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Sample records for bradykinin b1 receptor

  1. B1 but not B2 bradykinin receptor agonists promote DU145 prostate ...

    African Journals Online (AJOL)

    both vital for cancer growth and progression. Objectives: To investigate the effect of two bradykinin receptor (B1R and B2R) agonists on growth and motility of prostate tumour (DU145) and micro-vascular endothelial cells (dMVECs). Methods: Increasing concentrations of selective B1R and B2R agonists were added to ...

  2. B1 but not B2 bradykinin receptor agonists promote DU145 prostate ...

    African Journals Online (AJOL)

    Background: The kallikrein-kinin system (KKS) is an endogenous pathway involved in angiogenesis and tumourigenesis, both vital for cancer growth and progression. Objectives: To investigate the effect of two bradykinin receptor (B1R and B2R) agonists on growth and motility of prostate tumour (DU145) and ...

  3. Cellular localization of kinin B1 receptor in the spinal cord of streptozotocin-diabetic rats with a fluorescent [Nα-Bodipy]-des-Arg9-bradykinin

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    Gaudreau Pierrette

    2009-03-01

    Full Text Available Abstract Background The kinin B1 receptor (B1R is upregulated by pro-inflammatory cytokines, bacterial endotoxins and hyperglycaemia-induced oxidative stress. In animal models of diabetes, it contributes to pain polyneuropathy. This study aims at defining the cellular localization of B1R in thoracic spinal cord of type 1 diabetic rats by confocal microscopy with the use of a fluorescent agonist, [Nα-Bodipy]-des-Arg9-BK (BdABK and selective antibodies. Methods Diabetes was induced by streptozotocin (STZ; 65 mg/kg, i.p.. Four days post-STZ treatment, B1R expression was confirmed by quantitative real-time PCR and autoradiography. The B1R selectivity of BdABK was determined by assessing its ability to displace B1R [125I]-HPP-desArg10-Hoe140 and B2R [125I]-HPP-Hoe 140 radioligands. The in vivo activity of BdABK was also evaluated on thermal hyperalgesia. Results B1R was increased by 18-fold (mRNA and 2.7-fold (binding sites in the thoracic spinal cord of STZ-treated rats when compared to control. BdABK failed to displace the B2R radioligand but displaced the B1R radioligand (IC50 = 5.3 nM. In comparison, IC50 values of B1R selective antagonist R-715 and B1R agonist des-Arg9-BK were 4.3 nM and 19 nM, respectively. Intraperitoneal BdABK and des-Arg9-BK elicited dose-dependent thermal hyperalgesia in STZ-treated rats but not in control rats. The B1R fluorescent agonist was co-localized with immunomarkers of microglia, astrocytes and sensory C fibers in the spinal cord of STZ-treated rats. Conclusion The induction and up-regulation of B1R in glial and sensory cells of the spinal cord in STZ-diabetic rats reinforce the idea that kinin B1R is an important target for drug development in pain processes.

  4. Kinin-B2 receptor mediated neuroprotection after NMDA excitotoxicity is reversed in the presence of kinin-B1 receptor agonists.

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    Antonio H Martins

    Full Text Available BACKGROUND: Kinins, with bradykinin and des-Arg(9-bradykinin being the most important ones, are pro-inflammatory peptides released after tissue injury including stroke. Although the actions of bradykinin are in general well characterized; it remains controversial whether the effects of bradykinin are beneficial or not. Kinin-B2 receptor activation participates in various physiological processes including hypotension, neurotransmission and neuronal differentiation. The bradykinin metabolite des-Arg(9-bradykinin as well as Lys-des-Arg(9-bradykinin activates the kinin-B1 receptor known to be expressed under inflammatory conditions. We have investigated the effects of kinin-B1 and B2 receptor activation on N-methyl-D-aspartate (NMDA-induced excitotoxicity measured as decreased capacity to produce synaptically evoked population spikes in the CA1 area of rat hippocampal slices. PRINCIPAL FINDINGS: Bradykinin at 10 nM and 1 µM concentrations triggered a neuroprotective cascade via kinin-B2 receptor activation which conferred protection against NMDA-induced excitotoxicity. Recovery of population spikes induced by 10 nM bradykinin was completely abolished when the peptide was co-applied with the selective kinin-B2 receptor antagonist HOE-140. Kinin-B2 receptor activation promoted survival of hippocampal neurons via phosphatidylinositol 3-kinase, while MEK/MAPK signaling was not involved in protection against NMDA-evoked excitotoxic effects. However, 100 nM Lys-des-Arg(9-bradykinin, a potent kinin-B1 receptor agonist, reversed bradykinin-induced population spike recovery. The inhibition of population spikes recovery was reversed by PD98059, showing that MEK/MAPK was involved in the induction of apoptosis mediated by the B1 receptor. CONCLUSIONS: Bradykinin exerted protection against NMDA-induced excitotoxicity which is reversed in the presence of a kinin-B1 receptor agonist. As bradykinin is converted to the kinin-B1 receptor metabolite des-Arg(9

  5. Regulation of bradykinin B2-receptor expression by oestrogen

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    Madeddu, Paolo; Emanueli, Costanza; Varoni, Maria Vittoria; Demontis, Maria Piera; Anania, Vittorio; Gorioso, Nicola; Chao, Julie

    1997-01-01

    Tissue kallikrein is overexpressed in the kidney of female rats, this sexual dimorphism being associated with a greater effect of early blockade of bradykinin B2-receptors on female blood pressure phenotype. We evaluated the effect of ovariectomy and oestradiol benzoate (50 μg kg−1 every two days for two weeks) on the vasodepressor response to intra-arterial injection of bradykinin (150–900 ng kg−1) and on the expression of bradykinin B2-receptors.Ovariectomy reduced the magnitude of the vasodepressor response to bradykinin and unmasked a secondary vasopressor effect. Oestrogen replacement restored the vasodepressor response to bradykinin in ovariectomized rats.The vasodepressor responses to sodium nitroprusside (3–18 μg kg−1), acetylcholine (30–600 ng kg−1), desArg9-bradykinin (150–900 ng kg−1) or prostaglandin E2 (30–600 ng kg−1) were significantly reduced by ovariectomy. Oestrogen restored to normal the responses to desArg9-bradykinin, acetylcholine and prostaglandin E2, but not that to sodium nitroprusside.B2-receptor mRNA levels were decreased by ovariectomy in the aorta and kidney and they were restored to normal levels by oestrogen. Neither ovariectomy nor oestradiol affected receptor expression in the heart and uterus.These results indicate that oestrogen regulates B2-receptor gene expression and function. Since kinins exert a cardiovascular protective action, reduction in their vasodilator activity after menopause might contribute to the increased risk of pathological cardiovascular events. Conversely, the cardioprotective effects of oestrogen replacement might be, at least in part, mediated by activation of the kallikrein-kinin system. PMID:9283715

  6. Nuclear localization of bradykinin B(2) receptors reflects binding to the nuclear envelope protein lamin C.

    Science.gov (United States)

    Takano, Masaoki; Kanoh, Akira; Amako, Katsumi; Otani, Mieko; Sano, Keiji; Kanazawa-Hamada, Michiko; Matsuyama, Shogo

    2014-01-15

    The mechanism of action of bradykinin (BK), a pro-inflammatory mediator, is thought to be mediated by specific cell surface membrane bradykinin B2 receptors. Some evidence suggests that there are both intracellular and nuclear bradykinin B2 receptors. This study identified proteins that interact with the C-terminus of the bradykinin B2 receptor (in particular, the nuclear membrane protein lamin C), using the yeast two-hybrid system. The motif of the C-terminal domain (CT) mutant 303-320 in bradykinin B2 receptor was identified as a lamin C protein binding motif. Immunohistochemistry revealed colocalization of FLAG- bradykinin B2 receptor with HA-lamin C in the nucleus of HEK 293T cells. In situ proximity ligation assay (PLA) showed that FLAG-bradykinin B2 receptor formed heterodimers with HA-lamin C in the nucleus. In addition, live cell fluorescence imaging showed that bradykinin B2 receptor-EGFP was located in the nucleus and co-localized with HcRed-lamin C. Interestingly, neither BK addition nor bradykinin B2 receptor CT mutation reduced the binding to lamin C or changed the distribution of bradykinin B2 receptor. Taken together, these findings demonstrate that bradykinin B2 receptor-lamin C heterodimers form in the nucleus independent of BK stimulation and CT mutation. We propose that heterodimerization of bradykinin B2 receptor with lamin C is essential to nuclear localization of bradykinin B2 receptor and plays an important role in cell signaling and function. © 2013 Elsevier B.V. All rights reserved.

  7. Bradykinin receptor blockade restores the baroreflex control of renal sympathetic nerve activity in cisplatin-induced renal failure rats.

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    Abdulla, M H; Duff, M; Swanton, H; Johns, E J

    2016-11-01

    This study investigated the effect of renal bradykinin B1 and B2 receptor blockade on the high- and low-pressure baroreceptor reflex regulation of renal sympathetic nerve activity (RSNA) in rats with cisplatin-induced renal failure. Cisplatin (5 mg/kg) or saline was given intraperitoneally 4 days prior to study. Following chloralose/urethane anaesthesia, rats were prepared for measurement of mean arterial pressure (MAP), heart rate and RSNA and received intrarenal infusions of either Lys-[des-Arg9 , Leu8 ]-bradykinin (LBK), a bradykinin B1 receptor blocker, or bradyzide (BZ), a bradykinin B2 receptor blocker. RSNA baroreflex gain curves and renal sympatho-inhibitory responses to volume expansion (VE) were obtained. In the control and renal failure groups, basal MAP (89 ± 3 vs. 80 ± 8 mmHg) and RSNA (2.0 ± 0.3 vs. 1.7 ± 0.6 μV.s) were similar but HR was lower in the latter group (331 ± 8 vs. 396 ± 9 beats/min). The baroreflex gain for RSNA in the renal failure rats was 39% (P renal failure rats. Intrarenal LBK infusion in the renal failure rats normalized the VE induced renal sympatho-inhibition whereas BZ only partially restored the response. These findings suggest that pro-inflammatory bradykinin acting at different receptors within the kidney generates afferent neural signals which impact differentially within the central nervous system on high- and low-pressure regulation of RSNA. © 2016 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.

  8. Bradykinin B2-receptor-mediated positive chronotropic effect of bradykinin in isolated rat atria

    NARCIS (Netherlands)

    Li, Q.; Zhang, J.; Loro, J. F.; Pfaffendorf, M.; van Zwieten, P. A.

    1998-01-01

    The positive chronotropic effect of bradykinin was investigated in isolated spontaneously beating atria of the rat. Cumulative additions of bradykinin (0.3-100 nM) caused a concentration-dependent increase in the beating rate of the atria by maximally 35+/-4 beats/min, approximately 25% of the 1

  9. The bradykinin B2 receptor in the early immune response against Listeria infection

    NARCIS (Netherlands)

    Kaman, W.E.; Wolterink, A.F.W.M.; Bader, M.; Boele, L.C.L.; Kleij, D. van der

    2009-01-01

    The endogenous danger signal bradykinin was recently found implicated in the development of immunity against parasites via dendritic cells. We here report an essential role of the B2 (B2R) bradykinin receptor in the early immune response against Listeria infection. Mice deficient in B2R (B2R-/-

  10. Kinin B1 Receptor Promotes Neurogenic Hypertension Through Activation of Centrally Mediated Mechanisms.

    Science.gov (United States)

    Sriramula, Srinivas; Lazartigues, Eric

    2017-12-01

    Hypertension is associated with increased activity of the kallikrein-kinin system. Kinin B1 receptor (B1R) activation leads to vasoconstriction and inflammation. Despite evidence supporting a role for the B1R in blood pressure regulation, the mechanisms by which B1R could alter autonomic function and participate in the pathogenesis of hypertension remain unidentified. We sought to explore whether B1R-mediated inflammation contributes to hypertension and investigate the molecular mechanisms involved. In this study, we tested the hypothesis that activation of B1R in the brain is involved in the pathogenesis of hypertension, using the deoxycorticosterone acetate-salt model of neurogenic hypertension in wild-type and B1R knockout mice. Deoxycorticosterone acetate-salt treatment in wild-type mice led to significant increases in B1R mRNA and protein levels and bradykinin levels, enhanced gene expression of carboxypeptidase N supporting an increase in the B1R ligand, associated with enhanced blood pressure, inflammation, sympathoexcitation, autonomic dysfunction, and impaired baroreflex sensitivity, whereas these changes were blunted or prevented in B1R knockout mice. B1R stimulation was further shown to involve activation of the ASK1-JNK-ERK1/2 and NF-κB pathways in the brain. To dismiss potential developmental alterations in knockout mice, we further used B1R blockade selectively in the brain of wild-type mice. Supporting the central origin of this mechanism, intracerebroventricular infusion of a specific B1R antagonist, attenuated the deoxycorticosterone acetate-salt-induced increase in blood pressure in wild-type mice. Our data provide the first evidence of a central role for B1R-mediated inflammatory pathways in the pathogenesis of deoxycorticosterone acetate-salt hypertension and offer novel insights into possible B1R-targeted therapies for the treatment of neurogenic hypertension. © 2017 American Heart Association, Inc.

  11. Bradykinin and adenosine receptors mediate desflurane induced postconditioning in human myocardium: role of reactive oxygen species

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    Gérard Jean-Louis

    2010-07-01

    Full Text Available Abstract Background Desflurane during early reperfusion has been shown to postcondition human myocardium, in vitro. We investigated the role of adenosine and bradykinin receptors, and generation of radical oxygen species in desflurane-induced postconditioning in human myocardium. Methods We recorded isometric contraction of human right atrial trabeculae hanged in an oxygenated Tyrode's solution (34 degrees Celsius, stimulation frequency 1 Hz. After a 30-min hypoxic period, desflurane 6% was administered during the first 5 min of reoxygenation. Desflurane was administered alone or with pretreatment of N-mercaptopropionylglycine, a reactive oxygen species scavenger, 8-(p-Sulfophenyltheophylline, an adenosine receptor antagonist, HOE140, a selective B2 bradykinin receptor antagonist. In separate groups, adenosine and bradykinin were administered during the first minutes of reoxygenation alone or in presence of N-mercaptopropionylglycine. The force of contraction of trabeculae was recorded continuously. Developed force at the end of a 60-min reoxygenation period was compared (mean ± standard deviation between the groups by a variance analysis and post hoc test. Results Desflurane 6% (84 ± 6% of baseline enhanced the recovery of force after 60-min of reoxygenation as compared to control group (51 ± 8% of baseline, P N-mercaptopropionylglycine (54 ± 3% of baseline, 8-(p-Sulfophenyltheophylline (62 ± 9% of baseline, HOE140 (58 ± 6% of baseline abolished desflurane-induced postconditioning. Adenosine (80 ± 9% of baseline and bradykinin (83 ± 4% of baseline induced postconditioning (P vs control, N-mercaptopropionylglycine abolished the beneficial effects of adenosine and bradykinin (54 ± 8 and 58 ± 5% of baseline, respectively. Conclusions In vitro, desflurane-induced postconditioning depends on reactive oxygen species production, activation of adenosine and bradykinin B2 receptors. And, the cardioprotective effect of adenosine and bradykinin

  12. Bradykinin-induced asthmatic fibroblast/myofibroblast activities via bradykinin B2 receptor and different MAPK pathways

    NARCIS (Netherlands)

    Sabatini, Federica; Luppi, Fabrizio; Petecchia, Loredana; Stefano, Antonino Di; Longo, Anna M.; Eva, Alessandra; Vanni, Cristina; Hiemstra, Pieter S.; Sterk, Peter J.; Sorbello, Valentina; Fabbri, Leonardo M.; Rossi, Giovanni A.; Ricciardolo, Fabio L. M.

    2013-01-01

    Bradykinin drives normal lung fibroblasts into myofibroblasts, induces fibroblast proliferation and activates mitogen activated protein kinase pathways (MAPK) but its effects on bronchial fibroblasts from asthmatics (HBAFb) have not been yet studied. We studied bradykinin-induced fibroblast

  13. Plasma extravasation mediated by lipopolysaccharide-induction of kinin B1 receptors in rat tissues

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    Paulo Roberto Wille

    2001-01-01

    Full Text Available The present study was performed to: (a evaluate the effects of kinin B1 (Sar{D-Phe8}-des-Arg9-BK; 10 nmol/kg and B2 (bradykinin (BK; 10 nmol/kg receptor agonists on plasma extravasation in selected rat tissues; (b determine the contribution of a lipopolysaccharide (LPS (100 μ g/kg to the effects triggered by B1 and B2 agonists; and (c characterize the selectivity of B1 ({Leu8}desArg9-BK; 10 nmol/kg and B2 (HOE 140; 10 nmol/kg antagonists as inhibitors of this kinin-induced phenomenon. B1 and B2 agonists were shown to increase plasma extravasation in the duodenum, ileum and also in the urinary bladder of the rat. LPS pretreatment enhanced the plasma extravasation mediated only by the B1 agonist in the duodenum, ileum, trachea, main and segmentar bronchi. These effects were prevented by the B1. but not the B2 antagonist. In normal rats, the B2 antagonist inhibited the effect of B2 agonist in all the tissues analyzed. However, in LPS-treated rats, the B2 antagonist was ineffective in the urinary bladder.

  14. Pharmacologic Targets and Prototype Therapeutics in the Kallikrein-Kinin System: Bradykinin Receptor Agonists or Antagonists

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    J. N. Sharma

    2006-01-01

    Full Text Available The kallikrein-kinin system (KKS is a complex system produced in various organs. This system includes kininogen (precursor for kinin, kallikreins, and pharmacologically active bradykinin (BK, which is considered to be proinflammatory and/or cardioprotective. It is a proinflammatory polypeptide that is involved in many pathological conditions and can cause pain, inflammation, increased vascular permeability, vasodilation, contraction of various smooth muscles, as well as cell proliferation. On the other hand, it has been shown that BK has cardioprotective effects, as all components of KKS are located in the cardiac muscles. Numerous observations have indicated that decreased activity of this system may lead to cardiovascular diseases, such as hypertension, cardiac failure, and myocardial infarction. BK acts on two receptors, B1 and B2, which are linked physiologically through their natural stimuli and their common participation in a variety of inflammatory responses. Recently, numerous BK antagonists have been developed in order to treat several diseases that are due to excessive BK formation. Although BK has many beneficial effects, it has been recognized to have some undesirable effects that can be reversed with BK antagonists. In addition, products of this system have multiple interactions with other important metabolic pathways, such as the renin-angiotensin system.

  15. 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

    not significantly compete with bradykinin and does not change the binding affinity of bradykinin on the B2R. Furthermore, Losartan but not Candesartan mimicked the ability of bradykinin to increase the recovery of contractile force after metabolic stress in rat atrial tissue strips. In conclusion, Losartan...

  16. Gene Variant of the Bradykinin B2 Receptor Influences Pulmonary Arterial Pressures in Heart Failure Patients.

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    Olson, Thomas P; Frantz, Robert P; Turner, Stephen T; Bailey, Kent R; Wood, Christina M; Johnson, Bruce D

    2009-01-01

    Pulmonary arterial pressure (PAP) varies considerably in heart failure (HF) despite similar degrees of left ventricular (LV) dysfunction. Bradykinin alters vascular tone and common variations in the kinin B2 receptor (BDKRB2) gene exists. We hypothesized that genetic variation in this receptor would influence PAP in HF. 131 HF patients (>1yr history systolic HF), without COPD, not currently smoking, BMI tone in stable HF.

  17. Pre- and post-junctional bradykinin B2 receptors regulate smooth muscle tension to the pig intravesical ureter.

    Science.gov (United States)

    Ribeiro, Ana S F; Fernandes, Vítor S; Martínez, María Pilar; López-Oliva, María Elvira; Barahona, María Victoria; Recio, Paz; Martínez, Ana Cristina; Blaha, Igor; Orensanz, Luis M; Bustamante, Salvador; García-Sacristán, Albino; Prieto, Dolores; Hernández, Medardo

    2016-01-01

    Neuronal and non-neuronal bradykinin (BK) receptors regulate the contractility of the bladder urine outflow region. The current study investigates the role of BK receptors in the regulation of the smooth muscle contractility of the pig intravesical ureter. Western blot and immunohistochemistry were used to show the expression of BK B1 and B2 receptors and myographs for isometric force recordings. B2 receptor expression was consistently detected in the intravesical ureter urothelium and smooth muscle layer, B1 expression was not detected where a strong B2 immunoreactivity was observed within nerve fibers among smooth muscle bundles. On ureteral strips basal tone, BK induced concentration-dependent contractions, were potently reduced by extracellular Ca(2+) removal and by B2 receptor and voltage-gated Ca(2+) (VOC) channel blockade. BK contraction did not change as a consequence of urothelium mechanical removal or cyclooxygenase and Rho-associated protein kinase inhibition. On 9,11-dideoxy-9a,11a-methanoepoxy prostaglandin F2α (U46619)-precontracted samples, under non-adrenergic non-cholinergic (NANC) and nitric oxide (NO)-independent NANC conditions, electrical field stimulation-elicited frequency-dependent relaxations which were reduced by B2 receptor blockade. Kallidin, a B1 receptor agonist, failed to increase preparation basal tension or to induce relaxation on U46619-induced tone. The present results suggest that BK produces contraction of pig intravesical ureter via smooth muscle B2 receptors coupled to extracellular Ca(2+) entry mainly via VOC (L-type) channels. Facilitatory neuronal B2 receptors modulating NO-dependent or independent NANC inhibitory neurotransmission are also demonstrated. © 2014 Wiley Periodicals, Inc.

  18. NSAID zaltoprofen possesses novel anti-nociceptive mechanism through blockage of B2-type bradykinin receptor in nerve endings.

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    Matsumoto, Misaki; Inoue, Makoto; Ueda, Hiroshi

    2006-04-24

    Zaltoprofen, a propionic acid derivative of non-steroidal anti-inflammatory drugs (NSAIDs), was shown to have more powerful inhibitory effects to bradykinin (BK)-nociception than other NSAIDs. However, the molecular mechanisms underlying this potent analgesia are not yet fully understood. Here we attempted to clarify the molecular mechanism underlying zaltoprofen-induced analgesia on BK-induced nociception by a novel algogenic-induced paw flexion (APF) test in mice. The intraplantar (i.pl.) injection of zaltoprofen at 1nmol showed strong analgesic action on BK (i.pl.)-induced nociceptive flexor responses, whereas loxoprofen or its active metabolite loxoprofen-SRS did not. Zaltoprofen also inhibited the nociception induced by [Tyr8]-BK, a specific agonist of B2-type BK receptor, but did not affect the nociception by [Lys-des-Arg9]-BK, a specific agonist of B1-type BK receptor. However, zaltoprofen did not affect the substance P-induced nociception, which is mediated by common post-receptor signaling through nociceptive fibers with BK-ones. All these results suggest that NSAID zaltoprofen possesses novel anti-nociceptive mechanism, which inhibits B2-type BK receptor function in nerve endings.

  19. Gene Variant of the Bradykinin B2 Receptor Influences Pulmonary Arterial Pressures in Heart Failure Patients

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    Thomas P. Olson

    2009-01-01

    Full Text Available Background Pulmonary arterial pressure (PAP varies considerably in heart failure (HF despite similar degrees of left ventricular (LV dysfunction. Bradykinin alters vascular tone and common variations in the kinin B2 receptor (BDKRB2 gene exists. We hypothesized that genetic variation in this receptor would influence PAP in HF. Methods 131 HF patients (>1yr history systolic HF, without COPD, not currently smoking, BMI < 40, without atrial fibrillation completed the study which included a blood draw for genotyping and neurohormones (ACE, A-II, Bradykinin, ANP, BNP, and catecholamines, an echocardiogram for cardiac function and systolic PAP (PAPsys. Results Mean LVEF was 29% ∓ 12%, NYHA class 2 ∓ 1, age 56 ∓ 12 yr, BMI 28 ∓ 5 kg/m 2 . Forty-six patients (35% were homozygous for the +9 allele, 58 (44% were heterozygous (+9/-9 and 27 (21% were homozygous for the -9 allele of the BDKRB2. PAPsys averaged 42 ∓ 13, 38 ∓ 12, and 35 ∓ 11 mmHg for +9/+9, +9/-9 and -9/-9, respectively (p = 0.03. There was a trend towards gene effect for plasma ACE with the highest values in +9/+9 and lowest in -9/-9 patients (9.5 ∓ 10.7, 7.1 ∓ 8.7, and 5.4 ∓ 6.4 U/L, respectively, p = 0.06. There were no differences in plasma bradykinin or A-II, LVEF, or NYHA across genotypes. Conclusion These data suggest the +9/+9 polymorphism of the BDKRB2 receptor influences pulmonary vascular tone in stable HF.

  20. Rupatadine effectively prevents the histamine-induced up regulation of histamine H1R and bradykinin B2R receptor gene expression in the rat paw.

    Science.gov (United States)

    Molyva, Dimitra; Kalokasidis, Konstantinos; Poulios, Christos; Dedi, Hara; Karkavelas, George; Mirtsou, Vassiliki; Goulas, Antonis

    2014-12-01

    Activation of histamine H1 receptor (H1R) is a well-known hallmark of allergic and inflammatory pathology. Both types of bradykinin receptors (B1R and B2R) are also known to contribute significantly to the latter and some sort of functional interaction between them and H1R has been alluded to in the past. Here we use an experimental model of rat paw oedema formation to examine the effect of exogenously added histamine on the gene expression of H1R and bradykinin receptors B1R and B2R, alone or in combination to rupatadine, a second generation antihistamine agent. Histamine-induced oedema formation was monitored with a plethysmometer. The gene expression of H1R, B1R and B2R was analyzed with both conventional and real-time PCR. Rupatadine fumarate was used in pure form and administered intraperitoneally, prior to histamine injection into the paw. Microscopy of haematoxylin and eosin-stained sections of paw tissue was used to examine effects on tissue architecture. Histamine injection into the paw resulted in significant up regulation of H1R and B2R without inducing significant cellular infiltration, but appears to affect less the expression of B1R. Rupatadine was, under the conditions used in this study, very effective in preventing this effect and in suppressing oedema formation through its antihistamine action. Rupatadine has a suppressing effect on H1R and B2R gene expression which could add to its efficacy towards allergy and allergy-like conditions. Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  1. Interaction between bradykinin B2 and Ang-(1-7) Mas receptors regulates erythrocyte invasion by Plasmodium falciparum.

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    Silva, Leandro de Souza; Peruchetti, Diogo de Barros; Silva, Claudio Teixeira Ferreira-Da; Ferreira-DaSilva, André Teixeira; Perales, Jonas; Caruso-Neves, Celso; Pinheiro, Ana Acacia Sá

    2016-11-01

    The molecular mechanisms involved in erythrocyte invasion by malaria parasite are well understood, but the contribution of host components is not. We recently reported that Ang-(1-7) impairs the erythrocytic cycle of P. falciparum through Mas receptor-mediated reduction of protein kinase A (PKA) activity. The effects of bradykinin (BK), a peptide of the kallikrein-kinin system (KKS), can be potentiated by Ang-(1-7), or angiotensin-converting enzyme (ACE) inhibitors, such as captopril. We investigated the coordinated action between renin-angiotensin system (RAS) and KKS peptides in the erythrocyte invasion by P. falciparum. We used human erythrocytes infected with P. falciparum to assess the influence of RAS and KKS peptides in the invasion of new erythrocytes. The inhibitory effects of Ang-(1-7) were mimicked by captopril. 10(-8)M BK decreased new ring forms and this effect was sensitive to 10(-8)M HOE-140 and 10(-7)M A779, B2 and Mas receptor antagonists, respectively. However, DALBK, a B1 receptor blocker, had no effect. The inhibitory effect of Ang-(1-7) was reversed by HOE-140 and A779 at the same concentrations. Co-immunoprecipitation assay revealed an association between B2 and Mas receptors. BK also inhibited PKA activity, which was sensitive to both HOE-140 and A779. The results suggest that B2 and Mas receptors are mediators of Ang-(1-7) and BK inhibitory effects, through a cross-signaling pathway, possibly by the formation of a heterodimer. Our results describe new elements in host signaling that could be involved in parasite invasion during the erythrocyte cycle of P. falciparum. Copyright © 2016. Published by Elsevier B.V.

  2. Receptor oligomerization in family B1 of G-protein-coupled receptors

    DEFF Research Database (Denmark)

    Roed, Sarah Norklit; Ørgaard, Anne; Jørgensen, Rasmus

    2012-01-01

    , the glucagon receptor, and the receptors for parathyroid hormone (PTHR1 and PTHR2). The dysregulation of several family B1 receptors is involved in diseases, such as diabetes, chronic inflammation, and osteoporosis which underlines the pathophysiological importance of this GPCR subfamily. In spite of this......, investigation of family B1 receptor oligomerization and especially its pharmacological importance is still at an early stage. Even though GPCR oligomerization is a well-established phenomenon, there is a need for more investigations providing a direct link between these interactions and receptor functionality...... in family B1 GPCRs. One example of the functional effects of GPCR oligomerization is the facilitation of allosterism including cooperativity in ligand binding to GPCRs. Here, we review the currently available data on family B1 GPCR homo- and heteromerization, mainly based on BRET investigations. Furthermore...

  3. Identification of B(2)-bradykinin receptors in guinea pig brain regions, spinal cord and peripheral tissues.

    Science.gov (United States)

    Sharif, N A; Whiting, R L

    1991-01-01

    The aim of this study was to characterize the biochemical and pharmacological properties of bradykinin receptors in the guinea pig central and peripheral tissues using radioligand binding techniques. Specific [(3)H]bradykinin ([(3)H]BK) receptor binding to homogenates of guinea pig cerebral cortex, hippocampus, spinal cord, ileum, kidney, heart, vas deferens and uterus was of high affinity, saturable and reversible. Scatchard analysis of saturation (0.005-1 nM) data revealed the presence of a single population of non-interacting nanomolar affinity (generally 0.14-0.38 nM) binding sites in all these tissues, with the ileum having the highest affinity (K(D) = 0.02 nM) and the greatest density of sites (B(max) = 5.8 +/- 1.8 pmol/g tissue). The rank order of tissue enrichment in terms of [(3)H]BK binding sites was: ileum > uterus > kidney > heart > vas deferens > spinal cord > cerebral cortex > hippocampus. Unlabelled BK and its analogs inhibited [(3)H]BK binding in the above tissues in a concentration-dependent manner and with the same rank order of potency: BK > Lys-BK > Met-Lys-BK > [ d -Arg (0)-Hyp (3)- d -Phe (7)]BK ? [ d -Arg (0)-Hyp (3)-Thi (5,8)- d -Phe (7)]BK ? Des-Arg (9)-BK . A similar rank order of potency of agonists was observed for their ability to contract guinea pig uterine and ileal smooth muscle strips. The pharmacological profile of [(3)H]BK receptor binding, using BK agonists and antagonists, and that of functional responses was consistent with the identification of BK receptors of the B(2)-type in the guinea pig central nervous system and peripheral tissues.

  4. Activity of Bradykinin B2 Receptor Is Regulated by Long-Chain Polyunsaturated Fatty Acids.

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    Jose Candelario

    Full Text Available The molecular and cellular mechanisms by which long-chain polyunsaturated fatty acids (LCPUFA exert their beneficial effects on cardiovascular health remain obscure. While both LCPUFA and bradykinin (BK signaling pathway play a role in the cardiovascular system, any direct link between the two is yet to be established. Using picosecond time-resolved fluorescence microscopy and a genetically engineered bradykinin B2 receptor (B2R sensor (B2K-CC, we detected LCPUFA-induced conformational responses in the B2R similar to those caused by its cognate ligand, BK. The selective B2R antagonist (HOE-140 blocked the eicosapentaenoic acid (EPA, C20∶5, n-3 induced conformational response of the B2K-CC. Further analysis suggests that LCPUFA are capable of direct, B2R-dependent activation of extracellular ligand-regulated kinases (ERK. From a wide range of fatty acids studied, varying in chain length, saturation, and position of double bonds, EPA, docosahexaenoic (DHA, C22∶6, n-3, docosadienoic (DDA, C22∶2, n-6, and dihomo-gamma linoleic (DGLA, C20∶3, n-6 fatty acids caused the highest ERK phosphorylation. EPA or DHA dependent ERK phosphorylation was inhibited by the selective B2R antagonist. We show that LCPUFA stimulates downstream signaling by B2R such as B2R-dependent phosphorylation and expression regulation of endothelial nitric-oxide synthase (eNOS. Further analysis indicated that LCPUFA also alters levels of the eNOS transcription factor, kruppel-like factor 2 (KLF2. Moreover we show that EPA increases membrane fluidity on the same time scale as B2R conformational response, suggesting that partitioning of LCPUFA into bilayer is a primary step required for receptor activation. In summary our data show that LCPUFA activate B2R receptor at nanomolar concentrations suggesting a novel molecular mechanism by which fatty acids may affect the cardiovascular system.

  5. Phosphorylation of epidermal growth factor receptor at serine 1047 in cultured lung alveolar epithelial cells by bradykinin B2 receptor stimulation.

    Science.gov (United States)

    Izumi, Shunsuke; Higa-Nakamine, Sayomi; Nishi, Hiroyuki; Torihara, Hidetsugu; Uehara, Ayako; Sugahara, Kazuhiro; Kakinohana, Manabu; Yamamoto, Hideyuki

    2017-09-09

    Accumulating evidence indicates that epidermal growth factor receptor (EGFR) is desensitized by phosphorylation of serine 1047 (Ser1047). We and other groups have reported that stimulation of a receptor of tumor-necrosis factor α (TNFα) and Toll-like receptor 5 (TLR5) induced the phosphorylation of Ser1047 through activation of p38 mitogen-activated protein kinase (p38 MAPK) in cultured lung alveolar epithelial A549 cells. However, phosphorylation of EGFR at Ser1047 by stimulation of any G-protein coupled receptors (GPCRs) has not been reported in any cultured cells. In the present study, we first confirmed that A549 cells expressed bradykinin (BK) B2 receptor, and then, we examined whether BK treatment of A549 cells activated MAPKs and induced the phosphorylation of EGFR at Ser1047. Immunoblotting analysis and reporter gene assays indicated that BK activated the pathways of extracellular signal-regulated kinase (ERK) and p38 MAPK. Inhibitor studies suggested that Gq/11 was mainly involved in the activation of ERK and p38 MAPK. We found that stimulation of the BK B2 receptor, but not the BK B1 receptor, induced phosphorylation of EGFR at Ser1047. Pharmacological experiments indicated that both ERK and p38 MAPK were involved in the phosphorylation of EGFR. These results strongly suggested that BK regulates EGFR functions in lung alveolar epithelial cells. In addition, we found that BK treatment increased the mRNA level of dual specificity MAPK phosphatase 5 (DUSP5) in an ERK-dependent manner, which suggested that a negative feedback mechanism of ERK existed in the cells. Copyright © 2017. Published by Elsevier Ltd.

  6. Abnormal Expressions of Age, RAGE, TGF- b1 and TGF- b1 Receptor in Colonic Wall Contributed to STZ-Induced Diabetic Colon Remodeling

    DEFF Research Database (Denmark)

    Zhao, Jingbo; Gregersen, Hans

    2016-01-01

    glycation end product (AGE) and AGE receptor (RAGE) were up-regulated in the diabetic colon wall (2). However, it lacks data in relation to the association between AGE, RAGE, transforming growth factor- b1 (TGF-b1) and TGFb1 receptor expressions with colon morphological and biomechanical remodeling...... glucose level was measured. The parameters of morphometric and biomechanical properties of colonic segments were obtained from diabetic (DM) and normal (Con) rats. The expressions of AGE, RAGE, TGF- b1 and TGF- b1 receptor were detected in different layers of the colon by immunohistochemistry. In order...... to determine the expressions of AGE, RAGE, TGF- b1 and TGF- b1 receptor in association with other parameters, and to see interrelation among AGE, RAGE, TGF- b1 and TGF- b1 receptor expressions, the multiple linear regression analysis was done. Results: The expressions of AGE, RAGE, TGF-b1 and TGF- b1 receptor...

  7. New Aspects of Ace Inhibition: Importance of ACE co-localization with angiotensin and bradykinin receptors

    NARCIS (Netherlands)

    B. Tom (Beril)

    2003-01-01

    textabstractThe beneficial effect of angiotensin-converting enzyme (ACE) inhibitors in hypertension and heart failure may relate, at least in part, to their capacity to interfere with bradykinin metabolism. In addition, recent studies have provided evidence for bradykinin-potentiating effects of

  8. Kinin B1 receptor antagonism is equally efficient as angiotensin receptor 1 antagonism in reducing renal fibrosis in experimental obstructive nephropathy, but is not additive.

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    Antoine eHuart

    2015-02-01

    Full Text Available Background: Renal tubulointerstitial fibrosis is the pathological hallmark of chronic kidney disease. Currently, inhibitors of the renin angiotensin system (RAS remain the sole therapy in human displaying antifibrotic properties. Further antifibrotic molecules are needed. We have recently reported that the delayed blockade of the bradykinin B1 receptor (B1R reduced the development of fibrosis in two animal models of renal fibrosis. The usefulness of new drugs also resides in outperforming the gold standards and eventually being additive or complementary to existing therapies. Methods: In this study we compared the efficacy of a B1R antagonist (B1Ra with that of an angiotensin type 1 receptor antagonist (AT1a in the unilateral ureteral obstruction (UUO model of renal fibrosis and determined whether bi-therapy presented higher efficacy than any of the drugs alone. Results: B1R antagonism was as efficient as the gold-standard AT1a treatment. However bitherapy did not improve the antifibrotic effects at the protein level. We sought for the reason of the absence of this additive effect by studying the expression of a panel of genes involved in the fibrotic process. Interestingly, at the molecular level the different drugs targeted different players of fibrosis that, however, in this severe model did not result in improved reduction of fibrosis at the protein level. Conclusions: As the B1R is induced specifically in the diseased organ and thus potentially displays low side effects it might be an interesting alternative in cases of poor tolerability to RAS inhibitors.

  9. Kinin B1 receptor antagonism is equally efficient as angiotensin receptor 1 antagonism in reducing renal fibrosis in experimental obstructive nephropathy, but is not additive

    Science.gov (United States)

    Huart, Antoine; Klein, Julie; Gonzalez, Julien; Buffin-Meyer, Bénédicte; Neau, Eric; Delage, Christine; Calise, Denis; Ribes, David; Schanstra, Joost P.; Bascands, Jean-Loup

    2015-01-01

    Background: Renal tubulointerstitial fibrosis is the pathological hallmark of chronic kidney disease (CKD). Currently, inhibitors of the renin–angiotensin system (RAS) remain the sole therapy in human displaying antifibrotic properties. Further antifibrotic molecules are needed. We have recently reported that the delayed blockade of the bradykinin B1 receptor (B1R) reduced the development of fibrosis in two animal models of renal fibrosis. The usefulness of new drugs also resides in outperforming the gold standards and eventually being additive or complementary to existing therapies. Methods: In this study we compared the efficacy of a B1R antagonist (B1Ra) with that of an angiotensin type 1 receptor antagonist (AT1a) in the unilateral ureteral obstruction (UUO) model of renal fibrosis and determined whether bi-therapy presented higher efficacy than any of the drugs alone. Results: B1R antagonism was as efficient as the gold-standard AT1a treatment. However, bitherapy did not improve the antifibrotic effects at the protein level. We sought for the reason of the absence of this additive effect by studying the expression of a panel of genes involved in the fibrotic process. Interestingly, at the molecular level the different drugs targeted different players of fibrosis that, however, in this severe model did not result in improved reduction of fibrosis at the protein level. Conclusions: As the B1R is induced specifically in the diseased organ and thus potentially displays low side effects it might be an interesting alternative in cases of poor tolerability to RAS inhibitors. PMID:25698969

  10. MATE-1 modulation by kinin B1 receptor enhances cisplatin efflux from renal cells.

    Science.gov (United States)

    Estrela, Gabriel R; Wasinski, Frederick; Felizardo, Raphael J F; Souza, Laura L; Câmara, Niels O S; Bader, Michael; Araujo, Ronaldo C

    2017-04-01

    Cisplatin is a drug widely used in chemotherapy that frequently causes severe renal dysfunction. Organic transporters have an important role to control the absorption and excretion of cisplatin in renal cells. Deletion and blockage of kinin B1 receptor has already been show to protect against cisplatin-induced acute kidney injury. To test whether it exerts its protective function by modulating the organic transporters in kidney, we studied kinin B1 receptor knockout mice and treatment with a receptor antagonist at basal state and in presence of cisplatin. Cisplatin administration caused downregulation of renal organic transporters; in B1 receptor knockout mice, this downregulation of organic transporters in kidney was absent; and treatment by a B1 receptor antagonist attenuated the downregulation of the transporter MATE-1. Moreover, kinin B1 receptor deletion and blockage at basal state resulted in higher renal expression of MATE-1. Moreover we observed that kinin B1 receptor deletion and blockage result in less accumulation of platinum in renal tissue. Thus, we propose that B1 receptor deletion and blockage protect the kidney from cisplatin-induced acute kidney injury by upregulating the expression of MATE-1, thereby increasing the efflux of cisplatin from renal cells.

  11. Bradykinin antagonist counteracts the acute effect of both angiotensin-converting enzyme inhibition and of angiotensin receptor blockade on the lower limit of autoregulation of cerebral blood flow

    DEFF Research Database (Denmark)

    Sigurdsson, Sigurdur T; Paulson, Olaf B; Høj Nielsen, Arne

    2014-01-01

    The lower limit of autoregulation of cerebral blood flow (CBF) can be modulated with both angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB). The influence of bradykinin antagonism on ARB-induced changes was the subject of this study. CBF was measured in Sprague......-Dawley rats with laser Doppler technique. The blood pressure was lowered by controlled bleeding. Six groups of rats were studied: a control group and five groups given drugs intravenously: an ACE inhibitor (enalaprilat), an ARB (candesartan), a bradykinin-2 receptor antagonist (Hoe 140), a combination...

  12. Activation of the kinin B1 receptor attenuates melanoma tumor growth and metastasis.

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    Patricia Dillenburg-Pilla

    Full Text Available Melanoma is a very aggressive tumor that does not respond well to standard therapeutic approaches, such as radio- and chemotherapies. Furthermore, acquiring the ability to metastasize in melanoma and many other tumor types is directly related to incurable disease. The B1 kinin receptor participates in a variety of cancer-related pathophysiological events, such as inflammation and angiogenesis. Therefore, we investigated whether this G protein-coupled receptor plays a role in tumor progression. We used a murine melanoma cell line that expresses the kinin B1 receptor and does not express the kinin B2 receptor to investigate the precise contribution of activation of the B1 receptor in tumor progression and correlated events using various in vitro and in vivo approaches. Activation of the kinin B1 receptor in the absence of B2 receptor inhibits cell migration in vitro and decreases tumor formation in vivo. Moreover, tumors formed from cells stimulated with B1-specific agonist showed several features of decreased aggressiveness, such as smaller size and infiltration of inflammatory cells within the tumor area, higher levels of pro-inflammatory cytokines implicated in the host anti-tumor immune response, lower number of cells undergoing mitosis, a poorer vascular network, no signs of invasion of surrounding tissues or metastasis and increased animal survival. Our findings reveal that activation of the kinin B1 receptor has a host protective role during murine melanoma tumor progression, suggesting that the B1 receptor could be a new anti-tumor GPCR and provide new opportunities for therapeutic targeting.

  13. Kinin B1 receptors contributes to acute pain following minor surgery in humans

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    Brahim Jaime S

    2010-02-01

    Full Text Available Abstract Background Kinins play an important role in regulation of pain and hyperalgesia after tissue injury and inflammation by activating two types of G-protein-coupled receptors, the kinin B1 and B2 receptors. It is generally accepted that the B2 receptor is constitutively expressed, whereas the B1 receptor is induced in response to inflammation. However, little is known about the regulatory effects of kinin receptors on the onset of acute inflammation and inflammatory pain in humans. The present study investigated the changes in gene expression of kinin receptors and the levels of their endogenous ligands at an early time point following tissue injury and their relation to clinical pain, as well as the effect of COX-inhibition on their expression levels. Results Tissue injury resulted in a significant up-regulation in the gene expression of B1 and B2 receptors at 3 hours post-surgery, the onset of acute inflammatory pain. Interestingly, the up-regulation in the gene expression of B1 and B2 receptors was positively correlated to pain intensity only after ketorolac treatment, signifying an interaction between prostaglandins and kinins in the inflammatory pain process. Further, the gene expression of both B1 and B2 receptors were correlated. Following tissue injury, B1 ligands des-Arg9-BK and des-Arg10-KD were significantly lower at the third hour compared to the first 2 hours in both the placebo and the ketorolac treatment groups but did not differ significantly between groups. Tissue injury also resulted in the down-regulation of TRPV1 gene expression at 3 hours post-surgery with no significant effect by ketorolac treatment. Interestingly, the change in gene expression of TRPV1 was correlated to the change in gene expression of B1 receptor but not B2 receptor. Conclusions These results provide evidence at the transcriptional level in a clinical model of tissue injury that up-regulation of kinin receptors are involved in the development of the

  14. SR-B1 Is a Silica Receptor that Mediates Canonical Inflammasome Activation

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    Misato Tsugita

    2017-01-01

    Full Text Available The inhalation of silica dust is associated with fibrosis and lung cancer, which are triggered by macrophage inflammatory responses; however, how macrophages recognize silica remains largely unknown. Here, we identify by functional expression cloning the class B scavenger receptor SR-B1 as a silica receptor. Through an extracellular α-helix, both mouse and human SR-B1 specifically recognized amorphous and crystalline silica, but not titanium dioxide nanoparticles, latex nanoparticles, or monosodium urate crystals, although all particles exhibited negative surface potentials. Genetic deletion of SR-B1 and masking of SR-B1 by monoclonal antibodies showed that SR-B1-mediated recognition of silica is associated with caspase-1-mediated inflammatory responses in mouse macrophages and human peripheral blood monocytes. Furthermore, SR-B1 was involved in silica-induced pulmonary inflammation in mice. These results indicate that SR-B1 is a silica receptor associated with canonical inflammasome activation.

  15. SR-B1 Is a Silica Receptor that Mediates Canonical Inflammasome Activation.

    Science.gov (United States)

    Tsugita, Misato; Morimoto, Nobuyuki; Tashiro, Manabu; Kinoshita, Kengo; Nakayama, Masafumi

    2017-01-31

    The inhalation of silica dust is associated with fibrosis and lung cancer, which are triggered by macrophage inflammatory responses; however, how macrophages recognize silica remains largely unknown. Here, we identify by functional expression cloning the class B scavenger receptor SR-B1 as a silica receptor. Through an extracellular α-helix, both mouse and human SR-B1 specifically recognized amorphous and crystalline silica, but not titanium dioxide nanoparticles, latex nanoparticles, or monosodium urate crystals, although all particles exhibited negative surface potentials. Genetic deletion of SR-B1 and masking of SR-B1 by monoclonal antibodies showed that SR-B1-mediated recognition of silica is associated with caspase-1-mediated inflammatory responses in mouse macrophages and human peripheral blood monocytes. Furthermore, SR-B1 was involved in silica-induced pulmonary inflammation in mice. These results indicate that SR-B1 is a silica receptor associated with canonical inflammasome activation. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  16. Release of biologically active kinin peptides, Met-Lys-bradykinin and Leu-Met-Lys-bradykinin from human kininogens by two major secreted aspartic proteases of Candida parapsilosis.

