-α mRNA were expressed in the liver and kidneys, but not in the small intestine, of infected mice. Conversely, high levels of IL-6 mRNA were expressed in the intestine. Importantly, treatment with Angiopoietin-1, which is known to stabilize blood vessels, prolonged the survival of DV3P12/08-infected mice. Taken together, the results suggest that an increased level of TNF-α together with concomitant upregulation of Tie2/Angiopoietin signaling have critical roles in severe dengue infection.

  15. Copper (II)

    African Journals Online (AJOL)

    CLEMENT O BEWAJI

    Valine (2 - amino - 3 – methylbutanoic acid), is a chemical compound containing .... Stability constant (Kf). Gibb's free energy. ) (. 1. −. ∆. Mol. JG. [CuL2(H2O)2] ... synthesis and characterization of Co(ii), Ni(ii), Cu (II), and Zn(ii) complexes with ...

  16. A bioluminescence resonance energy transfer 2 (BRET2) assay for monitoring seven transmembrane receptor and insulin receptor crosstalk

    DEFF Research Database (Denmark)

    Sanni, Samra Joke; Kulahin, Nikolaj; Jorgensen, Rasmus

    2017-01-01

    The angiotensin AT1 receptor is a seven transmembrane (7TM) receptor, which mediates the regulation of blood pressure. Activation of angiotensin AT1 receptor may lead to impaired insulin signaling indicating crosstalk between angiotensin AT1 receptor and insulin receptor signaling pathways....... To elucidate the molecular mechanisms behind this crosstalk, we applied the BRET2 technique to monitor the effect of angiotensin II on the interaction between Rluc8 tagged insulin receptor and GFP2 tagged insulin receptor substrates 1, 4, 5 (IRS1, IRS4, IRS5) and Src homology 2 domain-containing protein (Shc......). We demonstrate that angiotensin II reduces the interaction between insulin receptor and IRS1 and IRS4, respectively, while the interaction with Shc is unaffected, and this effect is dependent on Gαq activation. Activation of other Gαq-coupled 7TM receptors led to a similar reduction in insulin...

  17. Expression of GABAergic receptors in mouse taste receptor cells.

    Directory of Open Access Journals (Sweden)

    Margaret R Starostik

    Full Text Available BACKGROUND: Multiple excitatory neurotransmitters have been identified in the mammalian taste transduction, with few studies focused on inhibitory neurotransmitters. Since the synthetic enzyme glutamate decarboxylase (GAD for gamma-aminobutyric acid (GABA is expressed in a subset of mouse taste cells, we hypothesized that other components of the GABA signaling pathway are likely expressed in this system. GABA signaling is initiated by the activation of either ionotropic receptors (GABA(A and GABA(C or metabotropic receptors (GABA(B while it is terminated by the re-uptake of GABA through transporters (GATs. METHODOLOGY/PRINCIPAL FINDINGS: Using reverse transcriptase-PCR (RT-PCR analysis, we investigated the expression of different GABA signaling molecules in the mouse taste system. Taste receptor cells (TRCs in the circumvallate papillae express multiple subunits of the GABA(A and GABA(B receptors as well as multiple GATs. Immunocytochemical analyses examined the distribution of the GABA machinery in the circumvallate papillae. Both GABA(A-and GABA(B- immunoreactivity were detected in the peripheral taste receptor cells. We also used transgenic mice that express green fluorescent protein (GFP in either the Type II taste cells, which can respond to bitter, sweet or umami taste stimuli, or in the Type III GAD67 expressing taste cells. Thus, we were able to identify that GABAergic receptors are expressed in some Type II and Type III taste cells. Mouse GAT4 labeling was concentrated in the cells surrounding the taste buds with a few positively labeled TRCs at the margins of the taste buds. CONCLUSIONS/SIGNIFICANCE: The presence of GABAergic receptors localized on Type II and Type III taste cells suggests that GABA is likely modulating evoked taste responses in the mouse taste bud.

  18. TLX: An elusive receptor.

    Science.gov (United States)

    Benod, Cindy; Villagomez, Rosa; Webb, Paul

    2016-03-01

    TLX (tailless receptor) is a member of the nuclear receptor superfamily and belongs to a class of nuclear receptors for which no endogenous or synthetic ligands have yet been identified. TLX is a promising therapeutic target in neurological disorders and brain tumors. Thus, regulatory ligands for TLX need to be identified to complete the validation of TLX as a useful target and would serve as chemical probes to pursue the study of this receptor in disease models. It has recently been proved that TLX is druggable. However, to identify potent and specific TLX ligands with desirable biological activity, a deeper understanding of where ligands bind, how they alter TLX conformation and of the mechanism by which TLX mediates the transcription of its target genes is needed. While TLX is in the process of escaping from orphanhood, future ligand design needs to progress in parallel with improved understanding of (i) the binding cavity or surfaces to target with small molecules on the TLX ligand binding domain and (ii) the nature of the TLX coregulators in particular cell and disease contexts. Both of these topics are discussed in this review. Copyright © 2015 Elsevier Ltd. All rights reserved.

  19. Clinical effects of prior trastuzumab on combination eribulin mesylate plus trastuzumab as first-line treatment for human epidermal growth factor receptor 2 positive locally recurrent or metastatic breast cancer: results from a Phase II, single-arm, multicenter study

    Directory of Open Access Journals (Sweden)

    Puhalla S

    2016-12-01

    Full Text Available Shannon Puhalla,1 Sharon Wilks,2 Adam M Brufsky,1 Joyce O’Shaughnessy,3 Lee S Schwartzberg,4 Erhan Berrak,5 James Song,5 Linda Vahdat6 1Department of Hematology and Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA, 2Department of Hematology Oncology, US Oncology-Cancer Care Centers of South Texas, San Antonio, TX, 3Department of Medical Oncology, Texas Oncology-Baylor Charles A. Sammons Cancer Center US Oncology, Dallas, TX, 4Department of Hematology/Oncology, West Cancer Center, University of Tennessee Health Science Center, Memphis, TN, 5Department of Medical Affairs, Formerly of Eisai Inc., Woodcliff Lake, NJ, 6Department of Medicine, Weill Cornell Medical College, New York, NY, USA Abstract: Eribulin mesylate, a novel nontaxane microtubule dynamics inhibitor in the halichondrin class of antineoplastic drugs, is indicated for the treatment of patients with metastatic breast cancer who previously received ≥2 chemotherapy regimens in the metastatic setting. Primary data from a Phase II trial for the first-line combination of ­eribulin plus trastuzumab in human epidermal growth factor receptor 2 positive patients showed a 71% objective response rate and tolerability consistent with the known profile of these agents. Here, we present prespecified analyses of efficacy of this combination based on prior trastuzumab use. Patients received eribulin mesylate 1.4 mg/m2 (equivalent to 1.23 mg/m2 eribulin [expressed as free base] intravenously on days 1 and 8 plus trastuzumab (8 mg/kg intravenously/cycle 1, then 6 mg/kg on day 1 of each 21-day cycle. Objective response rates, progression-free survival, and tolerability were assessed in patients who had and had not received prior adjuvant or neoadjuvant (neo/adjuvant trastuzumab treatment. Fifty-two patients (median age: 59.5 years received eribulin/trastuzumab for a median treatment duration of ~31 weeks; 40.4% (n=21 had been previously treated with neo/adjuvant trastuzumab prior to

  20. Impact of liposomal doxorubicin-based adjuvant chemotherapy on autonomy in women over 70 with hormone-receptor-negative breast carcinoma: A French Geriatric Oncology Group (GERICO) phase II multicentre trial.

    Science.gov (United States)

    Brain, Etienne G C; Mertens, Cécile; Girre, Véronique; Rousseau, Frédérique; Blot, Emmanuel; Abadie, Sophie; Uwer, Lionel; Bourbouloux, Emmanuelle; Van Praagh-Doreau, Isabelle; Mourey, Loic; Kirscher, Sylvie; Laguerre, Brigitte; Fourme, Emmanuelle; Luneau, Sylvia; Genève, Jean; Debled, Marc

    2011-10-01

    Breast cancer is a disease of ageing. Functional independence in elderly patients, measured with the Katz activities of daily living (ADL) scale, predicts overall survival and the need for welfare support. Few prospective studies have examined the feasibility of adjuvant chemotherapy and its impact on autonomy in women over 70 years of age with high-risk breast cancer. This multicentre phase II trial was designed to assess the impact of adjuvant anthracycline-based chemotherapy on these patients' autonomy. In a two-stage Fleming design, women aged ≥70 years with histologically proven hormone-receptor-negative early breast cancer and a significant risk of recurrence (pN+ or "high risk" pN0) received 4 cycles of nonpegylated liposomal doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2) every 3 weeks postoperatively, on an outpatient basis. The primary endpoint was the change in the ADL score during chemotherapy. Secondary endpoints include comprehensive geriatric, quality-of-life and acceptability assessments, tolerability, and long-term outcome. The results for the primary endpoint and other scales at completion of adjuvant chemotherapy are reported here, while long-term follow-up is not yet complete. Forty patients (median age 75 [70-82]) were enrolled between February 2006 and November 2007. Chemotherapy had no deleterious impact on ADL, cognition, mental status, or the frequency of comorbidities. In contrast, the number of patients at risk of malnutrition, based on the Mini Nutritional Assessment, more than doubled between baseline and the end of chemotherapy, rising from 15% to 38%. Quality-of-life deteriorated in terms of social and role functioning, likely owing to fatigue, loss of appetite, nausea and vomiting. Treatment acceptability was good. The main adverse effect was neutropenia, 15% of the patients experiencing febrile neutropenia. No cardiac toxicity or toxic deaths occurred. This study demonstrates the feasibility of an adjuvant chemotherapy

  1. Translational Breast Cancer Research Consortium (TBCRC) 022: A Phase II Trial of Neratinib for Patients With Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer and Brain Metastases

    Science.gov (United States)

    Gelman, Rebecca S.; Wefel, Jeffrey S.; Melisko, Michelle E.; Hess, Kenneth R.; Connolly, Roisin M.; Van Poznak, Catherine H.; Niravath, Polly A.; Puhalla, Shannon L.; Ibrahim, Nuhad; Blackwell, Kimberly L.; Moy, Beverly; Herold, Christina; Liu, Minetta C.; Lowe, Alarice; Agar, Nathalie Y.R.; Ryabin, Nicole; Farooq, Sarah; Lawler, Elizabeth; Rimawi, Mothaffar F.; Krop, Ian E.; Wolff, Antonio C.; Winer, Eric P.; Lin, Nancy U.