    Science.gov (United States)

    Bras, Grazyna; Bochenska, Oliwia; Rapala-Kozik, Maria; Guevara-Lora, Ibeth; Faussner, Alexander; Kamysz, Wojciech; Kozik, Andrzej

    2013-10-01

    In terms of infection incidence, the yeast Candida parapsilosis is the second after Candida albicans as causative agent of candidiases in humans. The major virulence factors of C. parapsilosis are secreted aspartic proteases (SAPPs) which help the pathogen to disseminate, acquire nutrients and dysregulate the mechanisms of innate immunity of the host. In the current work we characterized the action of two major extracellular proteases of C. parapsilosis, SAPP1 and SAPP2, on human kininogens, proteinaceous precursors of vasoactive and proinflammatory bradykinin-related peptides, collectively called the kinins. The kininogens, preferably the form with lower molecular mass, were effectively cleaved by SAPPs, with the release of two uncommon kinins, Met-Lys-bradykinin and Leu-Met-Lys-bradykinin. While optimal at acidic pH (4-5), the kinin release yield was only 2-3-fold lower at neutral pH. These peptides were able to interact with cellular kinin receptors of B2 subtype and to stimulate the human endothelial cells HMEC-1 to increased secretion of proinflammatory interleukins (ILs), IL-1β and IL-6. The analysis of the stability of SAPP-generated kinins in plasma suggested that they are biologically equivalent to bradykinin, the best agonist of B2 receptor subtype and can be quickly converted to des-Arg(9)-bradykinin, the agonist of inflammation-inducible B1 receptors. Copyright © 2013 Elsevier Inc. All rights reserved.

  17. Kinin B1 receptor regulates interactions between neutrophils and endothelial cells by modulating the levels of Mac-1, LFA-1 and intercellular adhesion molecule-1.

    Science.gov (United States)

    Figueroa, Carlos D; Matus, Carola E; Pavicic, Francisca; Sarmiento, Jose; Hidalgo, Maria A; Burgos, Rafael A; Gonzalez, Carlos B; Bhoola, Kanti D; Ehrenfeld, Pamela

    2015-04-01

    Kinins are pro-inflammatory peptides that mimic the cardinal features of inflammation. We examined the concept that expression levels of endothelial intercellular adhesion molecule-1 (ICAM-1) and neutrophil integrins Mac-1 and LFA-1 are modulated by the kinin B1 receptor (B1R) agonist, Lys-des[Arg(9)]bradykinin (LDBK). Stimulation of endothelial cells with LDBK increased the levels of ICAM-1 mRNA transcripts/protein, and also of E-selectin and platelet endothelial adhesion molecule-1. ICAM-1 levels increased in a magnitude comparable with that produced by TNF-α. This stimulatory effect was reduced when endothelial cells, which had been previously transfected with a B1R small interfering RNA, were stimulated with LDBK, under comparable conditions. Similarly, LDBK produced a significant increase in protein levels of LFA-1 and Mac-1 integrins in human neutrophils, an effect that was reversed by pretreatment of cells with 10 µg/ml cycloheximide or a B1R antagonist. Functional experiments performed with post-confluent monolayers of endothelial cells stimulated with LDBK and neutrophils primed with TNF-α, and vice versa, resulted in enhanced adhesiveness between both cells. Neutralizing Abs to ICAM-1 and Mac-1 reduced the adhesion between them. Our results indicate that kinin B1R is a novel modulator that promotes adhesion of leukocytes to endothelial cells, critically enhancing the movement of neutrophils from the circulation to sites of inflammation. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

  18. Targeting the SR-B1 receptor as a gateway for cancer therapy and tumor imaging

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    Linda K Mooberry

    2016-12-01

    Full Text Available Malignant tumors display remarkable heterogeneity to the extent that even at the same tissue site different types of cells with varying genetic background may be found. In contrast, a relatively consistent marker the scavenger receptor type B1 (SR-B1 has been found to be consistently over expressed by most tumor cells. In addition, the SR-B1 receptor has been shown to serve as a potential gateway for the delivery of therapeutic agents when reconstituted high density lipoprotein (rHDL nanoparticles are used for their transport to cancer cells and tumors. Opportunities for the development of new technologies, particularly in the areas of cancer therapy and tumor imaging are discussed.

  19. Scavenger receptor B1 facilitates macrophage uptake of silver nanoparticles and cellular activation

    Energy Technology Data Exchange (ETDEWEB)

    Aldossari, Abdullah A.; Shannahan, Jonathan H. [The University of Colorado Anschutz Medical Campus, Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences (United States); Podila, Ramakrishna [Clemson University, Department of Physics and Astronomy (United States); Brown, Jared M., E-mail: jared.brown@ucdenver.edu [The University of Colorado Anschutz Medical Campus, Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences (United States)

    2015-07-15

    Due to increased use of silver nanoparticles (AgNPs) for their antimicrobial activity, concerns have risen regarding potential adverse human health effects. Scavenger receptor B1 (SR-B1), a major receptor for high-density lipoprotein (HDL), is expressed by macrophages and has also been reported to play a role in recognition of negatively charged particles. We, therefore, hypothesized that SR-B1 mediates macrophage uptake of AgNPs and inflammatory activation. To test this hypothesis, we exposed a mouse macrophage cell line RAW264.7 (RAW) and bone marrow-derived macrophages (BMDM) to 20 nm citrate-suspended AgNPs. To verify the role of the SR-B1 receptor, we utilized a SR-B1 inhibitor (Blt2). In vitro studies demonstrated uptake of AgNPs and HDL-coated AgNPs by macrophages which were significantly reduced following pretreatment with Blt2. Inflammatory cytokine arrays revealed that macrophages exposed to AgNPs up-regulated expression of Tnf-α, Oncostatin m (OSM), Ccl4, Il17f, Ccl7, and Ccl2, whereas Il16 was found to be down-regulated. Macrophage activation was observed following AgNP and HDL-coated AgNP exposure as measured by OSM protein production and increased surface expression of CD86. These markers of activation were reduced with Blt2 pretreatment. The in vitro findings were confirmed in vivo through pulmonary instillation of AgNPs in mice. Pulmonary instillation of AgNPs resulted in a recruitment of inflammatory cells that were reduced in SR-B1-deficient mice or following Blt2 pretreatment. This study suggests that SR-B1 plays a major role in cellular recognition of AgNPs and the induction of cell responses that could contribute to inflammation caused by AgNP exposure.

  20. Key role for spinal dorsal horn microglial kinin B1 receptor in early diabetic pain neuropathy

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    Couture Réjean

    2010-06-01

    Full Text Available Abstract Background The pro-nociceptive kinin B1 receptor (B1R is upregulated on sensory C-fibres, astrocytes and microglia in the spinal cord of streptozotocin (STZ-diabetic rat. This study aims at defining the role of microglial kinin B1R in diabetic pain neuropathy. Methods Sprague-Dawley rats were made diabetic with STZ (65 mg/kg, i.p., and 4 days later, two specific inhibitors of microglial cells (fluorocitrate, 1 nmol, i.t.; minocycline, 10 mg/kg, i.p. were administered to assess the impact on thermal hyperalgesia, allodynia and mRNA expression (qRT-PCR of B1R and pro-inflammatory markers. Spinal B1R binding sites ((125I-HPP-desArg10-Hoe 140 were also measured by quantitative autoradiography. Inhibition of microglia was confirmed by confocal microscopy with the specific marker Iba-1. Effects of intrathecal and/or systemic administration of B1R agonist (des-Arg9-BK and antagonists (SSR240612 and R-715 were measured on neuropathic pain manifestations. Results STZ-diabetic rats displayed significant tactile and cold allodynia compared with control rats. Intrathecal or peripheral blockade of B1R or inhibition of microglia reversed time-dependently tactile and cold allodynia in diabetic rats without affecting basal values in control rats. Microglia inhibition also abolished thermal hyperalgesia and the enhanced allodynia induced by intrathecal des-Arg9-BK without affecting hyperglycemia in STZ rats. The enhanced mRNA expression (B1R, IL-1β, TNF-α, TRPV1 and Iba-1 immunoreactivity in the STZ spinal cord were normalized by fluorocitrate or minocycline, yet B1R binding sites were reduced by 38%. Conclusion The upregulation of kinin B1R in spinal dorsal horn microglia by pro-inflammatory cytokines is proposed as a crucial mechanism in early pain neuropathy in STZ-diabetic rats.

  1. Aflatoxin B1 invokes apoptosis via death receptor pathway in hepatocytes.

    Science.gov (United States)

    Mughal, Muhammad Jameel; Xi, Peng; Yi, Zhou; Jing, Fang

    2017-01-31

    The fungal metabolites produced by Aspergillus flavus and Aspergillus parasiticus cause detrimental health effects on humans and animals. Particularly aflatoxin B1 (AFB1) is the most studied and a well-known global carcinogen, producing hepatotoxic, genotoxic and immunotoxic effects in multiple species. AFB1 is shown to provoke liver dysfunctioning by causing hepatocytes apoptosis and disturbing cellular enzymatic activities. In liver, AFB1 causes apoptosis via extrinsic mechanism because of high expression of death receptor pathway. The detailed mechanism of AFB1 induced hepatocytes apoptosis, via death receptor pathway still remains elusive. So the present study was conducted to explore apoptotic mechanism initiated by death receptors and associated genes in aflatoxin B1 induced liver apoptosis in chickens fed with AFB1 for 3 weeks. Results from the present study displayed histopathological and ultrastructural changes in liver such as hydropic degeneration, fatty vacuolar degeneration and proliferation of bile duct in hepatocytes in AFB1 group, along with imbalance between reactive oxygen species (ROS) and antioxidant defense system upon AFB1 ingestion. Moreover, AFB1 intoxicated chickens showed upregulation of death receptors FAS, TNFR1 and associated genes and downregulation of inhibitory apoptotic proteins XIAP and BCL-2. The results obtained from this novel and comprehensive study including histopathological, ultrastructural, flow cytometrical and death receptor pathway gene expression profiles, will facilitate better understanding of mechanisms and involvement of death receptor pathway in hepatocytes apoptosis induced by AFB1 and ultimately may be helpful in bringing down the toxigenic potential of AFB1.

  2. Targeting the SR-B1 Receptor as a Gateway for Cancer Therapy and Imaging.

    Science.gov (United States)

    Mooberry, Linda K; Sabnis, Nirupama A; Panchoo, Marlyn; Nagarajan, Bhavani; Lacko, Andras G

    2016-01-01

    Malignant tumors display remarkable heterogeneity to the extent that even at the same tissue site different types of cells with varying genetic background may be found. In contrast, a relatively consistent marker the scavenger receptor type B1 (SR-B1) has been found to be consistently overexpressed by most tumor cells. Scavenger Receptor Class B Type I (SR-BI) is a high density lipoprotein (HDL) receptor that facilitates the uptake of cholesterol esters from circulating lipoproteins. Additional findings suggest a critical role for SR-BI in cholesterol metabolism, signaling, motility, and proliferation of cancer cells and thus a potential major impact in carcinogenesis and metastasis. Recent findings indicate that the level of SR-BI expression correlate with aggressiveness and poor survival in breast and prostate cancer. Moreover, genomic data show that depending on the type of cancer, high or low SR-BI expression may promote poor survival. This review discusses the importance of SR-BI as a diagnostic as well as prognostic indicator of cancer to help elucidate the contributions of this protein to cancer development, progression, and survival. In addition, the SR-B1 receptor has been shown to serve as a potential gateway for the delivery of therapeutic agents when reconstituted high density lipoprotein nanoparticles are used for their transport to cancer cells and tumors. Opportunities for the development of new technologies, particularly in the areas of cancer therapy and tumor imaging are discussed.

  3. Identification of a novel antagonist of the ErbB1 receptor capable of inhibiting migration of human glioblastoma cells

    DEFF Research Database (Denmark)

    Staberg, Mikkel; Riemer, Christian; Xu, Ruodan

    2013-01-01

    BACKGROUND: Receptors of the ErbB family are involved in the development of various cancers, and the inhibition of these receptors represents an attractive therapeutic concept. Upon ligand binding, ErbB receptors become activated as homo- or heterodimers, leading to the activation of downstream......B1 targeting peptide, termed Herfin-1, was designed based on a model of the tertiary structure of the EGF-EGFR ternary complex. The binding kinetics of this peptide were determined employing surface plasmon resonance analyses. ErbB1-4 expression and phosphorylation in human glioblastoma cell lines U....... Additionally, Herfin-1 was found to increase neurite outgrowth in cerebellar granule neurons, likely through the inhibition of a sustained weak ErbB1 activation. CONCLUSIONS: Targeting the ErbB1 receptor dimerization interface is a promising strategy to inhibit receptor activation in ErbB1-expressing glioma...

  4. Intermittent activation of bradykinin B2 receptors and mitochondrial KATP channels trigger cardiac postconditioning through redox signaling.

    Science.gov (United States)

    Penna, Claudia; Mancardi, Daniele; Rastaldo, Raffaella; Losano, Gianni; Pagliaro, Pasquale

    2007-07-01

    Postconditioning (PostC) maneuvers allow post-ischemic accumulation of autacoids, which trigger protection. We tested if PostC-triggering includes bradykinin (BK) B2 receptor activation and its downstream pathway. Isolated rat hearts underwent 30 min ischemia and 120 min reperfusion. Infarct size was evaluated using nitro-blue tetrazolium staining. In Control hearts infarct size was 61+/-5% of risk area. PostC (5 cycles of 10 s reperfusion/ischemia) reduced infarct size to 22+/-4% (pIntermittent-BK infusion were used to mimic PostC: a) 5 cycles of 10 s oxygenated-no-BK/oxygenated+BK buffer; b) 5 cycles of 10 s oxygenated-no-BK/hypoxic+BK buffer. Both protocols with Intermittent-BK attenuated infarct size (36+/-5% and 38+/-4%, respectively; pIntermittent-BK protection was abolished by the same antagonists used to prevent PostC protection. Intermittence of re-oxygenation only (5 cycles of 10 s oxygenated/hypoxic buffer) did not reproduce PostC. Yet, cardioprotection was triggered by intermittent mK(ATP) activation with diazoxide, but not by intermittent reactive oxygen species (ROS) generation with purine/xanthine oxidase. ROS scavengers (N-acetyl-L-cysteine or 2-mercaptopropionylglycine), given for 3 min only, abolished PostC-, Intermittent BK-and diazoxide-induced protection. Intermittent targeting of specific cellular sites (i.e. BK B2 receptors and mK(ATP) channels) during early reperfusion triggers PostC protection via ROS signaling. Since neither intermittent oxygenation nor exogenous ROS generators can trigger protection, it is likely that intermittent autacoid accumulation and ROS compartmentalization may play a pivotal role in PostC-triggering.

  5. Identification of bradykinins in solitary wasp venoms.

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    Konno, Katsuhiro; Palma, Mario Sergio; Hitara, Izaura Yoshico; Juliano, Maria Aparecida; Juliano, Luiz; Yasuhara, Tadashi

    2002-03-01

    Bradykinins were identified in three solitary wasp venoms. Purification and characterization of the venom extract of the scoliid wasp Megacampsomeris prismatica led to the identification of bradykinin and threonine(6)-bradykinin as the major peptide components. The survey of a number of extracts from solitary wasp venom by MALDI-TOF MS revealed that the venoms of two other scoliid wasps, Campsomeriella annulata annulata and Carinoscolia melanosoma fascinata, also contained Thr(6)-BK as one of the major components. Thus, this study showed the presence of bradykinins in some of the solitary wasp venoms. Moreover, it indicated that these peptides play a major role in their paralyzing action for prey capture because these bradykinins have been shown to block the synaptic transmission of the nicotinic acetylcholine receptor in the insect central nervous system.

  6. Icatibant, an inhibitor of bradykinin receptor 2, for hereditary angioedema attacks: prospective experimental single-cohort study

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    Regis Albuquerque Campos

    Full Text Available CONTEXT AND OBJECTIVE: Hereditary angioedema (HAE with C1 inhibitor deficiency manifests as recurrent episodes of edema involving the skin, upper respiratory tract and gastrointestinal tract. It can be lethal due to asphyxia. The aim here was to evaluate the response to therapy for these attacks using icatibant, an inhibitor of the bradykinin receptor, which was recently introduced into Brazil.DESIGN AND SETTING: Prospective experimental single-cohort study on the efficacy and safety of icatibant for HAE patients.METHODS: Patients with a confirmed HAE diagnosis were enrolled according to symptoms and regardless of the time since onset of the attack. Icatibant was administered in accordance with the protocol that has been approved in Brazil. Symptom severity was assessed continuously and adverse events were monitored.RESULTS: 24 attacks in 20 HAE patients were treated (female/male 19:1; 19-55 years; median 29 years of age. The symptoms were: subcutaneous edema (22/24; abdominal pain (15/24 and upper airway obstruction (10/24. The time taken until onset of relief was: 5-10 minutes (5/24; 20.8%; 10-20 (5/24; 20.8%; 20-30 (8/24; 33.4%; 30-60 (5/24; 20.8%; and 2 hours (1/24; 4.3%. The time taken for complete resolution of symptoms ranged from 4.3 to 33.4 hours. Adverse effects were only reported at injection sites. Mild to moderate erythema and/or feelings of burning were reported by 15/24 patients, itching by 3 and no adverse effects in 6.CONCLUSION: HAE type I patients who received icatibant responded promptly; most achieved improved symptom severity within 30 minutes. Local adverse events occurred in 75% of the patients.

  7. Scavenger receptor B1 (SR-B1) profoundly excludes high density lipoprotein (HDL) apolipoprotein AII as it nibbles HDL-cholesteryl ester.

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    Gillard, Baiba K; Bassett, G Randall; Gotto, Antonio M; Rosales, Corina; Pownall, Henry J

    2017-05-26

    Reverse cholesterol transport (transfer of macrophage-cholesterol in the subendothelial space of the arterial wall to the liver) is terminated by selective high density lipoprotein (HDL)-cholesteryl ester (CE) uptake, mediated by scavenger receptor class B, type 1 (SR-B1). We tested the validity of two models for this process: "gobbling," i.e. one-step transfer of all HDL-CE to the cell and "nibbling," multiple successive cycles of SR-B1-HDL association during which a few CEs transfer to the cell. Concurrently, we compared cellular uptake of apoAI with that of apoAII, which is more lipophilic than apoAI, using HDL-[(3)H]CE labeled with [(125)I]apoAI or [(125)I]apoAII. The studies were conducted in CHO-K1 and CHO-ldlA7 cells (LDLR(-/-)) with (CHO-SR-B1) and without SR-B1 overexpression and in human Huh7 hepatocytes. Relative to CE, both apoAI and apoAII were excluded from uptake by all cells. However, apoAII was more highly excluded from uptake (2-4×) than apoAI. To distinguish gobbling versus nibbling mechanisms, media from incubations of HDL with CHO-SR-B1 cells were analyzed by non-denaturing PAGE, size-exclusion chromatography, and the distribution of apoAI, apoAII, cholesterol, and phospholipid among HDL species as a function of incubation time. HDL size gradually decreased, i.e. nibbling, with the concurrent release of lipid-free apoAI; apoAII was retained in an HDL remnant. Our data support an SR-B1 nibbling mechanism that is similar to that of streptococcal serum opacity factor, which also selectively removes CE and releases apoAI, leaving an apoAII-rich remnant. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  8. Protein expression, biochemical pharmacology of signal transduction, and relation to intraocular pressure modulation by bradykinin B₂ receptors in ciliary muscle.

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    Sharif, Najam A; Xu, Shouxi; Li, Linya; Katoli, Parvaneh; Kelly, Curtis R; Wang, Yu; Cao, Shutong; Patil, Rajkumar; Husain, Shahid; Klekar, Laura; Scott, Daniel

    2013-01-01

    To examine the bradykinin (BK) B₂-receptor system in human and monkey ciliary muscle (CM) using immunohistochemical techniques, and to pharmacologically characterize the associated biochemical signal transduction systems in human CM (h-CM) cells. BK-induced modulation of intraocular pressure (IOP) in pigmented Dutch-Belt rabbits and cynomolgus monkeys was also studied. Previously published procedures were used throughout these studies. The human and monkey ciliary bodies expressed high levels of B₂-receptor protein immunoreactivity. Various kinins differentially stimulated [Ca²⁺](i) mobilization in primary h-CM cells (BK EC₅₀=2.4±0.2 nM > Hyp³,β-(2-thienyl)-Ala⁵,Tyr(Me)⁸-(®)-Arg⁹-BK (RMP-7) > Des-Arg⁹-BK EC₅₀=4.2 µM [n=3-6]), and this was blocked by B₂-selective antagonists, HOE-140 (IC₅₀=1.4±0.1 nM) and WIN-63448 (IC₅₀=174 nM). A phospholipase C inhibitor (U73122; 10-30 µM) and ethylene glycol tetraacetic acid (1-2 mM) abolished the BK-induced [Ca²⁺](i) mobilization. Total prostaglandin (primarily PGE₂) secretion stimulated by BK and other kinins in h-CM cells was attenuated by the cyclooxygenase inhibitors bromfenac and flurbiprofen, and by the B₂-antagonists. BK and RMP-7 (100 nM) induced a twofold increase in extracellular signal-regulated kinase-1/2 phosphorylation, and BK (0.1-1 µM; at 24 h) caused a 1.4-3.1-fold increase in promatrix metalloproteinases-1-3 release. Topical ocular BK (100 µg) failed to alter IOP in cynomolgus monkeys. However, intravitreal injection of 50 µg of BK, but not Des-Arg⁹-BK, lowered IOP in rabbit eyes (22.9±7.3% and 37.0±5.6% at 5 h and 8 h post-injection; n=7-10). These studies have provided evidence of a functional endogenously expressed B₂-receptor system in the CM that appears to be involved in modulating IOP.

  9. Kinin B1 receptors mediate depression-like behavior response in stressed mice treated with systemic E. coli lipopolysaccharide

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    Campos Maria M

    2010-12-01

    Full Text Available Abstract Background Kinin B1 receptors are inducible molecules up-regulated after inflammatory stimuli. This study evaluated the relevance of kinin B1 receptors in a mouse depression behavior model. Methods Mice were exposed to a 5-min swimming session, and 30 min later they were injected with E. coli lipopolysaccharide (LPS. Depression-like behavior was assessed by determining immobility time in a tail suspension test. Different brain structures were collected for molecular and immunohistochemical studies. Anhedonia was assessed by means of a sucrose intake test. Results Our protocol elicited an increase in depression-like behavior in CF1 mice, as assessed by the tail-suspension test, at 24 h. This behavior was significantly reduced by treatment with the selective B1 receptor antagonists R-715 and SSR240612. Administration of SSR240612 also prevented an increase in number of activated microglial cells in mouse hippocampus, but did not affect a reduction in expression of mRNA for brain-derived neurotrophic factor. The increased immobility time following LPS treatment was preceded by an enhancement of hippocampal and cortical B1 receptor mRNA expression (which were maximal at 1 h, and a marked production of TNFα in serum, brain and cerebrospinal fluid (between 1 and 6 h. The depression-like behavior was virtually abolished in TNFα p55 receptor-knockout mice, and increased B1 receptor mRNA expression was completely absent in this mouse strain. Furthermore, treatment with SSR240612 was also effective in preventing anhedonia in LPS-treated mice, as assessed using a sucrose preference test. Conclusion Our data show, for the first time, involvement of kinin B1 receptors in depressive behavioral responses, in a process likely associated with microglial activation and TNFα production. Thus, selective and orally active B1 receptor antagonists might well represent promising pharmacological tools for depression therapy.

  10. Knockdown of EphB1 receptor decreases medulloblastoma cell growth and migration and increases cellular radiosensitization.

    Science.gov (United States)

    Bhatia, Shilpa; Baig, Nimrah A; Timofeeva, Olga; Pasquale, Elena B; Hirsch, Kellen; MacDonald, Tobey J; Dritschilo, Anatoly; Lee, Yi Chien; Henkemeyer, Mark; Rood, Brian; Jung, Mira; Wang, Xiao-Jing; Kool, Marcel; Rodriguez, Olga; Albanese, Chris; Karam, Sana D

    2015-04-20

    The expression of members of the Eph family of receptor tyrosine kinases and their ephrin ligands is frequently dysregulated in medulloblastomas. We assessed the expression and functional role of EphB1 in medulloblastoma cell lines and engineered mouse models. mRNA and protein expression profiling showed expression of EphB1 receptor in the human medulloblastoma cell lines DAOY and UW228. EphB1 downregulation reduced cell growth and viability, decreased the expression of important cell cycle regulators, and increased the percentage of cells in G1 phase of the cell cycle. It also modulated the expression of proliferation, and cell survival markers. In addition, EphB1 knockdown in DAOY cells resulted in significant decrease in migration, which correlated with decreased β1-integrin expression and levels of phosphorylated Src. Furthermore, EphB1 knockdown enhanced cellular radiosensitization of medulloblastoma cells in culture and in a genetically engineered mouse medulloblastoma model. Using genetically engineered mouse models, we established that genetic loss of EphB1 resulted in a significant delay in tumor recurrence following irradiation compared to EphB1-expressing control tumors. Taken together, our findings establish that EphB1 plays a key role in medulloblastoma cell growth, viability, migration, and radiation sensitivity, making EphB1 a promising therapeutic target.

  11. Role of the bradykinin B2 receptor in a rat model of local heart irradiation.

    Science.gov (United States)

    Lieblong, Benjamin J; Sridharan, Vijayalakshmi; Srivastava, Anup K; Moros, Eduardo G; Sharma, Sunil K; Boerma, Marjan

    2015-08-01

    Radiation-induced heart disease (RIHD) is a delayed effect of radiotherapy for cancers of the chest, such as breast, esophageal, and lung. Kinins are small peptides with cardioprotective properties. We previously used a rat model that lacks the precursor kininogen to demonstrate that kinins are involved in RIHD. Here, we examined the role of the kinin B2 receptor (B2R) in early radiation-induced signaling in the heart. Male Brown Norway rats received the B2R-selective antagonist HOE-140 (icatibant) via osmotic minipump from 5 days before until 4 weeks after 21 Gy local heart irradiation. At 4 weeks, signaling events were measured in left ventricular homogenates and nuclear extracts using western blotting and real-time polymerase chain reaction. Numbers of CD68-positive (monocytes/macrophages), CD2-positive (T-lymphocytes), and mast cells were measured using immunohistochemistry. Radiation-induced c-Jun phosphorylation and nuclear translocation were enhanced by HOE-140. HOE-140 did not modify endothelial nitric oxide synthase (eNOS) phosphorylation or alter numbers of CD2-positive or mast cells, but enhanced CD68-positive cell counts in irradiated hearts. B2R signaling may regulate monocyte/macrophage infiltration and c-Jun signals in the irradiated heart. Although eNOS is a main target for kinins, the B2R may not regulate eNOS phosphorylation in response to radiation.

  12. CA2+-DEPENDENT AND CA2+-INDEPENDENT MECHANISM OF CYCLIC-AMP REDUCTION - MEDIATION BY BRADYKININ B-2 RECEPTORS

    NARCIS (Netherlands)

    SIPMA, H; DENHERTOG, A; NELEMANS, A

    1 Bradykinin caused a transient reduction of about 25% in the cyclic AMP level in forskolin prestimulated DDT1 MF-2 smooth muscle cells (IC50: 36.4 +/- 4.9 nM) and a pronounced, sustained inhibition (40%) of the isoprenaline-stimulated cyclic AMP level (IC50: 37.5 +/- 1.1 nM). 2 The Ca2+ ionophore,

  13. Receptor oligomerization in family B1 of G-protein-coupled receptors: focus on BRET investigations and the link between GPCR oligomerization and binding cooperativity.

    Science.gov (United States)

    Roed, Sarah Norklit; Orgaard, Anne; Jorgensen, Rasmus; De Meyts, Pierre

    2012-01-01

    The superfamily of the seven transmembrane G-protein-coupled receptors (7TM/GPCRs) is the largest family of membrane-associated receptors. GPCRs are involved in the pathophysiology of numerous human diseases, and they constitute an estimated 30-40% of all drug targets. During the last two decades, GPCR oligomerization has been extensively studied using methods like bioluminescence resonance energy transfer (BRET) and today, receptor-receptor interactions within the GPCR superfamily is a well-established phenomenon. Evidence of the impact of GPCR oligomerization on, e.g., ligand binding, receptor expression, and signal transduction indicates the physiological and pharmacological importance of these receptor interactions. In contrast to the larger and more thoroughly studied GPCR subfamilies A and C, the B1 subfamily is small and comprises only 15 members, including, e.g., the secretin receptor, the glucagon receptor, and the receptors for parathyroid hormone (PTHR1 and PTHR2). The dysregulation of several family B1 receptors is involved in diseases, such as diabetes, chronic inflammation, and osteoporosis which underlines the pathophysiological importance of this GPCR subfamily. In spite of this, investigation of family B1 receptor oligomerization and especially its pharmacological importance is still at an early stage. Even though GPCR oligomerization is a well-established phenomenon, there is a need for more investigations providing a direct link between these interactions and receptor functionality in family B1 GPCRs. One example of the functional effects of GPCR oligomerization is the facilitation of allosterism including cooperativity in ligand binding to GPCRs. Here, we review the currently available data on family B1 GPCR homo- and heteromerization, mainly based on BRET investigations. Furthermore, we cover the functional influence of oligomerization on ligand binding as well as the link between oligomerization and binding cooperativity.

  14. Activation of TRPV1 by capsaicin induces functional Kinin B1 receptor in rat spinal cord microglia

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    Talbot Sébastien

    2012-01-01

    Full Text Available Abstract Background The kinin B1 receptor (B1R is upregulated by pro-inflammatory cytokines and oxydative stress, which are enhanced by transient receptor potential vanilloid subtype 1 (TRPV1 activation. To examine the link between TRPV1 and B1R in inflammatory pain, this study aimed to determine the ability of TRPV1 to regulate microglial B1R expression in the spinal cord dorsal horn, and the underlying mechanism. Methods B1R expression (mRNA, protein and binding sites was measured in cervical, thoracic and lumbar spinal cord in response to TRPV1 activation by systemic capsaicin (1-50 mg/kg, s.c in rats pre-treated with TRPV1 antagonists (capsazepine or SB-366791, the antioxidant N-acetyl-L-cysteine (NAC, or vehicle. B1R function was assessed using a tail-flick test after intrathecal (i.t. injection of a selective B1R agonist (des-Arg9-BK, and its microglial localization was investigated by confocal microscopy with the selective fluorescent B1R agonist, [Nα-bodipy]-des-Arg9-BK. The effect of i.t. capsaicin (1 μg/site was also investigated. Results Capsaicin (10 to 50 mg/kg, s.c. enhanced time-dependently (0-24h B1R mRNA levels in the lumbar spinal cord; this effect was prevented by capsazepine (10 mg/kg, i.p.; 10 μg/site, i.t. and SB-366791 (1 mg/kg, i.p.; 30 μg/site, i.t.. Increases of B1R mRNA were correlated with IL-1β mRNA levels, and they were significantly less in cervical and thoracic spinal cord. Intrathecal capsaicin (1 μg/site also enhanced B1R mRNA in lumbar spinal cord. NAC (1 g/kg/d × 7 days prevented B1R up-regulation, superoxide anion production and NF-kB activation induced by capsaicin (15 mg/kg. Des-Arg9-BK (9.6 nmol/site, i.t. decreased by 25-30% the nociceptive threshold at 1 min post-injection in capsaicin-treated rats (10-50 mg/kg while it was without effect in control rats. Des-Arg9-BK-induced thermal hyperalgesia was blocked by capsazepine, SB-366791 and by antagonists/inhibitors of B1R (SSR240612, 10 mg/kg, p

  15. Consequences of epidermal growth factor receptor (ErbB1) loss for vascular smooth muscle cells from mice with targeted deletion of ErbB1.

    Science.gov (United States)

    Schreier, Barbara; Döhler, Maria; Rabe, Sindy; Schneider, Bettina; Schwerdt, Gerald; Ruhs, Stefanie; Sibilia, Maria; Gotthardt, Michael; Gekle, Michael; Grossmann, Claudia

    2011-07-01

    Pathophysiological effects of the epidermal growth factor receptor (EGFR or ErbB1) include vascular remodeling. EGFR transactivation is proposed to contribute significantly to heterologous signaling and remodeling in vascular smooth muscle cells (VSMC). We investigated the importance of EGFR in primary VSMC from aorta of mice with targeted deletion of the EGFR (EGFR(Δ/Δ VSMC)→VSMC(EGFR-/-) and EGFR(Δ/+ VSMC)→VSMC(EGFR+/-)) and the respective littermate controls (EGFR(+/+ VSMC)→VSMC(EGFR+/+)) with respect to survival, pentose phosphate pathway activity, matrix homeostasis, extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation, and Ca(2+) homeostasis. In VSMC(EGFR-/-), epidermal growth factor-induced signaling was abolished; VSMC(EGFR+/-) showed an intermediate phenotype. EGFR deletion enhanced spontaneous cell death, reduced pentose phosphate pathway activity, disturbed cellular matrix homeostasis (collagen III and fibronectin), and abolished epidermal growth factor sensitivity. In VSMC(EGFR-/-) endothelin-1- or α(1)-adrenoceptor-induced ERK1/2 phosphorylation and the fraction of Ca(2+) responders were significantly reduced, whereas responsive cells showed a significantly stronger Ca(2+) signal. Oxidative stress (H(2)O(2)) induced ERK1/2 activation in VSMC(EGFR+/+) and VSMC(EGFR+/-) but not in VSMC(EGFR-/-). The Ca(2+) signal was enhanced in VSMC(EGFR-/-), similar to purinergic stimulation by ATP. In conclusion, EGFR was found to be important for basal VSMC homeostasis and ERK1/2 activation by the tested G-protein-coupled receptors or radical stress. Ca(2+) signaling was modulated by EGFR differentially with respect to the fraction of responders and magnitude of the signal. Thus, EGFR seems to be Janus-faced for VSMC biology.

  16. Photobiomodulation therapy in the modulation of inflammatory mediators and bradykinin receptors in an experimental model of acute osteoarthritis.

    Science.gov (United States)

    de Oliveira, Vanessa Lima Cavalcante; Silva, José Antonio; Serra, Andrey Jorge; Pallotta, Rodney Capp; da Silva, Evela Aparecida Pereira; de Farias Marques, Anna Cristina; Feliciano, Regiane Dos Santos; Marcos, Rodrigo Labat; Leal-Junior, Ernesto Cesar Pinto; de Carvalho, Paulo de Tarso Camillo

    2017-01-01

    The objective of this study was to evaluate the effects of photobiomodulation therapy (PBMT) on inflammatory indicators, i.e., inflammatory mediators (TNF-α and CINC-1), and pain characterized by hyperalgesia and B1 and B2 receptor activation at 6, 24, and 48 h after papain-induced osteoarthritis (OA) in rats. Fifty-four rats were subjected to hyperalgesia evaluations and then divided randomly into three groups-a control group and two groups OA and OA PBMT group by using laser parameters at wavelength (808 nm), output power (50 mW), energy per point (4 Joules), power density (1.78 W/cm(2)), laser beam (0.028 cm(2)), and energy density (144 J/cm(2))-the induction of osteoarthritis was then performed with 20-μl injections of a 4 % papain solution dissolved in 10 μl of saline solution, to which 10 μl of cysteine solution (0.03 M). The statistical analysis was performed using two-way ANOVA with Bonferroni's post hoc test for comparisons between the 6, 24, and 48 h and team points within each group, and between the control, injury, and PBMT groups, and p osteoarthritis.

  17. 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

  18. Interruption of the ionic lock in the bradykinin B2 receptor results in constitutive internalization and turns several antagonists into strong agonists.

    Science.gov (United States)

    Leschner, Jasmin; Wennerberg, Goeran; Feierler, Jens; Bermudez, Marcel; Welte, Benjamin; Kalatskaya, Irina; Wolber, Gerhard; Faussner, Alexander

    2013-01-01

    The DRY motif with the highly conserved R3.50 is a hallmark of family A G protein-coupled receptors (GPCRs). The crystal structure of rhodopsin revealed a salt bridge between R135(3.50) and another conserved residue, E247(6.30), in helix 6. This ionic lock was shown to maintain rhodopsin in its inactive state. Thus far, little information is available on how interruption of this ionic bond affects signaling properties of nonrhodopsin GPCRs, because the focus has been on mutations of R3.50, although this residue is indispensable for G protein activation. To investigate the importance of an ionic lock for overall receptor activity in a nonrhodopsin GPCR, we mutated R128(3.50) and E238(6.30) in the bradykinin (BK) B(2) receptor (B(2)R) and stably expressed the constructs in HEK293 cells. As expected, mutation of R3.50 resulted in lack of G protein activation. In addition, this mutation led to considerable constitutive receptor internalization. Mutation of E6.30 (mutants E6.30A and E6.30R) also caused strong constitutive internalization. Most intriguingly, however, although the two E6.30 mutants displayed no increased basal phosphatidylinositol hydrolysis, they gave a response to three different B(2)R antagonists that was almost comparable to that obtained with BK. In contrast, swapping of R3.50 and E6.30, thus allowing the formation of an inverse ionic bond, resulted in rescue of the wild type phenotype. These findings demonstrate for the first time, to our knowledge, that interruption of the ionic lock in a family A GPCR can have distinctly different effects on receptor internalization and G protein stimulation, shedding new light on its role in the activation process.

  19. Bradykinin type 2 receptor -9/-9 genotype is associated with triceps brachii muscle hypertrophy following strength training in young healthy men

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    Popadic Gacesa Jelena Z

    2012-11-01

    Full Text Available Abstract Background Bradykinin type 2 receptor (B2BRK genotype was reported to be associated with changes in the left-ventricular mass as a response to aerobic training, as well as in the regulation of the skeletal muscle performance in both athletes and non-athletes. However, there are no reports on the effect of B2BRK 9-bp polymorphism on the response of the skeletal muscle to strength training, and our aim was to determine the relationship between the B2BRK SNP and triceps brachii functional and morphological adaptation to programmed physical activity in young adults. Methods In this 6-week pretest-posttest exercise intervention study, twenty nine healthy young men (21.5 ± 2.7 y, BMI 24.2 ± 3.5 kg/m2 were put on a 6-week exercise protocol using an isoacceleration dynamometer (5 times a week, 5 daily sets with 10 maximal elbow extensions, 1 minute rest between sets. Triceps brachii muscle volumes were assessed by using magnetic resonance imaging before and after the strength training. Bradykinin type 2 receptor 9 base pair polymorphism was determined for all participants. Results Following the elbow extensors training, an average increase in the volume of both triceps brachii was 5.4 ± 3.4% (from 929.5 ± 146.8 cm3 pre-training to 977.6 ± 140.9 cm3 after training, p9 allele compared to individuals with one or two +9 alleles (−9/-9, 8.5 ± 3.8%; vs. -9/+9 and +9/+9 combined, 4.7 ± 4.5%, p B2BRK genotype (−9/-9, 50.2 ± 19.2%; vs. -9/+9 and +9/+9 combined, 46.8 ± 20.7%, p > 0.05. Conclusions We found that muscle morphological response to targeted training – hypertrophy – is related to polymorphisms of B2BRK. However, no significant influence of different B2BRK genotypes on functional muscle properties after strength training in young healthy non athletes was found. This finding could be relevant, not only in predicting individual muscle adaptation capacity to training or sarcopenia related to aging and inactivity, but also in

  20. A Peptide Antagonist of the ErbB1 Receptor Inhibits Receptor Activation, Tumor Cell Growth and Migration In Vitro and Xenograft Tumor Growth In Vivo

    Science.gov (United States)

    Xu, Ruodan; Povlsen, Gro Klitgaard; Soroka, Vladislav; Bock, Elisabeth; Berezin, Vladimir

    2010-01-01

    The epidermal growth factor family of receptor tyrosine kinases (ErbBs) plays essential roles in tumorigenesis and cancer disease progression, and therefore has become an attractive target for structure-based drug design. ErbB receptors are activated by ligand-induced homo- and heterodimerization. Structural studies have revealed that ErbB receptor dimers are stabilized by receptor–receptor interactions, primarily mediated by a region in the second extracellular domain, termed the “dimerization arm”. The present study is the first biological characterization of a peptide, termed Inherbin3, which constitutes part of the dimerization arm of ErbB3. Inherbin3 binds to the extracellular domains of all four ErbB receptors, with the lowest peptide binding affinity for ErbB4. Inherbin3 functions as an antagonist of epidermal growth factor (EGF)-ErbB1 signaling. We show that Inherbin3 inhibits EGF-induced ErbB1 phosphorylation, cell growth, and migration in two human tumor cell lines, A549 and HN5, expressing moderate and high ErbB1 levels, respectively. Furthermore, we show that Inherbin3 inhibits tumor growth in vivo and induces apoptosis in a tumor xenograft model employing the human non-small cell lung cancer cell line A549. The Inherbin3 peptide may be a useful tool for investigating the mechanisms of ErbB receptor homo- and heterodimerization. Moreover, the here described biological effects of Inherbin3 suggest that peptide-based targeting of ErbB receptor dimerization is a promising anti-cancer therapeutic strategy. PMID:20364069

  1. A Peptide Antagonist of the ErbB1 Receptor Inhibits Receptor Activation, Tumor Cell Growth and Migration In Vitro and Xenograft Tumor Growth In Vivo

    Directory of Open Access Journals (Sweden)

    Ruodan Xu

    2010-01-01

    Full Text Available The epidermal growth factor family of receptor tyrosine kinases (ErbBs plays essential roles in tumorigenesis and cancer disease progression, and therefore has become an attractive target for structure-based drug design. ErbB receptors are activated by ligand-induced homo- and heterodimerization. Structural studies have revealed that ErbB receptor dimers are stabilized by receptor–receptor interactions, primarily mediated by a region in the second extracellular domain, termed the “dimerization arm”. The present study is the first biological characterization of a peptide, termed Inherbin3, which constitutes part of the dimerization arm of ErbB3. Inherbin3 binds to the extracellular domains of all four ErbB receptors, with the lowest peptide binding affinity for ErbB4. Inherbin3 functions as an antagonist of epidermal growth factor (EGF-ErbB1 signaling. We show that Inherbin3 inhibits EGF-induced ErbB1 phosphorylation, cell growth, and migration in two human tumor cell lines, A549 and HN5, expressing moderate and high ErbB1 levels, respectively. Furthermore, we show that Inherbin3 inhibits tumor growth in vivo and induces apoptosis in a tumor xenograft model employing the human non-small cell lung cancer cell line A549. The Inherbin3 peptide may be a useful tool for investigating the mechanisms of ErbB receptor homo- and heterodimerization. Moreover, the here described biological effects of Inherbin3 suggest that peptide-based targeting of ErbB receptor dimerization is a promising anti-cancer therapeutic strategy.

  2. Polimorfismos del receptor adrenérgico b1 y sus implicaciones farmacodinámicas

    Directory of Open Access Journals (Sweden)

    Ignacio Rodríguez

    2000-02-01

    Full Text Available

    Introducción: Los betabloqueadores son uno de los grupos farmacológicos que cuentan con mayor efectividad clínica comprobada; se ha demostrado que disminuyen la mortalidad y morbilidad por enfermedad cerebrovascular, eventos coronarios y falla cardíaca. Todos estos medicamentos tienen como común denominador el antagonismo de los receptores adrenérgicos b1, los cuales, se encuentran ubicados principalmente en cardiomiocitos, células yuxtaglomerulares y adipocitos; donde producen, en respuesta al estimulo por catecolaminas, aumento de la contractilidad y frecuencia cardíacas, liberación de renina y lipólisis respectivamente. Recientemente se descubrieron dos polimorfismos en este receptor. El primero de ellos, una sustitución de A por G en el nucleótido 145, genera un cambio del aminoácido Serina por Glicina en la posición 49 (Gly49Ser. El segundo polimorfismo, una sustitución de G por C en el nucleótido 1165, produce un cambio del aminoácido Arginina por Glicina en la posición 389 (Arg389Gly ubicado en la cola citoplasmática del receptor, que es una de las regiones de interacción con la proteína G(1. Estudios in vitro con las dos variantes polimórficas Arg389Gly del receptor, han demostrado que los receptores con Arg389 TGF-α/HA complex promotes tympanic membrane keratinocyte migration and proliferation via ErbB1 receptor

    Energy Technology Data Exchange (ETDEWEB)

    Mei Teh, Bing, E-mail: bing.teh@earscience.org.au [Ear Sciences Centre, School of Surgery, The University of Western Australia, Nedlands, WA (Australia); Ear Science Institute Australia, Subiaco, WA (Australia); Department of Otolaryngology, Head, Neck and Skull Base Surgery, Sir Charles Gairdner Hospital, Nedlands, WA (Australia); Redmond, Sharon L. [Ear Sciences Centre, School of Surgery, The University of Western Australia, Nedlands, WA (Australia); Ear Science Institute Australia, Subiaco, WA (Australia); Shen, Yi [Ear Sciences Centre, School of Surgery, The University of Western Australia, Nedlands, WA (Australia); Ear Science Institute Australia, Subiaco, WA (Australia); Department of Otolaryngology, Head and Neck, Ningbo Lihuili Hospital (Ningbo Medical Centre), Ningbo, Zhejiang (China); Atlas, Marcus D. [Ear Sciences Centre, School of Surgery, The University of Western Australia, Nedlands, WA (Australia); Ear Science Institute Australia, Subiaco, WA (Australia); Department of Otolaryngology, Head, Neck and Skull Base Surgery, Sir Charles Gairdner Hospital, Nedlands, WA (Australia); Marano, Robert J.; Dilley, Rodney J. [Ear Sciences Centre, School of Surgery, The University of Western Australia, Nedlands, WA (Australia); Ear Science Institute Australia, Subiaco, WA (Australia)

    2013-04-01

    Tympanic membrane perforations are common and represent a management challenge to clinicians. Current treatments for chronic perforations involve a graft surgery and require general anaesthesia, including associated costs and morbidities. Bioactive molecules (e.g. growth factors, cytokines) play an important role in promoting TM wound healing following perforation and the use of growth factors as a topical treatment for tympanic membrane perforations has been suggested as an alternative to surgery. However, the choice of bioactive molecules best suited to promote wound healing has yet to be identified. We investigated the effects of hyaluronic acid, vitronectin, TGF-α, IL-24 and their combinations on migration, proliferation and adhesion of cultured human tympanic membrane-derived keratinocytes (hTM), in addition to their possible mechanisms of action. We found that TGF-α, TGF-α/HA and TGF-α/IL-24 promoted wound healing by significantly increasing both migration and proliferation. TGF-α and/or HA treated cells showed comparable cell–cell adhesion whilst maintaining an epithelial cell phenotype. With the use of receptor binding inhibitors for ErbB1 (AG1478) and CD44 (BRIC235), we revealed that the activation of ErbB1 is required for TGF-α/HA-mediated migration and proliferation. These results suggest factors that may be incorporated into a tissue-engineered membrane or directly as topical treatment for tympanic membrane perforations and hence reduce the need for a surgery. - Highlights: ► TGF-α, TGF-α/HA and TGF-α/IL-24 improved hTM keratinocyte migration and proliferation. ► TGF-α and/or HA maintained epithelial cell phenotype. ► TGF-α/HA-mediated migration and proliferation requires activation of ErbB1 receptor.

  3. A peptide antagonist of ErbB receptors, Inherbin3, induces neurite outgrowth from rat cerebellar granule neurons through ErbB1 inhibition

    DEFF Research Database (Denmark)

    Xu, Ruodan; Pankratova, Stanislava; Christiansen, Søren Hofman

    2013-01-01

    ErbB receptors not only function in cancer, but are also key developmental regulators in the nervous system. We previously identified an ErbB1 peptide antagonist, Inherbin3, that is capable of inhibiting tumor growth in vitro and in vivo. In this study, we found that inhibition of ErbB1 kinase ac...

  4. Role of Mas Receptor Antagonist A799 in Renal Blood Flow Response to Ang 1-7 after Bradykinin Administration in Ovariectomized Estradiol-Treated Rats

    Directory of Open Access Journals (Sweden)

    Aghdas Dehghani

    2015-01-01

    Full Text Available Background. The accompanied role of Mas receptor (MasR, bradykinin (BK, and female sex hormone on renal blood flow (RBF response to angiotensin 1-7 is not well defined. We investigated the role of MasR antagonist (A779 and BK on RBF response to Ang 1-7 infusion in ovariectomized estradiol-treated rats. Methods. Ovariectomized Wistar rats received estradiol (OVE or vehicle (OV for two weeks. Catheterized animals were subjected to BK and A799 infusion and mean arterial pressure (MAP, RBF, and renal vascular resistance (RVR responses to Ang 1-7 (0, 100, and 300 ng kg−1 min−1 were determined. Results. Percentage change of RBF (%RBF in response to Ang1-7 infusion increased in a dose-dependent manner. In the presence of BK, when MasR was not blocked, %RBF response to Ang 1-7 in OVE group was greater than OV group significantly (P<0.05. Infusion of 300 ng kg−1 min−1 Ang 1-7 increased RBF by 6.9±1.9% in OVE group versus 0.9±1.8% in OV group. However when MasR was blocked, %RBF response to Ang 1-7 in OV group was greater than OVE group insignificantly. Conclusion. Coadministration of BK and A779 compared to BK alone increased RBF response to Ang 1-7 in vehicle treated rats. Such observation was not seen in estradiol treated rats.

  5. Bradykinin B2 Receptors of dendritic cells, acting as sensors of kinins proteolytically released by Trypanosoma cruzi, are critical for the development of protective type-1 responses.

    Directory of Open Access Journals (Sweden)

    Ana Carolina Monteiro

    2007-11-01

    Full Text Available Although the concept that dendritic cells (DCs recognize pathogens through the engagement of Toll-like receptors is widely accepted, we recently suggested that immature DCs might sense kinin-releasing strains of Trypanosoma cruzi through the triggering of G-protein-coupled bradykinin B2 receptors (B2R. Here we report that C57BL/6.B2R-/- mice infected intraperitoneally with T. cruzi display higher parasitemia and mortality rates as compared to B2R+/+ mice. qRT-PCR revealed a 5-fold increase in T. cruzi DNA (14 d post-infection [p.i.] in B2R-/- heart, while spleen parasitism was negligible in both mice strains. Analysis of recall responses (14 d p.i. showed high and comparable frequencies of IFN-gamma-producing CD4+ and CD8+ T cells in the spleen of B2R-/- and wild-type mice. However, production of IFN-gamma by effector T cells isolated from B2R-/- heart was significantly reduced as compared with wild-type mice. As the infection continued, wild-type mice presented IFN-gamma-producing (CD4+CD44+ and CD8+CD44+ T cells both in the spleen and heart while B2R-/- mice showed negligible frequencies of such activated T cells. Furthermore, the collapse of type-1 immune responses in B2R-/- mice was linked to upregulated secretion of IL-17 and TNF-alpha by antigen-responsive CD4+ T cells. In vitro analysis of tissue culture trypomastigote interaction with splenic CD11c+ DCs indicated that DC maturation (IL-12, CD40, and CD86 is controlled by the kinin/B2R pathway. Further, systemic injection of trypomastigotes induced IL-12 production by CD11c+ DCs isolated from B2R+/+ spleen, but not by DCs from B2R-/- mice. Notably, adoptive transfer of B2R+/+ CD11c+ DCs (intravenously into B2R-/- mice rendered them resistant to acute challenge, rescued development of type-1 immunity, and repressed TH17 responses. Collectively, our results demonstrate that activation of B2R, a DC sensor of endogenous maturation signals, is critically required for development of acquired

  6. The relevance of preclinical research models for the development of antimigraine drugs: Focus on 5-HT1B/1D and CGRP receptors

    DEFF Research Database (Denmark)

    Gupta, S.; Villalon, C.M.

    2010-01-01

    approaches, have significantly contributed to the two antimigraine principles in therapeutics, namely: 5-HT1B/1D receptor agonists (known as triptans) and CGRP receptor antagonists (known as gepants). This review will analyze the preclinical experimental models currently known for the development...

  7. Brain kinin B1 receptor is upregulated by the oxidative stress and its activation leads to stereotypic nociceptive behavior in insulin-resistant rats.

    Science.gov (United States)

    Dias, Jenny Pena; Gariépy, Helaine De Brito; Ongali, Brice; Couture, Réjean

    2015-07-01

    Kinin B1 receptor (B1R) is virtually absent under physiological condition, yet it is highly expressed in models of diabetes mellitus. This study aims at determining: (1) whether B1R is induced in the brain of insulin-resistant rat through the oxidative stress; (2) the consequence of B1R activation on stereotypic nocifensive behavior; (3) the role of downstream putative mediators in B1R-induced behavioral activity. Sprague-Dawley rats were fed with 10% D-glucose in their drinking water or tap water (controls) for 4 or 12 weeks, combined either with a standard chow diet or a diet enriched with α-lipoic acid (1 g/kg feed) for 4 weeks. The distribution and density of brain B1R binding sites were assessed by autoradiography. Behavioral activity evoked by i.c.v. injection of the B1R agonist Sar-[D-Phe(8)]-des-Arg(9)-BK (10 μg) was measured before and after i.c.v. treatments with selective antagonists (10 μg) for kinin B1 (R-715, SSR240612), tachykinin NK1 (RP-67580) and glutamate NMDA (DL-AP5) receptors or with the inhibitor of NOS (L-NNA). Results showed significant increases of B1R binding sites in various brain areas of glucose-fed rats that could be prevented by the diet containing α-lipoic acid. The B1R agonist elicited head scratching, grooming, sniffing, rearing, digging, licking, face washing, wet dog shake, teeth chattering and biting in glucose-fed rats, which were absent after treatment with α-lipoic acid or antagonists/inhibitors. Data suggest that kinin B1R is upregulated by the oxidative stress in the brain of insulin-resistant rats and its activation causes stereotypic nocifensive behavior through the release of substance P, glutamate and NO. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. Ocular application of the kinin B1 receptor antagonist LF22-0542 inhibits retinal inflammation and oxidative stress in streptozotocin-diabetic rats.

    Directory of Open Access Journals (Sweden)

    Mylène Pouliot

    Full Text Available Kinin B(1 receptor (B(1R is upregulated in retina of Streptozotocin (STZ-diabetic rats and contributes to vasodilation of retinal microvessels and breakdown of the blood-retinal barrier. Systemic treatment with B(1R antagonists reversed the increased retinal plasma extravasation in STZ rats. The present study aims at determining whether ocular application of a water soluble B(1R antagonist could reverse diabetes-induced retinal inflammation and oxidative stress.Wistar rats were made diabetic with STZ (65 mg/kg, i.p. and 7 days later, they received one eye drop application of LF22-0542 (1% in saline twice a day for a 7 day-period. The impact was determined on retinal vascular permeability (Evans blue exudation, leukostasis (leukocyte infiltration using Fluorescein-isothiocyanate (FITC-coupled Concanavalin A lectin, retinal mRNA levels (by qRT-PCR of inflammatory (B(1R, iNOS, COX-2, ICAM-1, VEGF-A, VEGF receptor type 2, IL-1β and HIF-1α and anti-inflammatory (B(2R, eNOS markers and retinal level of superoxide anion (dihydroethidium staining.Retinal plasma extravasation, leukostasis and mRNA levels of B(1R, iNOS, COX-2, VEGF receptor type 2, IL-1β and HIF-1α were significantly increased in diabetic retinae compared to control rats. All these abnormalities were reversed to control values in diabetic rats treated with LF22-0542. B(1R antagonist also significantly inhibited the increased production of superoxide anion in diabetic retinae.B(1R displays a pathological role in the early stage of diabetes by increasing oxidative stress and pro-inflammatory mediators involved in retinal vascular alterations. Hence, topical application of kinin B(1R antagonist appears a highly promising novel approach for the treatment of diabetic retinopathy.

  9. A role for the high-density lipoprotein receptor SR-B1 in synovial inflammation via serum amyloid-A.

    LENUS (Irish Health Repository)

    Mullan, Ronan Hugh

    2012-02-01

    Acute phase apoprotein Serum Amyloid A (A-SAA), which is strongly expressed in rheumatoid arthritis synovial membrane (RA SM), induces angiogenesis, adhesion molecule expression, and matrix metalloproteinase production through the G-coupled receptor FPRL-1. Here we report alternative signaling through the high-density lipoprotein receptor scavenger receptor-class B type 1 (SR-B1). Quantitative expression\\/localization of SR-B1 in RA SM, RA fibroblast-like cells (FLCs), and microvascular endothelial cells (ECs) was assessed by Western blotting and immunohistology\\/fluorescence. A-SAA-mediated effects were examined using a specific antibody against SR-B1 or amphipathic alpha-Helical Peptides (the SR-B1 antagonists L-37pA and D-37pA), in RA FLCs and ECs. Adhesion molecule expression and cytokine production were quantified using flow cytometry and ELISA. SR-B1 was strongly expressed in the RA SM lining layer and endothelial\\/perivascular regions compared with osteoarthritis SM or normal control synovium. Differential SR-B1 expression in RA FLC lines (n = 5) and ECs correlated closely with A-SAA, but not tumor necrosis factor alpha-induced intercellular adhesion molecule-1 upregulation. A-SAA-induced interleukin-6 and -8 production was inhibited in the presence of anti-SR-B1 in human microvascular endothelial cells and RA FLCs. Moreover, D-37pA and L-37pA inhibited A-SAA-induced vascular cell adhesion molecule-1 and intercellular adhesion molecule expression from ECs in a dose-dependent manner. As SR-B1 is expressed in RA synovial tissue and mediates A-SAA-induced pro-inflammatory pathways, a better understanding of A-SAA-mediated inflammatory pathways may lead to novel treatment strategies for RA.

  10. The physiological expression of scavenger receptor SR-B1 in canine endometrial and placental epithelial cells and its potential involvement in pathogenesis of pyometra.

    Science.gov (United States)

    Gabriel, C; Becher-Deichsel, A; Hlavaty, J; Mair, G; Walter, I

    2016-06-01

    Pyometra, the purulent inflammation of the uterus, is a common uterine disease of bitches that has potentially life-threatening consequences. The opportunistic bacterial infection of the uterus often progresses into the serious systemic inflammatory response syndrome. In a previous study, we characterized epithelial foam cells in the canine endometrial surface occurring in metestrus, and we regularly observed pronounced epithelial foam-cell formations in pyometra-affected uteri. Therefore, it was assumed that the mechanism behind lipid droplet accumulation in surface epithelial cells might even increase bacterial binding capacity and promote pyometra development. Lipid droplet accumulation in epithelial cells is accomplished via specialized lipid receptors called scavenger receptors (SR). Scavenger receptor class B type 1 (SR-B1) is an important receptor for lipid accumulation in diverse cell types, but it is also a strong binding partner for bacteria, and thereby enhances bacterial adhesion and clinical signs of systemic inflammatory response syndrome. In the present study, after the isolation of metestrous surface epithelial cells from canine uteri by laser capture microdissection, SR-B1 was identified at the messenger RNA (mRNA) level by quantitative real time polymerase chain reaction and also at the protein level by means of immunohistochemistry. In pyometra-affected uteri, SR-B1 mRNA expression was higher than that in the healthy control samples, and SR-B1 protein was expressed in the surface and crypt epithelial cells. Furthermore, to understand the physiological role of SR-B1 expression in the metestrus surface epithelial cells, we investigated its expression in the epithelial cells of the glandular chambers of canine placenta in different stages of gestation because these cells are also characterized by lipid droplet accumulation. SR-B1 was present in the placental epithelial cells of the glandular chambers from 25 to 30 and 45 to 50 days of gestation

  11. Blockade of sensory abnormalities and kinin B(1) receptor expression by N-acetyl-L-cysteine and ramipril in a rat model of insulin resistance.

    Science.gov (United States)

    Ismael, Mahmoud Ali; Talbot, Sébastien; Carbonneau, Cynthia L; Beauséjour, Christian M; Couture, Réjean

    2008-07-28

    Glucose-fed rat is a model of insulin resistance that displays sensory polyneuropathy and hypertension. This study aimed at comparing the beneficial effects of N-acetyl-L-cysteine (NAC, antioxidant) and ramipril (angiotensin-1 converting enzyme inhibitor) on tactile and cold allodynia induced by chronic glucose feeding. Impact of these treatments was also assessed on hypertension, plasma glucose and insulin concentrations, insulin resistance and kinin B(1) receptor expression. Male Wistar rats (50-75 g) were given 10% d-glucose in their drinking water for 11 weeks or tap water (controls). Glucose-fed rats were treated either with NAC (1 g/kg/day, gavage), ramipril (1 mg/kg/day in drinking water) or no drug during the last 5 weeks. Glucose feeding for 6 weeks induced a significant increase in systolic blood pressure and hyperglycaemia which was accompanied by tactile and cold allodynia. At 11 weeks, plasma insulin, insulin resistance (HOMA index), kinin B(1) receptor mRNA in spinal cord and renal cortex and B(1) receptor binding sites in spinal cord were enhanced in glucose-fed rats. NAC and ramipril caused a progressive to complete inhibition of tactile and cold allodynia from 6 to 11 weeks. High systolic blood pressure, hyperinsulinemia, insulin resistance and kinin B(1) receptor expression were also normalized or attenuated in glucose-fed rats by either treatment. Results suggest that chronic treatment with an antioxidant or an ACE inhibitor provides similar beneficial effects on sensory polyneuropathy, hypertension and insulin resistance in glucose-fed rats. Both therapies were associated with a reduction of the expression of the pro-nociceptive kinin B(1) receptor.

  12. Metformin suppresses CYP1A1 and CYP1B1 expression in breast cancer cells by down-regulating aryl hydrocarbon receptor expression

    Energy Technology Data Exchange (ETDEWEB)

    Do, Minh Truong; Kim, Hyung Gyun; Tran, Thi Thu Phuong; Khanal, Tilak; Choi, Jae Ho [Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon (Korea, Republic of); Chung, Young Chul [Department of Food Science and Culinary, International University of Korea, Jinju (Korea, Republic of); Jeong, Tae Cheon, E-mail: taecheon@ynu.ac.kr [College of Pharmacy, Yeungnam University, Gyeongsan (Korea, Republic of); Jeong, Hye Gwang, E-mail: hgjeong@cnu.ac.kr [Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon (Korea, Republic of)

    2014-10-01

    Induction of cytochrome P450 (CYP) 1A1 and CYP1B1 by environmental xenobiotic chemicals or endogenous ligands through the activation of the aryl hydrocarbon receptor (AhR) has been implicated in a variety of cellular processes related to cancer, such as transformation and tumorigenesis. Here, we investigated the effects of the anti-diabetes drug metformin on expression of CYP1A1 and CYP1B1 in breast cancer cells under constitutive and inducible conditions. Our results indicated that metformin down-regulated the expression of CYP1A1 and CYP1B1 in breast cancer cells under constitutive and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced conditions. Down-regulation of AhR expression was required for metformin-mediated decreases in CYP1A1 and CYP1B1 expression, and the metformin-mediated CYP1A1 and CYP1B1 reduction is irrelevant to estrogen receptor α (ERα) signaling. Furthermore, we found that metformin markedly down-regulated Sp1 protein levels in breast cancer cells. The use of genetic and pharmacological tools revealed that metformin-mediated down-regulation of AhR expression was mediated through the reduction of Sp1 protein. Metformin inhibited endogenous AhR ligand-induced CYP1A1 and CYP1B1 expression by suppressing tryptophan-2,3-dioxygenase (TDO) expression in MCF-7 cells. Finally, metformin inhibits TDO expression through a down-regulation of Sp1 and glucocorticoid receptor (GR) protein levels. Our findings demonstrate that metformin reduces CYP1A1 and CYP1B1 expression in breast cancer cells by down-regulating AhR signaling. Metformin would be able to act as a potential chemopreventive agent against CYP1A1 and CYP1B1-mediated carcinogenesis and development of cancer. - Graphical abstract: Schematic of the CYP1A1 and CYP1B1 gene regulation by metformin. - Highlights: • Metformin inhibits CYP1A1 and CYP1B1 expression. • Metformin down-regulates the AhR signaling. • Metformin reduces Sp1 protein expression. • Metformin suppresses TDO expression.

  13. The influence of angiotensin converting enzyme and bradykinin receptor B2 gene variants on voluntary fluid intake and fluid balance in healthy men during moderate-intensity exercise in the heat.

    Science.gov (United States)

    Yau, Adora M W; Moss, Andrew D; James, Lewis John; Gilmore, William; Ashworth, Jason J; Evans, Gethin H

    2015-02-01

    Angiotensin converting enzyme (ACE) and bradykinin receptor B2 (B2R) genetic variation may affect thirst because of effects on angiotensin II production and bradykinin activity, respectively. To examine this, 45 healthy Caucasian men completed 60 min of cycle exercise at 62% ± 5% peak oxygen uptake in a room heated to 30.5 ± 0.3 °C with ad libitum fluid intake. Blood samples were collected pre-, mid-, and immediately post-cycle. Fluid intake, body mass loss (BML), sweat loss (determined via changes in body mass and fluid intake), and thirst sensation were recorded. All participants were genotyped for the ACE insert fragment (I) and the B2R insert sequence (P). Participants were homozygous for the wild-type allele (WW or MM), heterozygous (WI or MP) or homozygous for the insert (II or PP). No differences between genotype groups were found in mean (±SD) voluntary fluid intake (WW: 613 ± 388, WI: 753 ± 385, II: 862 ± 421 mL, p = 0.31; MM: 599 ± 322, MP: 745 ± 374, PP: 870 ± 459 mL, p = 0.20), percentage BML or any other fluid balance variables for both the ACE and B2R genes, respectively. Mean thirst perception in the B2R PP group, however, was higher (p fluid intake and fluid balance in healthy men performing 60 min of moderate-intensity exercise in the heat are not predominantly influenced by ACE or B2R genetic variation.

  14. Antiproliferative effect of the Ginkgo biloba extract is associated with the enhancement of cytochrome P450 1B1 expression in estrogen receptor-negative breast cancer cells

    Science.gov (United States)

    ZHAO, XIAO-DAN; DONG, NI; MAN, HONG-TAO; FU, ZHONG-LIN; ZHANG, MEI-HONG; KOU, SHUANG; MA, SHI-LIANG

    2013-01-01

    Ginkgo biloba is a dioecious tree and its extract is a complex mixture that has been used for thousands of years to treat a variety of ailments in traditional Chinese medicine. The aim of this study was to present our observations on the inhibitory effects of different Ginkgo biloba extracts on human breast cancer cell proliferation and growth. Our results demonstrated that treatment of MCF-7 and MDA-MB-231 human breast cancer cells with Ginkgo biloba leaves and ginkgo fruit extract inhibited cell proliferation. It was also observed that this inhibition was accompanied by the enhancement of cytochrome P450 (CYP) 1B1 expression in MDA-MB-231 cells. In addition, treatment with ginkgo fruit extract resulted in a higher CYP1B1 expression in MDA-MB-231 cells compared to treatment with the Ginkgo biloba leaves extract. Our results suggested that the inhibitory effects of the Ginkgo biloba extract on estrogen receptor-negative breast cancer proliferation and the induction of CYP1B1 expression may be exerted through an alternative pathway, independent of the estrogen receptor or the aryl hydrocarbon receptor pathway. PMID:24649031

  15. Biological Roles of Hydroxysteroid (11-Beta) Dehydrogenase 1 (HSD11B1), HSD11B2, and Glucocorticoid Receptor (NR3C1) in Sheep Conceptus Elongation.

    Science.gov (United States)

    Brooks, Kelsey; Burns, Gregory; Spencer, Thomas E

    2015-08-01

    In sheep, the elongating conceptus synthesizes and secretes interferon tau (IFNT) as well as prostaglandins (PGs) and cortisol. The enzymes, hydroxysteroid (11-beta) dehydrogenase 1 (HSD11B1) and HSD11B2 interconvert cortisone and cortisol. In sheep, HSD11B1 is expressed and active in the conceptus trophectoderm as well as in the endometrial luminal epithelia; in contrast, HSD11B2 expression is most abundant in conceptus trophectoderm. Cortisol is a biologically active glucocorticoid and ligand for the glucocorticoid receptor (NR3C1 or GR) and mineralocorticoid receptor (NR3C2 or MR). Expression of MR is not detectable in either the ovine endometrium or conceptus during early pregnancy. In tissues that do not express MR, HSD11B2 protects cells from the growth-inhibiting and/or proapoptotic effects of cortisol, particularly during embryonic development. In study one, an in utero loss-of-function analysis of HSD11B1 and HSD11B2 was conducted in the conceptus trophectoderm using morpholino antisense oligonucleotides (MAOs) that inhibit mRNA translation. Elongating, filamentous conceptuses were recovered on Day 14 from ewes infused with control morpholino or HSD11B2 MAO. In contrast, HSD11B1 MAO resulted in severely growth-retarded conceptuses or conceptus fragments with apoptotic trophectoderm. In study two, clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 genome editing was used to determine the role of GR in conceptus elongation and development. Elongating, filamentous-type conceptuses (12-14 cm in length) were recovered from ewes gestating control embryos (n = 7/7) and gestating GR-edited embryos (n = 6/7). These results support the idea that the effects of HSD11B1-derived cortisol on conceptus elongation are indirectly mediated by the endometrium and are not directly mediated through GR in the trophectoderm. © 2015 by the Society for the Study of Reproduction, Inc.

  16. Crosslinking photosensitized by a ruthenium chelate as a tool for labeling and topographical studies of G-protein-coupled receptors.

    Science.gov (United States)

    Duroux-Richard, Isabelle; Vassault, Philippe; Subra, Guy; Guichou, Jean-François; Richard, Eric; Mouillac, Bernard; Barberis, Claude; Marie, Jacky; Bonnafous, Jean-Claude

    2005-01-01

    The purpose was to apply oxidative crosslinking reactions to the study of recognition and signaling mechanisms associated to G-protein-coupled receptors. Using a ruthenium chelate, Ru(bipy)(3)(2+), as photosensitizer and visible light irradiation, in the presence of ammonium persulfate, we performed fast and efficient covalent labeling of the B(2) bradykinin receptor by agonist or antagonist ligands possessing a radio-iodinated phenol moiety. The chemical and topographical specificities of these crosslinking experiments were investigated. The strategy could also be applied to the covalent labeling of the B(1) bradykinin receptor, the AT(1) angiotensin II receptor, the V(1a) vasopressin receptor and the oxytocin receptor. Interestingly, we demonstrated the possibility to covalently label the AT(1) and B(2) receptors with functionalized ligands. The potential applications of metal-chelate chemistry to receptor structural and signaling studies through intramolecular or intermolecular crosslinking are presented.

  17. Characterisation and mechanisms of bradykinin-evoked pain in man using iontophoresis.

    Science.gov (United States)

    Paterson, Kathryn J; Zambreanu, Laura; Bennett, David L H; McMahon, Stephen B

    2013-06-01

    Bradykinin (BK) is an inflammatory mediator that can evoke oedema and vasodilatation, and is a potent algogen signalling via the B1 and B2 G-protein coupled receptors. In naïve skin, BK is effective via constitutively expressed B2 receptors (B2R), while B1 receptors (B1R) are purported to be upregulated by inflammation. The aim of this investigation was to optimise BK delivery to investigate the algesic effects of BK and how these are modulated by inflammation. BK iontophoresis evoked dose- and temperature-dependent pain and neurogenic erythema, as well as thermal and mechanical hyperalgesia (P skin was pretreated with compound 4880 to degranulate the MCs prior to BK challenge. The early phase of BK-evoked pain was reduced in degranulated skin (P wheal, and flare were still evident. In contrast to BK, the B1R selective agonist des-Arg9-BK failed to induce pain or sensitise naïve skin. However, following skin inflammation induced by ultraviolet B irradiation, this compound produced a robust pain response. We have optimised a versatile experimental model by which BK and its analogues can be administered to human skin. We have found that there is an early phase of BK-induced pain which partly depends on the release of inflammatory mediators by MCs; however, subsequent hyperalgesia is not dependent on MC degranulation. In naïve skin, B2R signaling predominates, however, cutaneous inflammation results in enhanced B1R responses. Copyright © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

  18. Endothelium-dependent relaxant responses to selective 5-HT(1B/1D) receptor agonists in the isolated middle cerebral artery of the rat

    DEFF Research Database (Denmark)

    Hansen-Schwartz, Jacob; Løvland Hoel, Natalie; Nilsson, Elisabeth

    2003-01-01

    response to 5-HT and triptans. Using the vessel bath technique, MCA segments were mounted on two metal wires. The relaxant responses to sumatriptan could not be reproduced using this model; instead, weak contractile responses (6 +/- 3% of submaximal contractile capacity) were observed. The difference...... perfused. Luminally added 5- hydroxytryptamine (5-HT), sumatriptan and rizatriptan induced maximal dilatations of 22 +/- 4, 10 +/- 2 and 13 +/- 5%, respectively, compared to the resting diameter. The relaxant effect of sumatriptan was blocked by the 5- HT(1B/1D) receptor selective antagonist GR 55562 (10......(-6)M). The use of N(omega)-nitro-L-arginine and charybdotoxin revealed that the dilatation involved both nitric oxide and endothelially derived hyperpolarising factor. Thus, the earlier demonstrated expression of 5-HT(1B/1D) immunoreactivity in the endothelium may well translate into a relaxant...

  19. Bradykinin does not acutely sensitize the reflex pressor response during hindlimb skeletal muscle stretch in decerebrate rats.

    Science.gov (United States)

    Rollins, Korynne S; Smith, Joshua R; Esau, Peter J; Kempf, Evan A; Hopkins, Tyler D; Copp, Steven W

    2017-10-01

    Hindlimb skeletal muscle stretch (i.e., selective activation of the muscle mechanoreflex) in decerebrate rats evokes reflex increases in blood pressure and sympathetic nerve activity. Bradykinin has been found to sensitize mechanogated channels through a bradykinin B2 receptor-dependent mechanism. Moreover, bradykinin B2 receptor expression on sensory neurons is increased following chronic femoral artery ligation in the rat (a model of simulated peripheral artery disease). We tested the hypothesis that injection of bradykinin into the arterial supply of a hindlimb in decerebrate, unanesthetized rats would acutely augment (i.e., sensitize) the increase in blood pressure and renal sympathetic nerve activity during hindlimb muscle stretch to a greater extent in rats with a ligated femoral artery than in rats with a freely perfused femoral artery. The pressor response during static hindlimb muscle stretch was compared before and after hindlimb arterial injection of 0.5 µg of bradykinin. Injection of bradykinin increased blood pressure to a greater extent in "ligated" (n = 10) than "freely perfused" (n = 10) rats. The increase in blood pressure during hindlimb muscle stretch, however, was not different before vs. after bradykinin injection in freely perfused (14 ± 2 and 15 ± 2 mmHg for pre- and post-bradykinin, respectively, P = 0.62) or ligated (15 ± 3 and 14 ± 2 mmHg for pre- and post-bradykinin, respectively, P = 0.80) rats. Likewise, the increase in renal sympathetic nerve activity during stretch was not different before vs. after bradykinin injection in either group of rats. We conclude that bradykinin did not acutely sensitize the pressor response during hindlimb skeletal muscle stretch in freely perfused or ligated decerebrate rats. Copyright © 2017 the American Physiological Society.

  1. A peptide antagonist of the ErbB1 receptor inhibits receptor activation, tumor cell growth and migration in vitro and xenograft tumor growth in vivo

    DEFF Research Database (Denmark)

    Xu, Ruodan; Povlsen, Gro Klitgaard; Soroka, Vladislav

    2010-01-01

    The epidermal growth factor family of receptor tyrosine kinases (ErbBs) plays essential roles in tumorigenesis and cancer disease progression, and therefore has become an attractive target for structure-based drug design. ErbB receptors are activated by ligand-induced homo- and heterodimerization...... lung cancer cell line A549. The Inherbin3 peptide may be a useful tool for investigating the mechanisms of ErbB receptor homo- and heterodimerization. Moreover, the here described biological effects of Inherbin3 suggest that peptide-based targeting of ErbB receptor dimerization is a promising anti-cancer...

  2. Dopamine D2-Receptor Antagonists Down-Regulate CYP1A1/2 and CYP1B1 in the Rat Liver.

    Directory of Open Access Journals (Sweden)

    P Harkitis

    Full Text Available Dopaminergic systems regulate the release of several hormones including growth hormone (GH, thyroid hormones, insulin, glucocorticoids and prolactin (PRL that play significant roles in the regulation of various Cytochrome P450 (CYP enzymes. The present study investigated the role of dopamine D2-receptor-linked pathways in the regulation of CYP1A1, CYP1A2 and CYP1B1 that belong to a battery of genes controlled by the Aryl Hydrocarbon Receptor (AhR and play a crucial role in the metabolism and toxicity of numerous environmental toxicants. Inhibition of dopamine D2-receptors with sulpiride (SULP significantly repressed the constitutive and benzo[a]pyrene (B[a]P-induced CYP1A1, CYP1A2 and CYP1B expression in the rat liver. The expression of AhR, heat shock protein 90 (HSP90 and AhR nuclear translocator (ARNT was suppressed by SULP in B[a]P-treated livers, whereas the AhRR expression was increased by the drug suggesting that the SULP-mediated repression of the CYP1 inducibility is due to inactivation of the AhR regulatory system. At signal transduction level, the D2-mediated down-regulation of constitutive CYP1A1/2 and CYP1B1 expression appears to be mediated by activation of the insulin/PI3K/AKT pathway. PRL-linked pathways exerting a negative control on various CYPs, and inactivation of the glucocorticoid-linked pathways that positively control the AhR-regulated CYP1 genes, may also participate in the SULP-mediated repression of both, the constitutive and induced CYP1 expression. The present findings indicate that drugs acting as D2-dopamine receptor antagonists can modify several hormone systems that regulate the expression of CYP1A1, CYP1A2 and CYP1B1, and may affect the toxicity and carcinogenicity outcome of numerous toxicants and pre-carcinogenic substances. Therefore, these drugs could be considered as a part of the strategy to reduce the risk of exposure to environmental pollutants and pre-carcinogens.

  3. HMG-CoA reductase, cholesterol 7alpha-hydroxylase, LDL receptor, SR-B1, and ACAT in diet-induced syndrome X.

    Science.gov (United States)

    Roberts, Christian K; Liang, Kaihui; Barnard, R James; Kim, Choong H; Vaziri, Nosratola D

    2004-10-01

    Long-term consumption of Western diets can lead to acquired syndrome X, which presents with obesity, insulin resistance, hypertension, hyperlipidemia, and risk of atherosclerotic cardiovascular disease. While plasma lipid abnormalities in syndrome X have been well characterized, their molecular basis remains unclear. This study explored potential mechanisms of hypercholesterolemia in diet-induced syndrome X. Female Fischer rats were fed a high-fat, refined-carbohydrate (sucrose) diet (HFS) or standard rat chow (low-fat, complex carbohydrate, LFCC) for 20 months. Plasma lipids and hepatic tissue mRNA, protein, and/or activities of the key enzymes and receptors involved in cholesterol metabolism were determined. The HFS group exhibited hypertension, hyperlipidemia, insulin resistance, obesity, significant down-regulation of hepatic cholesterol 7alpha-hydroxylase (the rate-limiting step in cholesterol catabolism) and low-density lipoprotein (LDL) receptor (LDL-R, the primary pathway of LDL clearance). In contrast, hepatic tissue acyl-coenzyme A:cholesterol acyltransferase (ACAT-2, the primary enzyme involved in intracellular esterification of cholesterol) and scavenger-receptor class B, type 1 (SR-B1 or HDL receptor) were up-regulated. While 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase mRNA expression was increased, its protein abundance and activity were unchanged, and HMG-CoA reductase-to-cholesterol 7alpha-hydroxylase ratio was increased in HFS-fed animals. Hypercholesterolemia in diet-induced syndrome X is associated with depressed cholesterol 7alpha-hydroxylase, diminished LDL-R, elevated ACAT, and increased HMG-CoA reductase-to-cholesterol 7alpha-hydroxylase ratio. These findings point to impaired hepatic catabolism and uptake of cholesterol and inappropriate cholesterol production capacity as the underlying causes of hypercholesterolemia in rats with diet-induced syndrome X.

  4. The three-dimensional structure of the N-terminal domain of corticotropin-releasing factor receptors: sushi domains and the B1 family of G protein-coupled receptors.

    Science.gov (United States)

    Perrin, Marilyn H; Grace, Christy R R; Riek, Roland; Vale, Wylie W

    2006-07-01

    The corticotropin-releasing factor (CRF) receptors, CRF-R1 and CRF-R2, belong to the B1 subfamily of G protein-coupled Receptors (GPCRs), including receptors for secretin, growth hormone-releasing hormone (GHRH), vasoactive intestinal peptide (VIP), pituitary adenylate cyclase-activating polypeptide (PACAP), calcitonin, parathyroid hormone (PTH), glucagon, and glucagon-like peptide-1 (GLP-1). The peptide ligand family comprises CRF, Ucn 1, 2, and 3. CRF plays the major role in integrating the response to stress. Additionally, the ligands exhibit many effects on muscle, pancreas, heart, and the GI, reproductive, and immune systems. CRF-R1 has higher affinity for CRF than does CRF-R2 while both receptors bind Ucn 1 equally. CRF-R2 shows specificity for Ucns 2 and 3. A major binding domain of the CRFRs is the N terminus/first extracellular domain (ECD1). Soluble proteins corresponding to the ECD1s of each receptor bind CRF ligands with nanomolar affinities. Our three-dimensional (3D) nuclear magnetic resonance (NMR) structure of a soluble protein corresponding to the ECD1 of CRF-R2beta (1) identified its structural fold as a Sushi domain/short consensus repeat (SCR), stabilized by three disulfide bridges, two tryptophan residues, and an internal salt bridge (Asp65-Arg101). Disruption of the bridge by D65A mutation abrogates ligand recognition and results in loss of the well-defined disulfide pattern and Sushi domain structure. NMR analysis of the ECD1 in complex with astressin identified key amino acids involved in ligand recognition. Mutation of some of these residues in the full-length receptor reduces its affinity for CRF ligands. A structure-based sequence comparison shows conservation of key amino acids in all the B1 subfamily receptors, suggesting a corresponding conservation of a Sushi domain structural fold of their ECD1s.

  5. The clinicopathological significance of lamin A/C, lamin B1 and lamin B receptor mRNA expression in human breast cancer.

    Science.gov (United States)

    Wazir, Umar; Ahmed, Mai Hassan; Bridger, Joanna M; Harvey, Amanda; Jiang, Wen G; Sharma, Anup K; Mokbel, Kefah

    2013-12-01

    Lamin A/C (LMNA), lamin B1 (LMNB1) and lamin B receptor (LBR) have key roles in nuclear structural integrity and chromosomal stability. In this study, we have studied the relationships between the mRNA expressions of A-type lamins, LMNB1 and LBR and the clinicopathological parameters in human breast cancer. Samples of breast cancer tissues (n = 115) and associated non-cancerous tissue (ANCT; n = 30) were assessed using reverse transcription and quantitative PCR. Transcript levels were correlated with clinicopathological data. Higher levels of A-type lamins and LMNB1 mRNA expression were seen in ANCT. Higher lamin A/C expression was associated with the early clinical stage (TNM1 vs. TNM3 - 13 vs. 0.21; p = 0.0515), with better clinical outcomes (disease-free survival vs. mortality - 11 vs. 1; p = 0.0326), and with better overall (p = 0.004) and disease-free survival (p = 0.062). The expression of LMNB1 declined with worsening clinical outcome (disease-free vs. mortalities - 0.0011 vs. 0.000; p = 0.0177). LBR mRNA expression was directly associated with tumor grade (grade 1 vs. grade 3 - 0.00 vs. 0.00; p = 0.0479) and Nottingham Prognostic Index (NPI1 vs. NPI3 - 0.00 vs. 0.00; p = 0.0551). To the best of our knowledge, this is the first study to suggest such a role for A-type lamins, lamin B1 and LBR in human breast cancer, identifying an important area for further research.

  6. Role of the aryl hydrocarbon receptor and Cyp1b1 in the antiestrogenic activity of 2,3,7,8-tetrachlorodibenzo-p-dioxin

    Energy Technology Data Exchange (ETDEWEB)

    Takemoto, Kei; Nakajima, Miki; Fujiki, Yuto; Katoh, Miki; Yokoi, Tsuyoshi [Division of Drug Metabolism, Faculty of Pharmaceutical Sciences, Kanazawa University, Takara-machi 13-1, 920-0934, Kanazawa (Japan); Gonzalez, Frank J. [National Cancer Institute, MD 20892, Bethesda (United States)

    2004-06-01

    The role of aryl hydrocarbon receptor (AhR) and cytochrome P450 (Cyp) 1 family in the antiestrogenic activity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was investigated in vivo. Immature (21 days old) AhR, Cyp1a2, or Cyp1b1 knockout (-/-) mice were treated intraperitoneally with estradiol (E2, 20 ng/mouse per day, for 14 consecutive days) and/or TCDD (200 ng/mouse per day, on days 7, 9, 11, and 13). Uterine wet weight and uterine peroxidase activity (UPA) were measured as markers of estrogen responsiveness. UPA was a better marker of estrogen responsiveness than the uterine wet weight. In AhR wild-type (+/+) mice, UPA (208.1{+-}81.6 units/g tissue) was increased by the administration of E2 (to 297.2{+-}178.7 units/g). The administration of TCDD significantly (p<0.01) decreased the UPA (10.5{+-}3.4 units/g) compared with that in the control mice. Co-administration of TCDD with E2 also significantly (p<0.05) decreased the UPA (18.8{+-}19.9 units/g) compared with that in E2-treated mice. In AhR(-/-) mice, UPA (162.9{+-}146.7 units/g) was significantly (p<0.01) increased by the administration of E2 (486.8{+-}108.2 units/g). In contrast to the results in AhR(+/+) mice, UPA was not affected by the administration of TCDD (51.8{+-}70.6 units/g) compared with control, and co-administration of TCDD with E2 (545.8{+-}189.4 units/g) compared with that in E2-treated mice. In Cyp1a2/1b1(+/+) mice, UPA was significantly (p<0.05) increased by the administration of E2 (70.0{+-}36.4 units/g). Co-administration of TCDD with E2 significantly (p<0.05) decreased the UPA (29.6{+-}22.2 units/g) compared with that in E2-treated mice. In Cyp1a2(-/-) mice, co-administration of TCDD with E2 significantly (p<0.01) decreased the UPA (6.8{+-}5.1 units/g) compared with that in E2-treated mice. In Cyp1b1(-/-) mice, UPA (5.5{+-}8.1 units/g) was significantly (p<0.05) increased by the administration of E2 (56.6{+-}34.1 units/g). In contrast to the results in Cyp1a2/1b1(+/+) mice or Cyp1a2

  7. Inhibitory effect of fentanyl citrate on the release of endothlin-1 induced by bradykinin in melanoma cells.

    Science.gov (United States)

    Andoh, Tsugunobu; Shinohara, Akira; Kuraishi, Yasushi

    2017-02-01

    Our previous study showed that the μ-opioid receptor agonist fentanyl citrate inhibits endothelin-1-and bradykinin-mediated pain responses in mice orthotopically inoculated with melanoma cells. We also demonstrated that bradykinin induces endothelin-1 secretion in melanoma cells. However, the analgesic mechanisms of fentanyl citrate remain unclear. Thus, the present study was conducted to determine whether fentanyl citrate affects bradykinin-induced endothelin-1 secretion in B16-BL6 melanoma cells. The amount of endothelin-1 in the culture medium was measured using an enzyme immunoassay. The expression of endothelin-1, kinin B2 receptors, and μ-opioid receptors in B16-BL/6 melanoma cells was determined using immunocytochemistry. Fentanyl citrate inhibited bradykinin-induced endothelin-1 secretion. The inhibitory effect of fentanyl citrate on the secretion of endothelin-1 was attenuated by the μ-opioid receptor antagonist naloxone methiodide. The immunoreactivities of endothelin-1, kinin B2 receptors, and μ-opioid receptors in B16-BL6 melanoma cells were observed. These results suggest that fentanyl citrate regulates bradykinin-induced endothelin-1 secretion through μ-opioid receptors in melanoma cells. Copyright © 2016 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  8. Bradykinin produces pain hypersensitivity by potentiating spinal cord glutamatergic synaptic transmission.

    Science.gov (United States)

    Wang, Haibin; Kohno, Tatsuro; Amaya, Fumimasa; Brenner, Gary J; Ito, Nobuko; Allchorne, Andrew; Ji, Ru-Rong; Woolf, Clifford J

    2005-08-31

    Bradykinin, an inflammatory mediator, sensitizes nociceptor peripheral terminals reducing pain threshold. We now show that the B2 kinin receptor is expressed in rat dorsal horn neurons and that bradykinin, a B2-specific agonist, augments AMPA- and NMDA-induced, and primary afferent-evoked EPSCs, and increases the frequency and amplitude of miniature EPSCs in superficial dorsal horn neurons in vitro. Administration of bradykinin to the spinal cord in vivo produces, moreover, an NMDA-dependent hyperalgesia. We also demonstrate that nociceptive inputs result in the production of bradykinin in the spinal cord and that an intrathecal B2-selective antagonist suppresses behavioral manifestations of central sensitization, an activity-dependent increase in glutamatergic synaptic efficacy. Primary afferent-evoked central sensitization is, in addition, reduced in B2 receptor knock-out mice. We conclude that bradykinin is released in the spinal cord in response to nociceptor inputs and acts as a synaptic neuromodulator, potentiating glutamatergic synaptic transmission to produce pain hypersensitivity.

  9. Aryl hydrocarbon receptor-dependent upregulation of Cyp1b1 by TCDD and diesel exhaust particles in rat brain microvessels

    Directory of Open Access Journals (Sweden)

    Jacob Aude

    2011-08-01

    Full Text Available Abstract Background AhR activates the transcription of several target genes including CYP1B1. Recently, we showed CYP1B1 as the major cytochrome P450 (CYP enzyme expressed in human brain microvessels. Here, we studied the effect of AhR activation by environmental pollutants on the expression of Cyp1b1 in rat brain microvessels. Methods Expression of AhR and Cyp1b1 was detected in isolated rat brain microvessels. AhR was immunovisualised in brain microvessel endothelial cells. The effect of AhR ligands on Cyp1b1 expression was studied using isolated brain microvessels after ex vivo and/or in vivo exposure to TCDD, heavy hydrocarbons containing diesel exhaust particles (DEP or Δ9-tetrahydrocannabinol (Δ9-THC. Results After ex vivo exposure to TCDD (a highly potent AhR ligand for 3 h, Cyp1b1 expression was significantly increased by 2.3-fold in brain microvessels. A single i.p. dose of TCDD also increased Cyp1b1 transcripts (22-fold and Cyp1b1 protein (2-fold in rat brain microvessels at 72 h after TCDD. Likewise, DEP treatment (in vivo and ex vivo strongly induced Cyp1b1 protein in brain microvessels. DEP-mediated Cyp1b1 induction was inhibited by actinomycin D, cycloheximide, or by an AhR antagonist. In contrast, a sub-chronic in vivo treatment with Δ9-THC once daily for 7 seven days had no effect on Cyp1b1 expression Conclusions Our results show that TCDD and DEP strongly induced Cyp1b1 in rat brain microvessels, likely through AhR activation.

  10. mRNA expression of 5-hydroxytryptamine 1B, 1D, and 1F receptors and their role in controlling the release of calcitonin gene-related peptide in the rat trigeminovascular system

    DEFF Research Database (Denmark)

    Amrutkar, Dipak V; Ploug, Kenneth B; Hay-Schmidt, Anders

    2012-01-01

    Triptans, a family of 5-hydroxytryptamine (5-HT) 1B, 1D, and 1F receptor agonists, are used in the acute treatment of migraine attacks. The site of action and subtypes of the 5-HT(1) receptor that mediate the antimigraine effect have still to be identified. This study investigated the m......RNA expression of these receptors and the role of 5-HT(1) receptor subtypes in controlling the release of calcitonin gene-related peptide (CGRP) in rat dura mater, trigeminal ganglion (TG), and trigeminal nucleus caudalis (TNC). The mRNA for each receptor subtype was quantified by quantitative real......-time polymerase chain reaction. A high potassium concentration was used to release CGRP from dura mater, isolated TG, and TNC in vitro. The immunoreactive CGRP (iCGRP) release was measured by enzyme-linked immunoassay. The mRNA transcripts of the 3 5-HT(1) receptor subtypes were detected in the trigeminovascular...

  11. Effect of 3-substituted 1,4-benzodiazepin-2-ones on bradykinin-induced smooth muscle contraction

    Directory of Open Access Journals (Sweden)

    P. A. Virych

    2017-02-01

    Full Text Available Biochemical properties of 3-substituted 1,4-benzodiazepine determined by the characteristics of their chemical structure. Influence of 3-substituted 1,4-benzodiazepin-2-ones on maximal normalized rate and amplitudes of isometric smooth muscle contraction in rats was investigated. Compounds MX-1775 and MX-1828 demonstrated the similar inhibition effect on bradykinin-induced contraction of smooth muscle like competitive inhibitor des-arg9-bradykinin-acetate to bradykinin B2-receptors. MX-1626 demonstrated unidirectional changes of maximal normalized rate and force of smooth muscle that proportionally depended on bradykinin concentration in the range 10-10-10-6 M. MX-1828 has statistically significant decrease of normalized rate of smooth muscle contraction for bradykinin concentrations 10-10 and 10-9 M by 20.7 and 8.6%, respectively, but for agonist concentration 10-6 M, this parameter increased by 10.7% and amplitude was reduced by 29.5%. Compounds MX-2011, MX-1785 and MX-2004 showed no natural effect on bradykinin-induced smooth muscle contraction. Compounds MX-1775, MX-1828, MX-1626 were selected for further research of their influence on kinin-kallikrein system and pain perception.