    2016-01-01

    Purpose Evidence-based treatments for metastatic, human epidermal growth factor receptor 2 (HER2)–positive breast cancer in the CNS are limited. Neratinib is an irreversible inhibitor of erbB1, HER2, and erbB4, with promising activity in HER2-positive breast cancer; however, its activity in the CNS is unknown. We evaluated the efficacy of treatment with neratinib in patients with HER2-positive breast cancer brain metastases in a multicenter, phase II open-label trial. Patients and Methods Eligible patients were those with HER2-positive brain metastases (≥ 1 cm in longest dimension) who experienced progression in the CNS after one or more line of CNS-directed therapy, such as whole-brain radiotherapy, stereotactic radiosurgery, and/or surgical resection. Patients received neratinib 240 mg orally once per day, and tumors were assessed every two cycles. The primary endpoint was composite CNS objective response rate (ORR), requiring all of the following: ≥50% reduction in volumetric sum of target CNS lesions and no progression of non-target lesions, new lesions, escalating corticosteroids, progressive neurologic signs/symptoms, or non-CNS progression—the threshold for success was five of 40 responders. Results Forty patients were enrolled between February 2012 and June 2013; 78% of patients had previous whole-brain radiotherapy. Three women achieved a partial response (CNS objective response rate, 8%; 95% CI, 2% to 22%). The median number of cycles received was two (range, one to seven cycles), with a median progression-free survival of 1.9 months. Five women received six or more cycles. The most common grade ≥ 3 event was diarrhea (occurring in 21% of patients taking prespecified loperamide prophylaxis and 28% of those without prophylaxis). Patients in the study experienced a decreased quality of life over time. Conclusion Although neratinib had low activity and did not meet our threshold for success, 12.5% of patients received six or more cycles. Studies

  2. Using a source-receptor approach to characterise VOC behaviour in a French urban area influenced by industrial emissions. Part II: source contribution assessment using the Chemical Mass Balance (CMB) model.

    Science.gov (United States)

    Badol, Caroline; Locoge, Nadine; Galloo, Jean-Claude

    2008-01-25

    In Part I of this study (Badol C, Locoge N, Leonardis T, Gallo JC. Using a source-receptor approach to characterise VOC behaviour in a French urban area influenced by industrial emissions, Part I: Study area description, data set acquisition and qualitative data analysis of the data set. Sci Total Environ 2007; submitted as companion manuscript.) the study area, acquisition of the one-year data set and qualitative analysis of the data set have been described. In Part II a source profile has been established for each activity present in the study area: 6 profiles (urban heating, solvent use, natural gas leakage, biogenic emissions, gasoline evaporation and vehicle exhaust) have been extracted from literature to characterise urban sources, 7 industrial profiles have been established via canister sampling around industrial plants (hydrocarbon cracking, oil refinery, hydrocarbon storage, lubricant storage, lubricant refinery, surface treatment and metallurgy). The CMB model is briefly described and its implementation is discussed through the selection of source profiles and fitting species. Main results of CMB modellings for the Dunkerque area are presented. (1) The daily evolution of source contributions for the urban wind sector shows that the vehicle exhaust source contribution varies between 40 and 55% and its relative increase at traffic rush hours is hardly perceptible. (2) The relative contribution of vehicle exhaust varies from 55% in winter down to 30% in summer. This decrease is due to the increase of the relative contribution of hydrocarbon storage source reaching up to 20% in summer. (3) The evolution of source contributions with wind directions has confirmed that in urban wind sectors the contribution of vehicle exhaust dominate with around 45-55%. For the other wind sectors that include some industrial plants, the contribution of industrial sources is around 60% and could reach 80% for the sector 280-310 degrees , which corresponds to the most dense

  3. (II) complexes

    African Journals Online (AJOL)

    activities of Schiff base tin (II) complexes. Neelofar1 ... Conclusion: All synthesized Schiff bases and their Tin (II) complexes showed high antimicrobial and ...... Singh HL. Synthesis and characterization of tin (II) complexes of fluorinated Schiff bases derived from amino acids. Spectrochim Acta Part A: Molec Biomolec.

  4. Angiotensin II Protects Primary Rat Hepatocytes against Bile Salt-Induced Apoptosis

    NARCIS (Netherlands)

    Karimian, Golnar; Buist-Homan, Manon; Mikus, Bojana; Henning, Robert H.; Faber, Klaas Nico; Moshage, Han

    2012-01-01

    Angiotensin II (AT-II) is a pro-fibrotic compound that acts via membrane-bound receptors (AT-1R/AT-2R) and thereby activates hepatic stellate cells (HSCs). AT-II receptor blockers (ARBs) are thus important candidates in the treatment of liver fibrosis. However, multiple case reports suggest that

  5. Ambulatory blood pressure parameters after canrenone addition to existing treatment regimens with maximum tolerated dose of angiotensin-converting enzyme inhibitors/angiotensin II type 1 receptor blockers plus hydrochlorothiazide in uncontrolled hypertensive patients

    Directory of Open Access Journals (Sweden)

    Guasti L

    2017-08-01

    Full Text Available Luigina Guasti,1,* Giovanni Gaudio,2,* Alessandro Lupi,3 Marinella D’Avino,4 Carla Sala,5,6 Amedeo Mugellini,7 Vito Vulpis,8 Salvatore Felis,9 Riccardo Sarzani,10,11 Massimo Vanasia,12 Pamela Maffioli,7 Giuseppe Derosa7 1Research Center on Dyslipidemia, Internal Medicine 1, University of Insubria, Varese, Italy; 2Internal Medicine Division, Ospedale Angelo Bellini, ASST Valle Olona Somma, Varese, Italy; 3Cardiology Unit, ASL VCO Verbania-Domodossola, Verbania, Italy; 4Unit for the Treatment of Arterial Hypertension, Ospedale Cardarelli, Napoli, Italy; 5Department of Clinical Sciences and Community Health, University of Milan, Milano, Italy; 6Cardiovascular Unit, Fondazione IRCCSS Policlinico, Milano, Italy; 7Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy; 8Unit for the Diagnosis and Treatment of Arterial Hypertension, Department of Internal Medicine, Policlinico di Bari, Bari, Italy; 9Cardiology Unit, Ospedale Garibaldi, Catania, Italy; 10ESH Center of Hypertension, Internal Medicine and Geriatrics, University Politecnica delle Marche, Ancona, Italy; 11IRCCS-INRCA, Ancona, Italy; 12THERABEL GiEnne Pharma, Milano, Italy *These authors contributed equally to this work Background: Blockade of the renin–angiotensin–aldosterone system is a cornerstone in cardiovascular disease prevention and hypertension treatment. The relevance of ambulatory blood pressure monitoring (ABPM has been widely confirmed for both increasing the accuracy of blood pressure (BP measurements, particularly in pharmacological trials, and focusing on 24 h BP prognostic parameters. The aim of this study was to assess the effects of canrenone addition on ambulatory BP in uncontrolled hypertensive patients already treated with the highest tolerated dose of angiotensin-converting enzyme (ACE inhibitors or angiotensin II type 1 receptor (AT1R antagonists plus hydrochlorothiazide (HCT. Methods: ABPM was performed at baseline and after 3

  6. Participation of L3T4 in T cell activation in the absence of class II major histocompatibility complex antigens. Inhibition by anti-L3T4 antibodies is a function both of epitope density and mode of presentation of anti-receptor antibody

    DEFF Research Database (Denmark)

    Owens, T; Fazekas de St Groth, B

    1987-01-01

    two monoclonal antibodies, KJ16-133.18 and F23.1, that recognize a determinant encoded by the T cell receptor V beta 8 gene family. These antibodies were used to select two clones of T cells with surface phenotype Thy-1.2+, L3T4+, Lyt-2-, KJ16-133.18+, F23.1+, IA-, IE-. One of these clones (E9.D4......The recognition of many class II major histocompatibility complex (MHC)-associated antigens by T cells requires the participation of the L3T4 molecule. It has been proposed that this molecule acts to stabilize low affinity binding to antigen in association with MHC and thereby increases the avidity...... of T cell/antigen interactions. By using antibodies against the T cell antigen receptor (TCR) to activate T cells, thereby circumventing the requirement for antigen presenting cells and MHC-associated antigen, we have been able to study the function of L3T4 in the absence of class II MHC. We have used...

  7. The therapeutic advantage of combination antihypertensive drug therapy using amlodipine and irbesartan in hypertensive patients: Analysis of the post-marketing survey data from PARTNER (Practical combination therapy of Amlodin and angiotensin II Receptor blocker; safety and efficacy in patients with hypertension) study.

    Science.gov (United States)

    Ishimitsu, Toshihiko; Fukuda, Hirofumi; Uchida, Masako; Ishibashi, Kazushi; Sato, Fusako; Nukui, Kazuhiko; Nagao, Munehiko

    2015-01-01

    Two-thirds of hypertensive patients need a combination antihypertensive therapy to achieve the target blood pressure (BP). The PARTNER (Practical combination therapy of Amlodin and angiotensin II Receptor blocker; Safety and efficacy in paTieNts with hypERtension) study is a prospective specific clinical use survey examining the efficacy and safety of 12-week treatment with amlodipine (AML) and Angiotensin II Receptor Blocker (ARB) in 5900 hypertensive patients. The current analysis was performed as to the BP control, adverse reactions, and the effects on laboratory data in patients treated with the combination of AML and irbesartan (IRB), namely the patients added AML to already taking IRB (AML add-on group, n = 1202) and the patients added IRB to AML (IRB add-on group, n = 1050). Both study groups showed distinct decreases in office BP at 4 week (p 7 mg/dl. The incidence of adverse reactions was as few as 1.11% and there were no severe adverse reactions which hampered the continuation of combination therapy. In conclusion, combination antihypertensive therapy with AML and IRB effectively lowers BP without particular safety problems, reduces serum uric acid especially in patients with hyperuricemia and exhibits renoprotective effects in patients with chronic kidney disease.