  12. Bradykinin inhibits oxidative stress-induced cardiomyocytes senescence via regulating redox state.

    Directory of Open Access Journals (Sweden)

    Ruolan Dong

    Full Text Available BACKGROUND: Cell senescence is central to a large body of age related pathology, and accordingly, cardiomyocytes senescence is involved in many age related cardiovascular diseases. In consideration of that, delaying cardiomyocytes senescence is of great importance to control clinical cardiovascular diseases. Previous study indicated that bradykinin (BK protected endothelial cells from senescence induced by oxidative stress. However, the effects of bradykinin on cardiomyocytes senescence remain to be elucidated. In this study, we investigated the effect of bradykinin on H2O2-induced H9C2 cells senescence. METHODS AND RESULTS: Bradykinin pretreatment decreased the senescence induced by H2O2 in cultured H9C2 cells in a dose dependent manner. Interestingly, 1 nmol/L of BK almost completely inhibited the increase in senescent cell number and p21 expression induced by H2O2. Since H2O2 induces senescence through superoxide-induced DNA damage, we also observed the DNA damage by comet assay, and BK markedly reduced DNA damage induced by H2O2, and moreover, BK treatment significantly prevented reactive oxygen species (ROS production in H9C2 cells treated with H2O2. Importantly, when co-incubated with bradykinin B2 receptor antagonist HOE-140 or eNOS inhibitor N-methyl-L-arginine acetate salt (L-NAME, the protective effects of bradykinin on H9C2 senescence were totally blocked. Furthermore, BK administration significantly prevented the increase in nicotinamide adenine dinucleotide phosphate (NADPH oxidase activity characterized by increased ROS generation and gp91 expression and increased translocation of p47 and p67 to the membrane and the decrease in superoxide dismutase (SOD activity and expression induced by H2O2 in H9C2 cells, which was dependent on BK B2 receptor mediated nitric oxide (NO release. CONCLUSIONS: Bradykinin, acting through BK B2 receptor induced NO release, upregulated antioxidant Cu/Zn-SOD and Mn-SOD activity and expression while

  13. Modulation of B1 and B2 kinin receptors expression levels in the hippocampus of rats after audiogenic kindling and with limbic recruitment, a model of temporal lobe epilepsy.

    Science.gov (United States)

    Pereira, Marilia G A G; Gitaí, Daniel L G; Paçó-Larson, Maria L; Pesquero, João B; Garcia-Cairasco, Norberto; Costa-Neto, Claudio M

    2008-02-01

    Epileptic seizures are hypersynchronous, paroxystic and abnormal neuronal discharges. Epilepsies are characterized by diverse mechanisms involving alteration of excitatory and inhibitory neurotransmission that result in hyperexcitability of the central nervous system (CNS). Enhanced neuronal excitability can also be achieved by inflammatory processes, including the participation of cytokines, prostaglandins or kinins, molecules known to be involved in either triggering or in the establishment of inflammation. Multiple inductions of audiogenic seizures in the Wistar audiogenic rat (WAR) strain are a model of temporal lobe epilepsy (TLE), due to the recruitment of limbic areas such as hippocampus and amygdala. In this study we investigated the modulation of the B1 and B2 kinin receptors expression levels in neonatal WARs as well as in adult WARs subjected to the TLE model. The expression levels of pro-inflammatory (IL-1 beta) and anti-inflammatory (IL-10) cytokines were also evaluated, as well as cyclooxygenase (COX-2). Our results showed that the B1 and B2 kinin receptors mRNAs were up-regulated about 7- and 4-fold, respectively, in the hippocampus of kindled WARs. On the other hand, the expressions of the IL-1 beta, IL-10 and COX-2 were not related to the observed increase of expression of kinin receptors. Based on those results we believe that the B1 and B2 kinin receptors have a pivotal role in this model of TLE, although their participation is not related to an inflammatory process. We believe that kinin receptors in the CNS may act in seizure mechanisms by participating in a specific kininergic neurochemical pathway.

  14. Cardiovascular and vasoconstrictive actions of skate bradykinin in the little skate, Leucoraja erinacea (Elasmobranchii).

    Science.gov (United States)

    Dasiewicz, Patricia J; Conlon, J Michael; Anderson, W Gary

    2011-11-01

    The vasoconstrictive and cardiovascular actions of a recently identified bradykinin (BK)-related peptide (Gly-Ile-Thr-Ser-Trp-Leu-Pro-Phe) from the little skate, Leucoraja erinacea were examined in the unanesthetised little skate. Intra-arterial administration of a skate BK (0.1-1 nmolkg(-1)) produced a hypertensive response with a rise in blood pressure reaching a maximum elevation of 28.7±4.8% over baseline (Pskate BK. Further, in vivo administration of 1 nmolkg(-1) skate BK induced a significant delayed increase in stroke volume (reaching a maximum of 54.4±14.7% above baseline) without significant effect on either cardiac output or heart rate. In vitro, skate BK constricted the 1st branchial, mesenteric (EC(50) 2.7×10(-9)M) and coeliac (EC(50) 3.1×10(-9)M) arterial preparations of the skate. In contrast, skate [Arg(9)]BK, the mammalian B(1) receptor agonist des-[Arg(9)]BK, and the mammalian B(2) receptor antagonist HOE-140 failed to induce vasoconstriction in these isolated arterial preparations. The vasoconstrictor actions of skate BK in the isolated mesenteric, coeliac and branchial arterial preparations were significantly inhibited when co-administrated with esculetin and phentolamine. Indomethacin also inhibited the vasoconstrictor actions of skate BK in the isolated branchial artery. We conclude that, as in mammals and teleost fish, multiple pathways involving at least the alpha adrenergic and leukotriene synthesis pathway are involved in mediating the vasoconstrictive actions of BK in vascular smooth muscle of the little skate. Copyright © 2011 Elsevier Inc. All rights reserved.

  15. Zolmitriptan (a 5-HT1B/1D receptor agonist with central action) does not increase symptoms in obsessive compulsive disorder

    NARCIS (Netherlands)

    Boshuisen, ML; den Boer, JA

    Rationale: Non-selective serotonin (5-HT) receptor agonists like meta-chlorophenylpiperazine and MK-212 have been used to explore the role of 5-HT in obsessive compulsive disorder (OCD). The results of these studies and the findings of autoradiography and neuroimaging studies, pointed to a possible

  16. Truncated ErbB2 receptor enhances ErbB1 signaling and induces reversible, ERK-independent loss of epithelial morphology

    DEFF Research Database (Denmark)

    Egeblad, M; Mortensen, Ole Hartvig; Jäättelä, M

    2001-01-01

    Shedding of the extracellular domain of the ErbB2 tyrosine kinase receptor and expression of the remaining NH(2)-terminally truncated ErbB2 correlates with lymph node metastases and adverse outcome in human breast cancer. To study the possible signaling from such a truncated receptor, MCF-7 human...... breast cancer cells expressing NH(2)-terminally truncated ErbB2 (DeltaNErbB2) were compared with cells overexpressing wild-type ErbB2. Expression of DeltaNErbB2 in MCF-7 cells resulted in sustained activation of extracellular signal-regulated kinases (ERK) 1/2, extensive loss of the epithelial morphology......, appearance of vesicles and long protrusions as well as pronounced scattering of the cells. Similar alterations were observed upon ErbB2 overexpression but at much lower levels. Employing cell clones with inducible expression of DeltaNErbB2, it was revealed that the morphological changes were fully reversible...

  17. Cloning of the gabaB Receptor Subunits B1 and B2 and their Expression in the Central Nervous System of the Adult Sea Lamprey

    Directory of Open Access Journals (Sweden)

    Daniel Romaus-Sanjurjo

    2016-12-01

    Full Text Available In vertebrates, γ-aminobutyric acid (GABA is the main inhibitory transmitter in the central nervous system acting through ionotropic (GABAA and metabotropic (GABAB receptors. The GABAB receptor produces a slow inhibition since it activates second messenger systems through the binding and activation of guanine nucleotide-binding proteins G-protein-coupled receptors (GPCRs. Lampreys are a key reference to understand molecular evolution in vertebrates. The importance of the GABAB receptor for the modulation of the circuits controlling locomotion and other behaviors has been shown in pharmacological/physiological studies in lampreys. However, there is no data about the sequence of the GABAB subunits or their expression in the central nervous system (CNS of lampreys. Our aim was to identify the sea lamprey gabab1 and gabab2 transcripts and study their expression in the CNS of adults. We cloned two partial sequences corresponding to the gabab1 and gabab2 cDNAs of the sea lamprey as confirmed by sequence analysis and comparison with known gabab sequences of other vertebrates. In phylogenetic analyses, the sea lamprey GABAB sequences clustered together with GABABs sequences of vertebrates and emerged as an outgroup to all gnathostome sequences. We observed a broad and overlapping expression of both transcripts in the entire CNS. Expression was mainly observed in neuronal somas of the periventricular regions including the identified reticulospinal cells. No expression was observed in identifiable fibers. Comparison of our results with those reported in other vertebrates indicates that a broad and overlapping expression of the GABAB subunits in the CNS is a conserved character shared by agnathans and gnathostomes.

  18. Cloning of the GABAB Receptor Subunits B1 and B2 and their Expression in the Central Nervous System of the Adult Sea Lamprey

    Science.gov (United States)

    Romaus-Sanjurjo, Daniel; Fernández-López, Blanca; Sobrido-Cameán, Daniel; Barreiro-Iglesias, Antón; Rodicio, María Celina

    2016-01-01

    In vertebrates, γ-aminobutyric acid (GABA) is the main inhibitory transmitter in the central nervous system (CNS) acting through ionotropic (GABAA) and metabotropic (GABAB) receptors. The GABAB receptor produces a slow inhibition since it activates second messenger systems through the binding and activation of guanine nucleotide-binding proteins [G-protein-coupled receptors (GPCRs)]. Lampreys are a key reference to understand molecular evolution in vertebrates. The importance of the GABAB receptor for the modulation of the circuits controlling locomotion and other behaviors has been shown in pharmacological/physiological studies in lampreys. However, there is no data about the sequence of the GABAB subunits or their expression in the CNS of lampreys. Our aim was to identify the sea lamprey GABAB1 and GABAB2 transcripts and study their expression in the CNS of adults. We cloned two partial sequences corresponding to the GABAB1 and GABAB2 cDNAs of the sea lamprey as confirmed by sequence analysis and comparison with known GABAB sequences of other vertebrates. In phylogenetic analyses, the sea lamprey GABAB sequences clustered together with GABABs sequences of vertebrates and emerged as an outgroup to all gnathostome sequences. We observed a broad and overlapping expression of both transcripts in the entire CNS. Expression was mainly observed in neuronal somas of the periventricular regions including the identified reticulospinal cells. No expression was observed in identifiable fibers. Comparison of our results with those reported in other vertebrates indicates that a broad and overlapping expression of the GABAB subunits in the CNS is a conserved character shared by agnathans and gnathostomes. PMID:28008311

  19. Bronchoconstriction induced by citric acid inhalation in guinea pigs: role of tachykinins, bradykinin, and nitric oxide.

    Science.gov (United States)

    Ricciardolo, F L; Rado, V; Fabbri, L M; Sterk, P J; Di Maria, G U; Geppetti, P

    1999-02-01

    Gastroesophageal acid reflux into the airways can trigger asthma attacks. Indeed, citric acid inhalation causes bronchoconstriction in guinea pigs, but the mechanism of this effect has not been fully clarified. We investigated the role of tachykinins, bradykinin, and nitric oxide (NO) on the citric acid- induced bronchoconstriction in anesthetized and artificially ventilated guinea pigs. Citric acid inhalation (2-20 breaths) caused a dose-dependent increase in total pulmonary resistance (RL). RL value obtained after 10 breaths of citric acid inhalation was not significantly different from the value obtained after 20 breaths (p = 0.22). The effect produced by a half-submaximum dose of citric acid (5 breaths) was halved by the bradykinin B2 receptor antagonist HOE 140 (0.1 micromol x kg-1, intravenous) and abolished by the tachykinin NK2 receptor antagonist SR 48968 (0.3 micromol x kg-1, intravenous). Bronchoconstriction induced by a submaximum dose of citric acid (10 breaths) was partially reduced by the administration of HOE 140, SR 48968, or the NK1 receptor antagonist CP-99,994 (8 micromol x kg-1, intravenous) alone and completely abolished by the combination of SR 48968 and CP-99,994. Pretreatment with the NO synthase inhibitor, L-NMMA (1 mM, 10 breaths every 5 min for 30 min) increased in an L-arginine-dependent manner the effect of citric acid inhalation on RL. HOE 140 and CP-99,994 markedly reduced the L-NMMA-potentiated bronchoconstriction to inhaled citric acid. We conclude that citric acid-induced bronchoconstriction is caused by tachykinin release from sensory nerves, which, in part, is mediated by endogenously released bradykinin. Simultaneous release of NO by citric acid inhalation counteracts tachykinin-mediated bronchoconstriction. Our study suggests a possible implication of these mechanisms in asthma associated with gastroesophageal acid reflux and a potential therapeutic role of tachykinin and bradykinin antagonists.

  20. MRP transporters as membrane machinery in the bradykinin-inducible export of ATP.

    Science.gov (United States)

    Zhao, Yumei; Migita, Keisuke; Sun, Jing; Katsuragi, Takeshi

    2010-04-01

    Adenosine triphosphate (ATP) plays the role of an autocrine/paracrine signal molecule in a variety of cells. So far, however, the membrane machinery in the export of intracellular ATP remains poorly understood. Activation of B2-receptor with bradykinin-induced massive release of ATP from cultured taenia coli smooth muscle cells. The evoked release of ATP was unaffected by gap junction hemichannel blockers, such as 18alpha-glycyrrhetinic acid and Gap 26. Furthermore, the cystic fibrosis transmembrane regulator (CFTR) coupled Cl(-) channel blockers, CFTR(inh)172, 5-nitro-2-(3-phenylpropylamino)-benzoic acid, Gd3(+) and glibenclamide, failed to suppress the export of ATP by bradykinin. On the other, the evoked release of ATP was greatly reduced by multidrug resistance protein (MRP) transporter inhibitors, MK-571, indomethacin, and benzbromarone. From western blotting analysis, blots of MRP 1 protein only, but not MRP 2 and MRP 3 protein, appeared at 190 kD. However, the MRP 1 protein expression was not enhanced after loading with 1 muM bradykinin for 5 min. Likewise, niflumic acid and fulfenamic acid, Ca2(+)-activated Cl(-) channel blockers, largely abated the evoked release of ATP. The possibility that the MRP transporter system couples with Ca2(+)-activated Cl(-) channel activities is discussed here. These findings suggest that MRP transporters, probably MRP 1, unlike CFTR-Cl(-) channels and gap junction hemichannels, may contribute as membrane machinery to the export of ATP induced by G-protein-coupled receptor stimulation.

  1. The Efficacy of Eslicarbazepine Acetate in Models of Trigeminal, Neuropathic, and Visceral Pain: The Involvement of 5-HT1B/1D Serotonergic and CB1/CB2 Cannabinoid Receptors.

    Science.gov (United States)

    Tomić, Maja A; Pecikoza, Uroš B; Micov, Ana M; Stepanović-Petrović, Radica M

    2015-12-01

    Many clinical pain states that are difficult to treat share a common feature of sensitization of nociceptive pathways. Drugs that could normalize hyperexcitable neural activity (e.g., antiepileptic drugs) may be useful in relieving these pain states. Eslicarbazepine acetate (ESL) is a novel antiepileptic drug derived from carbamazepine/oxcarbazepine with a more favorable metabolic profile and potentially better tolerability. We examined the efficacy of ESL in models of inflammatory and neuropathic pain and the potential mechanism involved in its action. The antinociceptive effects of ESL were assessed in mice models of trigeminal (orofacial formalin test), neuropathic (streptozotocin-induced diabetic neuropathy model), and visceral pain (writhing test). The influence of 5-HT1B/1D serotonin receptor (GR 127935) and CB1 (AM251) and CB2 cannabinoid receptor (AM630) antagonists on the antinociceptive effect of ESL was tested in the model of trigeminal pain. ESL exhibited significant and dose-dependent antinociceptive effects in the second phase of the orofacial formalin test (P ≤ 0.011), in the tail-flick test in diabetic mice (P ≤ 0.013), and in the writhing test (P ≤ 0.003). GR 127935 (P ≤ 0.038) and AM251 and AM630 (P ≤ 0.013 for both antagonists) significantly inhibited the antinociceptive effect of ESL in a dose-related manner. ESL exhibited efficacy in models of trigeminal, neuropathic, and visceral pain. In the trigeminal pain model, the antinociceptive effect of ESL is, at least in part, mediated by 5-HT1B/1D serotonin and CB1/CB2 cannabinoid receptors. This study indicates that ESL could be useful in the clinical treatment of inflammatory and neuropathic pain.

  2. B1 Aerogels

    DEFF Research Database (Denmark)

    Duer, Karsten; Svendsen, Sv Aa Højgaard

    1996-01-01

    The report summarizes the work that has been carried out within the project "B1 AEROGELS" as a part of the IEA SH&CP Task 18 "Advanced Glazing and Associated Materials For Solar And Building Applications".By providing at the same time thermal insulation and transparency the silica aerogel is a very......, engineering and architectural basis which will support the appropriate use of aerogels in windows, solar collectors and passive solar applications, with the aim of saving or producing thermal energy for use in buildings".This objective is in very good agreement with the general scope of task 18 but where Task...... of aerogel as a material for window applications. It was not a part of the project to make a further development of the aerogel material.The project was carried out in three main steps:1. Collection of information on aerogel production methods2. Measurements and evaluation of optical and thermal properties...

  3. Purification, structural characterization, and myotropic activity of a peptide related to des-Arg(9)-bradykinin from an elasmobranch fish, the little skate, Leucoraja erinacea.

    Science.gov (United States)

    Anderson, W Gary; Leprince, Jérôme; Conlon, J Michael

    2008-08-01

    A bradykinin (BK)-related peptide was isolated from heat-denaturated plasma from an elasmobranch fish, the little skate, Leucoraja erinacea after incubation with porcine pancreatic kallikrein. The primary structure of the peptide (H-Gly-Ile-Thr-Ser-Trp-Leu-Pro-Phe-OH; skate BK) shows limited structural similarity to the mammalian B1 receptor agonist, des-Arg(9)-BK. The myotropic activities of synthetic skate BK, and the analog skate [Arg(9)]BK, were examined in isolated skate vascular and intestinal smooth muscle preparations. Skate BK produced a concentration-dependent constriction of the mesenteric artery (EC(50)=4.37x10(-8)M; maximum response=103.4+/-10.23% of the response to 60mM KCl) but the response to skate [Arg(9)]BK was appreciably weaker (response to 10(-6)M=73.0+/-23.4% of the response to 60mM KCl). Neither the first branchial gill arch nor the ventral aorta responded to either purified peptide. Skate BK also produced a concentration-dependent constriction of intestinal smooth muscle preparations (EC(50)=2.74x10(-7)M; maximum response 31.0+/-12.2% of the response to 10(-5)M acetylcholine). Skate [Arg(9)]BK was without effect on the intestinal preparation. The data provide evidence for the existence of the kallikrein-kinin system in a phylogenetically ancient vertebrate group and the greater potency of skate BK compared with the analog skate [Arg(9)]BK suggests that the receptor mediating vascular responses resembles the mammalian B1 receptor more closely than the B2 receptor.

  4. aflatoxina b1

    Directory of Open Access Journals (Sweden)

    A. Valdivia

    2004-01-01

    Full Text Available Con el objetivo de probar que la suplementación dietética de ácido elágico (AE o N-Acetilcisteína (NAC en pollos de engorda, atenúa los efectos de una intoxicación aguda por la aflatoxina B1 (AFB1, se intoxicaron con AFB1 pura, tres grupos de diez pollos cada uno (3.0 mb/kg pc, IP. Otros tres grupos recibieron solamente el vehículo (aceite de maíz 2.0 ml/kg pc, IP. Cuatro días antes se administró un alimento testigo, o bien, la misma dieta adicionada con AE (2.5 g/kg o NAC (200 mg/kg pc/6 h. A las 24 horas de la administración de AFB1, se cuantificaron las concentraciones hepáticas de glutatión (GSH, de actividad enzimática específica de la transferasa de glutatión (GST, alanina aminotransferasa, aspartato aminotransferasa y de proteínas hepáticas totales. Los resultados mostraron que NAC atenúa el impacto negativo de la AFB1 sobre el crecimiento corporal y al igual que AE, incrementa la GST y revierte parcialmente los efectos de AFB1 sobre GSH, lo cual sugiere que ambas sustancias pudieran conferir un efecto protector de las aves

  5. NCBI nr-aa BLAST: CBRC-PABE-15-0053 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-PABE-15-0053 sp|Q3BCU0|BKRB1_MACFA B1 bradykinin receptor (BK-1 receptor) (B1R) gb|AAK95386.1| B1 brad...ykinin receptor [Macaca mulatta] gb|AAX14712.1| bradykinin receptor B1 [Macaca fascicularis] Q3BCU0 0.0 95% ...

  6. NCBI nr-aa BLAST: CBRC-BTAU-01-2412 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-BTAU-01-2412 sp|Q3BCU0|BKRB1_MACFA B1 bradykinin receptor (BK-1 receptor) (B1R) gb|AAK95386.1| B1 brad...ykinin receptor [Macaca mulatta] gb|AAX14712.1| bradykinin receptor B1 [Macaca fascicularis] Q3BCU0 1e-161 77% ...

  7. NCBI nr-aa BLAST: CBRC-PTRO-15-0054 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-PTRO-15-0054 ref|NP_001075816.1| bradykinin B1 receptor [Oryctolagus cuniculus...] sp|P48748|BKRB1_RABIT B1 bradykinin receptor (BK-1 receptor) (B1R) gb|AAC48482.1| bradykinin B1 receptor NP_001075816.1 1e-157 77% ...

  8. NCBI nr-aa BLAST: CBRC-MMUS-12-0037 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-MMUS-12-0037 ref|NP_001075816.1| bradykinin B1 receptor [Oryctolagus cuniculus...] sp|P48748|BKRB1_RABIT B1 bradykinin receptor (BK-1 receptor) (B1R) gb|AAC48482.1| bradykinin B1 receptor NP_001075816.1 1e-138 74% ...

  9. NCBI nr-aa BLAST: CBRC-GGAL-05-0033 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-GGAL-05-0033 sp|Q3BCU0|BKRB1_MACFA B1 bradykinin receptor (BK-1 receptor) (B1R) gb|AAK95386.1| B1 brad...ykinin receptor [Macaca mulatta] gb|AAX14712.1| bradykinin receptor B1 [Macaca fascicularis] Q3BCU0 2e-78 41% ...

  10. NCBI nr-aa BLAST: CBRC-PMAR-01-0707 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-PMAR-01-0707 ref|NP_001075816.1| bradykinin B1 receptor [Oryctolagus cuniculus...] sp|P48748|BKRB1_RABIT B1 bradykinin receptor (BK-1 receptor) (B1R) gb|AAC48482.1| bradykinin B1 receptor NP_001075816.1 2e-48 34% ...

  11. NCBI nr-aa BLAST: CBRC-HSAP-14-0065 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-HSAP-14-0065 sp|Q3BCU0|BKRB1_MACFA B1 bradykinin receptor (BK-1 receptor) (B1R) gb|AAK95386.1| B1 brad...ykinin receptor [Macaca mulatta] gb|AAX14712.1| bradykinin receptor B1 [Macaca fascicularis] Q3BCU0 0.0 96% ...

  12. NCBI nr-aa BLAST: CBRC-PTRO-15-0054 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-PTRO-15-0054 sp|Q3BCU0|BKRB1_MACFA B1 bradykinin receptor (BK-1 receptor) (B1R) gb|AAK95386.1| B1 brad...ykinin receptor [Macaca mulatta] gb|AAX14712.1| bradykinin receptor B1 [Macaca fascicularis] Q3BCU0 0.0 95% ...

  13. NCBI nr-aa BLAST: CBRC-OANA-01-2126 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-OANA-01-2126 sp|Q3BCU0|BKRB1_MACFA B1 bradykinin receptor (BK-1 receptor) (B1R) gb|AAK95386.1| B1 brad...ykinin receptor [Macaca mulatta] gb|AAX14712.1| bradykinin receptor B1 [Macaca fascicularis] Q3BCU0 1e-109 56% ...

  14. NCBI nr-aa BLAST: CBRC-CPOR-01-0824 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-CPOR-01-0824 sp|Q3BCU0|BKRB1_MACFA B1 bradykinin receptor (BK-1 receptor) (B1R) gb|AAK95386.1| B1 brad...ykinin receptor [Macaca mulatta] gb|AAX14712.1| bradykinin receptor B1 [Macaca fascicularis] Q3BCU0 5e-39 65% ...

  15. NCBI nr-aa BLAST: CBRC-DNOV-01-0867 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-DNOV-01-0867 ref|NP_001075816.1| bradykinin B1 receptor [Oryctolagus cuniculus...] sp|P48748|BKRB1_RABIT B1 bradykinin receptor (BK-1 receptor) (B1R) gb|AAC48482.1| bradykinin B1 receptor NP_001075816.1 4e-37 69% ...

  16. NCBI nr-aa BLAST: CBRC-RMAC-07-0088 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-RMAC-07-0088 sp|Q3BCU0|BKRB1_MACFA B1 bradykinin receptor (BK-1 receptor) (B1R) gb|AAK95386.1| B1 brad...ykinin receptor [Macaca mulatta] gb|AAX14712.1| bradykinin receptor B1 [Macaca fascicularis] Q3BCU0 1e-122 97% ...

  17. NCBI nr-aa BLAST: CBRC-MMUS-12-0037 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-MMUS-12-0037 sp|Q3BCU0|BKRB1_MACFA B1 bradykinin receptor (BK-1 receptor) (B1R) gb|AAK95386.1| B1 brad...ykinin receptor [Macaca mulatta] gb|AAX14712.1| bradykinin receptor B1 [Macaca fascicularis] Q3BCU0 1e-138 73% ...

  18. NCBI nr-aa BLAST: CBRC-GACU-15-0012 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-GACU-15-0012 sp|Q3BCU0|BKRB1_MACFA B1 bradykinin receptor (BK-1 receptor) (B1R) gb|AAK95386.1| B1 brad...ykinin receptor [Macaca mulatta] gb|AAX14712.1| bradykinin receptor B1 [Macaca fascicularis] Q3BCU0 6e-66 40% ...

  19. NCBI nr-aa BLAST: CBRC-TGUT-08-0028 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-TGUT-08-0028 sp|Q3BCU0|BKRB1_MACFA B1 bradykinin receptor (BK-1 receptor) (B1R) gb|AAK95386.1| B1 brad...ykinin receptor [Macaca mulatta] gb|AAX14712.1| bradykinin receptor B1 [Macaca fascicularis] Q3BCU0 1e-81 44% ...

  20. NCBI nr-aa BLAST: CBRC-ETEL-01-0091 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-ETEL-01-0091 sp|Q3BCU0|BKRB1_MACFA B1 bradykinin receptor (BK-1 receptor) (B1R) gb|AAK95386.1| B1 brad...ykinin receptor [Macaca mulatta] gb|AAX14712.1| bradykinin receptor B1 [Macaca fascicularis] Q3BCU0 9e-71 69% ...

  1. NCBI nr-aa BLAST: CBRC-OANA-01-2126 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-OANA-01-2126 ref|NP_001075816.1| bradykinin B1 receptor [Oryctolagus cuniculus...] sp|P48748|BKRB1_RABIT B1 bradykinin receptor (BK-1 receptor) (B1R) gb|AAC48482.1| bradykinin B1 receptor NP_001075816.1 1e-105 56% ...

  2. NCBI nr-aa BLAST: CBRC-RMAC-07-0088 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-RMAC-07-0088 ref|NP_001075816.1| bradykinin B1 receptor [Oryctolagus cuniculus...] sp|P48748|BKRB1_RABIT B1 bradykinin receptor (BK-1 receptor) (B1R) gb|AAC48482.1| bradykinin B1 receptor NP_001075816.1 1e-96 76% ...

  3. NCBI nr-aa BLAST: CBRC-OGAR-01-0906 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-OGAR-01-0906 sp|Q3BCU0|BKRB1_MACFA B1 bradykinin receptor (BK-1 receptor) (B1R) gb|AAK95386.1| B1 brad...ykinin receptor [Macaca mulatta] gb|AAX14712.1| bradykinin receptor B1 [Macaca fascicularis] Q3BCU0 3e-48 72% ...

  4. NCBI nr-aa BLAST: CBRC-OCUN-01-1241 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-OCUN-01-1241 ref|NP_001075816.1| bradykinin B1 receptor [Oryctolagus cuniculus...] sp|P48748|BKRB1_RABIT B1 bradykinin receptor (BK-1 receptor) (B1R) gb|AAC48482.1| bradykinin B1 receptor NP_001075816.1 8e-82 97% ...

  5. NCBI nr-aa BLAST: CBRC-CJAC-01-0695 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-CJAC-01-0695 sp|Q3BCU0|BKRB1_MACFA B1 bradykinin receptor (BK-1 receptor) (B1R) gb|AAK95386.1| B1 brad...ykinin receptor [Macaca mulatta] gb|AAX14712.1| bradykinin receptor B1 [Macaca fascicularis] Q3BCU0 0.0 91% ...

  6. NCBI nr-aa BLAST: CBRC-DNOV-01-0867 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-DNOV-01-0867 sp|Q3BCU0|BKRB1_MACFA B1 bradykinin receptor (BK-1 receptor) (B1R) gb|AAK95386.1| B1 brad...ykinin receptor [Macaca mulatta] gb|AAX14712.1| bradykinin receptor B1 [Macaca fascicularis] Q3BCU0 8e-38 66% ...

  7. NCBI nr-aa BLAST: CBRC-CPOR-01-0095 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-CPOR-01-0095 sp|Q3BCU0|BKRB1_MACFA B1 bradykinin receptor (BK-1 receptor) (B1R) gb|AAK95386.1| B1 brad...ykinin receptor [Macaca mulatta] gb|AAX14712.1| bradykinin receptor B1 [Macaca fascicularis] Q3BCU0 1e-44 52% ...

  8. Analysis of erectile responses to bradykinin in the anesthetized rat

    Science.gov (United States)

    Edward, Justin A.; Pankey, Edward A.; Jupiter, Ryan C.; Lasker, George F.; Yoo, Daniel; Reddy, Vishwaradh G.; Peak, Taylor C.; Chong, Insun; Jones, Mark R.; Feintech, Samuel V.; Lindsey, Sarah H.

    2015-01-01

    The kallikrein-kinin system is expressed in the corpus cavernosa, and bradykinin (BK) relaxes isolated corpora cavernosal strips. However, erectile responses to BK in the rat have not been investigated in vivo. In the present study, responses to intracorporal (ic) injections of BK were investigated in the anesthetized rat. BK, in doses of 1–100 μg/kg ic, produced dose-related increases in intracavernosal pressure (ICP) and dose-related deceases in mean arterial pressure (MAP). When decreases in MAP were prevented by intravenous injections of angiotensin II (Ang II), increases in ICP, in response to BK, were enhanced. Increases in ICP, ICP/MAP ratio, and area under the curve and decreases in MAP in response to BK were inhibited by the kinin B2 receptor antagonist HOE-140 and enhanced by the angiotensin-converting enzyme (ACE) inhibitor captopril and by Ang-(1–7). Increases in ICP, in response to BK, were not attenuated by the nitric oxide (NO) synthase inhibitor (Nω-nitro-l-arginine methyl ester) or the soluble guanylate cyclase inhibitor (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one) but were attenuated by the cyclooxygenase inhibitor, sodium meclofenamate. Decreases in MAP were not attenuated by either inhibitor. These data suggest that erectile responses are mediated by kinin B2 receptors and modulated by decreases in MAP. These data indicate that ACE is important in the inactivation of BK and that erectile and hypotensive responses are independent of NO in the penis or the systemic vascular bed. Erectile responses to cavernosal nerve stimulation are not altered by BK or HOE-140, suggesting that BK and B2 receptors do not modulate nerve-mediated erectile responses under physiologic conditions. These data suggest that erectile responses to BK are mediated, in part, by the release of cyclooxygenase products. PMID:26055796

  9. Bradykinin-induced relaxation of coronary microarteries: S-nitrosothiols as EDHF?

    NARCIS (Netherlands)

    W.W. Batenburg (Wendy); R. Popp (Rudiger); I. Fleming (Ingrid); R. de Vries (René); I.M. Garrelds (Ingrid); P.R. Saxena (Pramod Ranjan); A.H.J. Danser (Jan)

    2004-01-01

    textabstract1. To investigate whether S-nitrosothiols, in addition to NO, mediate bradykinin-induced vasorelaxation, porcine coronary microarteries (PCMAs) were mounted in myographs. 2. Following preconstriction, concentration-response curves (CRCs) were constructed to bradykinin,

  10. Lys-63-linked Ubiquitination of γ-Aminobutyric Acid (GABA), Type B1, at Multiple Sites by the E3 Ligase Mind Bomb-2 Targets GABAB Receptors to Lysosomal Degradation*

    Science.gov (United States)

    Zemoura, Khaled; Trümpler, Claudia; Benke, Dietmar

    2016-01-01

    GABAB receptors are heterodimeric G protein-coupled receptors, which control neuronal excitability by mediating prolonged inhibition. The magnitude of GABAB receptor-mediated inhibition essentially depends on the amount of receptors in the plasma membrane. However, the factors regulating cell surface expression of GABAB receptors are poorly characterized. Cell surface GABAB receptors are constitutively internalized and either recycled to the plasma membrane or degraded in lysosomes. The signal that sorts GABAB receptors to lysosomes is currently unknown. Here we show that Mind bomb-2 (MIB2)-mediated Lys-63-linked ubiquitination of the GABAB1 subunit at multiple sites is the lysosomal sorting signal for GABAB receptors. We found that inhibition of lysosomal activity in cultured rat cortical neurons increased the fraction of Lys-63-linked ubiquitinated GABAB receptors and enhanced the expression of total as well as cell surface GABAB receptors. Mutational inactivation of four putative ubiquitination sites in the GABAB1 subunit significantly diminished Lys-63-linked ubiquitination of GABAB receptors and prevented their lysosomal degradation. We identified MIB2 as the E3 ligase triggering Lys-63-linked ubiquitination and lysosomal degradation of GABAB receptors. Finally, we show that sustained activation of glutamate receptors, a condition occurring in brain ischemia that down-regulates GABAB receptors, considerably increased the expression of MIB2 and Lys-63-linked ubiquitination of GABAB receptors. Interfering with Lys-63-linked ubiquitination by overexpressing ubiquitin mutants or GABAB1 mutants deficient in Lys-63-linked ubiquitination prevented glutamate-induced down-regulation of the receptors. These findings indicate that Lys-63-linked ubiquitination of GABAB1 at multiple sites by MIB2 controls sorting of GABAB receptors to lysosomes for degradation under physiological and pathological conditions. PMID:27573246

  11. BENEFICIAL-EFFECTS OF BRADYKININ ON PORCINE ISCHEMIC MYOCARDIUM

    NARCIS (Netherlands)

    TIO, RA; TOBE, TJM; BEL, KJ; DELANGEN, CDJ; VANGILST, WH; WESSELING, H

    1991-01-01

    Exogenous bradykinin was administered to pigs in which an experimental infarction was evoked by ischemia and reperfusion. Ischemia (45 min) was induced in a closed-chest model with a balloon catheter in the left anterior descending artery, reperfusion by deflating and removing the balloon. The pigs

  12. Synthesis and sar study of 2-substituted imidazo[2,1-b] [1,3]benzothiazoles and related compounds endowed with affinity for dopamine D2 receptors as potential antipsychotics

    OpenAIRE

    Asproni, Battistina; Kehler, Jan; Simula, Sergio; Mura, Stefania; Porcu, Giovanna

    2008-01-01

    Typical antipsychotic agents such as chlorpromazine and haloperidol block the D2 subtype of dopamine receptors in a direct relation to their clinical potency. In this context we have developed a series of (1,2-diphenyl-imidazolyl)piperazine derivatives (1) that are endowed with substantial affinities for both dopamine D2 receptors as well as 5-HT1A and 5-HT2A serotonin receptors, compound 1a (R = o-OCH3) of which is representative. We have extended our study on other series of compou...

  13. SerpinB1 Promotes Pancreatic β Cell Proliferation

    Energy Technology Data Exchange (ETDEWEB)

    El Ouaamari, Abdelfattah; Dirice, Ercument; Gedeon, Nicholas; Hu, Jiang; Zhou, Jian-Ying; Shirakawa, Jun; Hou, Lifei; Goodman, Jessica; Karampelias, Christos; Qiang, Guifeng; Boucher, Jeremie; Martinez, Rachael; Gritsenko, Marina A.; De Jesus, Dario F.; Kahraman, Sevim; Bhatt, Shweta; Smith, Richard D.; Beer, Hans-Dietmar; Jungtrakoon, Prapaporn; Gong, Yanping; Goldfine, Allison B.; Liew, Chong Wee; Doria, Alessandro; Andersson, Olov; Qian, Wei-Jun; Remold-O’Donnell, Eileen; Kulkarni, Rohit N.

    2016-01-01

    Compensatory β-cell growth in response to insulin resistance is a common feature in diabetes. We recently reported that liver-derived factors participate in this compensatory response in the liver insulin receptor knockout (LIRKO) mouse, a model of significant islet hyperplasia. Here we show that serpinB1 is a liver-derived secretory protein that controls β-cell proliferation. SerpinB1 is abundant in the hepatocyte secretome and sera derived from LIRKO mice. SerpinB1 and small molecule compounds that partially mimic serpinB1 activity enhanced proliferation of zebrafish, mouse and human β-cells. We report that serpinB1-induced β-cell replication requires protease inhibition activity and mice lacking serpinB1 exhibit attenuated β-cell replication in response to insulin resistance. Finally, SerpinB1-treatment of islets modulated signaling proteins in growth and survival pathways such as MAPK, PKA and GSK3. Together, these data implicate SerpinB1 as a protein that can potentially be harnessed to enhance functional β-cell mass in patients with diabetes.

  14. Improvement of left ventricular contractility and relaxation with the B1-adrenergic receptor partial agonist in Xamoterol at rest and during exercise in patients with postinfarction left ventricular dysfunction

    NARCIS (Netherlands)

    P.J. de Feyter (Pim); P.W.J.C. Serruys (Patrick); H. Suryapranara

    1990-01-01

    textabstractA new cardioselective beta 1-adrenergic receptor agonist xamoterol (Corwin) has been developed for the treatment of heart failure. To study the acute hemodynamic effects of xamoterol, 24 patients, 39-70 years old, with mild-to-moderate postinfarction left ventricular dysfunction entered

  15. Omeprazole induces gastric transmucosal permeability to the peptide bradykinin

    Science.gov (United States)

    Gabello, Melissa; Valenzano, Mary Carmen; Zurbach, E Peter; Mullin, James M

    2010-01-01

    AIM: To investigate omeprazole-induced transepithelial gastric leak and its effects on the permeability of the peptides bradykinin and oxytocin. METHODS: Rat gastric corpus tissue was isolated and mounted in an Ussing chamber apparatus to evaluate the permeability of 3H-bradykinin, 3H-oxytocin, and 14C-EDTA in the presence or absence of omeprazole. Thin-layer chromatography was performed to identify any metabolic breakdown products of the peptides resulting from permeation through the gastric tissue, and thereby calculate the true flux of the peptide. RESULTS: The flux rate of intact 3H-bradykinin increased substantially after omeprazole addition (109.5%) compared to the DMSO vehicle control (14%). No corresponding change in flux of intact 3H-oxytocin was observed under the same conditions (11.9% and 6.4% in the DMSO- and omeprazole-treated conditions, respectively). After exposure to omeprazole, the flux rate of 14C-EDTA also increased dramatically (122.3%) compared to the DMSO condition (36.3%). CONCLUSION: The omeprazole-induced gastric leak allows for transmucosal permeability to charged molecules as well as non-electrolytes. This induced leak will allow certain peptides to permeate. PMID:20205280

  16. Gene : CBRC-GGOR-01-1364 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available bradykinin receptor B1 [Homo sapiens] sp|P46663|BKRB1_HUMAN RecName: Full=B1 bradykinin receptor; AltName: ...Full=BK-1 receptor; Short=B1R emb|CAB45650.1| bradykinin B1 receptor [Homo sapiens] dbj|BAC06112.1| seven tr...ansmembrane helix receptor [Homo sapiens] gb|AAH34705.1| Bradykinin receptor B1 [Homo sapi...ens] gb|AAP32296.1| bradykinin receptor B1 [Homo sapiens] gb|EAW81632.1| bradykinin receptor B1 [Homo sapi...1 [synthetic construct] dbj|BAF84659.1| unnamed protein product [Homo sapiens] 1e

  17. 34 CFR 5b.1 - Definitions.

    Science.gov (United States)

    2010-07-01

    ... Education. (l) Statistical record means a record maintained for statistical research or reporting purposes... 34 Education 1 2010-07-01 2010-07-01 false Definitions. 5b.1 Section 5b.1 Education Office of the Secretary, Department of Education PRIVACY ACT REGULATIONS § 5b.1 Definitions. As used in this part: (a...

  18. Primary chemotherapy in breast invasive carcinoma: predictive value of the immunohistochemical detection of hormonal receptors, p53, c-erbB-2, MiB1, pS2 and GST pi.

    Science.gov (United States)

    MacGrogan, G.; Mauriac, L.; Durand, M.; Bonichon, F.; Trojani, M.; de Mascarel, I.; Coindre, J. M.

    1996-01-01

    Primary chemotherapy in operable breast invasive carcinoma enables tumour reduction and conservative surgery. In order to search for one or more biological factors capable of predicting tumour behaviour under primary chemotherapy, and subsequent patient survival, an immunohistochemical study was performed with specific antibodies to p53, c-erbB-2 (Her-2/neu), Mib1 (antiKi-67), pS2, GST pi, oestrogen receptors (ERs) and progesterone receptors (PRs). Core biopsies, obtained before primary chemotherapy, were available from a series of 128 breast invasive carcinomas treated between January 1985 and April 1989, with a median follow-up of 93.3 months. Univariate statistical analysis showed that negative ER detection by immunohistochemistry (IHC) was highly correlated with chemosensitivity (P = 0.001). A high percentage of Mib1-positive tumour cells (> 40%), as well as initial tumour size less than 4 cm, were also correlated with tumour responsiveness to chemotherapy (P = 0.009 and P = 0.03). By multivariate analysis IHC-ER, Mib1 and initial tumour size were independent predictors, the last parameter being the most important. Concerning subsequent patient survival, c-erbB-2 overexpression, as detected by IHC, was significant with respect to overall survival (OS) (P = 0.0006), disease-free interval (DFI) (P = 0.03) and metastasis-free interval (MFI) (P = 0.008) by univariate analysis. Furthermore, c-erbB-2 was the major independent prognostic factor for OS and MFI by multivariate analysis. Images Figure 1 Figure 2 PMID:8912545

  19. PKA and Epac cooperate to augment bradykinin-induced interleukin-8 release from human airway smooth muscle cells

    Directory of Open Access Journals (Sweden)

    Halayko Andrew J

    2009-09-01

    Full Text Available Abstract Background Airway smooth muscle contributes to the pathogenesis of pulmonary diseases by secreting inflammatory mediators such as interleukin-8 (IL-8. IL-8 production is in part regulated via activation of Gq-and Gs-coupled receptors. Here we study the role of the cyclic AMP (cAMP effectors protein kinase A (PKA and exchange proteins directly activated by cAMP (Epac1 and Epac2 in the bradykinin-induced IL-8 release from a human airway smooth muscle cell line and the underlying molecular mechanisms of this response. Methods IL-8 release was assessed via ELISA under basal condition and after stimulation with bradykinin alone or in combination with fenoterol, the Epac activators 8-pCPT-2'-O-Me-cAMP and Sp-8-pCPT-2'-O-Me-cAMPS, the PKA activator 6-Bnz-cAMP and the cGMP analog 8-pCPT-2'-O-Me-cGMP. Where indicated, cells were pre-incubated with the pharmacological inhibitors Clostridium difficile toxin B-1470 (GTPases, U0126 (extracellular signal-regulated kinases ERK1/2 and Rp-8-CPT-cAMPS (PKA. The specificity of the cyclic nucleotide analogs was confirmed by measuring phosphorylation of the PKA substrate vasodilator-stimulated phosphoprotein. GTP-loading of Rap1 and Rap2 was evaluated via pull-down technique. Expression of Rap1, Rap2, Epac1 and Epac2 was assessed via western blot. Downregulation of Epac protein expression was achieved by siRNA. Unpaired or paired two-tailed Student's t test was used. Results The β2-agonist fenoterol augmented release of IL-8 by bradykinin. The PKA activator 6-Bnz-cAMP and the Epac activator 8-pCPT-2'-O-Me-cAMP significantly increased bradykinin-induced IL-8 release. The hydrolysis-resistant Epac activator Sp-8-pCPT-2'-O-Me-cAMPS mimicked the effects of 8-pCPT-2'-O-Me-cAMP, whereas the negative control 8-pCPT-2'-O-Me-cGMP did not. Fenoterol, forskolin and 6-Bnz-cAMP induced VASP phosphorylation, which was diminished by the PKA inhibitor Rp-8-CPT-cAMPS. 6-Bnz-cAMP and 8-pCPT-2'-O-Me-cAMP induced GTP

  20. Procollagen C-endopeptidase Enhancer Protein 2 (PCPE2) Reduces Atherosclerosis in Mice by Enhancing Scavenger Receptor Class B1 (SR-BI)-mediated High-density Lipoprotein (HDL)-Cholesteryl Ester Uptake.

    Science.gov (United States)

    Pollard, Ricquita D; Blesso, Christopher N; Zabalawi, Manal; Fulp, Brian; Gerelus, Mark; Zhu, Xuewei; Lyons, Erica W; Nuradin, Nebil; Francone, Omar L; Li, Xiang-An; Sahoo, Daisy; Thomas, Michael J; Sorci-Thomas, Mary G

    2015-06-19

    Studies in human populations have shown a significant correlation between procollagen C-endopeptidase enhancer protein 2 (PCPE2) single nucleotide polymorphisms and plasma HDL cholesterol concentrations. PCPE2, a 52-kDa glycoprotein located in the extracellular matrix, enhances the cleavage of C-terminal procollagen by bone morphogenetic protein 1 (BMP1). Our studies here focused on investigating the basis for the elevated concentration of enlarged plasma HDL in PCPE2-deficient mice to determine whether they protected against diet-induced atherosclerosis. PCPE2-deficient mice were crossed with LDL receptor-deficient mice to obtain LDLr(-/-), PCPE2(-/-) mice, which had elevated HDL levels compared with LDLr(-/-) mice with similar LDL concentrations. We found that LDLr(-/-), PCPE2(-/-) mice had significantly more neutral lipid and CD68+ infiltration in the aortic root than LDLr(-/-) mice. Surprisingly, in light of their elevated HDL levels, the extent of aortic lipid deposition in LDLr(-/-), PCPE2(-/-) mice was similar to that reported for LDLr(-/-), apoA-I(-/-) mice, which lack any apoA-I/HDL. Furthermore, LDLr(-/-), PCPE2(-/-) mice had reduced HDL apoA-I fractional clearance and macrophage to fecal reverse cholesterol transport rates compared with LDLr(-/-) mice, despite a 2-fold increase in liver SR-BI expression. PCPE2 was shown to enhance SR-BI function by increasing the rate of HDL-associated cholesteryl ester uptake, possibly by optimizing SR-BI localization and/or conformation. We conclude that PCPE2 is atheroprotective and an important component of the reverse cholesterol transport HDL system. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  1. Growth suppression activity of bradykinin antagonists in glioma cells

    Directory of Open Access Journals (Sweden)

    Avdieiev S. S.