  8. Sex differences in angiotensin II- induced hypertension

    Directory of Open Access Journals (Sweden)

    B. Xue

    2007-05-01

    Full Text Available Sex differences in the development of hypertension and cardiovascular disease have been described in humans and in animal models. In this paper we will review some of our studies which have as their emphasis the examination of the role of sex differences and sex steroids in modulating the central actions of angiotensin II (ANG II via interactions with free radicals and nitric oxide, generating pathways within brain circumventricular organs and in central sympathomodulatory systems. Our studies indicate that low-dose infusions of ANG II result in hypertension in wild-type male mice but not in intact wild-type females. Furthermore, we have demonstrated that ANG II-induced hypertension in males is blocked by central infusions of the androgen receptor antagonist, flutamide, and by central infusions of the superoxide dismutase mimetic, tempol. We have also found that, in comparison to females, males show greater levels of intracellular reactive oxygen species in circumventricular organ neurons following long-term ANG II infusions. In female mice, ovariectomy, central blockade of estrogen receptors or total knockout of estrogen a receptors augments the pressor effects of ANG II. Finally, in females but not in males, central blockade of nitric oxide synthase increases the pressor effects of ANG II. Taken together, these results suggest that sex differences and estrogen and testosterone play important roles in the development of ANG II-induced hypertension.

  9. Laminar pattern of cholinergic and adrenergic receptors in rat visual cortex using quantitative receptor autoradiography

    International Nuclear Information System (INIS)

    Schliebs, R.; Walch, C.

    1989-01-01

    The laminar distribution of muscarinic acetylcholine receptors, including the M1-receptor subtype, of beta-adrenergic receptors, and noradrenaline uptake sites, was studied in the adult rat visual, frontal, somatosensory and motor cortex, using quantitative receptor autoradiography. In the visual cortex, the highest density of muscarinic acetylcholine receptors was found in layer I. From layer II/III to layer V binding decreases continueously reaching a constant binding level in layers V and VI. This laminar pattern of muscarinic receptor density differs somewhat from that observed in the non-visual cortical regions examined: layer II/III contained the highest receptor density followed by layer I and IV: lowest density was found in layer V and VI. The binding profile of the muscarinic cholinergic M1-subtype through the visual cortex shows a peak in cortical layer II and in the upper part of layer VI, whereas in the non-visual cortical regions cited the binding level was high in layer II/III, moderate in layer I and IV, and low in layer VI. Layers I to IV of the visual cortex contained the highest beta-adrenergic receptor densities, whereas only low binding levels were observed in the deeper layers. A similar laminar distribution was found also in the frontal, somatosensory and motor cortex. The density of noradrenaline uptake sites was high in all layers of the cortical regions studied, but with noradrenaline uptake sites somewhat more concentrated in the superficial layers than in deeper ones. The distinct laminar pattern of cholinergic and noradrenergic receptor sites indicates a different role for acetylcholine and noradrenaline in the functional anatomy of the cerebral cortex, and in particular, the visual cortex. (author)

  10. Laminar pattern of cholinergic and adrenergic receptors in rat visual cortex using quantitative receptor autoradiography

    Energy Technology Data Exchange (ETDEWEB)

    Schliebs, R; Walch, C [Leipzig Univ. (German Democratic Republic). Bereich Medizin; Stewart, M G [Open Univ., Milton Keynes (UK)

    1989-01-01

    The laminar distribution of muscarinic acetylcholine receptors, including the M1-receptor subtype, of beta-adrenergic receptors, and noradrenaline uptake sites, was studied in the adult rat visual, frontal, somatosensory and motor cortex, using quantitative receptor autoradiography. In the visual cortex, the highest density of muscarinic acetylcholine receptors was found in layer I. From layer II/III to layer V binding decreases continueously reaching a constant binding level in layers V and VI. This laminar pattern of muscarinic receptor density differs somewhat from that observed in the non-visual cortical regions examined: layer II/III contained the highest receptor density followed by layer I and IV: lowest density was found in layer V and VI. The binding profile of the muscarinic cholinergic M1-subtype through the visual cortex shows a peak in cortical layer II and in the upper part of layer VI, whereas in the non-visual cortical regions cited the binding level was high in layer II/III, moderate in layer I and IV, and low in layer VI. Layers I to IV of the visual cortex contained the highest beta-adrenergic receptor densities, whereas only low binding levels were observed in the deeper layers. A similar laminar distribution was found also in the frontal, somatosensory and motor cortex. The density of noradrenaline uptake sites was high in all layers of the cortical regions studied, but with noradrenaline uptake sites somewhat more concentrated in the superficial layers than in deeper ones. The distinct laminar pattern of cholinergic and noradrenergic receptor sites indicates a different role for acetylcholine and noradrenaline in the functional anatomy of the cerebral cortex, and in particular, the visual cortex. (author).

  11. Dopamine modulates male sexual behavior in Japanese quail in part via actions on noradrenergic receptors.

    Science.gov (United States)

    Cornil, Charlotte A; Dejace, Christel; Ball, Gregory F; Balthazart, Jacques

    2005-08-30

    In rats, dopamine (DA) facilitates male sexual behavior through its combined action on D1- and D2-like receptors, in the medial preoptic area (MPOA) as well as other brain areas. In Japanese quail, systemic injections of dopaminergic drugs suggested a similar pharmacology but central injections have never been performed. Recent electrophysiological experiments demonstrated that DA effects in the MPOA of quail are mediated mainly through the activation of alpha2-noradrenergic receptors. Previous studies of DA action on behavior used specific dopaminergic agonists/antagonists and therefore unintentionally avoided the potential cross-reaction with alpha2-receptors. The present study was thus designed to investigate directly the effects of DA on male sexual behavior and to test whether the interaction of DA with heterologous receptors affects this behavior. Intracerebroventricular (i.c.v.) injection of DA or NE inhibited copulation in a dose-dependent manner. Systemic injections of yohimbine, an alpha2-noradrenergic antagonist, modulated copulation in a bimodal manner depending on the dose injected. Interestingly, a behaviorally ineffective dose of yohimbine markedly reduced the inhibitory effects of DA when injected 15min before. Together, these results show for the first time that i.c.v. injections of DA itself inhibit male sexual behavior in quail and suggest that the interaction of DA with alpha2-receptors has behavioral significance.

  12. Investigation of the immunological and receptor activity of human growth hormone in patients with acromegaly

    International Nuclear Information System (INIS)

    Dietz, A.

    1982-01-01

    Human growth hormone (hGH) was measured by means of the radioimmunoassay (RIA) and the radioreceptor assay (RRA). The receptors were liver plasma membranes (LPM) of pregnant rabbits. In the RIA, no cross-reaction was found with hPRL, whereas in the RRA the cross-reaction was 3 p.c. The Scatchard analysis revealed two binding sites for hGH at the receptor. Pre-treatment with hGH and Cortisol brought about an enhanced affinity without change of the specific bonding, whereas pre-treatment with bromocriptin showed no significant effect. Hypophyseal hGH was separated by means of gel chromatography into big-big and big-little hGH and a reduced receptor activity of the higher molecular hGH fraction was shown. The Scatchard analysis indicated a more unspecific bonding characteristic of the big hGH. Stimulation of hGH secretion by insulin hypoglycemia provoked an overproportional increase in big hGH in healthy persons, whereas in patients with acromegaly the secretion of little hGH was enhanced. The suppression of hGH secretion by long-term bromocriptin treatment led to a significant rise of the RIA/RRA quotient in patients with post-operative florid acromegaly. Acute administration of BC was shown to induce a stronger hGH drop in the RRA of responders than in their RIA, as compared to non-responders. By chromatographic separation it was found that in responders the secretion of little hGH is selectively inhibited, but no in non-responders. (orig.) [de

  13. Management of hyperkalaemia consequent to mineralocorticoid-receptor antagonist therapy

    NARCIS (Netherlands)

    Roscioni, Sara S.; de Zeeuw, Dick; Bakker, Stephan J. L.; Lambers Heerspink, Hiddo J.

    2012-01-01

    Mineralocorticoid-receptor antagonists (MRAs) reduce blood pressure and albuminuria in patients treated with angiotensin-converting-enzyme inhibitors or angiotensin-II-receptor blockers. The use of MRAs, however, is limited by the occurrence of hyperkalaemia, which frequently occurs in patients

  14. Stimulation of accumbal GABAA receptors inhibits delta2-, but not delta1-, opioid receptor-mediated dopamine efflux in the nucleus accumbens of freely moving rats.

    Science.gov (United States)

    Aono, Yuri; Kiguchi, Yuri; Watanabe, Yuriko; Waddington, John L; Saigusa, Tadashi

    2017-11-15

    The nucleus accumbens contains delta-opioid receptors that may reduce inhibitory neurotransmission. Reduction in GABA A receptor-mediated inhibition of accumbal dopamine release due to delta-opioid receptor activation should be suppressed by stimulating accumbal GABA A receptors. As delta-opioid receptors are divided into delta2- and delta1-opioid receptors, we analysed the effects of the GABA A receptor agonist muscimol on delta2- and delta1-opioid receptor-mediated accumbal dopamine efflux in freely moving rats using in vivo microdialysis. Drugs were administered intracerebrally through the dialysis probe. Doses of compounds indicate total amount administered (mol) during 25-50min infusions. The delta2-opioid receptor agonist deltorphin II (25.0nmol)- and delta1-opioid receptor agonist DPDPE (5.0nmol)-induced increases in dopamine efflux were inhibited by the delta2-opioid receptor antagonist naltriben (1.5nmol) and the delta1-opioid receptor antagonist BNTX (150.0pmol), respectively. Muscimol (250.0pmol) inhibited deltorphin II (25.0nmol)-induced dopamine efflux. The GABA A receptor antagonist bicuculline (50.0pmol), which failed to affect deltorphin II (25.0nmol)-induced dopamine efflux, counteracted the inhibitory effect of muscimol on deltorphin II-induced dopamine efflux. Neither muscimol (250.0pmol) nor bicuculline (50.0 and 500.0pmol) altered DPDPE (5.0nmol)-induced dopamine efflux. The present results show that reduction in accumbal GABA A receptor-mediated inhibition of dopaminergic activity is necessary to produce delta2-opioid receptor-induced increase in accumbal dopamine efflux. This study indicates that activation of delta2- but not delta1-opioid receptors on the cell bodies and/or terminals of accumbal GABAergic interneurons inhibits GABA release and, accordingly, decreases GABA A receptor-mediated inhibition of dopaminergic terminals, resulting in enhanced accumbal dopamine efflux. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Analysis of responses to angiotensin II in the mouse

    Directory of Open Access Journals (Sweden)

    Trinity J Bivalacqua

    2001-03-01

    Full Text Available Responses to angiotensin II (Ang II were investigated in anaesthetised CD1 mice. Injections of Ang II caused dose-related increases in systemic arterial pressure that were antagonised by candesartan. Responses to Ang II were not altered by PD 123319. At the lowest dose studied (20 µg/kg i.v., the inhibitory effects of candesartan were competitive, whereas at the highest dose (100 µg/kg i.v., the dose-response curve for Ang II was shifted to the right in a non-parallel manner. The inhibitory effects of candesartan were selective and were similar in animals pretreated with enalaprilat to reduce endogenous Ang II production. Pressor responses to Ang II were not altered by propranolol, phentolamine or atropine, but were enhanced by hexamethonium. Increases in total peripheral resistance were inhibited by the AT1-receptor antagonist (ARB but were not altered by AT2-receptor, alpha- or beta-receptor antagonists. These results suggest that pressor responses to Ang II are mediated by AT 1-receptors, are buffered by the baroreceptors, are not modulated by effects on AT2receptors, and that activation of the sympathetic nervous system plays little role in mediating rapid haemodynamic responses to the peptide in anaesthetised mice.

  16. TBscore II

    DEFF Research Database (Denmark)

    Rudolf, Frauke; Lemvik, Grethe; Abate, Ebba

    2013-01-01

    Abstract Background: The TBscore, based on simple signs and symptoms, was introduced to predict unsuccessful outcome in tuberculosis patients on treatment. A recent inter-observer variation study showed profound variation in some variables. Further, some variables depend on a physician assessing...... them, making the score less applicable. The aim of the present study was to simplify the TBscore. Methods: Inter-observer variation assessment and exploratory factor analysis were combined to develop a simplified score, the TBscore II. To validate TBscore II we assessed the association between start...

  17. Angiotensin II type 1 receptor blockade by telmisartan prevents stress-induced impairment of memory via HPA axis deactivation and up-regulation of brain-derived neurotrophic factor gene expression.

    Science.gov (United States)

    Wincewicz, D; Juchniewicz, A; Waszkiewicz, N; Braszko, J J

    2016-09-01

    Physical and psychological aspects of chronic stress continue to be a persistent clinical problem for which new pharmacological treatment strategies are aggressively sought. By the results of our previous work it has been demonstrated that telmisartan (TLM), an angiotensin type 1 receptor (AT1) blocker (ARB) and partial agonist of peroxisome proliferator-activated receptor gamma (PPARγ), alleviates stress-induced cognitive decline. Understanding of mechanistic background of this phenomenon is hampered by both dual binding sites of TLM and limited data on the consequences of central AT1 blockade and PPARγ activation. Therefore, a critical need exists for progress in the characterization of this target for pro-cognitive drug discovery. An unusual ability of novel ARBs to exert various PPARγ binding activities is commonly being viewed as predominant over angiotensin blockade in terms of neuroprotection. Here we aimed to verify this hypothesis using an animal model of chronic psychological stress (Wistar rats restrained 2.5h daily for 21days) with simultaneous oral administration of TLM (1mg/kg), GW9662 - PPARγ receptor antagonist (0.5mg/kg), or both in combination, followed by a battery of behavioral tests (open field, elevated plus maze, inhibitory avoidance - IA, object recognition - OR), quantitative determination of serum corticosterone (CORT) and evaluation of brain-derived neurotrophic factor (BDNF) gene expression in the medial prefrontal cortex (mPFC) and hippocampus (HIP). Stressed animals displayed decreased recall of the IA behavior (pBDNF in the mPFC (paxis deactivation associated with changes in primarily cortical gene expression. This study confirms the dual activities of TLM that controls hypertension and cognition through AT1 blockade. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Phase II Study of Neoadjuvant Anthracycline-Based Regimens Combined With Nanoparticle Albumin-Bound Paclitaxel and Trastuzumab for Human Epidermal Growth Factor Receptor 2-Positive Operable Breast Cancer.

    Science.gov (United States)

    Tanaka, Satoru; Iwamoto, Mitsuhiko; Kimura, Kosei; Matsunami, Nobuki; Morishima, Hirotaka; Yoshidome, Katsuhide; Nomura, Takashi; Morimoto, Takashi; Yamamoto, Daigo; Tsubota, Yu; Kobayashi, Toshihiro; Uchiyama, Kazuhisa

    2015-06-01

    We treated patients with operable human epidermal growth factor receptor 2-positive breast cancer with neoadjuvant anthracycline regimens followed by nanoparticle albumin-bound paclitaxel plus trastuzumab. Of the 44 patients, 49% achieved a pathologic complete response (pCR). The pCR rate was 36% and 71% in the patients with estrogen receptor-positive and -negative cancer, respectively. Neoadjuvant therapy using this combination appears to be effective and safe. Introduction: Neoadjuvant chemotherapy plus trastuzumab. Neoadjuvant chemotherapy plus trastuzumab results in a 30% to 50% pathologic complete response (pCR) rate in human epidermal growth factor receptor 2 (HER2)-positive breast cancer and has been associated with improved therapeutic outcomes. Thus, the pCR rate can be useful in evaluating novel agents in this patient population. Nanoparticle albumin-bound (nab)-paclitaxel (PTX) can reduce the toxicity of PTX while maintaining its efficacy. The present study evaluated the activity and safety of nab-PTX as a neoadjuvant treatment of HER2(+) breast cancer. We treated patients with stage I to IIIA breast cancer using neoadjuvant epirubicin/cyclophosphamide (EC) or 5-fluorouracil/epirubicin/cyclophosphamide every 3 weeks (q3w) for 4 cycles, followed by nab-PTX (260 mg/m(2)) plus trastuzumab q3w for 4 cycles. The primary endpoint was the pCR rate. The secondary endpoints included the clinical response rate, disease-free survival, pathologic response rate (defined as pCR or minimal residual invasive disease only in the breast), breast-conserving surgery rate, and safety. Forty-six patients were enrolled. One patient met the exclusion criteria because of the coexistence of another malignant disease; therefore, we evaluated 45 patients in the entire study. One patient experienced rapid disease progression during EC therapy, leaving 44 patients evaluable for nab-PTX treatment. Of the 45 patients, 49% achieved a pCR. The pCR rate was 36% and 71% in those with

  19. The LDL receptor.

    Science.gov (United States)

    Goldstein, Joseph L; Brown, Michael S

    2009-04-01

    In this article, the history of the LDL receptor is recounted by its codiscoverers. Their early work on the LDL receptor explained a genetic cause of heart attacks and led to new ways of thinking about cholesterol metabolism. The LDL receptor discovery also introduced three general concepts to cell biology: receptor-mediated endocytosis, receptor recycling, and feedback regulation of receptors. The latter concept provides the mechanism by which statins selectively lower plasma LDL, reducing heart attacks and prolonging life.

  20. Pb II

    African Journals Online (AJOL)

    Windows User

    This investigation describes the use of non-living biomass of Aspergillus caespitosus for removal of ... Pb(II) production has exceeded 3.5 million tons per year. It has been used in the ... This biomass was selected after screening a wide range of microbes. .... prolonged, which proved better biopolymer in metal uptake (Gadd ...

  1. Introductory statement: Of receptors and analogs in renin-angiotensin-aldosterone and adrenergic systems

    International Nuclear Information System (INIS)

    Eliahou, H.E.; Iaina, A.

    1980-01-01

    This article reports on the role of the octapeptides angiotensin II (A II)-effector and its receptor on hypertensive patients and in animal experiments. By applying the A-II-receptor blockers, vasodilates drugs, β-receptor blockers and by sodium depletion, the behaviour of the blood pressure, the plasmareninactivity, and of the aldosteron were investigated; a comparative investigation between the A II and A III effectors was also carried out. The iodo-hippurate uptake was reduced with an artificially produced renal arterial ischemia. In general, this investigation provided new viewpoints in the understanding of the possible pathogenetic mechanism of essential hypertonism. (APR) [de

  2. Phase I/II trial of vorinostat (SAHA) and erlotinib for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations after erlotinib progression.

    Science.gov (United States)

    Reguart, Noemi; Rosell, Rafael; Cardenal, Felipe; Cardona, Andres F; Isla, Dolores; Palmero, Ramon; Moran, Teresa; Rolfo, Christian; Pallarès, M Cinta; Insa, Amelia; Carcereny, Enric; Majem, Margarita; De Castro, Javier; Queralt, Cristina; Molina, Miguel A; Taron, Miquel

    2014-05-01

    Vorinostat or suberoylanilide hydroxamic acid (SAHA) is a novel histone deacetylase inhibitor with demonstrated antiproliferative effects due to drug-induced accumulation of acetylated proteins, including the heat shock protein 90. We prospectively studied the activity of vorinostat plus erlotinib in EGFR-mutated NSCLC patients with progression to tyrosine kinase inhibitors. We conducted this prospective, non-randomized, multicenter, phase I/II trial to evaluate the maximum tolerated dose, toxicity profile and efficacy of erlotinib and vorinostat. Patients with advanced NSCLC harboring EGFR mutations and progressive disease after a minimum of 12 weeks on erlotinib were included. The maximum tolerated dose of vorinostat plus erlotinib was used as recommended dose for the phase II (RDP2) to assess the efficacy of the combination. The primary end point was progression-free-survival rate at 12 weeks (PFSR12w). Pre-treatment plasma samples were required to assess T790M resistant mutation. A total of 33 patients were enrolled in the phase I-II trial. The maximum tolerated dose was erlotinib 150 mg p.o., QD, and 400mg p.o., QD, on days 1-7 and 15-21 in a 28-day cycle. Among the 25 patients treated at the RDP2, the most common toxicities included anemia, fatigue and diarrhea. No responses were observed. PFSR12w was 28% (IC 95%: 18.0-37.2); median progression-free survival (PFS) was 8 weeks (IC 95%: 7.43-8.45) and overall survival (OS) 10.3 months (95% CI: 2.4-18.1). Full dose of continuous erlotinib with vorinostat 400mg p.o., QD on alternative weeks can be safely administered. Still, the combination has no meaningful activity in EGFR-mutated NSCLC patients after TKI progression. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  3. A randomized, phase II study of the anti-insulin-like growth factor receptor type 1 (IGF-1R) monoclonal antibody robatumumab (SCH 717454) in patients with advanced colorectal cancer