    2014-01-01

    Full Text Available The present study was Aimed at analyzing the effect of bradykinin (BK antagonists on proliferation of the human glioblastoma cells U373. Methods. MTT-based cell proliferation assay. Results. BKM-570 revealed a significant antiproliferative activity in the U373 cells with LC50 3,8 M. Conclusions. The antiproliferative properties of BK antagonists were shown in vitro using the glioma cells. Further investigations of the molecular mechanisms of their action and pre-clinical studies on animal models are needed for the evaluation of these compounds as new anti-cancer drugs.

  2. EphB1 as a Novel Drug Target to Combat Pain and Addiction

    Science.gov (United States)

    2015-09-01

    including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing ...extracellular domain to form protein- protein interactions with the NR1 subunit of the NMDA receptor and inappropriately strengthen the synapses and neural ...15. SUBJECT TERMS Chronic neuropathic pain, opioid addiction, synaptic plasticity , EphB1 receptor, NMDA receptor, drug discovery 16. SECURITY

  3. Elevated Aminopeptidase P Attenuates Cerebral Arterial Responses to Bradykinin in Fawn-Hooded Hypertensive Rats.

    Directory of Open Access Journals (Sweden)

    Md Abdul Hye Khan

    Full Text Available Cerebral arterial myogenic and autoregulatory responses are impaired in Fawn Hooded hypertensive (FHH rats. Cerebral autoregulatory responses are restored in the congenic rat strain in which a segment of chromosome 1 from the Brown Norway (BN rat was transferred into the FHH genetic background (FHH.1BN. The impact of this region on cerebral arterial dilator responses remains unknown. Aminopeptidase is a gene that was transferred into the FHH genetic background to generate the FHH.1BN rats and is responsible for degradation of the vasodilator bradykinin. Thus, we hypothesized that FHH rats will have increased aminopeptidase P levels with impaired cerebral arterial responses to bradykinin compared to BN and FHH.1BN rats. We demonstrated higher cerebral arterial expression of aminopeptidase P in FHH compared to BN rats. Accordingly, we demonstrated markedly impaired cerebral arterial dilation to bradykinin in FHH compared to BN rats. Interestingly, aminopeptidase P expression was lower in FHH.1BN compared to FHH rats. Decreased aminopeptidase P levels in FHH.1BN rats were associated with increased cerebral arterial bradykinin-induced dilator responses. Aminopeptidase P inhibition by apstatin improved cerebral arterial bradykinin dilator responses in FHH rats to a level similar to FHH.1BN rats. Unlike bradykinin, cerebral arterial responses to acetylcholine were similar between FHH and FHH.1BN groups. These findings indicate decreased bradykinin bioavailability contributes to impaired cerebral arterial dilation in FHH rats. Overall, these data indicate an important role of aminopeptidase P in the impaired cerebral arterial function in FHH rat.

  4. Gene : CBRC-HSAP-14-0065 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available radykinin receptor B1 [Homo sapiens] sp|P46663|BKRB1_HUMAN B1 bradykinin receptor (BK-1 receptor) (B1R) emb|...CAB45650.1| bradykinin B1 receptor [Homo sapiens] dbj|BAC06112.1| seven transmembrane helix receptor [Homo sapi...ens] gb|AAH34705.1| Bradykinin receptor B1 [Homo sapiens] gb|AAP32296.1| brady...kinin receptor B1 [Homo sapiens] gb|EAW81632.1| bradykinin receptor B1 [Homo sapiens] gb|ABM82202.1| bradyki...59.1| unnamed protein product [Homo sapiens] 0.0 100% gnl|UG|Hs#S1726331 Homo sapi

  5. EphB1 as a Novel Drug Target to Combat Pain and Addiction

    Science.gov (United States)

    2016-09-01

    opioid /morphine addiction. Our hypothesis is that postsynaptic EphB1 participates in pain through the ability of its extracellular domain to form...SUBJECT TERMS Chronic neuropathic pain, opioid addiction, synaptic plasticity, EphB1 receptor, ephrin-B2, NMDA receptor, drug discovery 16. SECURITY...symptoms from the highly addictive opioid family of drugs (e.g. morphine, hydrocodone, and heroin). Whether due to nerve damage and/or withdrawal

  6. Exercise-induced increase in interstitial bradykinin and adenosine concentrations in skeletal muscle and peritendinous tissue in humans

    DEFF Research Database (Denmark)

    Langberg, H; Bjørn, C; Boushel, Robert Christopher

    2002-01-01

    Bradykinin is known to cause vasodilatation in resistance vessels and may, together with adenosine, be an important regulator of tissue blood flow during exercise. Whether tissue concentrations of bradykinin change with exercise in skeletal muscle and tendon-related connective tissue has not yet......, range 22-33 years). Interstitial bradykinin and adenosine concentrations were determined using an internal reference to determine relative recovery ([2,3,prolyl-3,4-(3)H(N)]-bradykinin and [2-(3)H]-adenosine). Bradykinin and adenosine recovery were closely related and in the range of 30......-50 %. The interstitial concentration of bradykinin rose in response to exercise both in skeletal muscle (from 23.1 +/- 4.9 nmol l(-1) to 110.5 +/- 37.9 nmol l(-1); P adenosine concentration...

  7. Bradykinin and vasopressin activate phospholipase D in rat Leydig cells by a protein kinase C-dependent mechanism

    DEFF Research Database (Denmark)

    Vinggaard, Anne Marie; Hansen, Harald S.

    1993-01-01

    In the present study we report that bradykinin stimulated phospholipase D activity in rat Leydig cells. Bradykinin added for 8 min stimulated choline formation in a dose-dependent manner and, in the presence of ethanol, bradykinin (100 nmol/l) stimulated transphosphatidylation by phospholipase D...... resulting in the formation of phosphatidylethanol. This stimulation was abolished after down-regulation of protein kinase C by long-term pretreatment for 22 h with phorbol 12-myristate 13-acetate (PMA). The stimulation of phospholipase D by the simultaneous addition for 8 min of maximum concentrations...... of PMA and vasopressin (AVP), PMA and bradykinin, or AVP and bradykinin produced no additive phosphatidylethanol or choline response, suggesting that AVP, bradykinin and PMA stimulated phospholipase D catalysed phosphatidylcholine hydrolysis by a similar protein kinase C-dependent mechanism. Furthermore...

  8. Multiple bradykinin-related peptides from the capture web of the spider Nephila clavipes (Araneae, Tetragnatidae).

    Science.gov (United States)

    Volsi, Evelyn C F R; Mendes, Maria Anita; Marques, Maurício Ribeiro; dos Santos, Lucilene Delazari; Santos, Keity Souza; de Souza, Bibiana Monson; Babieri, Eduardo Feltran; Palma, Mario Sergio

    2006-04-01

    Three bradykinin-related peptides (nephilakinins-I to -III) and bradykinin itself were isolated from the aqueous washing extract of the capture web of the spider Nephila clavipes by gel permeation chromatography on a Sephacryl S-100 column, followed by chromatography in a Hi-Trap Sephadex-G25 Superfine column. The novel peptides occurred in low concentrations and were sequenced through ESI-MS/MS analysis: nephilakinin-I (G-P-N-P-G-F-S-P-F-R-NH2), nephilakinin-II (E-A-P-P-G-F-S-P-F-R-NH2) and nephilakinin-III (P-S-P-P-G-F-S-P-F-R-NH2). Synthetic peptides replicated the novel bradykinin-related peptides, which were submitted to biological characterizations. Nephilakinins were shown to cause constriction on isolated rat ileum preparations and relaxation on rat duodenum muscle preparations at amounts higher than bradykinin; apparently these peptides constitute B2-type agonists of ileal and duodenal smooth muscles. All peptides including the bradykinin were moderately lethal to honeybees. These bradykinin peptides may be related to the predation of insects by the webs of N. clavipes.

  9. A novel bradykinin-like peptide from skin secretions of rufous-spotted torrent frog, Amolops loloensis.

    Science.gov (United States)

    Liang, Jianguo; Han, Yaoping; Li, Jianxu; Xu, Xueqing; Rees, Huw H; Lai, Ren

    2006-11-01

    A bradykinin-like peptide has been isolated from skin secretions of rufous-spotted torrent frog, Amolops loloensis. This bradykinin-like peptide was named amolopkinin. Its primary structure, RAPVPPGFTPFR, was determined by Edman degradation and mass spectrometry. It is structurally related to bradykinin-like peptides identified from skin secretions of other amphibians. Amolopkinin is composed of 12 amino acid residues and is related to bradykinin composed of nine amino acid residues, identified from the skin secretions of Odorrana schmackeri. Amolopkinin was found to elicit concentration-dependent contractile effects on isolated guinea pig ileum. cDNA clones encoding the precursor of amolopkinin were isolated by screening a skin cDNA library of A. loloensis and then sequenced. The amino acid sequences deduced from the cDNA sequences match well with the results from Edman degradation. Analysis of different amphibian bradykinin cDNA structures revealed that a deficiency of an18-nucleotide fragment (TCAAGAATGATCAGACGC in the cDNA encoding bradykinin from O. schmackeri) in the peptide-coding region resulted in absence of a di-basic site for trypsin-like proteinases and an unusual - APV - insertion in the N-terminal part of amolopkinin. This is the first report of a bradykinin-like peptide comprised of bradykinin with an insertion in its N-terminal part. Our results demonstrate the hypervariability of amphibian bradykinin-like peptides, as well as the diversity of antimicrobial peptides in amphibians.

  10. Bradykinin preconditioning improves therapeutic potential of human endothelial progenitor cells in infarcted myocardium.

    Directory of Open Access Journals (Sweden)

    Zulong Sheng

    Full Text Available OBJECTIVES: Stem cell preconditioning (PC is a powerful approach in reducing cell death after transplantation. We hypothesized that PC human endothelial progenitor cells (hEPCs with bradykinin (BK enhance cell survival, inhibit apoptosis and repair the infarcted myocardium. METHODS: The hEPCs were preconditioned with or without BK. The hEPCs apoptosis induced by hypoxia along with serum deprivation was determined by annexin V-fluorescein isothiocyanate/ propidium iodide staining. Cleaved caspase-3, Akt and eNOS expressions were determined by Western blots. Caspase-3 activity and vascular endothelial growth factor (VEGF levels were assessed in hEPCs. For in vivo studies, the survival and cardiomyocytes apoptosis of transplanted hEPCs were assessed using 1,1'-dioctadecyl-3,3,3',3'-tetramethylindodi- carbocyanine,4-chlorobenzenesul-fonate salt labeled hEPCs and TUNEL staining. Infarct size and cardiac function were measured at 10 days after transplantation, and the survival of transplanted hEPCs were visualized using near-infrared optical imaging. RESULTS: In vitro data showed a marked suppression in cell apoptosis following BK PC. The PC reduced caspase-3 activation, increased the Akt, eNOS phosphorylation and VEGF levels. In vivo data in preconditioned group showed a robust cell anti-apoptosis, reduction in infarct size, and significant improvement in cardiac function. The effects of BK PC were abrogated by the B2 receptor antagonist HOE140, the Akt and eNOS antagonists LY294002 and L-NAME, respectively. CONCLUSIONS: The activation of B2 receptor-dependent PI3K/Akt/eNOS pathway by BK PC promotes VEGF secretion, hEPC survival and inhibits apoptosis, thereby improving cardiac function in vivo. The BK PC hEPC transplantation for stem cell-based therapies is a novel approach that has potential for clinical used.

  11. Targeting Sulfotransferase (SULT) 2B1b as a regulator of Cholesterol Metabolism in Prostate Cancer

    Science.gov (United States)

    2016-10-01

    SULT2B1b activity pro- motes hepatocellular carcinoma cell growth in vitro and in vivo, and SULT2B1b expression correlates with poor prognosis and...rescues cell growth in LNCaP with SULT2B1b KD. A) Western blot showing expression levels of indicated proteins . Cells were harvested 60 hours after...induces cell death. SULT2B1b KD also decreases androgen receptor (AR) activity and expression at mRNA and protein levels. While AR overexpression hasno

  12. Effect of 3-substituted 1,4-benzodiazepin-2-ones on maximal normalized rate of bradykinin-induced smooth muscle contraction in the presence of calcium channel blockers

    Directory of Open Access Journals (Sweden)

    P. A. Virych

    2017-05-01

    Full Text Available The development of modern organic chemistry and molecular modeling technologies simplify the search for potential inhibitors of various receptor systems and biological processes. The one of the directions is the development of analgesics of broad spectrum and low toxicity. It is important to search for inhibitors of the kinin-kallikrein system that regulates many functions: inflammation, pain, carcinogenesis, vascular tone, smooth muscle contraction and other. Derivatives of 3-substituted 1,4-benzodiazepine-2-ones have a unique spatial conformation that allows one to simulate β-structures of bioactive peptides. The functional activity of compounds is determined by properties of their peripheral chemical radicals. We analyzed the effect of 3-substituted 1,4-benzodiazepin-2-ones derivatives on the normalized maximal rate of bradykinin-induced smooth muscle contraction and relaxation of the stomach in the presence of calcium channel blockers: verapamil (1 μM, gadolinium (300 μM and 2-aminoethyl diphenylborinate (0.1 μM. The levels of bradykinin and 3-arylamino-1,2-dihydro-3H-1,4-benzodiazepine-2-ones in incubation solution were 10–6 M. Data processing on dynamics of contraction was performed according to the method of Burdyha and Kosterin. Compounds MX-1775 and MX-1925 reduced maximal normalized rate (Vn of bradykinin-induced smooth muscle contraction in the presence of Gd3+ by 21.2% and 31.0% respectively. Compound MX-1925 increased Vn of relaxation by 11.6%. A similar effect is typical for MX-2011, where there is an increase by 34.6%. In the presence of verapamil this compound additionally decreased Vn contraction by 20.5%. Substances MX-1775, MX-2004 and MX-1925 restored maximal normalized rate of relaxation to original values of bradykinin-induced contraction. In the presence of 2-aminoethyldiphenylborinate MX-1775 additionally reduced Vn of contractions by 7.5%. 3-substituted 1,4-benzo­diazepine-2-ones did not change the maximal

  13. Bradykinin stimulation of nitric oxide production is not sufficient for gamma-globin induction

    Directory of Open Access Journals (Sweden)

    Čokić Vladan P.

    2014-01-01

    Full Text Available Introduction. Hydroxycarbamide, used in therapy of hemoglobinopathies, enhances nitric oxide (NO production both in primary human umbilical vein endothelial cells (HUVECs and human bone marrow endothelial cell line (TrHBMEC. Moreover, NO increases γ-globin and fetal hemoglobin levels in human erythroid progenitors. Objective. In order to find out whether simple physiologic stimulation of NO production by components of hematopoietic microenvironment can increase γ-globin gene expression, the effects of NO-inducer bradykinin were examined in endothelial cells. Methods. The study was performed in co-cultures of human erythroid progenitors, TrHBMEC and HUVECs by ozone-based chemiluminescent determination of NO and real-time quantitative RT-PCR. Results. In accordance with previous reports, the endogenous factor bradykinin increased endothelial cell production of NO in a dose- and time-dependent manner (0.1-0.6 μM up to 30 minutes. This induction of NO in HUVECs and TrHBMEC by bradykinin was blocked by competitive inhibitors of NO synthase (NOS, demonstrating NOS-dependence. It has been shown that bradykinin significantly reduced endothelial NOS (eNOS mRNA level and eNOS/Я-actin ratio in HUVEC (by twofold. In addition, bradykinin failed to increase γ-globin mRNA expression in erythroid progenitors only, as well as in co-culture studies of erythroid progenitors with TrHBMEC and HUVEC after 24 hours of treatment. Furthermore, bradykinin did not induce γ/β globin ratio in erythroid progenitors in co-cultures with HUVEC. Conclusion. Bradykinin mediated eNOS activation leads to short time and low NO production in endothelial cells, insufficient to induce γ-globin gene expression. These results emphasized the significance of elevated and extended NO production in augmentation of γ-globin gene expression. [Projekat Ministarstva nauke Republike Srbije, br. 175053

  14. Observation of B-meson decays to b_1 pi and b_1 K

    CERN Document Server

    Aubert, B; Boutigny, D; Karyotakis, Yu; Lees, J P; Poireau, V; Prudent, X; Tisserand, V; Zghiche, A; Garra Tico, J; Graugès-Pous, E; López, L; Palano, A; Pappagallo, M; Eigen, G; Stugu, B; Sun, L; Abrams, G S; Battaglia, M; Brown, D N; Button-Shafer, J; Cahn, R N; Groysman, Y; Jacobsen, R G; Kadyk, J A; Kerth, L T; Kolomensky, Yu G; Kukartsev, G; Lopes-Pegna, D; Lynch, G; Mir, L M; Orimoto, T J; Osipenkov, I L; Ronan, M T; Tackmann, K; Tanabé, T; Wenzel, W A; Del Amo-Sánchez, P; Hawkes, C M; Watson, A T; Held, T; Koch, H; Pelizaeus, M; Schröder, T; Steinke, M; Walker, D; Asgeirsson, D J; Çuhadar-Dönszelmann, T; Fulsom, B G; Hearty, C; Mattison, T S; McKenna, J A; Khan, A; Saleem, M; Teodorescu, L; Blinov, V E; Bukin, A D; Druzhinin, V P; Golubev, V B; Onuchin, A P; Serednyakov, S I; Skovpen, Yu I; Solodov, E P; Todyshev, K Yu; Bondioli, M; Curry, S; Eschrich, I; Kirkby, D; Lankford, A J; Lund, P; Mandelkern, M; Martin, E C; Stoker, D P; Abachi, S; Buchanan, C; Foulkes, S D; Gary, J W; Liu, F; Long, O; Shen, B C; Zhang, L; Paar, H P; Rahatlou, S; Sharma, V; Berryhill, J W; Campagnari, C; Cunha, A; Dahmes, B; Hong, T M; Kovalskyi, D; Richman, J D; Beck, T W; Eisner, A M; Flacco, C J; Heusch, C A; Kroseberg, J; Lockman, W S; Schalk, T; Schumm, B A; Seiden, A; Wilson, M G; Winstrom, L O; Chen, E; Cheng, C H; Fang, F; Hitlin, D G; Narsky, I; Piatenko, T; Porter, F C; Andreassen, R; Mancinelli, G; Meadows, B T; Mishra, K; Sokoloff, M D; Blanc, F; Bloom, P C; Chen, S; Ford, W T; Hirschauer, J F; Kreisel, A; Nagel, M; Nauenberg, U; Olivas, A; Smith, J G; Ulmer, K A; Wagner, S R; Zhang, J; Gabareen, A M; Soffer, A; Toki, W H; Wilson, R J; Winklmeier, F; Altenburg, D D; Feltresi, E; Hauke, A; Jasper, H; Merkel, J; Petzold, A; Spaan, B; Wacker, K; Klose, V; Kobel, M J; Lacker, H M; Mader, W F; Nogowski, R; Schubert, J; Schubert, K R; Schwierz, R; Sundermann, J E; Volk, A; Bernard, D; Bonneaud, G R; Latour, E; Lombardo, V; Thiebaux, C; Verderi, M; Clark, P J; Gradl, W; Muheim, F; Playfer, S; Robertson, A I; Watson, J E; Xie, Y; Andreotti, M; Bettoni, D; Bozzi, C; Calabrese, R; Cecchi, A; Cibinetto, G; Franchini, P; Luppi, E; Negrini, M; Petrella, A; Piemontese, L; Prencipe, E; Santoro, V; Anulli, F; Baldini-Ferroli, R; Calcaterra, A; De Sangro, R; Finocchiaro, G; Pacetti, S; Patteri, P; Peruzzi, I M; Piccolo, M; Rama, M; Zallo, A; Buzzo, A; Contri, R; Lo Vetere, M; Macri, M M; Monge, M R; Passaggio, S; Patrignani, C; Robutti, E; Santroni, A; Tosi, S; Chaisanguanthum, K S; Morii, M; Wu, J; Dubitzky, R S; Marks, J; Schenk, S; Uwer, U; Bard, D J; Dauncey, P D; Flack, R L; Nash, J A; Panduro-Vazquez, W; Tibbetts, M; Behera, P K; Chai, X; Charles, M J; Mallik, U; Ziegler, V; Cochran, J; Crawley, H B; Dong, L; Eyges, V; Meyer, W T; Prell, S; Rosenberg, E I; Rubin, A E; Gao, Y Y; Gritsan, A V; Guo, Z J; Lae, C K; Denig, A G; Fritsch, M; Schott, G; Arnaud, N; Bequilleux, J; D'Orazio, A; Davier, M; Grosdidier, G; Höcker, A; Lepeltier, V; Le Diberder, F; Lutz, A M; Pruvot, S; Rodier, S; Roudeau, P; Schune, M H; Serrano, J; Sordini, V; Stocchi, A; Wang, W F; Wormser, G; Lange, D J; Wright, D M; Bingham, I; Burke, J P; Chavez, C A; Forster, I J; Fry, J R; Gabathuler, E; Gamet, R; Hutchcroft, D E; Payne, D J; Schofield, K C; Touramanis, C; Bevan, A J; George, K A; Di Lodovico, F; Menges, W; Sacco, R; Cowan, G; Flächer, H U; Hopkins, D A; Paramesvaran, S; Salvatore, F; Wren, A C; Brown, D N; Davis, C L; Allison, J; Barlow, N R; Barlow, R J; Chia, Y M; Edgar, C L; Lafferty, G D; West, T J; Yi, J I; Anderson, J; Chen, C; Jawahery, A; Roberts, D A; Simi, G; Tuggle, J M; Blaylock, G; Dallapiccola, C; Hertzbach, S S; Li, X; Moore, T B; Salvati, E; Saremi, S; Cowan, R; Dujmic, D; Fisher, P H; Koeneke, K; Sciolla, G; Sekula, S J; Spitznagel, M; Taylor, F; Yamamoto, R K; Zhao, M; Zheng, Y; Mclachlin, S E; Patel, P M; Robertson, S H; Lazzaro, A; Palombo, F; Bauer, J M; Cremaldi, L; Eschenburg, V; Godang, R; Kroeger, R; Sanders, D A; Summers, D J; Zhao, H W; Brunet, S; Côté, D; Simard, M; Taras, P; Viaud, F B; Nicholson, H; De Nardo, Gallieno; Fabozzi, F; Lista, L; Monorchio, D; Sciacca, C; Baak, M A; Raven, G; Snoek, H L; Jessop, C P; Knoepfel, K J; LoSecco, J M; Benelli, G; Corwin, L A; Honscheid, K; Kagan, H; Kass, R; Morris, J P; Rahimi, A M; Regensburger, J J; Wong, Q K; Blount, N L; Brau, J E; Frey, R; Igonkina, O; Kolb, J A; Lu, M; Rahmat, R; Sinev, N B; Strom, D; Strube, J; Torrence, E; Gagliardi, N; Gaz, A; Margoni, M; Morandin, M; Pompili, A; Posocco, M; Rotondo, M; Simonetto, F; Stroili, R; Voci, C; Ben-Haim, E; Briand, H; Calderini, G; Chauveau, J; David, P; Del Buono, L; De La Vaissière, C; Hamon, O; Leruste, P; Malcles, J; Ocariz, J; Pérez, A; Prendki, J; Gladney, L; Biasini, M; Covarelli, R; Manoni, E; Angelini, C; Batignani, G; Bettarini, S; Carpinelli, M; Cenci, R; Cervelli, A; Forti, F; Giorgi, M A; Lusiani, A; Marchiori, G; Mazur, M A; Morganti, M; Neri, N; Paoloni, E; Rizzo, G; Walsh, J J; Haire, M; Biesiada, J; Elmer, P; Lau, Y P; Lü, C; Olsen, J; Smith, A J S; Telnov, A V; Baracchini, E; Bellini, F; Cavoto, G; Del Re, D; Di Marco, E; Faccini, R; Ferrarotto, F; Ferroni, F; Gaspero, M; Jackson, P D; Li Gioi, L; Mazzoni, M A; Morganti, S; Piredda, G; Polci, F; Renga, F; Voena, C; Ebert, M; Hartmann, T; Schröder, H; Waldi, R; Adye, T; Castelli, G; Franek, B; Olaiya, E O; Ricciardi, S; Röthel, W; Wilson, F F; Emery, S; Escalier, M; Gaidot, A; Ganzhur, S F; Hamel de Monchenault, G; Kozanecki, W; Vasseur, G; Yéche, C; Zito, M; Chen, X R; Liu, H; Park, W; Purohit, M V; Wilson, J R; Allen, M T; Aston, D; Bartoldus, R; Bechtle, P; Berger, N; Claus, R; Coleman, J P; Convery, M R; Dingfelder, J C; Dorfan, J; Dubois-Felsmann, G P; Dunwoodie, W; Field, R C; Glanzman, T; Gowdy, S J; Graham, M T; Grenier, P; Hast, C; Hrynóva, T; Innes, W R; Kaminski, J; Kelsey, M H; Kim, H; Kim, P; Kocian, M L; Leith, D W G S; Li, S; Luitz, S; Lüth, V; Lynch, H L; MacFarlane, D B; Marsiske, H; Messner, R; Müller, D R; O'Grady, C P; Ofte, I; Perazzo, A; Perl, M; Pulliam, T; Ratcliff, B N; Roodman, A; Salnikov, A A; Schindler, R H; Schwiening, J; Snyder, A; Stelzer, J; Su, D; Sullivan, M K; Suzuki, K; Swain, S K; Thompson, J M; Vavra, J; Van Bakel, N; Wagner, A P; Weaver, M; Wisniewski, W J; Wittgen, M; Wright, D H; Yarritu, A K; Yi, K; Young, C C; Burchat, P R; Edwards, A J; Majewski, S A; Petersen, B A; Wilden, L; Ahmed, S; Alam, M S; Bula, R; Ernst, J A; Jain, V; Pan, B; Saeed, M A; Wappler, F R; Zain, S B; Krishnamurthy, M; Spanier, S M; Eckmann, R; Ritchie, J L; Ruland, A M; Schilling, C J; Schwitters, R F; Izen, J M; Lou, X C; Ye, S; Bianchi, F; Gallo, F; Gamba, D; Pelliccioni, M; Bomben, M; Bosisio, L; Cartaro, C; Cossutti, F; Della Ricca, G; Lanceri, L; Vitale, L; Azzolini, V; Lopez-March, N; Martínez-Vidal, F; Milanes, D A; Oyanguren, A; Albert, J; Banerjee, Sw; Bhuyan, B; Hamano, K; Kowalewski, R; Nugent, I M; Roney, J M; Sobie, R J; Harrison, P F; Ilic, J; Latham, T E; Mohanty, G B; Band, H R; Chen, X; Dasu, S; Flood, K T; Hollar, J J; Kutter, P E; Pan, Y; Pierini, M; Prepost, R; Wu, S L; Neal, H

    2007-01-01

    We present the results of searches for decays of B mesons to final states with a b_1 meson and a charged pion or kaon. The data, collected with the BaBar detector at the Stanford Linear Accelerator Center, represent 382 million B-Bbar pairs produced in e+e- annihilation. The results for the branching fractions are, in units of 10^{-6}, B(B+ -> b1^0 pi+) = 6.7 +/- 1.7 +/- 1.0 (4.0 sigma), B(B+ -> b1^0 K+ = 9.1+/- 1.7+/- 1.0 (5.3 sigma), B(B0 -> b1^-/+ pi^+/-) = 10.9 +/- 1.2 +/- 0.9 (8.9 sigma), and B(B0 -> b1^-K+) = 7.4 +/- 1.0 +/- 1.0 (6.1 sigma), with the assumption that B(b_1 -> omega pi)=1. We also measure charge and flavor asymmetries Ach(B+ -> b1^0 pi+) = 0.05 +/- 0.16 +/- 0.02, Ach(B+ -> b1^0 K+ = -0.46 +/- 0.20 +/- 0.02, Ach(B0 -> b1^-/+ pi^+/-) = -0.05 +/- 0.10 +/- 0.02, C(B0 -> b1^-/+ pi^+/-) = -0.22 +/- 0.23 +/- 0.05, deltaC(B0 -> b1^-/+ pi^+/-) = -1.04 +/- 0.23 +/- 0.08, and Ach(B0 -> b1^-K+) = -0.07 +/- 0.12 +/- 0.02, The first error quoted is statistical, the second systematic, and for the branch...

  15. 18 CFR 1b.1 - Definitions.

    Science.gov (United States)

    2010-04-01

    ... ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.1 Definitions. For purposes of this part— (a) Formal investigation means an investigation instituted by a Commission Order of Investigation. (b) Preliminary Investigation means an inquiry conducted by the Commission or its staff, other than a formal...

  16. DMPD: Multifunctional effects of bradykinin on glial cells in relation to potentialanti-inflammatory effects. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17669557 Multifunctional effects of bradykinin on glial cells in relation to potent... Epub 2007 Jun 27. (.png) (.svg) (.html) (.csml) Show Multifunctional effects of bradykinin on glial cells i...n relation to potentialanti-inflammatory effects. PubmedID 17669557 Title Multifunction

  17. Inflammatory mediator bradykinin increases population of sensory neurons expressing functional T-type Ca(2+) channels.

    Science.gov (United States)

    Huang, Dongyang; Liang, Ce; Zhang, Fan; Men, Hongchao; Du, Xiaona; Gamper, Nikita; Zhang, Hailin

    2016-04-29

    T-type Ca(2+) channels are important regulators of peripheral sensory neuron excitability. Accordingly, T-type Ca(2+) currents are often increased in various pathological pain conditions, such as inflammation or nerve injury. Here we investigated effects of inflammation on functional expression of T-type Ca(2+) channels in small-diameter cultured dorsal root ganglion (DRG) neurons. We found that overnight treatment of DRG cultures with a cocktail of inflammatory mediators bradykinin (BK), adenosine triphosphate (ATP), norepinephrine (NE) and prostaglandin E2 (PGE2) strongly increased the population size of the small-diameter neurons displaying low-voltage activated (LVA, T-type) Ca(2+) currents while having no effect on the peak LVA current amplitude. When applied individually, BK and ATP also increased the population size of LVA-positive neurons while NE and PGE2 had no effect. The PLC inhibitor U-73122 and B2 receptor antagonist, Hoe-140, both abolished the increase of the population of LVA-positive DRG neurons. Inflammatory treatment did not affect CaV3.2 mRNA or protein levels in DRG cultures. Furthermore, an ubiquitination inhibitor, MG132, did not increase the population of LVA-positive neurons. Our data suggest that inflammatory mediators BK and ATP increase the abundance of LVA-positive DRG neurons in total neuronal population by stimulating the recruitment of a 'reserve pool' of CaV3.2 channels, particularly in neurons that do not display measurable LVA currents under control conditions. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

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

    DEFF Research Database (Denmark)

    Jing, Fei; Mogi, Masaki; Sakata, Akiko

    2012-01-01

    evaluated by the Morris water maze test in C57BL6 mice, but this effect was not observed in AT(2) receptor-deficient mice. However, C21-induced cognitive enhancement in C57BL6 mice was attenuated by coadministration of icatibant, a bradykinin B(2) receptor antagonist. Administration of C21 dose dependently...

  19. Plasma bradykinin and early diabetic nephropathy lesions in type 1 diabetes mellitus.

    Directory of Open Access Journals (Sweden)

    Kevin M Wheelock

    Full Text Available To examine the association of bradykinin and related peptides with the development of diabetic nephropathy lesions in 243 participants with type 1 diabetes (T1D from the Renin-Angiotensin System Study who, at baseline, were normoalbuminuric, normotensive and had normal or increased glomerular filtration rate (GFR.Plasma concentrations of bradykinin and related peptides were measured at baseline by quantitative mass spectrometry. All participants were randomly assigned at baseline to receive placebo, enalapril or losartan during the 5 years between kidney biopsies. Kidney morphometric data were available from kidney biopsies at baseline and after 5 years. Relationships of peptides with changes in morphometric variables were assessed using multiple linear regression after adjustment for age, sex, diabetes duration, HbA1c, mean arterial pressure, treatment assignment and, for longitudinal analyses, baseline structure.Baseline median albumin excretion rate of study participants was 5.0 μg/min, and mean GFR was 128 mL/min/1.73 m2. After multivariable adjustment, higher plasma concentration of bradykinin (1-8 was associated with greater glomerular volume (partial r = 0.191, P = 0.019 and total filtration surface area (partial r = 0.211, P = 0.010, and higher bradykinin (1-7 and hyp3-bradykinin (1-7 were associated with lower cortical interstitial fractional volume (partial r = -0.189, P = 0.011; partial r = -0.164, P = 0.027 respectively. In longitudinal analyses, higher bradykinin was associated with preservation of surface density of the peripheral glomerular basement membrane (partial r = 0.162, P = 0.013, and for participants randomized to losartan, higher hyp3-bradykinin (1-8 was associated with more limited increase in cortical interstitial fractional volume (partial r = -0.291, P = 0.033.Higher plasma bradykinin and related peptide concentrations measured before clinical onset of diabetic nephropathy in persons with T1D were associated with

  20. B-1 AFT Nacelle Flow Visualization Study

    Science.gov (United States)

    Celniker, Robert

    1975-01-01

    A 2-month program was conducted to perform engineering evaluation and design tasks to prepare for visualization and photography of the airflow along the aft portion of the B-1 nacelles and nozzles during flight test. Several methods of visualizing the flow were investigated and compared with respect to cost, impact of the device on the flow patterns, suitability for use in the flight environment, and operability throughout the flight. Data were based on a literature search and discussions with the test personnel. Tufts were selected as the flow visualization device in preference to several other devices studied. A tuft installation pattern has been prepared for the right-hand aft nacelle area of B-1 air vehicle No.2. Flight research programs to develop flow visualization devices other than tufts for use in future testing are recommended. A design study was conducted to select a suitable motion picture camera, to select the camera location, and to prepare engineering drawings sufficient to permit installation of the camera. Ten locations on the air vehicle were evaluated before the selection of the location in the horizontal stabilizer actuator fairing. The considerations included cost, camera angle, available volume, environmental control, flutter impact, and interference with antennas or other instrumentation.

  1. GMS measurement of B1 liner deformation

    Energy Technology Data Exchange (ETDEWEB)

    Vonka, V.

    1992-11-01

    The GMS system is successfully used to measure gaps between the liner tube and the disc in the B1 hole. GMS was designed for evaluation of minimum tube diameter. In this report measured results are used to evaluate the tube deformation as a function of salt pressure acting on the liner tube from outside. The salt pressure corresponding to the minimum ovality is compared with the pressure derived from the tube compression in the report ECN-I--92-044. A good agreement is found between both results. A significant increase of the minimum ovality in time is observed. This fact suggests that a subtle deformation of the B1 liner tube has built up in the course of time. The validity of this statement is not influenced by the uncertainty in the salt pressure, only by the measurement accuracy. A significant minimum ovality simply means that there is no circular liner tube solution for the measured gap dimensions. (author). 2 refs., 50 figs., 37 tabs.

  2. Unveiling the participation of avian kinin ornithokinin and its receptors in the chicken inflammatory response.

    Science.gov (United States)

    Guabiraba, Rodrigo; Garrido, Damien; Bailleul, Geoffrey; Trotereau, Angélina; Pinaud, Mélanie; Lalmanach, Anne-Christine; Chanteloup, Nathalie K; Schouler, Catherine

    2017-06-01

    Vasoactive peptides are key early mediators of inflammation released through activation of different enzymatic systems. The mammalian kinin-kallikrein (K-KLK) system produces bradykinin (BK) through proteolytic cleavage of a kininogen precursor by enzymes named kallikreins. BK acts through specific ubiquitous G-protein coupled receptors (B1R and B2R) to participate in physiological processes and inflammatory responses, such as activation of mononuclear phagocytes. In chickens, the BK-like nonapeptide ornithokinin (OK) has been shown to promote intracellular calcium increase in embryonic fibroblasts and to be vasodilatory in vivo. Also, one of its receptors (B2R) was already cloned. However, the participation of chicken K-KLK system components in the inflammatory response remains unknown and was therefore investigated. We first showed that B1R, B2R and kininogen 1 (KNG1) are expressed in unstimulated chicken tissues and macrophages. We next showed that chicken B1R and B2R are expressed at transcript and protein levels in chicken macrophages and are upregulated by E. coli LPS or avian pathogenic E. coli (APEC) infection. Interestingly, exogenous OK induced internalization and degradation of OK receptors protein, notably B2R. Also, OK induced intracellular calcium increase and potentiated zymosan-induced ROS production and Dextran-FITC endocytosis by chicken macrophages. Exogenous OK itself did not promote APEC killing and had no pro-inflammatory effect. However, when combined with LPS or APEC, OK upregulated cytokine/chemokine gene expression and NO production by chicken macrophages. This effect was not blocked by canonical non-peptide B1R or B2R receptor antagonists but was GPCR- and PI3K/Akt-dependent. In vivo, pulmonary colibacillosis led to upregulation of OK receptors expression in chicken lungs and liver. Also, colibacillosis led to significant upregulation of OK precursor KNG1 expression in liver and in cultured hepatocytes (LMH). We therefore provide hitherto

  3. Factor XII-independent activation of the bradykinin-forming cascade

    DEFF Research Database (Denmark)

    Joseph, Kusumam; Tholanikunnel, Baby G; Bygum, Anette

    2013-01-01

    BACKGROUND: We have previously reported that prekallikrein expresses an active site when it is bound to high-molecular-weight kininogen (HK) and can digest HK to produce bradykinin. The reaction is stoichiometric and inhibited by C1 inhibitor (C1-INH) or corn trypsin inhibitor. Addition of heat s...

  4. Pain, wheal and flare in human forearm skin induced by bradykinin and 5-hydroxytryptamine

    DEFF Research Database (Denmark)

    Jensen, Kai; Tuxen, C; Pedersen-Bjergaard, U

    1990-01-01

    Pain was induced in 19 healthy individuals by double-blind injections into the forearm skin of 0.05 ml of physiological saline with or without active substances added. Bradykinin (0.5 nmol), 5-hydroxytryptamine (0.5 nmol) and a mixture of the two substances in half dosage (0.25 nmol + 0.25 nmol) ...

  5. Bradykinin or acetylcholine as vasodilators to test endothelial venous function in healthy subjects

    Directory of Open Access Journals (Sweden)

    Eneida R. Rabelo

    2008-01-01

    Full Text Available INTRODUCTION: The evaluation of endothelial function has been performed in the arterial bed, but recently evaluation within the venous system has also been explored. Endothelial function studies employ different drugs that act as endothelium-dependent vasodilatory response inductors. OBJECTIVES: The aim of this study is to compare the endothelium-dependent venous vasodilator response mediated by either acetylcholine or bradykinin in healthy volunteers. METHODS AND RESULTS: Changes in vein diameter after phenylephrine-induced venoconstriction were measured to compare venodilation induced by acetylcholine or bradykinin (linear variable differential transformer dorsal hand vein technique. We studied 23 healthy volunteers; 31% were male, and the subject had a mean age of 33 ± 8 years and a mean body mass index of 23 ± 2 kg/m². The maximum endothelium-dependent venodilation was similar for both drugs (p = 0.13, as well as the mean responses for each dose of both drugs (r = 0.96. The maximum responses to acetylcholine and bradykinin also had good agreement. CONCLUSION: There were no differences between acetylcholine and bradykinin as venodilators in this endothelial venous function investigation.

  6. UNC93B1 mediates host resistance to infection with Toxoplasma gondii.

    Directory of Open Access Journals (Sweden)

    Mariane B Melo

    2010-08-01

    Full Text Available UNC93B1 associates with Toll-Like Receptor (TLR 3, TLR7 and TLR9, mediating their translocation from the endoplasmic reticulum to the endolysosome, hence allowing proper activation by nucleic acid ligands. We found that the triple deficient '3d' mice, which lack functional UNC93B1, are hyper-susceptible to infection with Toxoplasma gondii. We established that while mounting a normal systemic pro-inflammatory response, i.e. producing abundant MCP-1, IL-6, TNFα and IFNγ, the 3d mice were unable to control parasite replication. Nevertheless, infection of reciprocal bone marrow chimeras between wild-type and 3d mice with T. gondii demonstrated a primary role of hemopoietic cell lineages in the enhanced susceptibility of UNC93B1 mutant mice. The protective role mediated by UNC93B1 to T. gondii infection was associated with impaired IL-12 responses and delayed IFNγ by spleen cells. Notably, in macrophages infected with T. gondii, UNC93B1 accumulates on the parasitophorous vacuole. Furthermore, upon in vitro infection the rate of tachyzoite replication was enhanced in non-activated macrophages carrying mutant UNC93B1 as compared to wild type gene. Strikingly, the role of UNC93B1 on intracellular parasite growth appears to be independent of TLR function. Altogether, our results reveal a critical role for UNC93B1 on induction of IL-12/IFNγ production as well as autonomous control of Toxoplasma replication by macrophages.

  7. In vivo and in vitro phagocytosis of Leishmania (Leishmania) amazonensis promastigotes by B-1 cells.

    Science.gov (United States)

    Geraldo, M M; Costa, C R; Barbosa, F M C; Vivanco, B C; Gonzaga, W F K M; Novaes E Brito, R R; Popi, A F; Lopes, J D; Xander, P

    2016-06-01

    Leishmaniasis is caused by Leishmania parasites that infect several cell types. The promastigote stage of Leishmania is internalized by phagocytic cells and transformed into the obligate intracellular amastigote form. B-1 cells are a subpopulation of B cells that are able to differentiate in vitro and in vivo into mononuclear phagocyte-like cells with phagocytic properties. B-1 cells use several receptors for phagocytosis, such as the mannose receptor and third complement receptor. Leishmania binds to the same receptors on macrophages. In this study, we demonstrated that phagocytes derived from B-1 cells (B-1 CDP) were able to internalize promastigotes of L. (L.) amazonensis in vitro. The internalized promastigotes differentiated into amastigotes. Our results showed that the phagocytic index was higher in B-1 CDP compared to peritoneal macrophages and bone marrow-derived macrophages. The in vivo phagocytic ability of B-1 cells was also demonstrated. Parasites were detected inside purified B-1 cells after intraperitoneal infection with L. (L.) amazonensis promastigotes. Intraperitoneal stimulation with the parasites led to an increase in both IL-10 and TNF-α. These results highlight the importance of studying B-1 CDP cells as phagocytic cells that can participate and contribute to immunity to parasites. © 2016 John Wiley & Sons Ltd.

  8. Adsorption of aflatoxin B1 on montmorillonite.

    Science.gov (United States)

    Desheng, Q; Fan, L; Yanhu, Y; Niya, Z

    2005-06-01

    The isothermal adsorption and the adsorptive mechanism of aflatoxin B1 (AFB1) on calcium montmorillonite (Mont) were studied in vitro trials. The maximum amounts of AFB1 on Mont in aqueous solution at 2 and pH 8 were 613.5 and 628.9 microg of AFB1 /g of Mont, respectively. The structure of AFB1-Mont was measured by x-ray diffraction and infrared absorption spectrum. The results suggested that the mechanism of AFB1 on Mont was AFB1 sorbed onto the edge of Mont by a double hydrogen bond, and AFB1 molecules did not penetrate into the interlayer area of Mont. The Mont, when added to the diet of broiler chicken at 0.5%, significantly diminished the adverse effects of feeding 200 microg of AFB1 /kg of feed. And the concentrations of Ca, P, Cu, Fe, Zn in the broiler bones were not affected by AFB1 and Mont, but the concentrations of Mn, Pb, and F were decreased by Mont.

  9. Effects of prolonged oral administration of fumonisin B1 and aflatoxin B1 in rats.

    Science.gov (United States)

    Pozzi, C R; Corrêa, B; Xavier, J G; Direito, G M; Orsi, R B; Matarazzo, S V

    2001-01-01

    The effects of prolonged oral administration (21 days) of fumonisin B1 (FB1) and aflatoxin B1 (AFB1) were evaluated on male Wistar rats. The animals were housed in individual metabolic cages and submitted to the following treatments: 1-0 microg AFB1 + 0 mg FB1/100g bw.; 2-72 microg AFB1+ 0 mg FB1/100 g bw; 3-0 microg AFB1 + 0.5 mg FB1 g bw; 4-0 microg AFB1 + 1.5 mg FB1/100 g bw; 5-72 microg AFB1 + 0.5 mg FB1/100g bw; 6-72 microgAFB1 + 1.5 mg FB1/100g bw. On day 21, the rats were sacrificed for evaluation. The results showed that treated animals presented differences in body weight and absolute/relative weights of liver and kidney as well as altered hepatic function and cholesterol blood levels. Rats fed with the greatest doses of AFB1 and FB1 gained less weight (2.79 g/day) at the end of the experimental period; their blood concentrations of liver enzymes aspartate aminotransferase (AST) and alkaline phosphatase (AP) were above control levels (130.35 micro/l and 471.00 micro/l, respectively). Blood cholesterol increased in the groups treated with the highest dose of FB1 or FB1 associated with AFB1. Histopathology revealed the occurrence of apoptosis in the liver of rats exposed to FB1. The association of aflatoxin B1 with fumonisin B1 at higher dose probably potentiated the effects of the higher dose of fumonisin B1 acting singly.

  10. Bradykinin-evoked changes in cytosolic calcium and membrane currents in cultured bovine pulmonary artery endothelial cells.

    Science.gov (United States)

    Cannell, M B; Sage, S O

    1989-12-01

    1. Cultured bovine pulmonary artery endothelial cells were voltage clamped using a single microelectrode while cytosolic free calcium concentration ([Ca2+]i) was simultaneously measured using the fluorescent calcium indicator, Indo-1. 2. The resting current-voltage relationship was non-linear and exhibited marked inward rectification near the resting potential. In about 60% of cells examined, superfusion of saline resulted in a hyperpolarization and decrease in inward current. This result did not depend on the presence of agonist and is consistent with the presence of extracellular potassium accumulation in restricted spaces around the cell and the known dependence of the inward rectifier. In other cells there was no effect. 3. Resting [Ca2+]i was sensitive to membrane potential, decreasing continuously with membrane depolarization over the range -70 to +60 mV. This result is consistent with a simple pump-leak model and suggests that voltage-dependent calcium channels are not present in these cells. 4. Bradykinin (10 microM) increased [Ca2+]i after a delay of approximately 3 s. [Ca2+]i reached a peak after a further 3 s and declined over several minutes. 5. During the rise in [Ca2+]i evoked by application of bradykinin, there were no changes in the current-voltage relationship of the cell. These results question the role of a receptor-operated non-selective cation channel in mediating the increase in [Ca2+]i. This observation, coupled with the observed delay in the agonist-evoked response suggests that a second messenger system is involved in mediating the increase in [Ca2+]i. 6. Changes in the current-voltage relation started to occur about 30 s after the application of agonist. These changes could be explained by the activation of large-conductance potassium and non-selective cation channels with a reversal potential near 0 mV. The latter channels may mediate the plateau phase of the agonist-evoked response. 7. The results are discussed with respect to the

  11. Comparative docking studies of CYP1b1 and its PCG-associated ...

    Indian Academy of Sciences (India)

    Molecular docking has been used to compare and contrast the binding modes of oestradiol with the wild-type and some disease-associated mutant forms of the human CYP1b1 protein. The receptor structures used for docking were derived from molecular dynamics simulations of homology-modelled structures. Earlier ...