    International Nuclear Information System (INIS)

    Lin, Edward H; Lenz, Heinz-Josef; Saleh, Mansoor N; Mackenzie, Mary J; Knost, James A; Pathiraja, Kumudu; Langdon, Ronald B; Yao, Siu-Long; Lu, Brian D

    2014-01-01

    Overexpression of insulin-like growth factor receptor type 1 (IGF-1R) may promote tumor development and progression in some cancer patients. Our objective was to assess tumor uptake of fluorodeoxyglucose by positron-emission tomography in patients with chemotherapy-refractory colorectal cancer treated with an anti-insulin-like growth factor receptor type 1 (anti-IGF-1R) monoclonal antibody, robatumumab. This was a randomized, open-label study with two periods (P1 and P2). Patients were randomized 3:1 into treatment arms R/R and C/R that received, respectively, one cycle of 0.3 mg/kg robatumumab or one or more cycles of second-line chemotherapy in P1, followed in either case by 10 mg/kg robatumumab biweekly in P2. The primary measure of fluorodeoxyglucose uptake was maximum standardized uptake value (SUV max ). The primary endpoint was the proportion of patients in the R/R arm having a mean percent decrease from baseline in SUV max (DiSUV) greater than 20% 12–14 days postdose in P2. Secondary endpoints included Response Evaluation Criteria in Solid Tumors (RECIST)-defined tumor response and pharmacodynamic measures of target engagement. Among 41 patients who were evaluable for the primary endpoint, seven (17%, 95% CI 7%–32%) had DiSUV greater than 20%. Fifty robatumumab-treated patients were evaluable for RECIST-defined tumor response and six (12%) had stable disease lasting greater than or equal to 7 weeks in P2. Pharmacodynamic endpoints indicated target engagement after dosing with 10 mg/kg robatumumab, but not 0.3 mg/kg. The most frequently reported adverse events were fatigue/asthenia, nausea, anorexia, and gastrointestinal disturbances. In this study, few patients with chemotherapy-refractory colorectal cancer appeared to benefit from treatment with the IGF-1R antagonist robatumumab

  4. Effect of neoadjuvant chemotherapy on low-density lipoprotein (LDL) receptor and LDL receptor-related protein 1 (LRP-1) receptor in locally advanced breast cancer

    International Nuclear Information System (INIS)

    Pires, L.A.; Hegg, R.; Freitas, F.R.; Tavares, E.R.; Almeida, C.P.; Baracat, E.C.; Maranhão, R.C.

    2012-01-01

    Low-density lipoprotein (LDL) receptors are overexpressed in most neoplastic cell lines and provide a mechanism for the internalization and concentration of drug-laden nanoemulsions that bind to these receptors. The aim of the present study was to determine whether the administration of standard chemotherapeutic schemes can alter the expression of LDL and LDL receptor-related protein 1 (LRP-1) receptors in breast carcinoma. Fragments of tumoral and normal breast tissue from 16 consecutive volunteer women with breast cancer in stage II or III were obtained from biopsies before the beginning of neoadjuvant chemotherapy and after chemotherapy, from fragments excised during mastectomy. Tissues were analyzed by immunohistochemistry for both receptors. Because complete response to treatment was achieved in 4 patients, only the tumors from 12 were analyzed. Before chemotherapy, there was overexpression of LDL receptor in the tumoral tissue compared to normal breast tissue in 8 of these patients. LRP-1 receptor overexpression was observed in tumors of 4 patients. After chemotherapy, expression of both receptors decreased in the tumors of 6 patients, increased in 4 and was unchanged in 2. Nonetheless, even when chemotherapy reduced receptors expression, the expression was still above normal. The fact that chemotherapy does not impair LDL receptors expression supports the use of drug carrier systems that target neoplastic cells by the LDL receptor endocytic pathway in patients on conventional chemotherapy

  5. Mediator-dependent Nuclear Receptor Functions

    Science.gov (United States)

    Chen, Wei; Roeder, Robert

    2011-01-01

    As gene-specific transcription factors, nuclear hormone receptors are broadly involved in many important biological processes. Their function on target genes requires the stepwise assembly of different coactivator complexes that facilitate chromatin remodeling and subsequent preinitiation complex (PIC) formation and function. Mediator has proved to be a crucial, and general, nuclear receptor-interacting coactivator, with demonstrated functions in transcription steps ranging from chromatin remodeling to subsequent PIC formation and function. Here we discuss (i) our current understanding of pathways that nuclear receptors and other interacting cofactors employ to recruit Mediator to target gene enhancers and promoters, including conditional requirements for the strong NR-Mediator interactions mediated by the NR AF2 domain and the MED1 LXXLLL motifs and (ii) mechanisms by which Mediator acts to transmit signals from enhancer-bound nuclear receptors to the general transcription machinery at core promoters to effect PIC formation and function. PMID:21854863

  6. Angiotensin receptors and norepinephrine neuromodulation: implications of functional coupling.

    Science.gov (United States)

    Gelband, C H; Sumners, C; Lu, D; Raizada, M K

    1998-02-27

    The objective of this review is to examine the role of neuronal angiotensin II (Ang II) receptors in vitro. Two types of G protein-coupled Ang II receptors have been identified in cardiovascularly relevant areas of the brain: the AT1 and the AT2. We have utilized neurons in culture to study the signaling mechanisms of AT1 and AT2 receptors. Neuronal AT1 receptors are involved in norepinephrine (NE) neuromodulation. NE neuromodulation can be either evoked or enhanced. Evoked NE neuromodulation involves AT1 receptor-mediated, losartan-dependent, rapid NE release, inhibition of K+ channels and stimulation of Ca2+ channels. AT1 receptor-mediated enhanced NE neuromodulation involves the Ras-Raf-MAP kinase cascade and ultimately leads to an increase in NE transporter, tyrosine hydroxylase and dopamine beta-hydroxylase mRNA transcription. Neuronal AT2 receptors signal via a Gi protein and are coupled to activation of PP2A and PLA2 and stimulation of K+ channels. Finally, putative cross-talk pathways between AT1 and AT2 receptors will be discussed.

  7. Functional relevance of G-protein-coupled-receptor-associated proteins, exemplified by receptor-activity-modifying proteins (RAMPs).

    Science.gov (United States)

    Fischer, J A; Muff, R; Born, W

    2002-08-01

    The calcitonin (CT) receptor (CTR) and the CTR-like receptor (CRLR) are close relatives within the type II family of G-protein-coupled receptors, demonstrating sequence identity of 50%. Unlike the interaction between CT and CTR, receptors for the related hormones and neuropeptides amylin, CT-gene-related peptide (CGRP) and adrenomedullin (AM) require one of three accessory receptor-activity-modifying proteins (RAMPs) for ligand recognition. An amylin/CGRP receptor is revealed when CTR is co-expressed with RAMP1. When complexed with RAMP3, CTR interacts with amylin alone. CRLR, initially classed as an orphan receptor, is a CGRP receptor when co-expressed with RAMP1. The same receptor is specific for AM in the presence of RAMP2. Together with human RAMP3, CRLR defines an AM receptor, and with mouse RAMP3 it is a low-affinity CGRP/AM receptor. CTR-RAMP1, antagonized preferentially by salmon CT-(8-32) and not by CGRP-(8-37), and CRLR-RAMP1, antagonized by CGRP-(8-37), are two CGRP receptor isotypes. Thus amylin and CGRP interact specifically with heterodimeric complexes between CTR and RAMP1 or RAMP3, and CGRP and AM interact with complexes between CRLR and RAMP1, RAMP2 or RAMP3.

  8. De-Escalation Strategies in Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Early Breast Cancer (BC): Final Analysis of the West German Study Group Adjuvant Dynamic Marker-Adjusted Personalized Therapy Trial Optimizing Risk Assessment and Therapy Response Prediction in Early BC HER2- and Hormone Receptor-Positive Phase II Randomized Trial-Efficacy, Safety, and Predictive Markers for 12 Weeks of Neoadjuvant Trastuzumab Emtansine With or Without Endocrine Therapy (ET) Versus Trastuzumab Plus ET.

    Science.gov (United States)

    Harbeck, Nadia; Gluz, Oleg; Christgen, Matthias; Kates, Ronald Ernest; Braun, Michael; Küemmel, Sherko; Schumacher, Claudia; Potenberg, Jochem; Kraemer, Stefan; Kleine-Tebbe, Anke; Augustin, Doris; Aktas, Bahriye; Forstbauer, Helmut; Tio, Joke; von Schumann, Raquel; Liedtke, Cornelia; Grischke, Eva-Maria; Schumacher, Johannes; Wuerstlein, Rachel; Kreipe, Hans Heinrich; Nitz, Ulrike Anneliese

    2017-09-10

    Purpose Human epidermal growth factor receptor 2 (HER2)-positive/hormone receptor (HR)-positive breast cancer is a distinct subgroup associated with lower chemotherapy sensitivity and slightly better outcome than HER2-positive/HR-negative disease. Little is known about the efficacy of the combination of endocrine therapy (ET) with trastuzumab or with the potent antibody-cytotoxic, anti-HER2 compound trastuzumab emtansine (T-DM1) with or without ET for this subgroup. The West German Study Group trial, ADAPT (Adjuvant Dynamic Marker-Adjusted Personalized Therapy Trial Optimizing Risk Assessment and Therapy Response Prediction in Early Breast Cancer) compares pathologic complete response (pCR) rates of T-DM1 versus trastuzumab with ET in early HER2-positive/HR-positive breast cancer. Patients and Methods In this prospective, neoadjuvant, phase II trial, 375 patients with early breast cancer with HER2-positive and HR-positive status (n = 463 screened) were randomly assigned to 12 weeks of T-DM1 with or without ET or to trastuzumab with ET. The primary end point was pCR (ypT0/is/ypN0). Early response was assessed in 3-week post-therapeutic core biopsies (proliferation decrease ≥ 30% Ki-67 or cellularity response). Secondary end points included safety and predictive impact of early response on pCR. Adjuvant therapy followed national standards. Results Baseline characteristics were well balanced among the arms. More than 90% of patients completed the therapy per protocol. pCR was observed in 41.0% of patients treated with T-DM1, 41.5% of patients treated with T-DM1 and ET, and 15.1% with trastuzumab and ET ( P < .001). Early responders (67% of patients with assessable response) achieved pCR in 35.7% compared with 19.8% in nonresponders (odds ratio, 2.2; 95% CI, 1.24 to 4.19). T-DM1 was associated with a significantly higher prevalence of grade 1 to 2 toxicities, especially thrombocytopenia, nausea, and elevation of liver enzymes. Overall toxicity was low; seventeen