  12. CD25+ B-1a Cells Express Aicda

    Directory of Open Access Journals (Sweden)

    Hiroaki Kaku

    2017-06-01

    Full Text Available B-1a cells are innate-like B-lymphocytes producing natural antibodies. Activation-induced cytidine deaminase (AID, a product of the Aicda gene, plays a central role in class-switch recombination and somatic hypermutation in B cells. Although a role for Aicda in B-1a cells has been suggested on the basis of experiments with knock out (KO mice, whether B-1a cells express Aicda, and if so, which B-1a cell subpopulation expresses Aicda, remains unknown. Here, we demonstrate that B-1 cells express Aicda, but at a level below that expressed by germinal center (GC B cells. We previously reported that B-1a cells can be subdivided based on CD25 expression. We show here that B-1a cell Aicda expression is concentrated in the CD25+ B-1a cell subpopulation. These results suggest the possibility that previous studies of memory B cells identified on the basis of Aicda expression may have inadvertently included an unknown number of CD25+ B-1a cells. Although B-1a cells develop normally in the absence of Aicda, a competitive reconstitution assay reveals enhanced vigor for AID KO B-1a cell bone marrow (BM progenitors, as compared with wild-type BM B-1 cell progenitors. These results suggest that AID inhibits the development of B-1a cells from BM B-1 cell progenitors in a competitive environment.

  13. Inhibitory effect of donepezil on bradykinin-induced increase in the intracellular calcium concentration in cultured cortical astrocytes.

    Science.gov (United States)

    Makitani, Kouki; Nakagawa, Shota; Izumi, Yasuhiko; Akaike, Akinori; Kume, Toshiaki

    2017-05-01

    Donepezil is a potent and selective acetylcholinesterase inhibitor developed for the treatment of Alzheimer's disease. In the present study, we investigated the responses of astrocytes to bradykinin, an inflammatory mediator, and the effect of donepezil on these responses using cultured cortical astrocytes. Bradykinin induced a transient increase of intracellular calcium concentration ([Ca(2+)]i) in cultured astrocytes. Bradykinin-induced [Ca(2+)]i increase was inhibited by the exposure to thapsigargin, which depletes Ca(2+) stores on endoplasmic reticulum, but not by the exclusion of extracellular Ca(2+). Twenty four hours pretreatment of donepezil reduced the bradykinin-induced [Ca(2+)]i increase. This reduction was inhibited not only by mecamylamine, a nAChR antagonist, but also by PI3K and Akt inhibitors. In addition, donepezil inhibited bradykinin-induced increase of the intracellular reactive oxygen species level in astrocytes. These results suggest that donepezil inhibits the inflammatory response induced by bradykinin via nAChR and PI3K-Akt pathway in astrocytes. Copyright © 2017 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

  14. Inhibitory effect of donepezil on bradykinin-induced increase in the intracellular calcium concentration in cultured cortical astrocytes

    Directory of Open Access Journals (Sweden)

    Kouki Makitani

    2017-05-01

    Full Text Available Donepezil is a potent and selective acetylcholinesterase inhibitor developed for the treatment of Alzheimer's disease. In the present study, we investigated the responses of astrocytes to bradykinin, an inflammatory mediator, and the effect of donepezil on these responses using cultured cortical astrocytes. Bradykinin induced a transient increase of intracellular calcium concentration ([Ca2+]i in cultured astrocytes. Bradykinin-induced [Ca2+]i increase was inhibited by the exposure to thapsigargin, which depletes Ca2+ stores on endoplasmic reticulum, but not by the exclusion of extracellular Ca2+. Twenty four hours pretreatment of donepezil reduced the bradykinin-induced [Ca2+]i increase. This reduction was inhibited not only by mecamylamine, a nAChR antagonist, but also by PI3K and Akt inhibitors. In addition, donepezil inhibited bradykinin-induced increase of the intracellular reactive oxygen species level in astrocytes. These results suggest that donepezil inhibits the inflammatory response induced by bradykinin via nAChR and PI3K-Akt pathway in astrocytes.

  15. Consensus statement on the diagnosis, management, and treatment of angioedema mediated by Bradykinin. Part. II: treatment, follow-up, and special situations

    OpenAIRE

    Caballero, T.; Baeza, M. L.; Cabañas, R.; Campos, A.; Cimbollek, S.; Gómez-Traseira, C.; González-Quevedo, T.; Guilarte, M.; Jurado-Palomo, J.; Larco, J. I.; López-Serrano, M. C.; López-Trascasa, M.; Marcos, C.; Muñoz- Caro, J. M.; Pedrosa, M.

    2011-01-01

    Background: There are no previous Spanish guidelines or consensus statements on bradykinin-induced angioedema. Aim: To draft a consensus statement on the management and treatment of angioedema mediated by bradykinin in light of currently available scientifi c evidence and the experience of experts. This statement will serve as a guideline to health professionals. Methods: The consensus was led by the Spanish Study Group on Bradykinin-Induced Angioedema, a working group of the Spanish...

  16. receptores

    Directory of Open Access Journals (Sweden)

    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”.

  17. A novel assay to diagnose hereditary angioedema utilizing inhibition of bradykinin-forming enzymes

    DEFF Research Database (Denmark)

    Joseph, Kusumam; Bains, Sonia; Tholanikunnel, Baby G

    2015-01-01

    BACKGROUND: Hereditary angioedema types I and II are caused by a functional deficiency of C1 inhibitor (C1-INH) leading to overproduction of bradykinin. The current functional diagnostic assays employ inhibition of activated C1s, however, an alternative, more physiologic method, is desirable...... dilutions of normal plasma were employed to validate the ability to detect known concentration of C1-INH in the plasma as a percent of normal. HAE types I and II were then tested. The level of functional C1-INH in all HAE types I and II plasma tested were less than 40% of our normal control...... samples were considered equivocal (4 controls and 38 patients). CONCLUSIONS: Diagnosis of HAE types I and II can be ascertained by inhibition of enzymes of the bradykinin-forming cascade; namely, factor XIIa and kallikrein. Either method yields functional C1-INH levels in HAE patients (types I & II...

  18. 26 CFR 301.7701(b)-1 - Resident alien.

    Science.gov (United States)

    2010-04-01

    ... 26 Internal Revenue 18 2010-04-01 2010-04-01 false Resident alien. 301.7701(b)-1 Section 301.7701... ADMINISTRATION PROCEDURE AND ADMINISTRATION Definitions § 301.7701(b)-1 Resident alien. (a) Scope. Section 301.7701(b)-1(b) provides rules for determining whether an alien individual is a lawful permanent resident...

  19. 26 CFR 54.4980B-1 - COBRA in general.

    Science.gov (United States)

    2010-04-01

    ... 26 Internal Revenue 17 2010-04-01 2010-04-01 false COBRA in general. 54.4980B-1 Section 54.4980B-1... TAXES (CONTINUED) PENSION EXCISE TAXES § 54.4980B-1 COBRA in general. The COBRA continuation coverage... requirements were added to section 162 by the Consolidated Omnibus Budget Reconciliation Act of 1985 (COBRA...

  20. Assessment of human exposure to fumonisin B1

    NARCIS (Netherlands)

    Nijs, M. de; Egmond, H.P. van; Nauta, M.; Rombouts, F.M.; Notermans, S.H.W.

    1998-01-01

    Fumonisin B1 is currently regarded as the most significant mycotoxin produced by Fusarium spp. It has carcinogenic properties and may play a role in the etiology of human esophageal cancer. The human population is exposed to fumonisin B1 primarily by intake of fumonisin B1-contaminated maize. Maize

  1. 78 FR 46579 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2013-08-01

    ... of the Secretary 36(b)(1) Arms Sales Notification AGENCY: Department of Defense, Defense Security... a section 36(b)(1) arms sales notification. This is published to fulfill the requirements of section... Letter of Offer Pursuant to Section 36(b)(1) of the Arms Export Control Act, as Amended (i) Prospective...

  2. 76 FR 46754 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2011-08-03

    ... of the Secretary 36(b)(1) Arms Sales Notification AGENCY: Department of Defense, Defense Security... a section 36(b)(1) arms sales notification. This is published to fulfill the requirements of section... Proposed Issuance of Letter of Offer, Pursuant to Section 36(b)(1) Of the Arms Export Control Act, as...

  3. 78 FR 26324 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2013-05-06

    ... of the Secretary 36(b)(1) Arms Sales Notification AGENCY: Defense Security Cooperation Agency... of a section 36(b)(1) arms sales notification. This is published to fulfill the requirements of... No. 13-20 Notice of Proposed Issuance of Letter of Offer Pursuant to Section 36(b)(1) of the Arms...

  4. 76 FR 72686 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2011-11-25

    ... of the Secretary 36(b)(1) Arms Sales Notification AGENCY: Defense Security Cooperation Agency... of a section 36(b)(1) arms sales notification. This is published to fulfill the requirements of... Letter of Offer Pursuant to Section 36(b)(1) of the Arms Export Control Act, as amended (i) Prospective...

  5. 78 FR 62588 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2013-10-22

    ... of the Secretary 36(b)(1) Arms Sales Notification AGENCY: Defense Security Cooperation Agency... of a section 36(b)(1) arms sales notification. This is published to fulfill the requirements of... Letter of Offer Pursuant to Section 36(b)(1) of the Arms Export Control Act, as amended (i) Prospective...

  6. Literatuuroverzicht analysemethodes voor vitamine B1 en B2

    OpenAIRE

    Oostenbrink, T.; Hollman, P.

    1982-01-01

    Inventarisatie analysemethodes vitamine B1 en B2. De extraktie van vitamine B1 en B2 dient voor een aantal levensmiddelen nader onderzocht te worden. Het is zinvol een automatische methode voor vitamine B1 en B2 op te starten. HPLC methodes zijn voor de levensmiddelenanalyse nog in een beginstadium.

  7. 49 CFR 178.33b-1 - Compliance.

    Science.gov (United States)

    2010-10-01

    ... 49 Transportation 2 2010-10-01 2010-10-01 false Compliance. 178.33b-1 Section 178.33b-1 Transportation Other Regulations Relating to Transportation PIPELINE AND HAZARDOUS MATERIALS SAFETY... Specifications for Inside Containers, and Linings § 178.33b-1 Compliance. (a) Required in all details. (b...

  8. 26 CFR 1.672(b)-1 - Nonadverse party.

    Science.gov (United States)

    2010-04-01

    ... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Nonadverse party. 1.672(b)-1 Section 1.672(b)-1...) INCOME TAXES Grantors and Others Treated As Substantial Owners § 1.672(b)-1 Nonadverse party. A nonadverse party is any person who is not an adverse party. ...

  9. Compound list: aflatoxin B1 [Open TG-GATEs

    Lifescience Database Archive (English)

    Full Text Available aflatoxin B1 AFB1 00165 ftp://ftp.biosciencedbc.jp/archive/open-tggates/LATEST/Human/in_vitro/aflat...oxin_B1.Human.in_vitro.Liver.zip ftp://ftp.biosciencedbc.jp/archive/open-tggates/LATEST/Rat/in_vivo/Liver/Single/aflatoxin_B1.Rat.in_vivo.Liver.Single.zip ...

  10. Bixa orellana leaves extract inhibits bradykinin-induced inflammation through suppression of nitric oxide production.

    Science.gov (United States)

    Yoke Keong, Y; Arifah, A K; Sukardi, S; Roslida, A H; Somchit, M N; Zuraini, A

    2011-01-01

    The present study was conducted to assess the anti-inflammatory effect of a crude aqueous extract of Bixa orellana leaves (AEBO) and to examine the possible involvement of nitric oxide (NO) in its anti-inflammatory mechanism. The air-dried, powdered leaves were soaked in distilled water (1:20 w/v) at 50°C for 24 h and the supernatant obtained was freeze-dried (yield 8.5% w/w). The dosage was recorded as the mass of extract per kg b.w. of rats in all inflammatory assays (bradykinin-induced paw edema, peritoneal vascular permeability and NO assay). Pretreatment with AEBO for 4 consecutive days exhibited significant inhibitory activity against inflammatory models, the bradykinin-induced hind paw edema model and bradykinin-induced increased peritoneal vascular permeability at both doses in dose-dependent manner. In addition, AEBO was also found to significantly suppress the production of NO at doses of 50 and 150 mg/kg. This study provides scientific data to support the traditional use of B. orellana leaves in treating inflammation. Results from this study suggest that AEBO exerts anti-inflammatory effects. Part of this anti-inflammatory effect may be associated with its antibradykinin activity and may be related to a reduction of the NO production. Copyright © 2011 S. Karger AG, Basel.

  11. Effects of oral administration of aflatoxin B1 and fumonisin B1 in rabbits (Oryctolagus cuniculus).

    Science.gov (United States)

    Orsi, R B; Oliveira, C A F; Dilkin, P; Xavier, J G; Direito, G M; Corrêa, B

    2007-12-15

    The effects of prolonged oral administration (21 days) of fumonisin B(1) (FB(1)) and aflatoxin B(1) (AFB(1)) were studied in male New Zealand rabbits by clinical, pathological, biochemical and sphingolipid analyses. Twenty-four animals were randomly divided into the following four experimental groups: (A) 0 mg FB(1)+0 microg AFB(1)/(kg body weight(bw)day) (control); (B) 0 mg FB(1)+30 microg AFB(1)/(kg bw day); (C) 1.5 mg FB(1)/(kg bw day)+30 microg AFB(1)/(kg bw day); (D) 1.5 mg FB(1)/(kg bw day)+0 microg AFB(1). Animals from group B and principally from group C presented clinical signs of intoxication. Rabbits from group C presented a lower body weight gain than controls. Differences were observed between intoxicated rabbits and controls with respect to absolute and relative liver and kidney weight, hepatic function, serum urea and creatinine levels and Sa/So ratio. The most frequent hepatic and renal injuries were vacuolar degeneration of the liver and kidney as shown by the histopathological and serum biochemical results. Combined administration of AFB(1) and FB(1) resulted in synergistic toxic effects both in the liver and in the kidney, but hepatic injuries were more marked.

  12. B1 -sensitivity analysis of quantitative magnetization transfer imaging.

    Science.gov (United States)

    Boudreau, Mathieu; Stikov, Nikola; Pike, G Bruce

    2017-03-27

    To evaluate the sensitivity of quantitative magnetization transfer (qMT) fitted parameters to B1 inaccuracies, focusing on the difference between two categories of T1 mapping techniques: B1 -independent and B1 -dependent. The B1 -sensitivity of qMT was investigated and compared using two T1 measurement methods: inversion recovery (IR) (B1 -independent) and variable flip angle (VFA), B1 -dependent). The study was separated into four stages: 1) numerical simulations, 2) sensitivity analysis of the Z-spectra, 3) healthy subjects at 3T, and 4) comparison using three different B1 imaging techniques. For typical B1 variations in the brain at 3T (±30%), the simulations resulted in errors of the pool-size ratio (F) ranging from -3% to 7% for VFA, and -40% to > 100% for IR, agreeing with the Z-spectra sensitivity analysis. In healthy subjects, pooled whole-brain Pearson correlation coefficients for F (comparing measured double angle and nominal flip angle B1 maps) were ρ = 0.97/0.81 for VFA/IR. This work describes the B1 -sensitivity characteristics of qMT, demonstrating that it varies substantially on the B1 -dependency of the T1 mapping method. Particularly, the pool-size ratio is more robust against B1 inaccuracies if VFA T1 mapping is used, so much so that B1 mapping could be omitted without substantially biasing F. Magn Reson Med, 2017. © 2017 International Society for Magnetic Resonance in Medicine. © 2017 International Society for Magnetic Resonance in Medicine.

  13. 29 CFR 2530.200b-1 - Computation periods.

    Science.gov (United States)

    2010-07-01

    ... 29 Labor 9 2010-07-01 2010-07-01 false Computation periods. 2530.200b-1 Section 2530.200b-1 Labor... Provisions § 2530.200b-1 Computation periods. (a) General. Under sections 202, 203 and 204 of the Act and... specified period—in general, a twelve-consecutive-month period—referred to herein as a “computation period...

  14. 26 CFR 1.280B-1 - Demolition of structures.

    Science.gov (United States)

    2010-04-01

    ... 26 Internal Revenue 3 2010-04-01 2010-04-01 false Demolition of structures. 1.280B-1 Section 1.280B-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES Items Not Deductible § 1.280B-1 Demolition of structures. (a) In general. Section 280B provides that, in the case of the...

  15. MAN1B1 deficiency: an unexpected CDG-II.

    Directory of Open Access Journals (Sweden)

    Daisy Rymen

    Full Text Available Congenital disorders of glycosylation (CDG are a group of rare metabolic diseases, due to impaired protein and lipid glycosylation. In the present study, exome sequencing was used to identify MAN1B1 as the culprit gene in an unsolved CDG-II patient. Subsequently, 6 additional cases with MAN1B1-CDG were found. All individuals presented slight facial dysmorphism, psychomotor retardation and truncal obesity. Generally, MAN1B1 is believed to be an ER resident alpha-1,2-mannosidase acting as a key factor in glycoprotein quality control by targeting misfolded proteins for ER-associated degradation (ERAD. However, recent studies indicated a Golgi localization of the endogenous MAN1B1, suggesting a more complex role for MAN1B1 in quality control. We were able to confirm that MAN1B1 is indeed localized to the Golgi complex instead of the ER. Furthermore, we observed an altered Golgi morphology in all patients' cells, with marked dilatation and fragmentation. We hypothesize that part of the phenotype is associated to this Golgi disruption. In conclusion, we linked mutations in MAN1B1 to a Golgi glycosylation disorder. Additionally, our results support the recent findings on MAN1B1 localization. However, more work is needed to pinpoint the exact function of MAN1B1 in glycoprotein quality control, and to understand the pathophysiology of its deficiency.

  16. Effects of the intra-arterial injection of bradykinin into the limbs, upon the activity of mesencephalic reticular units.

    Science.gov (United States)

    Lombard, M C; Guilbaud, G; Besson, J M

    1975-02-01

    The changes in firing rate of mesencephalic reticular units after intra-arterial injection into the limbs of a potent nociceptive agent, bradykinin, were studied in cats (unanesthetized, immobilized with flaxedil and hyperventilated). 30 per cent of the d35 studied cells were affected, 56 per cent were excited, 23 per cent inhibited and 5 per cent had mixed effects. Among the 75 excited cells, the activation of 16 of them seemed to related to the arousa- processes (group A); for 56 cells the increase seemed dire-tly dependent on the nociceptive stimulation itself (group B). The changes of firing rate were repruducible; their latencies and durations were of the same order as the latencies and duration of the nociceptive reactions and painful sensation s, which have been obtained in animals and men after bradykinin injections. The modifications induced by bradykinin administration were suppressed by Ketamin and Thiopental.

  17. Exogenous Bradykinin Inhibits Tissue Factor Induction and Deep Vein Thrombosis via Activating the eNOS/Phosphoinositide 3-Kinase/Akt Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Ruolan Dong

    2015-11-01

    Full Text Available Background/Aims: Bradykinin has been shown to exert a variety of protective effects against vascular injury, and to reduce the levels of several factors involved in the coagulation cascade. A key determinant of thrombin generation is tissue factor (TF. However, whether bradykinin can regulate TF expression remains to be investigated. Methods: To study the effect of bradykinin on TF expression, we used Lipopolysaccharides (LPS to induce TF expression in human umbilical vein endothelial cells and monocytes. Transcript levels were determined by RT-PCR, protein abundance by Western blotting. In the in vivo study, bradykinin and equal saline were intraperitoneally injected into mice for three days ahead of inferior cava vein ligation that we took to induce thrombus formation, after which bradykinin and saline were injected for another two days. Eventually, the mice were sacrificed and tissues were harvested for tests. Results: Exogenous bradykinin markedly inhibited TF expression in mRNA and protein level induced by LPS in a dose-dependent manner. Moreover, the NO synthase antagonist L-NAME and PI3K inhibitor LY294002 dramatically abolished the inhibitory effects of bradykinin on tissue factor expression. PI3K/Akt signaling pathway activation induced by bradykinin administration reduced the activity of GSK-3ß and MAPK, and reduced NF-κB level in the nucleus, thereby inhibiting TF expression. Consistent with this, intraperitoneal injection of C57/BL6 mice with bradykinin also inhibited the thrombus formation induced by ligation of inferior vena cava. Conclusion: Bradykinin suppressed TF protein expression in human umbilical vein endothelial cells and monocytes in vitro; in line with this, it inhibits thrombus formation induced by ligation of inferior vena cava in vivo.

  18. 76 FR 37078 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2011-06-24

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF DEFENSE Office of the Secretary 36(b)(1) Arms Sales Notification AGENCY: Department of Defense, Defense Security... a section 36(b)(1) arms sales notification. This is published to fulfill the requirements of section...

  19. 75 FR 69947 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2010-11-16

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF DEFENSE Office of the Secretary 36(b)(1) Arms Sales Notification AGENCY: Defense Security Cooperation Agency... of a section 36(b)(1) arms sales notification. This is published to fulfill the requirements of...

  20. 75 FR 69957 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2010-11-16

    ... From the Federal Register Online via the Government Publishing Office ] DEPARTMENT OF DEFENSE Office of the Secretary 36(b)(1) Arms Sales Notification AGENCY: Department of Defense, Defense Security... a section 36(b)(1) arms sales notification. This is published to fulfill the requirements of section...

  1. 75 FR 69922 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2010-11-16

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF DEFENSE Office of the Secretary 36(b)(1) Arms Sales Notification AGENCY: Defense Security Cooperation Agency... of a section 36(b)(1) arms sales notification. This is published to fulfill the requirements of...

  2. 75 FR 60424 - 36(b)(1) Arms Sales Notifications

    Science.gov (United States)

    2010-09-30

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF DEFENSE Office of the Secretary 36(b)(1) Arms Sales Notifications AGENCY: Defense Security Cooperation Agency, DoD...(b)(1) arms sales notifications to fulfill the requirements of section 155 of Public Law 104-164...

  3. 76 FR 29212 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2011-05-20

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF DEFENSE Office of the Secretary 36(b)(1) Arms Sales Notification AGENCY: Defense Security Cooperation Agency... of a section 36(b)(1) arms sales notification. This is published to fulfill the requirements of...

  4. 75 FR 69960 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2010-11-16

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF DEFENSE Office of the Secretary 36(b)(1) Arms Sales Notification AGENCY: Department of Defense, Defense Security... a section 36(b)(1) arms sales notification. This is published to fulfill the requirements of section...

  5. 75 FR 69926 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2010-11-16

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF DEFENSE Office of the Secretary 36(b)(1) Arms Sales Notification AGENCY: Defense Security Cooperation Agency... of a section 36(b)(1) arms sales notification. This is published to fulfill the requirements of...

  6. 75 FR 48646 - 36(b)(1) Arms Sales Notifications

    Science.gov (United States)

    2010-08-11

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF DEFENSE Office of the Secretary 36(b)(1) Arms Sales Notifications AGENCY: Defense Security Cooperation Agency, DoD... 36(b)(1) arms sales notifications to fulfill the requirements of section 155 of Public Law 104-164...

  7. 75 FR 69971 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2010-11-16

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF DEFENSE Office of the Secretary 36(b)(1) Arms Sales Notification AGENCY: Department of Defense, Defense Security... a section 36(b)(1) arms sales notification. This is published to fulfill the requirements of section...

  8. 75 FR 69953 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2010-11-16

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF DEFENSE Office of the Secretary 36(b)(1) Arms Sales Notification AGENCY: Department of Defense, Defense Security... a section 36(b)(1) arms sales notification. This is published to fulfill the requirements of section...

  9. 75 FR 69931 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2010-11-16

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF DEFENSE Office of the Secretary 36(b)(1) Arms Sales Notification AGENCY: Defense Security Cooperation Agency... of a section 36(b)(1) arms sales notification. This is published to fulfill the requirements of...

  10. 75 FR 74014 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2010-11-30

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF DEFENSE Office of the Secretary 36(b)(1) Arms Sales Notification AGENCY: Department of Defense, Defense Security... a section 36(b)(1) arms sales notification. This is published to fulfill the requirements of section...

  11. 76 FR 37071 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2011-06-24

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF DEFENSE Office of the Secretary 36(b)(1) Arms Sales Notification AGENCY: Department of Defense, Defense Security... a section 36(b)(1) arms sales notification. This is published to fulfill the requirements of section...

  12. 75 FR 74011 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2010-11-30

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF DEFENSE Office of the Secretary 36(b)(1) Arms Sales Notification AGENCY: Department of Defense, Defense Security... a section 36(b)(1) arms sales notification. This is published to fulfill the requirements of section...

  13. 76 FR 37075 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2011-06-24

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF DEFENSE Office of the Secretary 36(b)(1) Arms Sales Notification AGENCY: Department of Defense, Defense Security... a section 36(b)(1) arms sales notification. This is published to fulfill the requirements of section...

  14. 75 FR 69938 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2010-11-16

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF DEFENSE Office of the Secretary 36(b)(1) Arms Sales Notification AGENCY: Defense Security Cooperation Agency... of a section 36(b)(1) arms sales notification. This is published to fulfill the requirements of...

  15. 78 FR 26330 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2013-05-06

    ... of the Secretary 36(b)(1) Arms Sales Notification AGENCY: Defense Security Cooperation Agency... of a section 36(b)(1) arms sales notification. This is published to fulfill the requirements of...)(1) of the Arms Export Control Act, as amended (i) Prospective Purchaser: United Kingdom (ii) Total...

  16. 26 CFR 301.6226(b)-1 - 5-percent group.

    Science.gov (United States)

    2010-04-01

    ... 26 Internal Revenue 18 2010-04-01 2010-04-01 false 5-percent group. 301.6226(b)-1 Section 301.6226... ADMINISTRATION PROCEDURE AND ADMINISTRATION Assessment In General § 301.6226(b)-1 5-percent group. (a) In general. All members of a 5-percent group shall join in filing any petition for judicial review. The...

  17. 26 CFR 301.6223(b)-1 - Notice group.

    Science.gov (United States)

    2010-04-01

    ... 26 Internal Revenue 18 2010-04-01 2010-04-01 false Notice group. 301.6223(b)-1 Section 301.6223(b... ADMINISTRATION PROCEDURE AND ADMINISTRATION Assessment In General § 301.6223(b)-1 Notice group. (a) In general. If a group of partners having in the aggregate a 5 percent or more interest in the profits of a...

  18. serum transforming growth factor b1 and prostate

    African Journals Online (AJOL)

    *, Suez Canal. University, Ismail/a, Egypt .... Human TGF-B1 was quantitatively esti- mated using a solid-phase enzyme immunoas- say method performed on a microtiter plate. (TGF-B1 EAS/A, Cat. No. KAC1681, Bio- sourc'e, Europe,SA).

  19. Determination of aflatoxin B1 in food products in Thailand ...

    African Journals Online (AJOL)

    Aflatoxin B1 is generally found in feed and food stuff, such as cereal and all products derived from cereals, including processed cereals since it has been proven to be at least partly resistant to food processing methods. Hence, the aim of this study was to determine the possibility of contamination of aflatoxin B1 in food ...

  20. 77 FR 781 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2012-01-06

    ... important force for political stability and economic progress in the Middle East. The proposed sale will... Office of the Secretary 36(b)(1) Arms Sales Notification AGENCY: Department of Defense, Defense Security... a section 36(b)(1) arms sales notification. This is published to fulfill the requirements of section...

  1. 78 FR 32632 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2013-05-31

    ... sale for the continuation of a Continental United States (CONUS)-based Royal Netherlands Air Force... of the Secretary 36(b)(1) Arms Sales Notification AGENCY: Defense Security Cooperation Agency... of a section 36(b)(1) arms sales notification. This is published to fulfill the requirements of...

  2. 76 FR 76954 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2011-12-09

    ... its air force. The proposed sale of this equipment and support will not alter the basic military... of the Secretary 36(b)(1) Arms Sales Notification AGENCY: Department of Defense, Defense Security... a section 36(b)(1) arms sales notification. This is published to fulfill the requirements of section...

  3. Fumonisin B 1 Reduction in Lactic Acid Bacteria Fermentation of ...

    African Journals Online (AJOL)

    This study investigated how fermentation can promote fumonisin B1 reduction in maize-based porridges. Four starter culture of lactic acid bacteria (Lactobacillus plantarum, Pediococcus pentosaceus, Lactobacillus casei and Lactobacillus fermentum) were used, porridge samples was spiked with fumonisins B1 and allowed ...

  4. 78 FR 41036 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2013-07-09

    ... of the Secretary 36(b)(1) Arms Sales Notification AGENCY: Department of Defense, Defense Security... a section 36(b)(1) arms sales notification. This is published to fulfill the requirements of section... maintenance support, site surveys and beddown planning, personnel training and training equipment, operational...

  5. Semaphorin-4D (Sema-4D, the Plexin-B1 ligand, is involved in mouse ovary follicular development

    Directory of Open Access Journals (Sweden)

    Goldman Shlomit

    2007-03-01

    Full Text Available Abstract Background Human Plexin-B1 is expressed in two truncated forms. The long form encodes a trans-membranal protein, while the short form, which is bound to the cell surface and partially secreted, possibly serves as a decoy receptor. Plexin receptors are trans-membrane proteins. The sema domain, found in the extracellular region, is common to all plexins, semaphorins, and the scatter factor receptors and is crucial for the biological activity and plexin receptor specificity. Semaphorin-4D/Plexin-B1 binding provides attractive and repulsive cues for the navigation of axonal growth cones, and new studies suggest that this system also plays a role in the regulation of the biological functions of endothelial cells, specifically in the control of angiogenesis. In a previous study, we have demonstrated the expression and possible role of Plexin-B1 in the mouse ovary. The present study was designed to test the hypothesis that Plexin-B1 effects are mediated by Semaphorin-4D. Methods In vivo expression and localization of mouse ovarian Sema-4D were tested by immunohisto-chemistry. The role of Sema-4D in follicular development was examined by in vitro growth of preantral follicles in the presence or absence of Semaphorin-4D, with or without neutralizing antibodies against Plexin-B1. Follicular growth and steroid hormone secretion rates were tested. Results Semaphorin-4D is expressed in the mouse ovary in vivo mostly in the granulosa cells and and its expression is modulated by PMSG and hCG. In the presence of Semaphorin-4D, in-vitro constant growth was observed as indicated by follicular diameter during the culture period and elevated steroid hormone secretion rates compared with control. These effects were abolished after addition of neutralizing antibodies against Plexin-B1. Conclusion In the ovarian follicle, the effect of Plexin-B1 is mediated by sema-4D.

  6. Co-Expression of Plexin-B1 and Met in Human Breast and Ovary Tumours Enhances the Risk of Progression

    Directory of Open Access Journals (Sweden)

    Guido Valente

    2009-01-01

    Full Text Available Background: Plex-B1, the receptor of Sema4D, has been implicated in tumour growth, angiogenesis and metastasis. The binding of Sema4D to Plex-B1 can trigger the activation of Met tyrosine kinase, thereby promoting cell dissociation and invasive growth. We tested the hypothesis that the expression of Plex-B1, either alone or in association with Met, can be of predictive value for tumour progression.

  7. Effects of angiotensin-converting enzyme inhibition and bradykinin peptides in rats with myocardial infarction.

    Science.gov (United States)

    Qu, Zhe; Xu, Hongxin; Tian, Yihao

    2015-01-01

    Angiotensin-converting enzyme (ACE) inhibitors have been reported to decrease myocardial remodeling and faciliate cardiac function improvement in the setting myocardial infarction by affecting bradykinin. The purpose of this study was to evaluate the combination effects of perindopril and bradykinin (BK) in rats with myocardial infarction. Wistar Rats underwent to left anterior descending (LAD) coronary artery ligation were allocated into MI group (n=6); Perindopril group (n=7); Perindopril+BK group (n=7). An additional sham operation group (Sham group, n=6) were also established. After 4 weeks, the left ventricle function, myocardial tissue morphology, myocardial collagen volume faction, infracted ventricular wall thickness, myocardial infarction area and neovascular formation were evaluated. Combination treatment with perindopril and BK were showed significant improvement on LVEDV, LVEF and LVFS than MI group. Moreover, a significant improvement on LVEF was found in Perindopril+BK group than Perindopril group but not on LVEDV and LVFS between these two groups. Furthermore, neo-vessel density was significantly increased in Perindopril+BK group than other groups while no significant improvement on vessel density was found after the treatment of perindopril. In addition, myocardial infarction thickness improvement was found in Perindopril and group than MI group while combination treatment with perindopril and BK can significant improve the myocardial infarction thickness than perindopril only. Combination treatment with ACE inhibitor perindopril and BK can significantly improve the ventricle function in the rat model of myocardial infarction. Our data suggest BK can serve as adjuvant treatment in myocardial infarction treatment.

  8. A liver metalloendopeptidase which degrades the circulating hypotensive peptide hormones bradykinin and atrial natriuretic peptide

    Directory of Open Access Journals (Sweden)

    Carvalho K.M.

    1999-01-01

    Full Text Available A new metalloendopeptidase was purified to apparent homogeneity from a homogenate of normal human liver using successive steps of chromatography on DEAE-cellulose, hydroxyapatite and Sephacryl S-200. The purified enzyme hydrolyzed the Pro7-Phe8 bond of bradykinin and the Ser25-Tyr26 bond of atrial natriuretic peptide. No cleavage was produced in other peptide hormones such as vasopressin, oxytocin or Met- and Leu-enkephalin. This enzyme activity was inhibited by 1 mM divalent cation chelators such as EDTA, EGTA and o-phenanthroline and was insensitive to 1 µM phosphoramidon and captopril, specific inhibitors of neutral endopeptidase (EC 3.4.24.11 and angiotensin-converting enzyme (EC 3.4.15.1, respectively. With Mr 85 kDa, the enzyme exhibits optimal activity at pH 7.5. The high affinity of this endopeptidase for bradykinin (Km = 10 µM and for atrial natriuretic peptide (Km = 5 µM suggests that it may play a physiological role in the inactivation of these circulating hypotensive peptide hormones.

  9. Properties of L=1 B1 and B2* Mesons

    Science.gov (United States)

    Abazov, V. M.; Abbott, B.; Abolins, M.; Acharya, B. S.; Adams, M.; Adams, T.; Aguilo, E.; Ahn, S. H.; Ahsan, M.; Alexeev, G. D.; Alkhazov, G.; Alton, A.; Alverson, G.; Alves, G. A.; Anastasoaie, M.; Ancu, L. S.; Andeen, T.; Anderson, S.; Andrieu, B.; Anzelc, M. S.; Arnoud, Y.; Arov, M.; Arthaud, M.; Askew, A.; Åsman, B.; Assis Jesus, A. C. S.; Atramentov, O.; Autermann, C.; Avila, C.; Ay, C.; Badaud, F.; Baden, A.; Bagby, L.; Baldin, B.; Bandurin, D. V.; Banerjee, S.; Banerjee, P.; Barberis, E.; Barfuss, A.-F.; Bargassa, P.; Baringer, P.; Barreto, J.; Bartlett, J. F.; Bassler, U.; Bauer, D.; Beale, S.; Bean, A.; Begalli, M.; Begel, M.; Belanger-Champagne, C.; Bellantoni, L.; Bellavance, A.; Benitez, J. A.; Beri, S. B.; Bernardi, G.; Bernhard, R.; Berntzon, L.; Bertram, I.; Besançon, M.; Beuselinck, R.; Bezzubov, V. A.; Bhat, P. C.; Bhatnagar, V.; Biscarat, C.; Blazey, G.; Blekman, F.; Blessing, S.; Bloch, D.; Bloom, K.; Boehnlein, A.; Boline, D.; Bolton, T. A.; Borissov, G.; Bos, K.; Bose, T.; Brandt, A.; Brock, R.; Brooijmans, G.; Bross, A.; Brown, D.; Buchanan, N. J.; Buchholz, D.; Buehler, M.; Buescher, V.; Burdin, S.; Burke, S.; Burnett, T. H.; Buszello, C. P.; Butler, J. M.; Calfayan, P.; Calvet, S.; Cammin, J.; Caron, S.; Carvalho, W.; Casey, B. C. K.; Cason, N. M.; Castilla-Valdez, H.; Chakrabarti, S.; Chakraborty, D.; Chan, K. M.; Chan, K.; Chandra, A.; Charles, F.; Cheu, E.; Chevallier, F.; Cho, D. K.; Choi, S.; Choudhary, B.; Christofek, L.; Christoudias, T.; Cihangir, S.; Claes, D.; Clément, C.; Clément, B.; Coadou, Y.; Cooke, M.; Cooper, W. E.; Corcoran, M.; Couderc, F.; Cousinou, M.-C.; Crépé-Renaudin, S.; Cutts, D.; Ćwiok, M.; da Motta, H.; Das, A.; Davies, G.; de, K.; de Jong, S. J.; de Jong, P.; de La Cruz-Burelo, E.; Martins, C. De Oliveira; Degenhardt, J. D.; Déliot, F.; Demarteau, M.; Demina, R.; Denisov, D.; Denisov, S. P.; Desai, S.; Diehl, H. T.; Diesburg, M.; Dominguez, A.; Dong, H.; Dudko, L. V.; Duflot, L.; Dugad, S. R.; Duggan, D.; Duperrin, A.; Dyer, J.; Dyshkant, A.; Eads, M.; Edmunds, D.; Ellison, J.; Elvira, V. D.; Enari, Y.; Eno, S.; Ermolov, P.; Evans, H.; Evdokimov, A.; Evdokimov, V. N.; Ferapontov, A. V.; Ferbel, T.; Fiedler, F.; Filthaut, F.; Fisher, W.; Fisk, H. E.; Ford, M.; Fortner, M.; Fox, H.; Fu, S.; Fuess, S.; Gadfort, T.; Galea, C. F.; Gallas, E.; Galyaev, E.; Garcia, C.; Garcia-Bellido, A.; Gavrilov, V.; Gay, P.; Geist, W.; Gelé, D.; Gerber, C. E.; Gershtein, Y.; Gillberg, D.; Ginther, G.; Gollub, N.; Gómez, B.; Goussiou, A.; Grannis, P. D.; Greenlee, H.; Greenwood, Z. D.; Gregores, E. M.; Grenier, G.; Gris, Ph.; Grivaz, J.-F.; Grohsjean, A.; Grünendahl, S.; Grünewald, M. W.; Guo, J.; Guo, F.; Gutierrez, P.; Gutierrez, G.; Haas, A.; Hadley, N. J.; Haefner, P.; Hagopian, S.; Haley, J.; Hall, I.; Hall, R. E.; Han, L.; Hanagaki, K.; Hansson, P.; Harder, K.; Harel, A.; Harrington, R.; Hauptman, J. M.; Hauser, R.; Hays, J.; Hebbeker, T.; Hedin, D.; Hegeman, J. G.; Heinmiller, J. M.; Heinson, A. P.; Heintz, U.; Hensel, C.; Herner, K.; Hesketh, G.; Hildreth, M. D.; Hirosky, R.; Hobbs, J. D.; Hoeneisen, B.; Hoeth, H.; Hohlfeld, M.; Hong, S. J.; Hooper, R.; Hossain, S.; Houben, P.; Hu, Y.; Hubacek, Z.; Hynek, V.; Iashvili, I.; Illingworth, R.; Ito, A. S.; Jabeen, S.; Jaffré, M.; Jain, S.; Jakobs, K.; Jarvis, C.; Jesik, R.; Johns, K.; Johnson, C.; Johnson, M.; Jonckheere, A.; Jonsson, P.; Juste, A.; Käfer, D.; Kahn, S.; Kajfasz, E.; Kalinin, A. M.; Kalk, J. R.; Kalk, J. M.; Kappler, S.; Karmanov, D.; Kasper, J.; Kasper, P.; Katsanos, I.; Kau, D.; Kaur, R.; Kaushik, V.; Kehoe, R.; Kermiche, S.; Khalatyan, N.; Khanov, A.; Kharchilava, A.; Kharzheev, Y. M.; Khatidze, D.; Kim, H.; Kim, T. J.; Kirby, M. H.; Kirsch, M.; Klima, B.; Kohli, J. M.; Konrath, J.-P.; Kopal, M.; Korablev, V. M.; Kothari, B.; Kozelov, A. V.; Krop, D.; Kryemadhi, A.; Kuhl, T.; Kumar, A.; Kunori, S.; Kupco, A.; Kurča, T.; Kvita, J.; Lacroix, F.; Lam, D.; Lammers, S.; Landsberg, G.; Lazoflores, J.; Lebrun, P.; Lee, W. M.; Leflat, A.; Lehner, F.; Lellouch, J.; Lesne, V.; Leveque, J.; Lewis, P.; Li, J.; Li, Q. Z.; Li, L.; Lietti, S. M.; Lima, J. G. R.; Lincoln, D.; Linnemann, J.; Lipaev, V. V.; Lipton, R.; Liu, Y.; Liu, Z.; Lobo, L.; Lobodenko, A.; Lokajicek, M.; Lounis, A.; Love, P.; Lubatti, H. J.; Lyon, A. L.; Maciel, A. K. A.; Mackin, D.; Madaras, R. J.; Mättig, P.; Magass, C.; Magerkurth, A.; Makovec, N.; Mal, P. K.; Malbouisson, H. B.; Malik, S.; Malyshev, V. L.; Mao, H. S.; Maravin, Y.; Martin, B.; McCarthy, R.; Melnitchouk, A.; Mendes, A.; Mendoza, L.; Mercadante, P. G.; Merkin, M.; Merritt, K. W.; Meyer, J.; Meyer, A.; Michaut, M.; Millet, T.; Mitrevski, J.; Molina, J.; Mommsen, R. K.; Mondal, N. K.; Moore, R. W.; Moulik, T.; Muanza, G. S.; Mulders, M.; Mulhearn, M.; Mundal, O.; Mundim, L.; Nagy, E.

    2007-10-01

    This Letter presents the first strong evidence for the resolution of the excited B mesons B1 and B2* as two separate states in fully reconstructed decays to B+(*)π-. The mass of B1 is measured to be 5720.6±2.4±1.4MeV/c2 and the mass difference ΔM between B2* and B1 is 26.2±3.1±0.9MeV/c2, giving the mass of the B2* as 5746.8±2.4±1.7MeV/c2. The production rate for B1 and B2* mesons is determined to be a fraction (13.9±1.9±3.2)% of the production rate of the B+ meson.