  9. Small Diameter Bomb Increment II (SDB II)

    Science.gov (United States)

    2015-12-01

    Selected Acquisition Report (SAR) RCS: DD-A&T(Q&A)823-439 Small Diameter Bomb Increment II (SDB II) As of FY 2017 President’s Budget Defense... Bomb Increment II (SDB II) DoD Component Air Force Joint Participants Department of the Navy Responsible Office References SAR Baseline (Production...Mission and Description Small Diameter Bomb Increment II (SDB II) is a joint interest United States Air Force (USAF) and Department of the Navy

  10. Phase 1 clinical study of {sup 123}I-IBF, a new radioligand for evaluating dopamine D{sub 2} receptor with SPECT (II). Pharmacokinetics study and quantification in the brain

    Energy Technology Data Exchange (ETDEWEB)

    Yonekura, Yoshiharu; Sadato, Norihiro; Nakamura, Satoshi [Fukui Medical Univ., Matsuoka (Japan). High Energy Medical Research Center; Tsuchida, Tatsuro; Uematsu, Hidemasa; Onishi, Yoshihiro; Yamamoto, Kazutaka; Ishii, Yasushi

    1999-02-01

    The pharmacokinetics of (S)-5-iodo-7-N-((1-ethyl-2-pyrrolidinyl)methyl) carboxamido-2,3-dihydro-benzofuran ({sup 123}I-IBF) in the brain were studied in 12 healthy male volunteers as a Phase 1 clinical study. The striatum-to-frontal cortex count ratio (-1)(St/Fc-1), which is a semi-quantitative index of the binding potential of {sup 123}I-IBF reached 1.81{+-}0.19 and 2.21{+-}0.39 at 90-120 min and 180-210 min after intravenous injection of {sup 123}I-IBF. St/Fc-1 obtained by SPECT at these times correlated well with the distribution volume ratio (-1)(Vd(St)/Vd(Fc)-1) based on three-compartment model analysis using an input function obtained by intermittent arterial sampling. The binding potential (BP{sub R}), calculated by the curvefitting method using the time-activity curve in the reference region, also correlated well with the Vd(St)/Vd(Fc)-1. The intra-observer and inter-observer reproducibilities of the striatum-to-cerebral cortex count ratios obtained using fixed-shape regions of interest (template ROIs) were superior to those obtained using manual ROIs. These results suggest that {sup 123}I-IBF is a promising agent for non-invasive quantification of the dopamine D{sub 2} receptor (D{sub 2}-R) binding potential by SPECT. (author)

  11. The Cannabinoid Receptor CB1 Modulates the Signaling Properties of the Lysophosphatidylinositol Receptor GPR55*

    Science.gov (United States)

    Kargl, Julia; Balenga, Nariman; Parzmair, Gerald P.; Brown, Andrew J.; Heinemann, Akos; Waldhoer, Maria

    2012-01-01

    The G protein-coupled receptor (GPCR) 55 (GPR55) and the cannabinoid receptor 1 (CB1R) are co-expressed in many tissues, predominantly in the central nervous system. Seven transmembrane spanning (7TM) receptors/GPCRs can form homo- and heteromers and initiate distinct signaling pathways. Recently, several synthetic CB1 receptor inverse agonists/antagonists, such as SR141716A, AM251, and AM281, were reported to activate GPR55. Of these, SR141716A was marketed as a promising anti-obesity drug, but was withdrawn from the market because of severe side effects. Here, we tested whether GPR55 and CB1 receptors are capable of (i) forming heteromers and (ii) whether such heteromers could exhibit novel signaling patterns. We show that GPR55 and CB1 receptors alter each others signaling properties in human embryonic kidney (HEK293) cells. We demonstrate that the co-expression of FLAG-CB1 receptors in cells stably expressing HA-GPR55 specifically inhibits GPR55-mediated transcription factor activation, such as nuclear factor of activated T-cells and serum response element, as well as extracellular signal-regulated kinases (ERK1/2) activation. GPR55 and CB1 receptors can form heteromers, but the internalization of both receptors is not affected. In addition, we observe that the presence of GPR55 enhances CB1R-mediated ERK1/2 and nuclear factor of activated T-cell activation. Our data provide the first evidence that GPR55 can form heteromers with another 7TM/GPCR and that this interaction with the CB1 receptor has functional consequences in vitro. The GPR55-CB1R heteromer may play an important physiological and/or pathophysiological role in tissues endogenously co-expressing both receptors. PMID:23161546

  12. Molecular pharmacology of promiscuous seven transmembrane receptors sensing organic nutrients.

    Science.gov (United States)

    Wellendorph, Petrine; Johansen, Lars Dan; Bräuner-Osborne, Hans

    2009-09-01

    A number of highly promiscuous seven transmembrane (7TM) receptors have been cloned and characterized within the last few years. It is noteworthy that many of these receptors are activated broadly by amino acids, proteolytic degradation products, carbohydrates, or free fatty acids and are expressed in taste tissue, the gastrointestinal tract, endocrine glands, adipose tissue, and/or kidney. These receptors thus hold the potential to act as sensors of food intake, regulating, for example, release of incretin hormones from the gut, insulin/glucagon from the pancreas, and leptin from adipose tissue. The promiscuous tendency in ligand recognition of these receptors is in contrast to the typical specific interaction with one physiological agonist seen for most receptors, which challenges the classic "lock-and-key" concept. We here review the molecular mechanisms of nutrient sensing of the calcium-sensing receptor, the G protein-coupled receptor family C, group 6, subtype A (GPRC6A), and the taste1 receptor T1R1/T1R3, which are sensing L-alpha-amino acids, the carbohydrate-sensing T1R2/T1R3 receptor, the proteolytic degradation product sensor GPR93 (also termed GPR92), and the free fatty acid (FFA) sensing receptors FFA1, FFA2, FFA3, GPR84, and GPR120. The involvement of the individual receptors in sensing of food intake has been validated to different degrees because of limited availability of specific pharmacological tools and/or receptor knockout mice. However, as a group, the receptors represent potential drug targets, to treat, for example, type II diabetes by mimicking food intake by potent agonists or positive allosteric modulators. The ligand-receptor interactions of the promiscuous receptors of organic nutrients thus remain an interesting subject of emerging functional importance.

  13. Receptor-receptor interactions within receptor mosaics. Impact on neuropsychopharmacology.

    Science.gov (United States)

    Fuxe, K; Marcellino, D; Rivera, A; Diaz-Cabiale, Z; Filip, M; Gago, B; Roberts, D C S; Langel, U; Genedani, S; Ferraro, L; de la Calle, A; Narvaez, J; Tanganelli, S; Woods, A; Agnati, L F

    2008-08-01

    Future therapies for diseases associated with altered dopaminergic signaling, including Parkinson's disease, schizophrenia and drug addiction or drug dependence may substantially build on the existence of intramembrane receptor-receptor interactions within dopamine receptor containing receptor mosaics (RM; dimeric or high-order receptor oligomers) where it is believed that the dopamine D(2) receptor may operate as the 'hub receptor' within these complexes. The constitutive adenosine A(2A)/dopamine D(2) RM, located in the dorsal striato-pallidal GABA neurons, are of particular interest in view of the demonstrated antagonistic A(2A)/D(2) interaction within these heteromers; an interaction that led to the suggestion and later demonstration that A(2A) antagonists could be used as novel anti-Parkinsonian drugs. Based on the likely existence of A(2A)/D(2)/mGluR5 RM located both extrasynaptically on striato-pallidal GABA neurons and on cortico-striatal glutamate terminals, multiple receptor-receptor interactions within this RM involving synergism between A(2A)/mGluR5 to counteract D(2) signaling, has led to the proposal of using combined mGluR5 and A(2A) antagonists as a future anti-Parkinsonian treatment. Based on the same RM in the ventral striato-pallidal GABA pathways, novel strategies for the treatment of schizophrenia, building on the idea that A(2A) agonists and/or mGluR5 agonists will help reduce the increased dopaminergic signaling associated with this disease, have been suggested. Such treatment may ensure the proper glutamatergic drive from the mediodorsal thalamic nucleus to the prefrontal cortex, one which is believed to be reduced in schizophrenia due to a dominance of D(2)-like signaling in the ventral striatum. Recently, A(2A) receptors also have been shown to counteract the locomotor and sensitizing actions of cocaine and increases in A(2A) receptors have also been observed in the nucleus accumbens after extended cocaine self-administration, probably

  14. Comparison of effects of angiotensin-converting enzyme inhibition with those of angiotensin II receptor antagonism on functional and metabolic recovery in postischemic working rat heart as studied by [31P] nuclear magnetic resonance.

    Science.gov (United States)

    Werrmann, J G; Cohen, S M

    1994-10-01

    To assess the role of angiotensin II (AII) in development of myocardial injury during ischemia and reperfusion, the effects of short-term treatment with the angiotensin-converting enzyme (ACE) inhibitor lisinopril were compared with the effects of short-term treatment with L-158,338, an AII antagonist, in isolated working rat heart. Myocardial function was assessed and correlated with simultaneous measurement of high-energy phosphate metabolism and intracellular pH by [31P] nuclear magnetic resonance (NMR) before, during, and after global ischemia. Hearts from rats treated with 1 mg/kg lisinopril in vivo recovered substantially more function than those of controls (p effect on functional recovery. A dose-dependent increase in functional recovery was observed in rat heart treated with 0.3, 1, or 3 mg/kg L-158,338 in vivo (p energy phosphate metabolism was essentially unchanged by any treatment regimen. AII antagonism alone resulted in a degree of improvement in functional recovery comparable to that observed with oral ACE inhibitor treatment.

  15. Melatonin membrane receptors in peripheral tissues: Distribution and functions

    Science.gov (United States)

    Slominski, Radomir M.; Reiter, Russel J.; Schlabritz-Loutsevitch, Natalia; Ostrom, Rennolds S.; Slominski, Andrzej T.

    2012-01-01

    Many of melatonin’s actions are mediated through interaction with the G-protein coupled membrane bound melatonin receptors type 1 and type 2 (MT1 and MT2, respectively) or, indirectly with nuclear orphan receptors from the RORα/RZR family. Melatonin also binds to the quinone reductase II enzyme, previously defined the MT3 receptor. Melatonin receptors are widely distributed in the body; herein we summarize their expression and actions in non-neural tissues. Several controversies still exist regarding, for example, whether melatonin binds the RORα/RZR family. Studies of the peripheral distribution of melatonin receptors are important since they are attractive targets for immunomodulation, regulation of endocrine, reproductive and cardiovascular functions, modulation of skin pigmentation, hair growth, cancerogenesis, and aging. Melatonin receptor agonists and antagonists have an exciting future since they could define multiple mechanisms by which melatonin modulates the complexity of such a wide variety of physiological and pathological processes. PMID:22245784

  16. Tomo II

    OpenAIRE

    Llano Zapata, José Eusebio

    2015-01-01

    Memorias, histórico, físicas, crítico, apologéticas de la América Meridional con unas breves advertencias y noticias útiles, a los que de orden de Su Majestad hubiesen de viajar y describir aquellas vastas regiones. Reino Vegetal, Tomo II. Por un anónimo americano en Cádiz por los años de 1757. Muy Señor mío, juzgo que los 20 artículos del libro que remití a Vuestra Merced le habrán hecho formar el concepto que merece la fecundidad de aquellos países en las producciones minerales. Y siendo es...

  17. [177Lu-DOTA]0-D-Phe1-Tyr3-Octreotide (177Lu-DOTATOC) For Peptide Receptor Radiotherapy in Patients with Advanced Neuroendocrine Tumours: A Phase-II Study

    Science.gov (United States)

    Baum, Richard P.; Kluge, Andreas W.; Kulkarni, Harshad; Schorr-Neufing, Ulrike; Niepsch, Karin; Bitterlich, Norman; van Echteld, Cees J.A.

    2016-01-01

    Purpose: To characterise efficacy and safety of 177Lu-DOTATOC as agent for peptide receptor radiotherapy (PRRT) of advanced neuroendocrine tumours (NET). Patients and methods: Fifty-six subjects with metastasized and progressive NET (50% gastroenteral, 26.8% pancreatic, 23.2% other primary sites) treated consecutively with 177Lu-DOTATOC were analysed retrospectively. Subjects were administered 177Lu-DOTATOC (mean 2.1 cycles; range 1-4) as 7.0GBq (median) doses at three-monthly intervals. Efficacy was analysed using CT and/or MRI according to RECIST 1.1 criteria and results were stratified for the number of administered cycles and the primary tumour origin. Results: In the total NET population (A), median progression-free (PFS) and overall survival (OS) were 17.4 and 34.2 months, respectively, assessed in a follow-up time (mean ± SD) of 16.1 ± 12.4 months. In patients receiving more than one cycle, mean follow-up time was 22.4 ± 11.0 months for all NETs (B) and PFS was 32.0 months for all NETs (B), 34.5 months for GEP-NET (C), and 11.9 months for other NETs (D). Objective response rates (Complete/Partial Responses) were 33.9%, 40.6%, 54.2%, and 0% for A, B, C, and D groups, respectively, while disease control rates in the same were 66.1%, 93.8%, 100%, and 75%. Complete responses (16.1%, 18.8% and 25.0% for groups A, B and C) were high, 78% of which were maintained throughout the follow up. There were no serious adverse events. One case of self-limiting grade 3 myelotoxicity was reported. Although 20% of patients had mild renal insufficiency at baseline, there was no evidence of exacerbated or de novo renal toxicity after treatment. Conclusion: 177Lu-DOTATOC is a novel agent for PRRT with major potential to induce objective tumour responses and sustained disease control in progressive neuroendocrine tumours, even when administered in moderate activities. The observed safety profile suggests a particularly favourable therapeutic index, including in patients with

  18. Acetylcholine receptor antibody

    Science.gov (United States)

    ... medlineplus.gov/ency/article/003576.htm Acetylcholine receptor antibody To use the sharing features on this page, please enable JavaScript. Acetylcholine receptor antibody is a protein found in the blood of ...

  19. Cooperative ethylene receptor signaling

    OpenAIRE

    Liu, Qian; Wen, Chi-Kuang

    2012-01-01

    The gaseous plant hormone ethylene is perceived by a family of five ethylene receptor members in the dicotyledonous model plant Arabidopsis. Genetic and biochemical studies suggest that the ethylene response is suppressed by ethylene receptor complexes, but the biochemical nature of the receptor signal is unknown. Without appropriate biochemical measures to trace the ethylene receptor signal and quantify the signal strength, the biological significance of the modulation of ethylene responses ...

  20. Pharmacological significance of the interplay between angiotensin receptors: MAS receptors as putative final mediators of the effects elicited by angiotensin AT1 receptors antagonists.

    Science.gov (United States)

    Pernomian, Larissa; Pernomian, Laena; Gomes, Mayara S; da Silva, Carlos H T P

    2015-12-15

    The interplay between angiotensin AT1 receptors and MAS receptors relies on several inward regulatory mechanisms from renin-angiotensin system (RAS) including the functional crosstalk between angiotensin II and angiotensin-(1-7), the competitive AT1 antagonism exhibited by angiotensin-(1-7), the antagonist feature assigned to AT1/MAS heterodimerization on AT1 signaling and the AT1-mediated downregulation of angiotensin-converting enzyme 2 (ACE2). Recently, such interplay has acquired an important significance to RAS Pharmacology since a few studies have supporting strong evidences that MAS receptors mediate the effects elicited by AT1 antagonists. The present Perspective provides an overview of the regulatory mechanisms involving AT1 and MAS receptors, their significance to RAS Pharmacology and the future directions on the interplay between angiotensin receptors. Copyright © 2015 Elsevier B.V. All rights reserved.

  1. Functionally Selective AT(1) Receptor Activation Reduces Ischemia Reperfusion Injury

    DEFF Research Database (Denmark)

    Hostrup, Anders; Christensen, Gitte Lund; Bentzen, Bo Hjort

    2012-01-01

    of the physiological functions of AngII. The AT(1)R mediates its effects through both G protein-dependent and independent signaling, which can be separated by functionally selective agonists. In the present study we investigate the effect of AngII and the ß-arrestin biased agonist [SII]AngII on ischemia......]AngII had a protective effect. Together these results demonstrate a cardioprotective effect of simultaneous blockade of G protein signaling and activation of G protein independent signaling through AT(1 )receptors....

  2. Crystal structure of NL63 respiratory coronavirus receptor-binding domain complexed with its human receptor

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Kailang; Li, Weikai; Peng, Guiqing; Li, Fang; (Harvard-Med); (UMM-MED)

    2010-03-04

    NL63 coronavirus (NL63-CoV), a prevalent human respiratory virus, is the only group I coronavirus known to use angiotensin-converting enzyme 2 (ACE2) as its receptor. Incidentally, ACE2 is also used by group II SARS coronavirus (SARS-CoV). We investigated how different groups of coronaviruses recognize the same receptor, whereas homologous group I coronaviruses recognize different receptors. We determined the crystal structure of NL63-CoV spike protein receptor-binding domain (RBD) complexed with human ACE2. NL63-CoV RBD has a novel {beta}-sandwich core structure consisting of 2 layers of {beta}-sheets, presenting 3 discontinuous receptor-binding motifs (RBMs) to bind ACE2. NL63-CoV and SARS-CoV have no structural homology in RBD cores or RBMs; yet the 2 viruses recognize common ACE2 regions, largely because of a 'virus-binding hotspot' on ACE2. Among group I coronaviruses, RBD cores are conserved but RBMs are variable, explaining how these viruses recognize different receptors. These results provide a structural basis for understanding viral evolution and virus-receptor interactions.

  3. Evidence of changes in alpha-1/AT1 receptor function generated by diet-induced obesity.

    Science.gov (United States)

    Juarez, Esther; Tufiño, Cecilia; Querejeta, Enrique; Bracho-Valdes, Ismael; Bobadilla-Lugo, Rosa A

    2017-11-01

    To study whether hypercaloric diet-induced obesity deteriorates vascular contractility of rat aorta through functional changes in α 1 adrenergic and/or AT1 Angiotensin II receptors. Angiotensin II- or phenylephrine-induced contraction was tested on isolated aorta rings with and without endothelium from female Wistar rats fed for 7 weeks with hypercaloric diet or standard diet. Vascular expression of Angiotensin II Receptor type 1 (AT1R), Angiotensin II Receptor type 2 (AT2R), Cyclooxygenase-1 (COX-1), Cyclooxygenase-2 (COX-2), inducible Nitric Oxide Synthase (iNOS) and endothelial Nitric Oxide Synthase (eNOS), as well as blood pressure, glucose, insulin and angiotensin II blood levels were measured. Diet-induced obesity did not significantly change agonist-induced contractions (Emax and pD 2 hypercaloric diet vs standard diet n.s.d.) of both intact (e+) or endothelium free (e-) vessels but significantly decrease both phenylephrine and angiotensin II contraction (Emax p obesity did not change angiotensin II AT1, AT2 receptor proteins expression but reduced COX-1 and NOS2 ( p obesity produces alterations in vascular adrenergic and angiotensin II receptor dynamics that suggest an endothelium-dependent adrenergic/angiotensin II crosstalk. These changes reflect early-stage vascular responses to obesity.

  4. Cd(II), Cu(II)

    African Journals Online (AJOL)

    user

    Depending on the way goethite was pretreated with oxalic acid, affinity for Cd(II) varied ...... Effects and mechanisms of oxalate on Cd(II) adsorption on goethite at different ... precipitation, surfactant mediation, hydrothermal and micro-emulsion.

  5. Mediator and p300/CBP-Steroid Receptor Coactivator Complexes Have Distinct Roles, but Function Synergistically, during Estrogen Receptor α-Dependent Transcription with Chromatin Templates

    OpenAIRE

    Acevedo, Mari Luz; Kraus, W. Lee

    2003-01-01

    Ligand-dependent transcriptional activation by nuclear receptors involves the recruitment of various coactivators to the promoters of hormone-regulated genes assembled into chromatin. Nuclear receptor coactivators include histone acetyltransferase complexes, such as p300/CBP-steroid receptor coactivator (SRC), as well as the multisubunit mediator complexes (“Mediator”), which may help recruit RNA polymerase II to the promoter. We have used a biochemical approach, including an in vitro chromat...