  10. Properties of L=1 B(1) and B(2)* mesons.

    Science.gov (United States)

    Abazov, V M; Abbott, B; Abolins, M; Acharya, B S; Adams, M; Adams, T; Aguilo, E; Ahn, S H; Ahsan, M; Alexeev, G D; Alkhazov, G; Alton, A; Alverson, G; Alves, G A; Anastasoaie, M; Ancu, L S; Andeen, T; Anderson, S; Andrieu, B; Anzelc, M S; Arnoud, Y; Arov, M; Arthaud, M; Askew, A; Asman, B; Assis Jesus, A C S; Atramentov, O; Autermann, C; Avila, C; Ay, C; Badaud, F; Baden, A; Bagby, L; Baldin, B; Bandurin, D V; Banerjee, S; Banerjee, P; Barberis, E; Barfuss, A-F; Bargassa, P; Baringer, P; Barreto, J; Bartlett, J F; Bassler, U; Bauer, D; Beale, S; Bean, A; Begalli, M; Begel, M; Belanger-Champagne, C; Bellantoni, L; Bellavance, A; Benitez, J A; Beri, S B; Bernardi, G; Bernhard, R; Berntzon, L; Bertram, I; Besançon, M; Beuselinck, R; Bezzubov, V A; Bhat, P C; Bhatnagar, V; Biscarat, C; Blazey, G; Blekman, F; Blessing, S; Bloch, D; Bloom, K; Boehnlein, A; Boline, D; Bolton, T A; Borissov, G; Bos, K; Bose, T; Brandt, A; Brock, R; Brooijmans, G; Bross, A; Brown, D; Buchanan, N J; Buchholz, D; Buehler, M; Buescher, V; Burdin, S; Burke, S; Burnett, T H; Buszello, C P; Butler, J M; Calfayan, P; Calvet, S; Cammin, J; Caron, S; Carvalho, W; Casey, B C K; Cason, N M; Castilla-Valdez, H; Chakrabarti, S; Chakraborty, D; Chan, K M; Chan, K; Chandra, A; Charles, F; Cheu, E; Chevallier, F; Cho, D K; Choi, S; Choudhary, B; Christofek, L; Christoudias, T; Cihangir, S; Claes, D; Clément, C; Clément, B; Coadou, Y; Cooke, M; Cooper, W E; Corcoran, M; Couderc, F; Cousinou, M-C; Crépé-Renaudin, S; Cutts, D; Cwiok, M; da Motta, H; Das, A; Davies, G; De, K; de Jong, S J; de Jong, P; De La Cruz-Burelo, E; Martins, C De Oliveira; Degenhardt, J D; Déliot, F; Demarteau, M; Demina, R; Denisov, D; Denisov, S P; Desai, S; Diehl, H T; Diesburg, M; Dominguez, A; Dong, H; Dudko, L V; Duflot, L; Dugad, S R; Duggan, D; Duperrin, A; Dyer, J; Dyshkant, A; Eads, M; Edmunds, D; Ellison, J; Elvira, V D; Enari, Y; Eno, S; Ermolov, P; Evans, H; Evdokimov, A; Evdokimov, V N; Ferapontov, A V; Ferbel, T; Fiedler, F; Filthaut, F; Fisher, W; Fisk, H E; Ford, M; Fortner, M; Fox, H; Fu, S; Fuess, S; Gadfort, T; Galea, C F; Gallas, E; Galyaev, E; Garcia, C; Garcia-Bellido, A; Gavrilov, V; Gay, P; Geist, W; Gelé, D; Gerber, C E; Gershtein, Y; Gillberg, D; Ginther, G; Gollub, N; Gómez, B; Goussiou, A; Grannis, P D; Greenlee, H; Greenwood, Z D; Gregores, E M; Grenier, G; Gris, Ph; Grivaz, J-F; Grohsjean, A; Grünendahl, S; Grünewald, M W; Guo, J; Guo, F; Gutierrez, P; Gutierrez, G; Haas, A; Hadley, N J; Haefner, P; Hagopian, S; Haley, J; Hall, I; Hall, R E; Han, L; Hanagaki, K; Hansson, P; Harder, K; Harel, A; Harrington, R; Hauptman, J M; Hauser, R; Hays, J; Hebbeker, T; Hedin, D; Hegeman, J G; Heinmiller, J M; Heinson, A P; Heintz, U; Hensel, C; Herner, K; Hesketh, G; Hildreth, M D; Hirosky, R; Hobbs, J D; Hoeneisen, B; Hoeth, H; Hohlfeld, M; Hong, S J; Hooper, R; Hossain, S; Houben, P; Hu, Y; Hubacek, Z; Hynek, V; Iashvili, I; Illingworth, R; Ito, A S; Jabeen, S; Jaffré, M; Jain, S; Jakobs, K; Jarvis, C; Jesik, R; Johns, K; Johnson, C; Johnson, M; Jonckheere, A; Jonsson, P; Juste, A; Käfer, D; Kahn, S; Kajfasz, E; Kalinin, A M; Kalk, J R; Kalk, J M; Kappler, S; Karmanov, D; Kasper, J; Kasper, P; Katsanos, I; Kau, D; Kaur, R; Kaushik, V; Kehoe, R; Kermiche, S; Khalatyan, N; Khanov, A; Kharchilava, A; Kharzheev, Y M; Khatidze, D; Kim, H; Kim, T J; Kirby, M H; Kirsch, M; Klima, B; Kohli, J M; Konrath, J-P; Kopal, M; Korablev, V M; Kothari, B; Kozelov, A V; Krop, D; Kryemadhi, A; Kuhl, T; Kumar, A; Kunori, S; Kupco, A; Kurca, T; Kvita, J; Lacroix, F; Lam, D; Lammers, S; Landsberg, G; Lazoflores, J; Lebrun, P; Lee, W M; Leflat, A; Lehner, F; Lellouch, J; Lesne, V; Leveque, J; Lewis, P; Li, J; Li, Q Z; Li, L; Lietti, S M; Lima, J G R; Lincoln, D; Linnemann, J; Lipaev, V V; Lipton, R; Liu, Y; Liu, Z; Lobo, L; Lobodenko, A; Lokajicek, M; Lounis, A; Love, P; Lubatti, H J; Lyon, A L; Maciel, A K A; Mackin, D; Madaras, R J; Mättig, P; Magass, C; Magerkurth, A; Makovec, N; Mal, P K; Malbouisson, H B; Malik, S; Malyshev, V L; Mao, H S; Maravin, Y; Martin, B; McCarthy, R; Melnitchouk, A; Mendes, A; Mendoza, L; Mercadante, P G; Merkin, M; Merritt, K W; Meyer, J; Meyer, A; Michaut, M; Millet, T; Mitrevski, J; Molina, J; Mommsen, R K; Mondal, N K; Moore, R W; Moulik, T; Muanza, G S; Mulders, M; Mulhearn, M; Mundal, O; Mundim, L; Nagy, E; Naimuddin, M; Narain, M; Naumann, N A; Neal, H A; Negret, J P; Neustroev, P; Nilsen, H; Nomerotski, A; Novaes, S F; Nunnemann, T; O'Dell, V; O'Neil, D C; Obrant, G; Ochando, C; Onoprienko, D; Oshima, N; Osta, J; Otec, R; Y Garzón, G J Otero; Owen, M; Padley, P; Pangilinan, M; Parashar, N; Park, S-J; Park, S K; Parsons, J; Partridge, R; Parua, N; Patwa, A; Pawloski, G; Penning, B; Perea, P M; Peters, K; Peters, Y; Pétroff, P; Petteni, M; Piegaia, R; Piper, J; Pleier, M-A; Podesta-Lerma, P L M; Podstavkov, V M; Pogorelov, Y; Pol, M-E; Polozov, P; Pompos, A; Pope, B G; Popov, A V; Potter, C; da Silva, W L Prado; Prosper, H B; Protopopescu, S; Qian, J; Quadt, A; Quinn, B; Rakitine, A; Rangel, M S; Rani, K J; Ranjan, K; Ratoff, P N; Renkel, P; Reucroft, S; Rich, P; Rijssenbeek, M; Ripp-Baudot, I; Rizatdinova, F; Robinson, S; Rodrigues, R F; Royon, C; Rubinov, P; Ruchti, R; Safronov, G; Sajot, G; Sánchez-Hernández, A; Sanders, M P; Santoro, A; Savage, G; Sawyer, L; Scanlon, T; Schaile, D; Schamberger, R D; Scheglov, Y; Schellman, H; Schieferdecker, P; Schliephake, T; Schmitt, C; Schwanenberger, C; Schwartzman, A; Schwienhorst, R; Sekaric, J; Sengupta, S; Severini, H; Shabalina, E; Shamim, M; Shary, V; Shchukin, A A; Shivpuri, R K; Shpakov, D; Siccardi, V; Simak, V; Sirotenko, V; Skubic, P; Slattery, P; Smirnov, D; Smith, R P; Snow, J; Snow, G R; Snyder, S; Söldner-Rembold, S; Sonnenschein, L; Sopczak, A; Sosebee, M; Soustruznik, K; Souza, M; Spurlock, B; Stark, J; Steele, J; Stolin, V; Stone, A; Stoyanova, D A; Strandberg, J; Strandberg, S; Strang, M A; Strauss, M; Strauss, E; Ströhmer, R; Strom, D; Strovink, M; Stutte, L; Sumowidagdo, S; Svoisky, P; Sznajder, A; Talby, M; Tamburello, P; Tanasijczuk, A; Taylor, W; Telford, P; Temple, J; Tiller, B; Tissandier, F; Titov, M; Tokmenin, V V; Tomoto, M; Toole, T; Torchiani, I; Trefzger, T; Tsybychev, D; Tuchming, B; Tully, C; Tuts, P M; Unalan, R; Uvarov, S; Uvarov, L; Uzunyan, S; Vachon, B; van den Berg, P J; van Eijk, B; Van Kooten, R; van Leeuwen, W M; Varelas, N; Varnes, E W; Vartapetian, A; Vasilyev, I A; Vaupel, M; Verdier, P; Vertogradov, L S; Verzocchi, M; Villeneuve-Seguier, F; Vint, P; Vokac, P; Von Toerne, E; Voutilainen, M; Vreeswijk, M; Wagner, R; Wahl, H D; Wang, L; Wang, M H L S; Warchol, J; Watts, G; Wayne, M; Weber, M; Weber, G; Weerts, H; Wenger, A; Wermes, N; Wetstein, M; White, A; Wicke, D; Wilson, G W; Williams, M R J; Wimpenny, S J; Wobisch, M; Wood, D R; Wyatt, T R; Xie, Y; Yacoob, S; Yamada, R; Yan, M; Yasuda, T; Yatsunenko, Y A; Yip, K; Yoo, H D; Youn, S W; Yu, J; Yu, C; Yurkewicz, A; Zatserklyaniy, A; Zeitnitz, C; Zhang, D; Zhao, T; Zhou, B; Zhu, J; Zielinski, M; Zieminska, D; Zieminski, A; Zivkovic, L; Zutshi, V; Zverev, E G

    2007-10-26

    This Letter presents the first strong evidence for the resolution of the excited B mesons B(1) and B(2)* as two separate states in fully reconstructed decays to B(+)(*)pi(-). The mass of B(1) is measured to be 5720.6+/-2.4+/-1.4 MeV/c(2) and the mass difference DeltaM between B(2)* and B(1) is 26.2+/-3.1+/-0.9 MeV/c;{2}, giving the mass of the B(2)* as 5746.8+/-2.4+/-1.7 MeV/c(2). The production rate for B(1) and B(2)* mesons is determined to be a fraction (13.9+/-1.9+/-3.2)% of the production rate of the B+ meson.

  11. MISR Level 1B1 Radiance Data V002

    Data.gov (United States)

    National Aeronautics and Space Administration — The MISR Level 1B1 Radiance data product contains spectral radiances for all MISR channels. Each radiance value represents the incident radiance averaged over the...

  12. (COX6b1) from the Ailuropoda melanoleuca

    African Journals Online (AJOL)

    Administrator

    2011-05-16

    gorf/gorf.html). Protein structure of the. COX6b1 sequence cloned was deduced using predict protein software (http:// cubic. Bioc. columbia.edu/predictprotein/). Multiple sequence alignment was performed by DNAMAN 6.0. The.

  13. Role of calcium-activated potassium channels with small conductance in bradykinin-induced vasodilation of porcine retinal arterioles

    DEFF Research Database (Denmark)

    Dalsgaard, Thomas; Kroigaard, Christel; Bek, Toke

    2009-01-01

    PURPOSE: Endothelial dysfunction and impaired vasodilation may be involved in the pathogenesis of retinal vascular diseases. In the present study, the mechanisms underlying bradykinin vasodilation were examined and whether calcium-activated potassium channels of small (SK(Ca)) and intermediate (I...

  14. Amolopkinins W1 and W2--novel bradykinin-related peptides (BRPs) from the skin of the Chinese torrent frog, Amolops wuyiensis: antagonists of bradykinin-induced smooth muscle contraction of the rat ileum.

    Science.gov (United States)

    Zhou, Xiaowei; Wang, Lei; Zhou, Mei; Chen, Tianbao; Ding, Anwei; Rao, Pingfan; Walker, Brian; Shaw, Chris

    2009-05-01

    Bradykinin-related peptides (BRPs) represent one of the most widespread and closely studied families of amphibian defensive skin secretion peptides. Apart from canonical bradykinin (RPPGFSPFR) that was first reported in skin extracts of the European brown frog, Rana temporaria, many additional site-substituted, N- and/or C-terminally extended peptides have been isolated from skin extracts and secretions from representative species of the families Ranidae, Hylidae, Bombinatoridae and Leiopelmatidae. The most diverse range of BRPs has been found in ranid frog skin secretions and this probably reflects the diversity and number of species studied and their associated life histories within this taxon. Amolops (torrent or cascade frogs) is a genus within the Ranidae that has been poorly studied. Here we report the presence of two novel BRPs in the skin secretions of the Chinese Wuyi Mountain torrent frog (Amolops wuyiensis). Amolopkinins W1 and W2 are dodecapeptides differing in only one amino acid residue at position 2 (Val/Ala) that are essentially (Leu(1), Thr(6))-bradykinins extended at the N-terminus by either RVAL (W1) or RAAL (W2). Amolopkinins W1 and W2 are structurally similar to amolopkinin L1 from Amolops loloensis and the major BRP (Leu(1), Thr(6), Trp(8))-bradykinin from the skin of the Japanese frog, Rana sakuraii. A. wuyiensis amolopkinins were separately encoded as single copies within discrete precursors of 61 amino acid residues as deduced from cloned skin cDNA. Synthetic replicates of both peptides were found to potently antagonize the contractile effects of canonical bradykinin on isolated rat ileum smooth muscle preparations. Amolopkinins thus appear to represent a novel sub-family of ranid frog skin secretion BRPs.

  15. Predictive value of serum bradykinin and desArg9-bradykinin levels for chemotherapeutic responses in active tuberculosis patients: A retrospective case series.

    Science.gov (United States)

    Qian, Xu; Nguyen, Duc T M; Li, Yaojun; Lyu, Jianxin; Graviss, Edward A; Hu, Tony Y

    2016-12-01

    There is an urgent need for methods that can rapidly and accurately assess therapeutic responses in patients with active tuberculosis (TB) in order to predict treatment outcomes. Exposure to bacterial pathogens can rapidly activate the plasma contact system, triggering the release of bradykinin (BK) and its metabolite desArg9-bradykinin (DABK) to induce inflammation and innate immune responses. We hypothesized that serum BK and DABK levels might act as sensitive immune response signatures for changes in Mycobacterium tuberculosis (Mtb) burden, and therefore examined how serum levels of these markers corresponded with anti-TB therapy in a small cohort of active TB cases. Nanotrap Mass-Spectrometry (MS) was used to analyze serial blood specimens from 13 HIV-negative adults with microbiologically confirmed active TB who were treated with first-line anti-TB chemotherapy. MS signal for BK (m/z 1060.5) and DABK (m/z 904.5) serum peptides were evaluated at multiple time-points (before, during, and after treatment) to evaluate how BK and DABK levels corresponded with disease status. Serum BK levels declined from pretreatment baseline levels during the early stage anti-TB therapy (induction phase) and tended to remain below baseline levels during extended treatment (consolidation phase) and after therapy completion. BK levels were consistent with induction phase sputum culture conversions indicative of decreased Mtb burden reflecting good treatment responses. Serum DABK levels tended to increase during the induction phase and decrease at consolidation and post-therapy time points, which may indicate a shift from active disease to chronic inflammation to a disease free state. Elevated BK and DABK levels after treatment completion in one patient may be related to the subsequent recurrent TB disease. Our pilot data suggests that changes in the circulating BK and DABK levels in adult TB patients can be used as potential surrogate markers of the host response both early and late

  16. Glaucoma and Cytochrome P4501B1 Gene Mutations

    Directory of Open Access Journals (Sweden)

    Mukesh Tanwar

    2010-01-01

    Full Text Available Developmental anomalies of the ocular anterior chamber angle may lead to an incomplete development of the structures that form the conventional aqueous outflow pathway. Thus, disorders that present with such dysfunction tend to be associated with glaucoma. Among them, Axenfeld-Rieger (ARS malformation is a rare clinical entity with an estimated prevalence of one in every 200,000 individuals. The changes in eye morphogenesis in ARS are highly penetrant and are associated with 50% risk of development of glaucoma. Mutations in the cytochrome P4501B1 (CYP1B1 gene have been reported to be associated with primary congenital glaucoma and other forms of glaucoma and mutations in pituitary homeobox 2 (PITX2 gene have been identified in ARS in various studies. This case was negative for PITX2 mutations and compound heterozygote for CYP1B1 mutations. Clinical manifestations of this patient include bilateral elevated intraocular pressure (>40 mmHg with increased corneal diameter (>14 mm and corneal opacity. Patient also had iridocorneal adhesions, anteriorly displaced Schwalbe line, anterior insertion of iris, broad nasal bridge and protruding umbilicus. This is the first study from north India reporting CYP1B1 mutations in Axenfeld-Rieger syndrome with bilateral buphthalmos and early onset glaucoma. Result of this study supports the role of CYP1B1 as a causative gene in ASD disorders and its role in oculogenesis.

  17. Pain and tenderness in human temporal muscle induced by bradykinin and 5-hydroxytryptamine

    DEFF Research Database (Denmark)

    Jensen, Kai; Tuxen, C; Pedersen-Bjergaard, U

    1990-01-01

    Pain was induced in 19 healthy individuals by double-blind injections into the temporal muscle of 0.2 ml of physiological saline with or without active substances added. 5-Hydroxytryptamine (2 nmol) caused pain similar to saline, bradykinin (2 nmol) only insignificantly more pain (0.05 less than p...... less than 0.1), while a mixture of the two substances in half dosage (1 nmol + 1 nmol) caused pain significantly above saline (p less than 0.01). Variations in the response to saline did not permit a conclusion to be made on the question of induced tenderness. However, the mixture of the two substances...... appeared to lower the pressure-pain threshold as measured by a pressure algometer (p less than 0.05)....

  18. Isolating Barley (Hordeum vulgare L.) B1 Hordein Gene Promoter ...

    African Journals Online (AJOL)

    Yomi

    2012-04-10

    Apr 10, 2012 ... region of B1 hordein gene was isolated from the genomic DNA of Walfajre and Alger barley by polymerase chain reaction. ..... also named an endosperm box and is the binding site of endosperm-specific nuclear .... and common structural features of the complete phenylalanine ammonia-lyase gene family ...

  19. Determination of aflatoxin B1 in food products in Thailand

    African Journals Online (AJOL)

    aghomotsegin

    2014-12-31

    Dec 31, 2014 ... alcoholic beverages, blue cheese, soybean, raw peanuts and peanut derived samples, respectively. Key words: Mycotoxins, aflatoxin B1, carcinogen. INTRODUCTION. Mycotoxins are a group of toxic secondary metabolites with no apparent function in the normal metabolism of fungi. They are produced by ...

  20. 77 FR 40023 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2012-07-06

    ... strategic partner in maintaining stability in the region. The acquisition of these helicopters will allow... Issuance of Letter of Offer Pursuant to Section 36(b)(1) of the Arms Export Control Act, as amended (i... Consideration for Purchase: 10 MH-60R SEAHAWK Multi-Mission Helicopters, 12 MH-60S SEAHAWK Multi-Mission...

  1. APRIL promotes B-1 cell-associated neoplasm

    NARCIS (Netherlands)

    Planelles, Lourdes; Carvalho-Pinto, Carla E.; Hardenberg, Gijs; Smaniotto, Salette; Savino, Wilson; Gómez-Caro, Ruth; Alvarez-Mon, Melchor; de Jong, Joan; Eldering, Eric; Martínez-A, Carlos; Medema, Jan Paul; Hahne, Michael

    2004-01-01

    A tumor-supporting role for the TNF-like ligand APRIL has been suggested. Here we describe that 9- to 12-month-old APRIL transgenic mice develop lymphoid tumors that originate from expansion of the peritoneal B-1 B cell population. Aging APRIL transgenic mice develop progressive hyperplasia in

  2. 26 CFR 1.269B-1 - Stapled foreign corporations.

    Science.gov (United States)

    2010-04-01

    ... foreign corporation within the meaning of paragraph (b)(1) of this section, such foreign corporation will... and a domestic corporation are stapled entities (as provided in paragraph (b) of this section) and... paragraph (c) of this section. (b) Definition of a stapled foreign corporation—(1) General rule. A foreign...

  3. Aflatoxin B 1 producing potential of Aspergillus flavus strains ...

    African Journals Online (AJOL)

    Aflatoxin B 1 (AFB1) producing potential of different strains of Aspergillus flavus, isolated from 1,200 stored rice grains collected from 43 locations in 20 rice growing states in India was investigated. Eighty-five strains of A. flavus were isolated from the discolored rice grains and tested for their AFB1 producing potential on ...

  4. Inhibiting Aspergillus flavus growth and degrading aflatoxin B1 by ...

    African Journals Online (AJOL)

    Aflatoxin B1 (AFB1) is a type of toxin produced by Aspergillus flavus, which has a negative effect on animal production and economic profits. In order to inhibit A. flavus growth and degrade aflatoxin, the optimal proportion of beneficial microbes such as Lactobacillus casei, Bacillus subtilis and Pichia anomala were selected.

  5. 26 CFR 1.512(b)-1 - Modifications.

    Science.gov (United States)

    2010-04-01

    ... computing unrelated business taxable income. (2) In the case of a college, university, or hospital, all...) INCOME TAXES (CONTINUED) Taxation of Business Income of Certain Exempt Organizations § 1.512(b)-1... foregoing items of income shall be excluded in computing unrelated business taxable income. (2) Limitations...

  6. 75 FR 11865 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2010-03-12

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF DEFENSE Office of the Secretary 36(b)(1) Arms Sales Notification AGENCY: Defense Security Cooperation Agency, DoD...)(1) arms sales notification to fulfill the requirements of section 155 of Public Law 104-164 dated 21...

  7. 77 FR 68742 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2012-11-16

    ... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This... the following components: a. Radar Enhancement Phase III (REP-3) Exciter Assemblies b. Radar Digital... Identification-3 (CDI-3) Digital Signal Processor f. CDI-3 Analog/Digital Converters g. Hardware-in-the-Loop and...

  8. 77 FR 32599 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2012-06-01

    ...) Military Department: Air Force (SAO) (v) Prior Related Cases, if any: None (vi) Sales Commission, Fee, etc... BAF and the U.S. Air Force. The proposed sale of support will help to modernize the BAF's aging cargo... of the Secretary 36(b)(1) Arms Sales Notification AGENCY: Department of Defense, Defense Security...

  9. Osmotic stress upregulates the transcription of thiamine (vitamin B1 ...

    African Journals Online (AJOL)

    Thiamine or vitamin B1 comprises a pyrimidine moiety and a thiazole moiety. Thiamine pyrophosphate (TPP), the active form of thiamine, acts as a cofactor for various major enzymes, for example, transketolase (TK), α-ketoglutarate dehydrogenase (KGDH) and pyruvate dehydrogenase (PDH). It is suggested that TPP plays ...

  10. 26 CFR 1.665(b)-1A - Accumulation distributions.

    Science.gov (United States)

    2010-04-01

    ...(b), and expenses allocable to corpus of $5,000. Distributable net income amounted to $13,000. The... 1.665(b)-1A Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME... distributable net income (determined under section 643(a)) of the trust, reduced (but not below zero) by the...

  11. Aflatoxin B1content in patients with hepatic diseases Aflatoxina B1 en pacientes con enfermedades hepáticas

    Directory of Open Access Journals (Sweden)

    Clara López

    2002-08-01

    Full Text Available Aflatoxins are toxic metabolites of some Aspergillus flavus, A. parasiticus and A. nomius strains that occur in many foods and feeds. There are four major natural occurring aflatoxins: B1, B2, G1 and G2. These toxins can cause illness in human beings and animals. Aflatoxin B1 is the most abundant and toxic member of the family, and it is also the most potent hepatocarcinogen known. In order to estimate the potential human health risk of AFB1, it is useful to measure blood concentration. The presence of aflatoxin B1 in patients was evaluated by high-performance liquid chromatography, in serum samples, obtained from 20 patient volunteers with hepatic disease. Out of the 20 patients, the presence of AFB1 was detected in only one of them, in a concentration of 0.47 ng/cm³. Nevertheless, this result should draw the attention of control organizations in Argentina to the need for a thorough food and feed inspection.Las aflatoxinas son metabolitos tóxicos producidos por cepas de Aspergillus flavus, A. parasiticus y A. nomius, presentes en alimentos y piensos. Las cuatro aflatoxinas principales son: aflatoxina B1, B2, G1 y G2. Dichas toxinas pueden causar enfermedades tanto en seres humanos como en animales. La aflatoxina B1 es la más abundante y la más tóxica del grupo y es también el más potente hepatocarcinógeno conocido. El objetivo de este trabajo fue detectar la presencia de aflatoxina B1 en sangre humana para estimar el riesgo potencial de la salud. La determinación de aflatoxina B1 fue realizada por cromatografía líquida de alto rendimiento, en suero de 20 pacientes voluntarios con enfermedades hepáticas. En sólo uno de estos pacientes se detectó la presencia de aflatoxina B1, en una concentración de 0.47ng/cm³. Estos resultados deberían ser tenidos en cuenta por los responsables de la vigilancia y control de los alimentos en la Argentina.

  12. Differences between zofenopril and ramipril, two ACE inhibitors, on cough induced by citric acid in guinea pigs: role of bradykinin and PGE2.

    Science.gov (United States)

    Cialdai, Cecilia; Giuliani, Sandro; Valenti, Claudio; Tramontana, Manuela; Maggi, Carlo Alberto

    2010-12-01

    Dry and persistent cough is one of the commonest side effects experienced by patients treated with angiotensin-converting enzyme (ACE) inhibitors for the therapy of hypertension and congestive heart failure. The present study investigated the effect of zofenopril and ramipril on cough induced by citric acid in guinea pig and the involvement of bradykinin (BK) and prostaglandin E2 (PGE2) in mediating the responses of these drugs. Zofenopril (10 mg/kg) or ramipril (3-10 mg/kg), which is threefold more potent than zofenopril, on a mg basis, in lowering blood pressure, was orally administered daily in drinking water for 2 weeks. At the end of this period, aerosol of citric acid solution (0.1 M) was performed and the number of cough counted for 10 min. The role of the kinin B(2) receptor was also investigated. BK and PGE2 levels in the bronchoalveolar lavage (BAL) fluid were measured after repeated oral treatment with zofenopril or ramipril (10 mg/kg). Ramipril (3-10 mg/kg) increased citric acid-induced cough by 40% and 60%, respectively, as compared to the vehicle control group (15.0 ± 1.8), while zofenopril (10 mg/kg) was without effect. The enhancement of citric acid-induced cough caused by ramipril (10 mg/kg) was reduced by the kinin B(2) receptor antagonist MEN16132 (0.25 mg/kg ip). BK and PGE2 levels in the BAL fluid were increased, in comparison to the control group, after ramipril treatment, while they were unchanged after zofenopril administration. Zofenopril, contrary to ramipril, did not affect either citric acid-induced cough in the guinea pigs or BK and PGE2 production in the airways.

  13. Bradykinin, insulin, and glycemia responses to exercise performed above and below lactate threshold in individuals with type 2 diabetes

    Directory of Open Access Journals (Sweden)

    R.Y. Asano

    2017-09-01

    Full Text Available The aim of this study was to analyze the acute responses of bradykinin, insulin, and glycemia to exercise performed above and below lactate threshold (LT in individuals with type 2 diabetes mellitus (T2D. Eleven participants with a diagnosis of T2D randomly underwent three experimental sessions 72 h apart: 1 20 min of exercise performed at 120% of LT (120%LT, 2 20 min of exercise performed at 80% of LT (80%LT, and 3 20 min of control session. Blood glucose was analyzed before, during, and at 45 min post-exercise. Bradykinin and insulin were analyzed before and at 45 min post-exercise. Both exercise sessions elicited a parallel decrease in glucose level during exercise (P≤0.002, with a greater decrease being observed for 120%LT (P=0.005. Glucose decreased 22.7 mg/dL (95%CI=10.3 to 35, P=0.001 at the 45 min post-exercise recovery period for 80%LT and decreased 31.2 mg/dL (95%CI=18.1 to 44.4, P<0.001 for 120%LT (P=0.004. Insulin decreased at post-exercise for 80%LT (P=0.001 and control (P≤0.035. Bradykinin increased at 45 min post-exercise only for 80%LT (P=0.013, but was unrelated to the decrease in glucose (r=-0.16, P=0.642. In conclusion, exercise performed above and below LT reduced glycemia independently of insulin, but exercise above LT was more effective in individuals with T2D. However, these changes were unrelated to the increase in circulating bradykinin.

  14. Salt pressure derived from GMS-B1 measurements

    Energy Technology Data Exchange (ETDEWEB)

    Vonka, V.

    1992-11-01

    The GMS system is successfully used to measure gaps between the liner tube and the disc in the B1 hole. GMS was designed for evaluation of minimum tube diameter. In this report measured results are used to estimate the tube compression. The compression is recalculated into the salt pressure acting on the liner tube from outside. It is concluded that the GMS measurements are accurately executed. Also the evaluation procedure to eliminate the thermal expansion effect is correctly applied. Through the B1 liner tube compression the salt pressure on the tube is evaluated. Apart from several thermocouples no other measuring instrument has been used. The resulting salt pressure estimate is consequently considered as independent of other HAW salt pressure measurements. (author). 6 refs., 10 figs., 2 tabs.

  15. On a generalization of B1( ) on C∗ -algebras

    Indian Academy of Sciences (India)

    a unitary operator U ∈ 多 (Ж ) such that F (λ) = UG(λ), ∀λ ∈ , then we call them unitarily equivalent, denoted by F ∼u G. In [6], it is shown that unitary equivalence of operator T can be deduced to the same problem of holomorphic curve F associated to it. Following Cowen and Doulgas [6], a curvature function for T ∈ B1( ) ...

  16. SLCO1B1 Polymorphisms and Statin-Induced Myopathy.

    Science.gov (United States)

    Stewart, Alison

    2013-12-04

    Statin drugs are highly effective in lowering blood concentrations of LDL-cholesterol, with concomitant reduction in risk of major cardiovascular events. Although statins are generally regarded as safe and well-tolerated, some users develop muscle symptoms that are mostly mild but in rare cases can lead to life-threatening rhabdomyolysis. The SEARCH genome-wide association study, which has been independently replicated, found a significant association between the rs4149056 (c.521T>C) single-nucleotide polymorphism (SNP) in the SLCO1B1 gene, and myopathy in individuals taking 80 mg simvastatin per day, with an odds ratio of 4.5 per rs4149056 C allele. The purpose of this paper is to assemble evidence relating to the analytical validity, clinical validity and clinical utility of using SLCO1B1 rs4149056 genotyping to inform choice and dose of statin treatment, with the aim of minimising statin-induced myopathy and increasing adherence to therapy. Genotyping assays for the rs4149056 SNP appear to be robust and accurate, though direct evidence for the performance of array-based platforms in genotyping individual SNPs was not found. Using data from the SEARCH study, calculated values for the clinical sensitivity, specificity, positive- and negative-predictive values of a test for the C allele to predict definite or incipient myopathy during 5 years of 80 mg/day simvastatin use were 70.4%, 73.7%, 4.1% and 99.4% respectively. There is a need for studies comparing the clinical validity of SLCO1B1 rs4149056 genotyping with risk scores for myopathy based on other factors such as racial background, statin type and dose, gender, body mass index, co-medications and co-morbidities. No direct evidence was found for clinical utility of statin prescription guided by SLCO1B1 genotype.

  17. Leptin induces CYP1B1 expression in MCF-7 cells through ligand-independent activation of the ERα pathway

    Energy Technology Data Exchange (ETDEWEB)

    Khanal, Tilak; Kim, Hyung Gyun; Do, Minh Truong; Choi, Jae Ho; Won, Seong Su [Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon (Korea, Republic of); Kang, Wonku [College of Pharmacy, Yeungnam University, Gyeongsan (Korea, Republic of); Chung, Young Chul [Department of Food Science and Culinary, International University of Korea, Jinju (Korea, Republic of); Jeong, Tae Cheon, E-mail: taecheon@ynu.ac.kr [College of Pharmacy, Yeungnam University, Gyeongsan (Korea, Republic of); Jeong, Hye Gwang, E-mail: hgjeong@cnu.ac.kr [Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon (Korea, Republic of)

    2014-05-15

    Leptin, a hormone with multiple biological actions, is produced predominantly by adipose tissue. Among its functions, leptin can stimulate tumour cell growth. Oestrogen receptor α (ERα), which plays an essential role in breast cancer development, can be transcriptionally activated in a ligand-independent manner. In this study, we investigated the effect of leptin on CYP1B1 expression and its mechanism in breast cancer cells. Leptin induced CYP1B1 protein, messenger RNA expression and promoter activity in ERα-positive MCF-7 cells but not in ERα-negative MDA-MB-231 cells. Additionally, leptin increased 4-hydroxyoestradiol in MCF-7 cells. Also, ERα knockdown by siRNA significantly blocked the induction of CYP1B1 expression by leptin, indicating that leptin induced CYP1B1 expression via an ERα-dependent mechanism. Transient transfection with CYP1B1 deletion promoter constructs revealed that the oestrogen response element (ERE) plays important role in the up-regulation of CYP1B1 by leptin. Furthermore, leptin stimulated phosphorylation of ERα at serine residues 118 and 167 and increased ERE-luciferase activity, indicating that leptin induced CYP1B1 expression by ERα activation. Finally, we found that leptin activated ERK and Akt signalling pathways, which are upstream kinases related to ERα phosphorylation induced by leptin. Taken together, our results indicate that leptin-induced CYP1B1 expression is mediated by ligand-independent activation of the ERα pathway as a result of the activation of ERK and Akt in MCF-7 cells. - Highlights: • Leptin increased 4-hydroxyoestradiol in MCF-7 breast cancer cells. • Leptin activated ERK and Akt kinases related to ERα phosphorylation. • Leptin induces phosphorylation of ERα at serine residues 118 and 167. • Leptin induces ERE-luciferase activity.

  18. Wind tunel tests of Risoe-B1-18 and Risoe-B1-24

    Energy Technology Data Exchange (ETDEWEB)

    Fuglsang, P.; Bak, C.; Gaunaa, M.; Antoniou, I.

    2003-01-01

    This report contains 2D measurements of the Risoe-B1-18 and Risoe-B1-24 airfoils. The aerodynamic properties were derived from pressure measurements on the airfoil surface and in the wake. The measurements were conducted in the VELUX open jet wind tunnel, which has a background turbulence intensity of 1%, and an inlet flow velocity of 42 m/s. The airfoil sections had a chord of 0.600 m giving a Reynolds number of 1.6Oe106. The span was 1.9 m and end plates were used to minimize 3D flow effects. The measurements comprised both static and dynamic inflow. Static inflow covered angles of attack from 5o to 30 deg. Dynamic inflow was obtained by pitching the airfoil in a harmonic motion around various mean angles of attack. The test matrix involved smooth flow, various kinds of leading edge roughness, stall strips, vortex generators and Gurney flaps in different combinations. The quality of the measurements was good and the agreement between measurements and numerical CFD predictions with EllipSys2D was good. For both airfoils predictions with turbulent flow captured very well the shapes of lift and drag curves as well as the magnitude of maximum lift. Measurements of Risoe-B1-18 showed that the maximum lift coefficient was 1.64 at an angle of attack of approximately 13 deg. The airfoil was not very sensitive to leading edge roughness despite its high maximum lift. Measurements with stall strips showed that stall strips could control the level of maximum lift. The Risoe-B1-24 measurements showed that the maximum lift coefficient was 1.62 at an angle of attack of approximately 14 deg. The airfoil was only little sensitive to leading edge roughness despite its high relative thickness and high maximum lift. Measurements with delta wing shaped vortex generators increased the maximum lift coefficient to 2.02 and measurements with Gurney flaps increased the maximum lift coefficient to 1.85. Measurements with combination of vortex generators and Gurney flaps showed a maximum

  19. SOFIA FIFI-LS Observations of Sgr B1

    Science.gov (United States)

    Simpson, Janet P.; Colgan, Sean; Cotera, Angela; Kaufman, Michael; Stolovy, Susan

    2018-01-01

    Although Sgr B1 is the third most luminous H II region in the Galactic Center, after the region ionized by the central star cluster Sgr A and the very young star-forming region Sgr B2, it has surprisingly not been well studied. Because Sgr B1 is found with Sgr B2 in a common envelope of molecular gas and far-infrared (FIR) emission, it has been assumed that the two sources are physically related, even though the ionized gas of Sgr B1 is much more extended and there are evolved-star indicators of a significantly greater age than Sgr B2. This presents a problem because the current paradigm of Galactic Center gas motions and star formation requires that the entire Sgr B complex must have reasonably similar ages. To clarify the situation, we have mapped Sgr B1 with the FIFI-LS spectrometer on SOFIA in the FIR lines of [O III] 52 and 88 micron, [O I] 146 micron, and [C II] 158 micron. For the most part, we find little correlation of the density-sensitive ratio of the [O III] lines with the radio VLA images or the FIR Herschel PACS images, from which we infer that the structures seen in those images are not due to density enhancements but are due to bubbles of gas and dust seen edge-on. The [C II] 158 micron line correlates much better with the structure seen in the Herschal PACS Blue 60-85 micron image than it does with the Red 130-210 micron image, which is dominated by the massive molecular cloud seen at higher Galactic latitude. Sgr B1 is largely covered by spectra from the Spitzer Infrared Spectrograph Archive, from which we measure mid-infrared lines of [Ne II], [Ne III], [Si II], [S III], and [Ar II]. From the ratios of these lines with the observed FIR lines we find that there are at least six small regions with significantly higher excitation than their surroundings; we infer that these regions contain the stars that excite the gas. Our presentation will describe these results in further detail.

  20. Effect of an esterified glucomannan on laying hens exposed to combined mycotoxins (aflatoxin B1, zearalenone and fumonisin B1

    Directory of Open Access Journals (Sweden)

    A. Zaghini

    2011-03-01

    Full Text Available Mycotoxin toxicity depends on species, exposure time, age, sex, health and possible synergistic effects of other mycotoxins present in feed. In poultry, aflatoxin B1 (AFB1 and fumonisin B1 (FB1 are associated with poor growth performance, lowered feed utilization efficiency, liver damage and immunosuppression; metabolites may persist in tissues and eggs. Exposure of mature hens to zearalenone (ZEN apparently does not cause adverse effects, but ZEN residues and α and β zearalenol persist in liver and muscle (Kuiper-Goodman et al., 1987 and may be transmitted to egg yolk (Dailey et al., 1990. Various treatments and dietary strategies have been tried to reduce mycotoxin levels in contaminated commodities...

  1. ErbB2, but not ErbB1, reinitiates proliferation and induces luminal repopulation in epithelial acini

    Energy Technology Data Exchange (ETDEWEB)

    Muthuswamy, Senthil K; Li, Dongmei; Lelievre, Sophie; Bissell, Mina J; Brugge, Joan S

    2001-08-08

    Both ErbB1 and ErbB2 are overexpressed or amplified in breast tumors. To examine the effects of activating ErbB receptors in a context that mimics polarized epithelial cells in vivo, we activated ErbB1 and ErbB2 homodimers in preformed, growth-arrested mammary acini cultured in three-dimensional basement membrane gels. Activation of ErbB2, but not that of ErbB1, led to a reinitiation of cell proliferation and altered the properties of mammary acinar structures. These altered structures share several properties with early-stage tumors, including a loss of proliferative suppression, an absence of lumen, retention of the basement membrane and a lack of invasive properties. ErbB2 activation also disrupted tight junctions and the cell polarity of polarized epithelia, whereas ErbB1 activation did not have any effect. Our results indicate that ErbB receptors differ in their ability to induce early stages of mammary carcinogenesis in vitro and this three-dimensional model system can reveal biological activities of oncogenes that cannot be examined in vitro in standard transformation assays.

  2. Met-Lys-bradykinin-Ser-Ser, a peptide produced by the neutrophil from kininogen, is metabolically activated by angiotensin converting enzyme in vascular tissue.

    Science.gov (United States)

    Gera, Lajos; Roy, Caroline; Bawolak, Marie-Thérèse; Bouthillier, Johanne; Adam, Albert; Marceau, François

    2011-11-01

    Bradykinin (BK) is a vasoactive nonapeptide cleaved from circulating kininogens and that is degraded by angiotensin converting enzyme (ACE). It has been reported that the PR3 protease from human neutrophil releases an alternate peptide of 13 amino acids, Met-Lys-BK-Ser-Ser, from high molecular weight kininogen. We have studied vascular actions of this kinin. Its affinity for recombinant B₁ and B₂ receptors is very low, as assessed by the binding competition of [³H]Lys-des-Arg⁹-BK and [³H]BK, respectively, but Met-Lys-BK-Ser-Ser effectively displaced a fraction of [³H]enalaprilat binding to recombinant ACE. Mutant recombinant ACE constructions revealed that affinity gap between BK and Met-Lys-BK-Ser-Ser is larger for the N-terminal catalytic site than for the C-terminal one, based on competition for the substrate Abz-Phe-Arg-Lys(Dnp)-Pro-OH in an enzymatic assay. Met-Lys-BK-Ser-Ser is a low potency stimulant of the rabbit aorta (bioassay for B₁ receptors), but the human isolated umbilical vein, a contractile bioassay for the B₂ receptors, responded to Met-Lys-BK-Ser-Ser more than expected from the radioligand binding assay, this agonist being ∼30-fold less potent than BK in the vein. Venous tissue treatment with the ACE inhibitor enalaprilat reduced the apparent potency of Met-Lys-BK-Ser-Ser by 15-fold, while not affecting that of BK. In the rabbit isolated jugular vein, Met-Lys-BK-Ser-Ser is nearly as potent as BK as a contractile stimulant of endogenous B₂ receptors (EC₅₀ values of 16.3 and 10.5 nM, respectively), but enalaprilat reduced the potency of Met-Lys-BK-Ser-Ser 13-fold while increasing that of BK 5.3-fold. In vascular tissue, ACE assumes a paradoxical activating role for Met-Lys-BK-Ser-Ser. Copyright © 2011 Elsevier Ltd. All rights reserved.

  3. A search for Cyanopolyynes in L1157-B1

    Science.gov (United States)

    Mendoza, Edgar; Lefloch, B.; Ceccarelli, C.; Kahane, C.; Jaber, A. A.; Podio, L.; Benedettini, M.; Codella, C.; Viti, S.; Jimenez-Serra, I.; Lepine, J.; Boechat-Roberty, H. M.; Bachiller, R.

    2018-01-01

    We present here a systematic search for cyanopolyynes in the shock region L1157-B1 and its associated protostar L1157-mm in the framework of the Large Program "Astrochemical Surveys At IRAM" (ASAI), dedicated to chemical surveys of solar-type star forming regions with the IRAM 30m telescope. Observations of the millimeter windows between 72 and 272 GHz permitted the detection of HC3N and its 13C isotopologues, and HC5N (for the first time in a protostellar shock region). In the shock, analysis of the line profiles shows that the emission arises from the outflow cavities associated with L1157-B1 and L1157-B2. Molecular abundances and excitation conditions were obtained from analysis of the Spectral Line Energy Distributions under the assumption of Local Thermodynamical Equilibrium or using a radiative transfer code in the Large Velocity Gradient approximation. Towards L1157mm, the HC3N emission arises from the cold envelope (Trot = 10K) and a higher-excitation region (Trot= 31 K) of smaller extent around the protostar. We did not find any evidence of 13C or D fractionation enrichment towards L1157-B1. We obtain a relative abundance ratio HC3N/HC5N of 3.3 in the shocked gas. We find an increase by a factor of 30 of the HC3N abundance between the envelope of L1157-mm and the shock region itself. Altogether, these results are consistent with a scenario in which the bulk of HC3N was produced by means of gas phase reactions in the passage of the shock. This scenario is supported by the predictions of a parametric shock code coupled with the chemical model UCL_CHEM.

  4. Data of evolutionary structure change: 1DC5B-1GYPB [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1DC5B-1GYPB 1DC5 1GYP B B -TIKVGINGFGRIGRIVFRAAQKRS----DIEIVAINDLL-DADYMAYMLKYDSTH...1GYP B 1GYPB ICDQGLIGTEIDVV...1GYP B 1GYPB RIKCVKAQRNP ...1GYP B 1GYPB HEYSPASHHVVS...1GYP B 1GYPB LTKENFGIETG

  5. Data of evolutionary structure change: 1DC6B-1GYPB [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1DC6B-1GYPB 1DC6 1GYP B B -TIKVGINGFGRIGRIVFRAAQKRS----DIEIVAINDLL-DADYMAYMLKYDSTH...1GYP B 1GYPB ICDQGLIGTEIDVV...1GYP B 1GYPB RIKCVKAQRNP ...1GYP B 1GYPB QHEYSPASHHVV...1GYP B 1GYPB LTKENFGIETG

  6. nr0b1 (DAX1) mutation in zebrafish causes female-to-male sex reversal through abnormal gonadal proliferation and differentiation.

    Science.gov (United States)

    Chen, Sijie; Zhang, Hefei; Wang, Fenghua; Zhang, Wei; Peng, Gang

    2016-09-15

    Sex determinations are diverse in vertebrates. Although many sex-determining genes and pathways are conserved, the mechanistic roles of these genes and pathways in the genetic sex determination are not well understood. DAX1 (encoded by the NR0B1 gene) is a vertebrate specific orphan nuclear receptor that regulates gonadal development and sexual determination. In human, duplication of the NR0B1 gene leads to male-to-female sex reversal. In mice, Nr0b1 shows both pro-testis and anti-testis functions. We generated inheritable nr0b1 mutation in the zebrafish and found the nr0b1 mutation caused homozygous mutants to develop as fertile males due to female-to-male sex reversal. The nr0b1 mutation did not increase Caspase-3 labeling nor tp53 expression in the developing gonads. Introduction of a tp53 mutation into the nr0b1 mutant did not rescue the sex-reversal phenotype. Further examination revealed reduction in cell proliferation and abnormal somatic cell differentiation in the nr0b1 mutant gonads at the undifferentiated and bi-potential ovary stages. Together, our results suggest nr0b1 regulates somatic cell differentiation and cell proliferation to ensure normal sex development in the zebrafish. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  7. First observation of the hadronic transition $ \\Upsilon(4S) \\to \\eta h_{b}(1P)$ and new measurement of the $h_b(1P)$ and $\\eta_b(1S)$ parameters

    CERN Document Server

    Tamponi, U; Abdesselam, A; Aihara, H; Arinstein, K; Asner, D M; Atmacan, H; Aushev, T; Ayad, R; Badhrees, I; Bakich, A M; Barberio, E; Bhardwaj, V; Bhuyan, B; Biswal, J; Bondar, A; Bonvicini, G; Bozek, A; Bračko, M; Browder, T E; Červenkov, D; Chen, A; Cheon, B G; Cho, K; Chobanova, V; Choi, S -K; Choi, Y; Cinabro, D; Danilov, M; Doležal, Z; Drásal, Z; Drutskoy, A; Eidelman, S; Epifanov, D; Farhat, H; Fast, J E; Ferber, T; Fulsom, B G; Gaur, V; Gabyshev, N; Garmash, A; Getzkow, D; Gillard, R; Goh, Y M; Golob, B; Haba, J; Hayasaka, K; Hayashii, H; He, X H; Hedges, M T; Hou, W -S; Iijima, T; Inami, K; Ishikawa, A; Jaegle, I; Joffe, D; Julius, T; Kato, E; Katrenko, P; Kichimi, H; Kiesling, C; Kim, D Y; Kim, H J; Kim, J H; Kim, K T; Kim, S H; Kinoshita, K; Kodyš, P; Korpar, S; Križan, P; Krokovny, P; Kumita, T; Kuzmin, A; Lange, J S; Lewis, P; Libby, J; Lukin, P; Matvienko, D; Miyabayashi, K; Miyata, H; Mizuk, R; Mohanty, G B; Moll, A; Mori, T; Nakano, E; Nakao, M; Nanut, T; Natkaniec, Z; Nayak, M; Nisar, N K; Nishida, S; Ogawa, S; Okuno, S; Olsen, S L; Ostrowicz, W; Oswald, C; Pakhlova, G; Pal, B; Park, H; Pedlar, T K; Pesántez, L; Pestotnik, R; Petriřc, M; Piilonen, L E; Ribežl, E; Ritter, M; Rostomyan, A; Ryu, S; Sakai, Y; Sandilya, S; Santelj, L; Sanuki, T; Sato, Y; Savinov, V; Schneider, O; Schnell, G; Schwanda, C; Semmler, D; Senyo, K; Sevior, M E; Shapkin, M; Shebalin, V; Shen, C P; Shibata, T -A; Shiu, J -G; Shwartz, B; Sibidanov, A; Simon, F; Sohn, Y -S; Sokolov, A; Starič, M; Steder, M; Stypula, J; Tanida, K; Teramoto, Y; Trabelsi, K; Uchida, M; Uglov, T; Unno, Y; Uno, S; Urquijo, P; Van Hulse, C; Vanhoefer, P; Varner, G; Vinokurova, A; Vossen, A; Wagner, M N; Wang, M -Z; Wang, X L; Watanabe, Y; Williams, K M; Won, E; Yamaoka, J; Yashchenko, S; Zhang, Z P; Zhilich, V; Zhulanov, V; Zupanc, A

    2015-01-01

    Using a sample of $771.6 \\times 10^{6}$ $\\Upsilon(4S)$ decays collected by the Belle experiment at the KEKB $e^+e^-$ collider, we observe for the first time the transition $\\Upsilon(4S) \\to \\eta h_b(1P)$ with the branching fraction ${\\cal B}[\\Upsilon(4S) \\to \\eta h_b(1P)]= (2.18 \\pm 0.11 \\pm 0.18) \\times 10^{-3}$ and we measure the $h_b(1P)$ mass $M_{h_{b}(1P)} = (9899.3 \\pm 0.4 \\pm 1.0)$ MeV/$c^{2}$, corresponding to the hyperfine splitting $\\Delta M_{\\mathrm HF}(1P) = (0.6 \\pm 0.4 \\pm 1.0)$ MeV/$c^{2}$. Using the transition $h_b(1P) \\to \\gamma \\eta_b(1S)$, we measure the $\\eta_b(1S)$ mass $M_{\\eta_{b}(1S)} = (9400.7 \\pm 1.7 \\pm 1.6)$ MeV/$c^{2}$, corresponding to $\\Delta M_{\\mathrm HF}(1S) = (59.6 \\pm 1.7 \\pm 1.6)$ MeV/$c^{2}$, the $\\eta_b(1S)$ width $\\Gamma_{\\eta_{b}(1S)} = (8 ^{+6}_{-5} \\pm 5)$ MeV/$c^{2}$ and the branching fraction ${\\cal B}[h_b(1P) \\to \\gamma \\eta_b(1S)]= (56 \\pm 8 \\pm 4) \\%$.