  6. Cu(II) AND Zn(II)

    African Journals Online (AJOL)

    Preferred Customer

    SYNTHESIS OF 2,2-DIMETHYL-4-PHENYL-[1,3]-DIOXOLANE USING ZEOLITE. ENCAPSULATED Co(II), Cu(II) AND Zn(II) COMPLEXES. B.P. Nethravathi1, K. Rama Krishna Reddy2 and K.N. Mahendra1*. 1Department of Chemistry, Bangalore University, Bangalore-560001, India. 2Department of Chemistry, Government ...

  7. Elizabeth II uus kunstigalerii

    Index Scriptorium Estoniae

    1999-01-01

    Tähistamaks oma troonile asumise 50. aastapäeva, avab Elizabeth II 6. II 2002 Buckinghami palees uue kunstigalerii, mis ehitatakse palee tiibhoonena. Arhitekt John Simpson. Elizabeth II kunstikogust

  8. Estrogen effects on angiotensin receptors are modulated by pituitary in female rats

    International Nuclear Information System (INIS)

    Douglas, J.G.

    1987-01-01

    The present studies were designed to test the hypothesis that changes in angiotensin II (ANG II) receptors might modulate the layered target tissue responsiveness accompanying estradiol administration. Estradiol was infused continuously in oophorectomized female rats. Aldosterone was also infused in control and experimental animals to avoid estrogen-induced changes in renin and ANG II. ANG II binding constants were determined in radioreceptor assays. Estradiol increased binding site concentration in adrenal glomerulosa by 76% and decreased binding sites of uterine myometrium and glomeruli by 45 and 24%, respectively. There was an accompanying increase in the affinity of ANG II binding to adrenal glomerulosa and uterine myometrium. Because estrogen is a potent stimulus of prolactin release from the pituitary of rodents, studies were also designed to test the hypothesis that prolactin may mediate some or all of the estrogen-induced effects observed. Hypophysectomy abolished estradiol stimulation of prolactin release and most ANG II receptor changes. Prolactin administration to pituitary intact rats was associated with a 50% increase in receptor density of adrenal glomerulosa simulating estradiol administration. However, the changes in glomeruli and uterine myometrium were opposite in that both tissues also increased receptor density, suggesting that prolactin was not the sole mediator of the estrogen-induced receptor changes. In conclusion, regulation of ANG II receptors in a number of diverse target tissues by estradiol is complex with contributions from estrogens and pituitary factors, which include but do not exclusively involve prolactin

  9. Cross reaction between P-61 sunflower seedlings oleosomal protein ...

    African Journals Online (AJOL)

    A true triacylglycerol lipase was detected in germinating sunflower (Helianthus annuus L.) seedlings associated to oleosomes. This enzyme that has not yet been identified was partially purified as shown by sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS PAGE) (10%); two protein bands, P-61 and P-66 ...

  10. GABA receptor imaging

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Jong Doo [Yonsei University College of Medicine, Seoul (Korea, Republic of)

    2007-04-15

    GABA is primary an inhibitory neurotransmitter that is localized in inhibitory interneurons. GABA is released from presynaptic terminals and functions by binding to GABA receptors. There are two types of GABA receptors, GABA{sub A}-receptor that allows chloride to pass through a ligand gated ion channel and GABA{sub B}-receptor that uses G-proteins for signaling. The GABA{sub A}-receptor has a GABA binding site as well as a benzodiazepine binding sites, which modulate GABA{sub A}-receptor function. Benzodiazepine GABAA receptor imaging can be accomplished by radiolabeling derivates that activates benzodiazepine binding sites. There has been much research on flumazenil (FMZ) labeled with {sup 11}C-FMZ, a benzodiazepine derivate that is a selective, reversible antagonist to GABAA receptors. Recently, {sup 18}F-fluoroflumazenil (FFMZ) has been developed to overcome {sup 11}C's short half-life. {sup 18}F-FFMZ shows high selective affinity and good pharmacodynamics, and is a promising PET agent with better central benzodiazepine receptor imaging capabilities. In an epileptic focus, because the GABA/benzodiazepine receptor amount is decreased, using '1{sup 1}C-FMZ PET instead of {sup 18}F-FDG, PET, restrict the foci better and may also help find lesions better than high resolution MR. GABA{sub A} receptors are widely distributed in the cerebral cortex, and can be used as an viable neuronal marker. Therefore it can be used as a neuronal cell viability marker in cerebral ischemia. Also, GABA-receptors decrease in areas where neuronal plasticity develops, therefore, GABA imaging can be used to evaluate plasticity. Besides these usages, GABA receptors are related with psychological diseases, especially depression and schizophrenia as well as cerebral palsy, a motor-related disorder, so further in-depth studies are needed for these areas.

  11. GABA receptor imaging

    International Nuclear Information System (INIS)

    Lee, Jong Doo

    2007-01-01

    GABA is primary an inhibitory neurotransmitter that is localized in inhibitory interneurons. GABA is released from presynaptic terminals and functions by binding to GABA receptors. There are two types of GABA receptors, GABA A -receptor that allows chloride to pass through a ligand gated ion channel and GABA B -receptor that uses G-proteins for signaling. The GABA A -receptor has a GABA binding site as well as a benzodiazepine binding sites, which modulate GABA A -receptor function. Benzodiazepine GABAA receptor imaging can be accomplished by radiolabeling derivates that activates benzodiazepine binding sites. There has been much research on flumazenil (FMZ) labeled with 11 C-FMZ, a benzodiazepine derivate that is a selective, reversible antagonist to GABAA receptors. Recently, 18 F-fluoroflumazenil (FFMZ) has been developed to overcome 11 C's short half-life. 18 F-FFMZ shows high selective affinity and good pharmacodynamics, and is a promising PET agent with better central benzodiazepine receptor imaging capabilities. In an epileptic focus, because the GABA/benzodiazepine receptor amount is decreased, using '1 1 C-FMZ PET instead of 18 F-FDG, PET, restrict the foci better and may also help find lesions better than high resolution MR. GABA A receptors are widely distributed in the cerebral cortex, and can be used as an viable neuronal marker. Therefore it can be used as a neuronal cell viability marker in cerebral ischemia. Also, GABA-receptors decrease in areas where neuronal plasticity develops, therefore, GABA imaging can be used to evaluate plasticity. Besides these usages, GABA receptors are related with psychological diseases, especially depression and schizophrenia as well as cerebral palsy, a motor-related disorder, so further in-depth studies are needed for these areas

  12. A novel human gene encoding a G-protein-coupled receptor (GPR15) is located on chromosome 3

    Energy Technology Data Exchange (ETDEWEB)

    Heiber, M.; Marchese, A.; O`Dowd, B.F. [Univ. of Toronto, Ontario (Canada)] [and others

    1996-03-05

    We used sequence similarities among G-protein-coupled receptor genes to discover a novel receptor gene. Using primers based on conserved regions of the opioid-related receptors, we isolated a PCR product that was used to locate the full-length coding region of a novel human receptor gene, which we have named GPR15. A comparison of the amino acid sequence of the receptor gene, which we have named GPR15. A comparison of the amino acid sequence of the receptor encoded by GPR15 with other receptors revealed that it shared sequence identity with the angiotensin II AT1 and AT2 receptors, the interleukin 8b receptor, and the orphan receptors GPR1 and AGTL1. GPR15 was mapped to human chromosome 3q11.2-q13.1. 12 refs., 2 figs.

  13. Structural Analysis of Botulinum Neurotoxin Type G Receptor Binding

    Energy Technology Data Exchange (ETDEWEB)

    Schmitt, John; Karalewitz, Andrew; Benefield, Desire A.; Mushrush, Darren J.; Pruitt, Rory N.; Spiller, Benjamin W.; Barbieri, Joseph T.; Lacy, D. Borden (Vanderbilt); (MCW)

    2010-10-19

    Botulinum neurotoxin (BoNT) binds peripheral neurons at the neuromuscular junction through a dual-receptor mechanism that includes interactions with ganglioside and protein receptors. The receptor identities vary depending on BoNT serotype (A-G). BoNT/B and BoNT/G bind the luminal domains of synaptotagmin I and II, homologous synaptic vesicle proteins. We observe conditions under which BoNT/B binds both Syt isoforms, but BoNT/G binds only SytI. Both serotypes bind ganglioside G{sub T1b}. The BoNT/G receptor-binding domain crystal structure provides a context for examining these binding interactions and a platform for understanding the physiological relevance of different Syt receptor isoforms in vivo.

  14. Molecular pharmacology of promiscuous seven transmembrane receptors sensing organic nutrients

    DEFF Research Database (Denmark)

    Wellendorph, Petrine; Johansen, Lars Dan; Bräuner-Osborne, Hans

    2009-01-01

    drug targets, to treat, for example, type II diabetes by mimicking food intake by potent agonists or positive allosteric modulators. The ligand-receptor interactions of the promiscuous receptors of organic nutrients thus remain an interesting subject of emerging functional importance....... in taste tissue, the gastrointestinal tract, endocrine glands, adipose tissue, and/or kidney. These receptors thus hold the potential to act as sensors of food intake, regulating, for example, release of incretin hormones from the gut, insulin/glucagon from the pancreas, and leptin from adipose tissue....... The promiscuous tendency in ligand recognition of these receptors is in contrast to the typical specific interaction with one physiological agonist seen for most receptors, which challenges the classic "lock-and-key" concept. We here review the molecular mechanisms of nutrient sensing of the calcium...

  15. Glucocorticoid receptor modulators.

    Science.gov (United States)

    Meijer, Onno C; Koorneef, Lisa L; Kroon, Jan

    2018-06-01

    The glucocorticoid hormone cortisol acts throughout the body to support circadian processes and adaptation to stress. The glucocorticoid receptor is the target of cortisol and of synthetic glucocorticoids, which are used widely in the clinic. Both agonism and antagonism of the glucocorticoid receptor may be beneficial in disease, but given the wide expression of the receptor and involvement in various processes, beneficial effects are often accompanied by unwanted side effects. Selective glucocorticoid receptor modulators are ligands that induce a receptor conformation that allows activation of only a subset of downstream signaling pathways. Such molecules thereby combine agonistic and antagonistic properties. Here we discuss the mechanisms underlying selective receptor modulation and their promise in treating diseases in several organ systems where cortisol signaling plays a role. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  16. Synthesis and characterisatio