  8. Nicotine impairs cyclooxygenase-2-dependent kinin-receptor-mediated murine airway relaxations

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Yuan, E-mail: yuan.xu@ki.se; Cardell, Lars-Olaf

    2014-02-15

    Introduction: Cigarette smoke induces local inflammation and airway hyperreactivity. In asthmatics, it worsens the symptoms and increases the risk for exacerbation. The present study investigates the effects of nicotine on airway relaxations in isolated murine tracheal segments. Methods: Segments were cultured for 24 h in the presence of vehicle, nicotine (10 μM) and/or dexamethasone (1 μM). Airway relaxations were assessed in myographs after pre-contraction with carbachol (1 μM). Kinin receptors, cyclooxygenase (COX) and inflammatory mediator expressions were assessed by real-time PCR and confocal-microscopy-based immunohistochemistry. Results: The organ culture procedure markedly increased bradykinin- (selective B{sub 2} receptor agonist) and des-Arg{sup 9}-bradykinin- (selective B{sub 1} receptor agonist) induced relaxations, and slightly increased relaxation induced by isoprenaline, but not that induced by PGE{sub 2}. The kinin receptor mediated relaxations were epithelium-, COX-2- and EP2-receptor-dependent and accompanied by drastically enhanced mRNA levels of kinin receptors, as well as inflammatory mediators MCP-1 and iNOS. Increase in COX-2 and mPGES-1 was verified both at mRNA and protein levels. Nicotine selectively suppressed the organ-culture-enhanced relaxations induced by des-Arg{sup 9}-bradykinin and bradykinin, at the same time reducing mPGES-1 mRNA and protein expressions. α7-nicotinic acetylcholine receptor inhibitors α-bungarotoxin and MG624 both blocked the nicotine effects on kinin B{sub 2} receptors, but not those on B{sub 1}. Dexamethasone completely abolished kinin-induced relaxations. Conclusion: It is tempting to conclude that a local inflammatory process per se could have a bronchoprotective component by increasing COX-2 mediated airway relaxations and that nicotine could impede this safety mechanism. Dexamethasone further reduced airway inflammation together with relaxations. This might contribute to the steroid resistance seen in

  9. DELF B1 200 activités

    CERN Document Server

    Bloomfield, Anatole

    2006-01-01

    L'ouvrage est organisé par compétences de réception et de production. Chaque partie propose d'abord une présentation de l'épreuve correspondante, puis les activités de préparation suivies d'épreuves-types et d'une auto-évaluation. Dans le cadre d'une approche actionnelle, les activités fournissent les outils nécessaires à la préparation des examens. Elles donnent des exemples concrets répondant aux attentes des candidats comme à celle des examinateurs. LeNouveau DELF B1 propose des activités précises en vue d'atteindre les compétences nécessaires aux épreuves (oral, écrit, réception, production); sa simplicité et sa pédagogie en font une méthode complète. Dans la tradition de la collection Nouvel Entraînez-vous, cet ouvrage est pratique, didactique et se prête à une utilisation en autonomie ou en classe.Le niveau B1 dit " avancé " évalue un niveau de compétence où l'apprenant peut se considérer comme étant indépendant. Arrivé à ce stade, il est apte de comprendre l'inform...

  10. Synthesis of Polyclonal Antibodies against Aflatoxin B1

    Directory of Open Access Journals (Sweden)

    Wiyogo Prio Wicaksono

    2015-09-01

    Full Text Available Polyclonal antibodies of aflatoxin B1 were successfully produced from New Zealand White female rabbits after immunization by the hapten of aflatoxin B1-carboxymethyl hydroxylamine hemihydrochloride (AFB1-CMO conjugated with bovine serum albumin (BSA as the antigen. The hapten was synthesized using the carbodiimide method with CMO as a linker. Absorption peaks at 362, 264, and 218 nm were observed as a result of characterization with UV-Vis spectroscopy, while IR spectroscopy showed peaks at 3448 cm-1 and 1642 cm-1 attributable to the hydroxyl and nitrile groups, respectively. Furthermore, mass spectrometry showed fragmentation at the m/z of 386, 368.2, and 310, which confirms that the hapten of AFB1-CMO was successfully synthesized. The hapten was then conjugated with BSA to serve as an antigen of AFB1 when it was injected into the rabbits. The specificity of the antigen towards its antibody and the confirmation of hapten-BSA conjugation were characterized using the dot blot immunoassay, which showed a BSA concentration of 1.74 mg/mL. Two weeks after the primary immunization by its antigen, agar gel precipitation testing showed that the rabbit blood serum had positive results for polyclonal antibodiest against AFB1 with the highest concentration of antibodiest of 2.19 mg/mL.

  11. Plasma kallikrein-bradykinin pathway promotes circulatory nitric oxide metabolite availability during hypoxia.

    Science.gov (United States)

    Padhy, Gayatri; Gangwar, Anamika; Sharma, Manish; Himashree, Gidugu; Singh, Krishan; Bhaumik, Gopinath; Bhargava, Kalpana; Sethy, Niroj Kumar

    2016-05-01

    Nitric oxide (NO) is an indispensible signalling molecule under hypoxic environment for both ethnic high altitude natives as well as lowland residents at high altitude. Several studies have reported higher levels of NO and bioactive NO products for both high altitude natives as well as healthy high altitude sojourners. But the metabolic pathways regulating the formation of NO and associated metabolites during hypoxia still remain elusive. In the present study, we profiled plasma proteomes of Ladakhi natives (3520 m) and lowland residents (post 1, 4 and 7 days stay) at the same altitude. This has resulted in the identification of 208 hypoxia responsive proteins (p hypoxia. In corroboration, we have also observed significant higher levels of plasma biomarkers for NO production (l-citrulline, nitrite, nitrate) for Ladakhi natives as compared to both lowland individuals healthy high altitude sojourners indicating higher NO availability. Since hypoxia-induced free radicals reduce NO availability, we also measured plasma levels of 8-isoprostanes, protein carbonyls and protein oxidation products in both Ladakhi natives and high altitude sojourners. Interestingly Ladakhi natives had significant lower levels of oxidative stress in comparison to high altitude sojourners but higher than lowland controls. These results suggest that plasma kallikrein-bradykinin-eNOS pathway along with moderate oxidative stress contributes to high altitude adaptation of Ladakhi natives. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. DAX1/NR0B1 was expressed during mammalian gonadal development and gametogenesis before it was recruited to the eutherian X chromosome.

    Science.gov (United States)

    Stickels, Robert; Clark, Kevin; Heider, Thomas N; Mattiske, Deidre M; Renfree, Marilyn B; Pask, Andrew J

    2015-01-01

    The nuclear receptor subfamily 0, group B, member 1 (NR0B1) gene is an orphan nuclear receptor that is X-linked in eutherian mammals and plays a critical role in the establishment and function of the hypothalamic-pituitary-adrenal-gonadal axis. Duplication or overexpression of NR0B1 in eutherian males causes male to female sex reversal, and mutation and deletions of NR0B1 cause testicular defects. Thus, gene dosage is critical for the function of NR0B1 in normal gonadogenesis. However, NR0B1 is autosomal in all noneutherian vertebrates, including marsupials and monotreme mammals, and two active copies of the gene are compatible with both male and female gonadal development. In the current study, we examined the evolution and expression of autosomal NR0B1 during gonadal development in a marsupial (the tammar wallaby) as compared to the role of its X-linked orthologues in a eutherian (the mouse). We show that NR0B1 underwent rapid evolutionary change when it relocated from its autosomal position in the nonmammalian vertebrates, monotremes, and marsupials to an X-linked location in eutherian mammals. Despite the acquisition of a novel genomic location and a unique N-terminal domain, NR0B1 protein distribution was remarkably similar between mice and marsupials both throughout gonadal development and during gamete formation. A conserved accumulation of NR0B1 protein was observed in developing oocytes, where its function appears to be critical in the early embryo, prior to zygotic genome activation. Together these findings suggest that NR0B1 had a conserved role in gonadogenesis that existed long before it moved to the X chromosome and despite undergoing significant evolutionary change. © 2015 by the Society for the Study of Reproduction, Inc.

  13. Reactive Oxygen Species-Dependent c-Fos/Activator Protein 1 Induction Upregulates Heme Oxygenase-1 Expression by Bradykinin in Brain Astrocytes.

    Science.gov (United States)

    Hsieh, Hsi-Lung; Wang, Hui-Hsin; Wu, Cheng-Ying; Yang, Chuen-Mao

    2010-12-15

    Heme oxygenase-1 (HO-1) plays a crucial role in tissue pathological changes such as brain injuries. Our previous studies have demonstrated that bradykinin (BK) induces the expression of several inflammatory proteins, including matrix metalloproteinase-9 and COX-2, via mitogen-activated protein kinases and nuclear factor-κB (NF-κB) in rat brain astrocytes (RBA-1). However, the molecular mechanisms underlying BK-induced HO-1 expression in RBA-1 cells remain poorly defined. Here we demonstrated that BK induced HO-1 expression and enzymatic activity via a B(2) BK receptor-activated reactive oxygen species (ROS)-dependent signaling pathway. NADPH oxidase (Nox)-dependent ROS generation led to activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun-N-terminal kinase (JNK) and then activated the downstream molecules NF-κB and c-Jun, respectively. The c-Fos, an activator protein 1 (AP-1) subunit, was upregulated by activation of NF-κB and c-Jun, which bound to HO-1 promoter and thereby turned on transcription of HO-1 gene. The rat HO-1 promoter containing a putative AP-1 cis-binding site was identified as a crucial domain linking to BK action. Taken together, these results suggested that in RBA-1 cells, activation of ERK/NF-κB and JNK/c-Jun cascades by a Nox/ROS-dependent event enhancing c-Fos/AP-1 activity is essential for HO-1 upregulation and activation induced by BK. Moreover, ROS-dependent NF-E2-related factor 2 activation also contributes to HO-1 induction by BK in astrocytes.

  14. Bradykinin induces matrix metalloproteinase-9 expression and cell migration through a PKC-delta-dependent ERK/Elk-1 pathway in astrocytes.

    Science.gov (United States)

    Hsieh, Hsi-Lung; Wu, Cheng-Ying; Yang, Chuen-Mao

    2008-04-15

    Many reports have shown that matrix metalloproteinase (MMP)-9 plays an important role in brain inflammation and diseases. In our previous study, bradykinin (BK) has been shown to induce proMMP-9 expression via MAPKs and NF-kappaB in rat brain astrocytes (RBA-1). However, the molecular mechanisms and physiological roles underlying BK-induced MMP-9 expression in RBA-1 remain unclear. Here we reported that BK induced proMMP-9 expression and promoted RBA-1 cell migration, via a B(2) BK receptor-activated protein kinase C-delta (PKC-delta)-dependent signaling pathway. Activation of PKC-delta led to phosphorylation and translocation of extracellular signal-regulated kinase 1/2 (ERK1/2) and then activated a transcription factor Elk-1. Phospho-Elk-1 bound to MMP-9 promoter and thereby induced transcription of MMP-9. The rat MMP-9 promoter containing an Elk-1 cis-binding site (Ets domain), that located at nucleotides -511 to -506 was identified as a crucial domain linking to BK action. Moreover, BK induced recruitment of p300 (as a transcriptional co-activator) to the MMP-9 promoter, leading to the acetylation of histone H4 in chromatin and facilitating MMP-9 gene transcription. Taken together, these results suggested that in RBA-1 cells, activation of ERK1/2 by a PKC-delta-dependent event mediated through Elk-1 pathway is essential for MMP-9 gene up-regulation and cell migration induced by BK. (c) 2008 Wiley-Liss, Inc.

  15. Molecular characterization of cytochrome P450 1B1 and effect of ...

    African Journals Online (AJOL)

    The deduced amino acid sequence of Nile tilapia CYP1B1 shows similarities of 79.7, 70.3, 65.7, 65.4, 65.0, and 63.7% with Plaice CYP1B1, Japanese eel CYP1B1, zebra fish CYP1B1, common carp CYP1B1, common carp CYP1B2 and Channel catfish CYP1B1, respectively. The phylogenetic tree based on the amino acid ...

  16. Rapid optimization of the post-column fluorogenic ninhydrin reaction for the HPLC-based determination of bradykinin and related fragments.

    Science.gov (United States)

    Wimalasena, R; Audus, K L; Stobaugh, J F

    2003-01-01

    A flow injection analysis scheme is demonstrated for the rapid optimization of reagent concentrations, flow rates, delay time and temperature using the guanidino moiety specific fluorogenic ninhydrin reaction. Using the amino acid arginine, non-arginine containing peptides, and the arginine-containing peptides, bradykinin and related fragments, specificity is demonstrated. These results serve to extend previous descriptions of the post-column reaction by offering a time efficient approach for the optimization of newly assembled post-column reactors using this chemistry. The reactor is subsequently added to a gradient elution HPLC system with the separation of bradykinin and bradykinin fragments demonstrated. Detection sensitivity in the high femtomole-low picomole mass range was achieved for these substances. Copyright 2003 John Wiley & Sons, Ltd.

  17. Vascular endothelium receptors and transduction mechanisms

    CERN Document Server

    Gillis, C; Ryan, Una; Proceedings of the Advanced Studies Institute on "Vascular Endothelium: Receptors and Transduction Mechanisms"

    1989-01-01

    Beyond their obvious role of a barrier between blood and tissue, vascular endothelial cells are now firmly established as active and essential participants in a host of crucial physiological and pathophysiological functions. Probably the two most important factors responsible for promoting the current knowledge of endothelial functions are 1) observations in the late sixties-early seventies that many non-ventilatory properties of the lung could be attributed to the pulmonary endothelium and 2) the establishment, in the early and mid-seventies of procedures for routine culture of vascular endothelial cells. Many of these endothelial functions require the presence of receptors on the surface of the plasma membrane. There is now evidence for the existence among others of muscarinic, a-and /3-adrenergic, purine, insulin, histamine, bradykinin, lipoprotein, thrombin, paf, fibronectin, vitronectin, interleukin and albumin receptors. For some of these ligands, there is evidence only for the existence of endothelial ...

  18. Interfering with the interaction between ErbB1, nucleolin and Ras as a potential treatment for glioblastoma

    Science.gov (United States)

    Kloog, Yoel; Pinkas-Kramarski, Ronit

    2014-01-01

    The three oncogenes, ErbB receptors, Ras proteins and nucleolin may contribute to malignant transformation. Previously, we demonstrated that nucleolin could bind both Ras protein and ErbB receptors. We also showed that the crosstalk between the three proteins facilitates anchorage independent growth and tumor growth in nude mice, and that inhibition of this interaction in prostate and colon cancer cells reduces tumorigenicity. In the present study, we show that treatment with Ras and nucleolin inhibitors reduces the oncogenic effect induced by ErbB1 receptor in U87-MG cells. This combined treatment enhances cell death, reduces cell proliferation and cell migration. Moreover, we demonstrate a pivotal role of nucleolin in ErbB1 activation by its ligand. Nucleolin inhibitor prevents EGF-induced receptor activation and its downstream signaling followed by reduced proliferation. Furthermore, inhibition of Ras by Salirasib (FTS), mainly reduces cell viability and motility. The combined treatment, which targets both Ras and nucleolin, additively reduces tumorigenicity both in vitro and in vivo. These results suggest that targeting both nucleolin and Ras may represent an additional opportunity for inhibiting cancers, including glioblastoma, that are driven by these oncogenes. PMID:25261371

  19. GENETICALLY INCREASED ANGIOTENSIN-I CONVERTING ENZYME ALTERS PERIPHERAL AND RENAL VASCULAR REACTIVITY TO ANGIOTENSIN II AND BRADYKININ IN MICE.

    Science.gov (United States)

    Chollet, Catherine; Placier, Sandrine; Chatziantoniou, Christos; Hus-Citharel, Annette; Caron, Nathalie; Roussel, Ronan; Alhenc-Gelas, Francois; Bouby, Nadine

    2017-11-03

    Angiotensin 1-converting enzyme (ACE) levels in man are under strong genetic influence. Genetic variation in ACE has been linked to risk for, and progression of, cardiovascular and renal diseases. Causality has been documented in genetically modified mice but mechanisms underlying causality are not completely elucidated. To further document the vascular and renal consequences of a moderate genetic increase in ACE synthesis, we studied genetically modified mice carrying three copies of the ACE gene (3-copy mice) and littermate wild type animals (2-copy mice). We investigated peripheral and renal vascular reactivity to angiotensin II and bradykinin in vivo by measuring blood pressure and renal blood flow after intravenous administration, and also reactivity of isolated glomerular arterioles by following intracellular calcium mobilisation. Carrying 3 copies of the ACE gene potentiated the systemic and renal vascular responses to angiotensin II over the whole range of peptide concentration tested. Consistently, response of isolated glomerular afferent arterioles to angiotensin II was enhanced in 3-copy mice. In these mice, signalling pathways triggered by endothelial activation by bradykinin or carbachol in glomerular arterioles were also altered. While the NOS-NO pathway was not functional in arterioles of 2-copy mice, in muscular efferent arterioles of 3-copy mice NOS3 gene expression was induced and NO mediated the effect of bradykinin or carbachol. These data document new and unexpected vascular consequences of a genetic increase in ACE synthesis. Enhanced vasoconstrictor effect of angiotensin II may contribute to the risk for cardiovascular and renal diseases linked to genetically high ACE level. Copyright © 2017, American Journal of Physiology-Heart and Circulatory Physiology.

  20. B1-control receive array coil (B-RAC) for reducing B1+ inhomogeneity in abdominal imaging at 3T-MRI

    Science.gov (United States)

    Kaneko, Yukio; Soutome, Yoshihisa; Habara, Hideta; Bito, Yoshitaka; Ochi, Hisaaki

    2018-02-01

    B1+ inhomogeneity in the human body increases as the nuclear magnetic resonance (NMR) frequency increases. Various methods have thus been developed to reduce B1+ inhomogeneity, such as a dielectric pad, a coupling coil, parallel transmit, and radio-frequency (RF) shimming. However, B1+ inhomogeneity still remains in some cases of abdominal imaging. In this study, we developed a B1-control receive array coil (B-RAC). Unlike the conventional receive array coil, B-RAC reduces B1+ inhomogeneity by using additional PIN diodes to generate the inductive loop during the RF transmit period. The inductive loop can generate dense and sparse regions of the magnetic flux, which can be used to compensate for B1+ inhomogeneity. First, B-RAC is modeled in the numerical simulation, and the spatial distributions of B1+ in a phantom and a human model were analyzed. Next, we fabricated a 12-channel B-RAC and measured receive sensitivity and B1+ maps in a 3T-MRI experiment. It was demonstrated that B-RAC can reduce B1+ inhomogeneity in the phantom and human model without increasing the maximum local specific absorption rate (SAR) in the body. B-RAC was also found to have almost the same the receive sensitivity as the conventional receive coil. Using RF shimming combined with B-RAC was revealed to more effectively reduce B1+ inhomogeneity than using only RF shimming. Therefore, B-RAC can reduce B1+ inhomogeneity while maintaining the receive sensitivity.

  1. Cetirizine inhibits bradykinin-induced cutaneous wheal and flare in atopic and healthy subjects.

    Science.gov (United States)

    Fadel, R; Ramboer, I; Chatterjee, N; Rihoux, J P; Derde, M P

    2000-04-01

    Kinins are vasoactive mediators involved in allergic reactions. When applied on the skin or in the nose, bradykinin (BK) elicits inflammation that is poorly affected by previous H1-blockade. The aim of this study was to compare the possible effect of cetirizine (an H1-antagonist) on wheal and flare responses to BK, histamine, and compound 48/80 in atopic and healthy subjects. In a randomized, double-blind, crossover study, eight atopic and eight healthy subjects received cetirizine (10 mg/day) or placebo for 3 days before cutaneous tests. Intradermal tests (IDT) and prick tests (PT) were performed with BK (20 nmol/ml for IDT and 20 micromol/ml for PT), histamine (100 microg/ml IDT and 100 mg/ml PT), and compound 48/80 (100 microg/ml IDT and 100 mg/ml PT) as positive controls and saline as negative control. The skin responses were monitored by measurement of wheal and flare areas. BK, histamine, and 48/80 induced wheal and flare reactions in all placebo-treated subjects. Histamine elicited larger wheal and flare reactions than BK and 48/80. IDT with BK induced four- to sixfold larger wheal and flare reaction than PT. No differences in BK-induced wheal and flare were observed between atopic and healthy subjects. In atopic subjects, cetirizine induced a significant reduction of flare reactions after the BK test (80% for IDT, and 94% for PT [P wheals by 70% for IDT (P wheal and flare reactions induced by BK challenge were markedly inhibited by previous intake of cetirizine. The mechanism by which this effect is mediated cannot be established at present.

  2. 75 FR 30687 - Airworthiness Directives; Turbomeca Arriel 2B1 Turboshaft Engines

    Science.gov (United States)

    2010-06-02

    ... 2B1 Turboshaft Engines AGENCY: Federal Aviation Administration (FAA), DOT. ACTION: Final rule. SUMMARY..., Engine Certification Office, FAA, Engine & Propeller Directorate, 12 New England Executive Park... Information The MCAI applies to the ARRIEL 2B1 and 2B1A engines. The ARRIEL 2B1A engine is not type...

  3. Solvent-dependent transformation of aflatoxin B1 in soil.

    Science.gov (United States)

    Starr, James M; Rushing, Blake R; Selim, Mustafa I

    2017-08-01

    To date, all studies of aflatoxin B1 (AFB1) transformation in soil or in purified mineral systems have identified aflatoxins B2 (AFB2) and G2 (AFG2) as the primary transformation products. However, identification in these studies was made using thin layer chromatography which has relatively low resolution, and these studies did not identify a viable mechanism by which such transformations would occur. Further, the use of methanol as the solvent delivery vehicle in these studies may have contributed to formation of artifactual transformation products. In this study, we investigated the role of the solvent vehicle in the transformation of AFB1 in soil. To do this, we spiked soils with AFB1 dissolved in water (93:7, water/methanol) or methanol and used HPLC-UV and HPLC-MS to identify the transformation products. Contrasting previous published reports, we did not detect AFB2 or AFG2. In an aqueous-soil environment, we identified aflatoxin B2a (AFB2a) as the single major transformation product. We propose that AFB2a is formed from hydrolysis of AFB1 with the soil acting as an acid catalyst. Alternatively, when methanol was used, we identified methoxy aflatoxin species likely formed via acid-catalyzed addition of methanol to AFB1. These results suggest that where soil moisture is adequate, AFB1 is hydrolyzed to AFB2a and that reactive organic solvents should be avoided when replicating natural conditions to study the fate of AFB1 in soil.

  4. Decomposition and detoxification of aflatoxin B1 by lactic acid.

    Science.gov (United States)

    Aiko, Visenuo; Edamana, Prasad; Mehta, Alka

    2016-04-01

    A degradation study of aflatoxin B1 (AFB1) was carried out using a combination of physical and chemical methods. AFB1 was heated at 80 °C in the presence of acetic, citric and lactic acids for various time periods. The cytotoxicity of the degraded AFB1 and its products were determined by MTT assay. The results showed that among the three organic acids lactic acid was most efficient in degrading AFB1. Although complete degradation was not observed, up to 85% degradation of AFB1 was obtained when heated for 120 min. Degradation of AFB1 was confirmed by the reduced toxicity on HeLa cells using MTT assay. Treatment with lactic acid resulted in the conversion of AFB1 into two degradation products. These products were observed at lower retention factors of 0.63 and 0.38, which were identified as AFB2 and AFB2a, respectively. The cytotoxicity of AFB2a exhibited much reduced toxicity on HeLa cells compared to that of AFB1. The results have shown the efficiency of lactic acid in degrading AFB1. This study suggest that lactic acid may be considered for use in the food and feed industry since it is present naturally in food and is considered safe. © 2015 Society of Chemical Industry.

  5. Regulation of nucleotide excision repair by nuclear lamin b1.

    Directory of Open Access Journals (Sweden)

    Veronika Butin-Israeli

    Full Text Available The nuclear lamins play important roles in the structural organization and function of the metazoan cell nucleus. Recent studies on B-type lamins identified a requirement for lamin B1 (LB1 in the regulation of cell proliferation in normal diploid cells. In order to further investigate the function of LB1 in proliferation, we disrupted its normal expression in U-2 OS human osteosarcoma and other tumor cell lines. Silencing LB1 expression induced G1 cell cycle arrest without significant apoptosis. The arrested cells are unable to mount a timely and effective response to DNA damage induced by UV irradiation. Several proteins involved in the detection and repair of UV damage by the nucleotide excision repair (NER pathway are down-regulated in LB1 silenced cells including DDB1, CSB and PCNA. We propose that LB1 regulates the DNA damage response to UV irradiation by modulating the expression of specific genes and activating persistent DNA damage signaling. Our findings are relevant to understanding the relationship between the loss of LB1 expression, DNA damage signaling, and replicative senescence.

  6. SLC9B1 methylation predicts fetal intolerance of labor.

    Science.gov (United States)

    Knight, Anna K; Conneely, Karen N; Kilaru, Varun; Cobb, Dawayland; Payne, Jennifer L; Meilman, Samantha; Corwin, Elizabeth J; Kaminsky, Zachary A; Dunlop, Anne L; Smith, Alicia K

    2018-01-01

    Fetal intolerance of labor is a common indication for delivery by Caesarean section. Diagnosis is based on the presence of category III fetal heart rate tracing, which is an abnormal heart tracing associated with increased likelihood of fetal hypoxia and metabolic acidemia. This study analyzed data from 177 unique women who, during their prenatal visits (7-15 weeks and/or 24-32 weeks) to Atlanta area prenatal care clinics, consented to provide blood samples for DNA methylation (HumanMethylation450 BeadChip) and gene expression (Human HT-12 v4 Expression BeadChip) analyses. We focused on 57 women aged 18-36 (mean 25.4), who had DNA methylation data available from their second prenatal visit. DNA methylation patterns at CpG sites across the genome were interrogated for associations with fetal intolerance of labor. Four CpG sites (P value intolerance of labor. DNA methylation and gene expression were negatively associated when examined longitudinally during pregnancy using a linear mixed-effects model. Positive predictive values of methylation of these four sites ranged from 0.80 to 0.89, while negative predictive values ranged from 0.91 to 0.92. The four CpG sites were also associated with fetal intolerance of labor in an independent cohort (the Johns Hopkins Prospective PPD cohort). Therefore, fetal intolerance of labor could be accurately predicted from maternal blood samples obtained between 24-32 weeks gestation. Fetal intolerance of labor may be accurately predicted from maternal blood samples obtained between 24-32 weeks gestation by assessing DNA methylation patterns of SLC9B1. The identification of pregnant women at elevated risk for fetal intolerance of labor may allow for the development of targeted treatments or management plans.

  7. Aflatoxin B1 Degradation by a Pseudomonas Strain

    Directory of Open Access Journals (Sweden)

    Lancine Sangare

    2014-10-01

    Full Text Available Aflatoxin B1 (AFB1, one of the most potent naturally occurring mutagens and carcinogens, causes significant threats to the food industry and animal production. In this study, 25 bacteria isolates were collected from grain kernels and soils displaying AFB1 reduction activity. Based on its degradation effectiveness, isolate N17-1 was selected for further characterization and identified as Pseudomonas aeruginosa. P. aeruginosa N17-1 could degrade AFB1, AFB2 and AFM1 by 82.8%, 46.8% and 31.9% after incubation in Nutrient Broth (NB medium at 37 °C for 72 h, respectively. The culture supernatant of isolate N17-1 degraded AFB1 effectively, whereas the viable cells and intra cell extracts were far less effective. Factors influencing AFB1 degradation by the culture supernatant were investigated. Maximum degradation was observed at 55 °C. Ions Mn2+ and Cu2+ were activators for AFB1 degradation, however, ions Mg2+, Li+, Zn2+, Se2+, Fe3+ were strong inhibitors. Treatments with proteinase K and proteinase K plus SDS significantly reduced the degradation activity of the culture supernatant. No degradation products were observed based on preliminary LC-QTOF/MS analysis, indicating AFB1 was metabolized to degradation products with chemical properties different from that of AFB1. The results indicated that the degradation of AFB1 by P. aeruginosa N17-1 was enzymatic and could have a great potential in industrial applications. This is the first report indicating that the isolate of P. aeruginosa possesses the ability to degrade aflatoxin.

  8. Determination of fumonisin B1levels in body fluids and hair from piglets fed fumonisin B1-contaminated diets.

    Science.gov (United States)

    Souto, Pollyana C M C; Jager, Alessandra V; Tonin, Fernando G; Petta, Tânia; Di Gregório, Mayra C; Cossalter, Anne-Marie; Pinton, Philippe; Oswald, Isabelle P; Rottinghaus, George E; Oliveira, Carlos A F

    2017-10-01

    The levels of fumonisin B 1 (FB 1 ) residues in plasma, urine, feces and hair from 24 piglets fed FB 1 -contaminated diets containing 3.1, 6.1 or 9.0 μg FB 1 .g -1 for 28 days were determined using liquid chromatography coupled to mass spectrometry (LC-MS/MS). The levels of FB 1 in plasma, urine, feces and pooled hair (n = 3) samples varied from 0.15 to 1.08 μg.L -1 , 16.09-75.01 μg.L -1 , 1.87-13.89 μg.g -1 and 2.08-8.09 ng.g -1 , respectively. Significant correlations (r = 0.808-0.885; P hair samples and FB 1 intake. Plasma and urinary FB 1 are good biomarkers of early exposure of pigs to low dietary FB 1 levels, although plasma is recommended to assess prolonged exposure (>14 days). The possibility to evaluate hair as a biomarker of fumonisin exposure was established, although further studies are needed to provide physiologically based toxicokinetics of residual FB 1 in the pig hair. Copyright © 2017 Elsevier Ltd. All rights reserved.

  9. Relationship of angiotensin I-converting enzyme (ACE) and bradykinin B2 receptor (BDKRB2) polymorphism with diabetic nephropathy.

    Science.gov (United States)

    Zou, Honghong; Wu, Guoqing; Lv, Jinlei; Xu, Gaosi

    2017-06-01

    To determine whether ACE2 I/D and BDKRB23 +9/-9 polymorphism causatively affect diabetic nephropathy progression RESULTS: STZ-induced metabolic disorder, as well as inflammatory responses, was significantly aggravated in ACE II-B2R4+9bp, ACE DD-B2R+9bp, or ACE DD-B2R-9bp diabetic mice but not ACE II-B2R-9bp, indicating the genetic susceptibility of ACE DD or B2R+9bp to diabetic nephropathy. Furthermore, ACE II-B2R+9bp, ACE DD-B2R+9bp, or ACE DD-B2R-9bp rather than ACE II-B2R-9bp, worsened renal performance and enhanced pathological alterations induced by STZ. Markedly elevated monocyte chemoattractant protein-1(MCP-1), podocin, osteopontin (OPN), transforming growth factor-β1 (TGF-β1), and reduced nephrin, podocin were also detected both in diabetic mice and podocytes under hyperglycemic conditions in response to ACE II-B2R+9bp, ACE DD-B2R+9bp, or ACE DD-B2R-9bp, versus ACE II-B2R-9bp. In addition, high glucose-induced mitochondrial oxidative stress and cell apoptosis were observably increased in response to ACE II-B2R+9bp, ACE DD-B2R+9bp, or ACE DD-B2R-9bp but not ACE II-B2R-9bp. We provide first evidence indicating the causation between ACE DD or B2R+9bp genotype and the increased risk for diabetic nephropathy, broadening our horizon about the role of genetic modulators in this disease. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Preclinical pharmacology of bilastine, a new selective histamine H1 receptor antagonist: receptor selectivity and in vitro antihistaminic activity.

    Science.gov (United States)

    Corcóstegui, Reyes; Labeaga, Luis; Innerárity, Ana; Berisa, Agustin; Orjales, Aurelio

    2005-01-01

    This study aimed to establish the receptor selectivity and antihistaminic activity of bilastine, a new selective antihistamine receptor antagonist. In vitro experiments were conducted using a receptor binding screening panel and guinea-pig and rat tissues. Antihistaminic activity was determined using H1 receptor binding studies and in vitro H1 antagonism studies conducted in guinea-pig tissues and human cell lines. Receptor selectivity was established using a receptor binding screening panel and a receptor antagonism screening conducted in guinea-pig, rat and rabbit tissues. Inhibition of inflammatory mediators was determined through the Schultz-Dale reaction in sensitised guinea-pig ileum. Bilastine binds to histamine H1-receptors as indicated by its displacement of [3H]-pyrilamine from H1-receptors expressed in guinea-pig cerebellum and human embryonic kidney (HEK) cell lines. The studies conducted on guinea-pig smooth muscle demonstrated the capability of bilastine to antagonise H1-receptors. Bilastine is selective for histamine H1-receptors as shown in receptor-binding screening conducted to determine the binding capacity of bilastine to 30 different receptors. The specificity of its H1-receptor antagonistic activity was also demonstrated in a series of in vitro experiments conducted on guinea-pig and rat tissues. The results of these studies confirmed the lack of significant antagonism against serotonin, bradykinin, leukotriene D4, calcium, muscarinic M3-receptors, alpha1-adrenoceptors, beta2-adrenoceptors, and H2- and H3-receptors. The results of the in vitro Schultz-Dale reaction demonstrated that bilastine also has anti-inflammatory activity. These preclinical studies provide evidence that bilastine has H1- antihistamine activity, with high specificity for H1-receptors, and poor or no affinity for other receptors. Bilastine has also been shown to have anti-inflammatory properties.

  11. Semaphorin4D-PlexinB1 Signaling Attenuates Photoreceptor Outer Segment Phagocytosis by Reducing Rac1 Activity of RPE Cells.

    Science.gov (United States)

    Bulloj, Ayelen; Maminishkis, Arvydas; Mizui, Masayuki; Finnemann, Silvia C

    2017-06-17

    Semaphorins form a family of secreted and membrane-bound molecules that were identified originally as axonal guidance factors during neuronal development. Given their wide distribution in many including mature tissues, semaphorin 4D (sema4D) and its main functional receptor plexin B1 (plxnB1) are expected to fulfill additional functions that remain to be uncovered. A main characteristic of the plexin receptor family is its ability to reorganize the cytoskeleton. PlxnB1 specifically may directly interact with Rho family GTPases to regulate F-actin driven pathways in cells in culture. Diurnal clearance phagocytosis by the retinal pigment epithelium (RPE) of photoreceptor outer segment fragments (POS) is critical for photoreceptor function and longevity. In this process, rearrangement of RPE cytoskeletal F-actin via activation of the Rho family GTPase Rac1 is essential for POS internalization. Here, we show a novel role in POS phagocytosis by RPE cells in culture and in vivo for plexin B1 and its ligand sema4D. Exogenous sema4D abolishes POS internalization (but not binding) by differentiated RPE cells in culture by decreasing the GTP load of Rac1. In the rat eye, sema4D localizes to retinal photoreceptors, while PlxnB1 is expressed by neighboring RPE cells. At the peak of diurnal retinal phagocytosis after light onset, plxnB1 phosphorylation and sema4D levels are reduced in wild-type rat retina in situ but not in mutant RCS rat retina in which the RPE lacks phagocytic activity. Finally, increased POS phagosome content after light onset is observed in the RPE in situ of mice with either plxnB1 or sema4D gene deletion. Altogether, our results demonstrate a novel physiological function for sema4D/plxnB1 signaling in RPE phagocytosis serving as attenuating brake prior to light onset whose release enables the diurnal phagocytic burst.

  12. PENGARUH KETEBALAN SUBSTRAT PADA FERMENTASI TEMPE TERHADAP KADAR VITAMIN B1 (THE INFLUENCE OF SUBSTRATE THICKNESS DURING TEMPE FERMENTATION ON VITAMINS B1 LEVEL

    Directory of Open Access Journals (Sweden)

    Fifi Retiaty

    2012-12-01

    Full Text Available ABSTRACT The level of vitamin B1 in tempe could be increased by modifying the surface of substrate during soybean fermentation. This research aimed to know the influence of substrate thickness during soybean fermentation into tempe to the levels of vitamin B1. The design of this research was completed randomized design with two replication. Vitamin B1 content was analyzed on raw soybeans, boiled soybeans, and tempe using spectrophotometer methods. The substrate thicknesses examined were 0.25 cm, 0.50 cm and 1.00cm. Vitamin B1 level on raw soybean was 0.7436 mg percent and on boiled soybean was 0.4898 mg percent, while in tempe with substrate thickness  0.25 cm, 0.50 cm and 1.00 cm, the vitamin B1 contents were 1.1413, 0.9044, and 0.7130 mg percent respectively. The thickness of tempe substrate affected on vitamin B1 content. A thinner substrate resulted on higher vitamin B1 level. Keywords: fermentation, tempe, vitamin B1   ABSTRAK Kadar vitamin B1 pada tempe dapat ditingkatkan dengan memodifikasi permukaan dari substrat dalam fermentasi kedelai. Tujuan penelitian ini adalah untuk mengetahui pengaruh ketebalan substrat pada fermentasi kedelai menjadi tempe terhadap kadar vitamin B1. Disain penelitian ini adalah Rancangan Acak Lengkap dengan dua kali ulangan. Kadar vitamin B1 dianalisis pada kedelai mentah, kedelai rebus, dan tempe dengan menggunakan metode spektrofotometri. Ketebalan substrat yang diteliti adalah 0.25 cm, 0,50 cm, 1,00 cm. Kadar vitamin B1 pada  kedelai mentah adalah 0,7436 mg persen dan pada kedelai rebus adalah 0.4898 mg persen. Sedangkan kadar vitamin B1 pada tempe dengan ketebalan 0,25, 0,5 dan 1 cm secara berturut-turut adalah 1,1413 mg persen , 0,9044 mg persen dan 0,7130 mg persen. Ketebalan substar tempe berpengaruh pada kandungan vitamin B1. Semakin tipis substrat, akan menghasilkan vitamin B1 yang semakin tinggi. [Penel Gizi Makan 2012, 35(2: 182-188]   Kata Kunci: fermentasi, tempe, vitamin B1

  13. Peptide IC-20, encoded by skin kininogen-1 of the European yellow-bellied toad, Bombina variegata, antagonizes bradykinin-induced arterial smooth muscle relaxation

    Directory of Open Access Journals (Sweden)

    Mu Yang

    2011-01-01

    Full Text Available Objectives: The objectives were to determine if the skin secretion of the European yellow-bellied toad (Bombina variegata, in common with other related species, contains a bradykinin inhibitor peptide and to isolate and structurally characterize this peptide. Materials and Methods: Lyophilized skin secretion obtained from this toad was subjected to reverse phase HPLC fractionation with subsequent bioassay of fractions for antagonism of the bradykinin activity using an isolated rat tail artery smooth muscle preparation. Subsequently, the primary structure of the peptide was established by a combination of microsequencing, mass spectroscopy, and molecular cloning, following which a synthetic replicate was chemically synthesised for bioassay. Results: A single peptide of molecular mass 2300.92 Da was resolved in HPLC fractions of skin secretion and its primary structure determined as IYNAIWP-KH-NK-KPGLL-. Database interrogation with this sequence indicated that this peptide was encoded by skin kininogen-1 previously cloned from B. variegata. The blank cycles were occupied by cysteinyl (C residues and the peptide was located toward the C-terminus of the skin kininogen, and flanked N-terminally by a classical -KR- propeptide convertase processing site. The peptide was named IC-20 in accordance (I = N-terminal isoleucine, C = C-terminal cysteine, 20 = number of residues. Like the natural peptide, its synthetic replicate displayed an antagonism of bradykinin-induced arterial smooth muscle relaxation. Conclusion: IC-20 represents a novel bradykinin antagonizing peptide from amphibian skin secretions and is the third such peptide found to be co-encoded with bradykinins within skin kininogens.

  14. Sex differences in the role of transient receptor potential (TRP) channels in endothelium-dependent vasorelaxation in porcine isolated coronary arteries.

    Science.gov (United States)

    Wong, Pui San; Roberts, Richard E; Randall, Michael D

    2015-03-05

    Endothelial and smooth muscle Transient Receptor Potential (TRP) channels contribute to regulation of vascular tone. We have previously reported sex differences in the endothelial function in porcine isolated coronary arteries (PCAs). The present study examined the role of TRP channels in endothelium-dependent and H2O2-induced vasorelaxations in male and female PCAs. Distal PCAs were mounted in a wire myograph and precontracted with U46619. Concentration-response curves to bradykinin, H2O2 and A23187 were constructed in the presence of TRP channel antagonists with or without L-NAME and indomethacin to inhibit NO synthase and cyclooxygenase respectively. 2-APB (TRPC & TRPM antagonist) inhibited the maximum relaxation (Rmax) of the bradykinin-induced vasorelaxation and abolished the EDH-type response in PCAs from both sexes. SKF96365 (TRPC antagonist) inhibited the Rmax of bradykinin-induced vasorelaxation in males, and inhibited Rmax of the EDH-type response in both sexes. Pyr3 (TRPC3 antagonist) inhibited both the NO and EDH components of the bradykinin-induced vasorelaxation in males, but not females. RN1734 (TRPV4 antagonist) reduced the potency of the NO component of the bradykinin-induced vasorelaxation in females only, but inhibited the Rmax of the EDH-type component in both sexes. 2-APB, SKF96365 and RN1734 all reduced the H2O2-induced vasorelaxation, whereas Pyr3 had no effect. No differences in expression level of TRPC3 and TRPV4 between sexes were detected using Western blot. Present study demonstrated a clear sex differences in the role TRP channels where TRPC3 play a role in the NO- and EDH-type response in males and TRPV4 play a role in the NO-mediated response in females. Copyright © 2015 Elsevier B.V. All rights reserved.

  15. MISR Level 1B1 Local Mode Radiance Data V002

    Data.gov (United States)

    National Aeronautics and Space Administration — The MISR Local Mode Level 1B1 Product contains the data numbers (DNs) radiometrically scaled to radiances with no geometric resampling.The MISR Level 1B1 Radiance...

  16. Hurricane Satellite (HURSAT) from International Satellite Cloud Climatology Project (ISCCP) B1, Version 6

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The Hurricane Satellite (HURSAT) from derived International Satellite Cloud Climatology Project (ISCCP) B1 observations of tropical cyclones worldwide. The B1 data...

  17. Loss of ephrinB1 in osteogenic progenitor cells impedes endochondral ossification and compromises bone strength integrity during skeletal development.

    Science.gov (United States)

    Nguyen, Thao M; Arthur, Agnieszka; Paton, Sharon; Hemming, Sarah; Panagopoulos, Romana; Codrington, John; Walkley, Carl R; Zannettino, Andrew C W; Gronthos, Stan

    2016-12-01

    The EphB receptor tyrosine kinase family and their ephrinB ligands have been implicated as mediators of skeletal development and bone homeostasis in humans, where mutations in ephrinB1 contribute to frontonasal dysplasia and coronal craniosynostosis. In mouse models, ephrinB1 has been shown to be a critical factor mediating osteoblast function. The present study examined the functional importance of ephrinB1 during endochondral ossification using the Cre recombination system with targeted deletion of ephrinB1 (EfnB1 fl/fl ) in osteogenic progenitor cells, under the control of the osterix (Osx:Cre) promoter. The Osx:EfnB1 -/- mice displayed aberrant bone growth during embryonic and postnatal skeletal development up to 4weeks of age, when compared to the Osx:Cre controls. Furthermore, compared to the Osx:Cre control mice, the Osx:EfnB1 -/- mice exhibited significantly weaker and less rigid bones, with a reduction in trabecular/ cortical bone formation, reduced trabecular architecture and a reduction in the size of the growth plates at the distal end of the femora from newborn through to 4weeks of age. The aberrant bone formation correlated with increased numbers of tartrate resistant acid phosphatase positive osteoclasts and decreased numbers of bone lining osteoblasts in 4week old Osx:EfnB1 -/- mice, compared to Osx:Cre control mice. Taken together, these observations demonstrate the importance of ephrinB1 signalling between cells of the skeleton required for endochondral ossification. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. ATP8B1 deficiency disrupts the bile canalicular membrane bilayer structure in hepatocytes, but FXR expression and activity are maintained.

    Science.gov (United States)

    Cai, Shi-Ying; Gautam, Samir; Nguyen, Trong; Soroka, Carol J; Rahner, Christoph; Boyer, James L

    2009-03-01

    Progressive familial intrahepatic cholestasis 1 (PFIC1) results from mutations in ATP8B1, a putative aminophospholipid flippase. Conflicting hypotheses have been proposed for the pathogenesis of PFIC1. The aim of this study was to determine whether ATP8B1 deficiency produces cholestasis by altering the activity of the farnesoid X receptor (FXR) or by impairing the structure of the canalicular membrane. ATP8B1/Atp8b1 was knocked down in human and rat hepatocytes and Caco2 cells using adenoviral and oligonucleotide small interfering RNAs. ATP8B1 messenger RNA and protein expression was greatly reduced in human and rat cells. In contrast, FXR expression and several FXR-dependent membrane transporters (bile salt export pump [BSEP], multidrug resistance-associated protein [MRP] 2) were unchanged at messenger RNA or protein levels in ATP8B1-deficient cells, whereas Mrp3 and Mrp4 were up-regulated in rat hepatocytes. FXR activity remained intact in these cells, as evidenced by 6alpha-ethyl chenodeoxycholic acid-mediated induction of small heterodimer partner, BSEP, and multidrug-resistant protein (MDR) 3/Mdr2. Fluorescent substrate excretion assays indicate that Bsep function was significantly reduced in Atp8b1-deficient rat hepatocytes, although Bsep remained localized to the canalicular membrane. Exposure to the hydrophobic bile acid CDCA resulted in focal areas of canalicular membrane disruption by electron microscopy and luminal accumulation of NBD-phosphatidylserine, consistent with the function of Atp8b1 as an aminophospholipid flippase. ATP8B1 deficiency predisposes to cholestasis by favoring bile acid-induced injury in the canalicular membrane but does not directly affect FXR expression, which may occur in PFIC1 as a secondary phenomenon associated with cholestasis.

  19. Optimized human CYP4B1 in combination with the alkylator prodrug 4-ipomeanol serves as a novel suicide gene system for adoptive T-cell therapies.

    Science.gov (United States)

    Roellecke, K; Virts, E L; Einholz, R; Edson, K Z; Altvater, B; Rossig, C; von Laer, D; Scheckenbach, K; Wagenmann, M; Reinhardt, D; Kramm, C M; Rettie, A E; Wiek, C; Hanenberg, H

    2016-07-01

    Engineering autologous or allogeneic T cells to express a suicide gene can control potential toxicity in adoptive T-cell therapies. We recently reported the development of a novel human suicide gene system that is based on an orphan human cytochrome P450 enzyme, CYP4B1, and the naturally occurring alkylator prodrug 4-ipomeanol. The goal of this study was to systematically develop a clinically applicable self-inactivating lentiviral vector for efficient co-expression of CYP4B1 as an ER-located protein with two distinct types of cell surface proteins, either MACS selection genes for donor lymphocyte infusions after allogeneic stem cell transplantation or chimeric antigen receptors for retargeting primary T cells. The U3 region of the myeloproliferative sarcoma virus in combination with the T2A site was found to drive high-level expression of our CYP4B1 mutant with truncated CD34 or CD271 as MACS suitable selection markers. This lentiviral vector backbone was also well suited for co-expression of CYP4B1 with a codon-optimized CD19 chimeric antigen receptor (CAR) construct. Finally, 4-ipomeanol efficiently induced apoptosis in primary T cells that co-express mutant CYP4B1 and the divergently located MACS selection and CAR genes. In conclusion, we here developed a clinically suited lentiviral vector that supports high-level co-expression of cell surface proteins with a potent novel human suicide gene.

  20. The effect of organic anion-transporting polypeptides 1B1, 1B3 and 2B1 on the antitumor activity of flavopiridol in breast cancer cells.

    Science.gov (United States)

    Brenner, Stefan; Riha, Juliane; Giessrigl, Benedikt; Thalhammer, Theresia; Grusch, Michael; Krupitza, Georg; Stieger, Bruno; Jäger, Walter

    2015-01-01

    The contribution of organic anion transporting polypeptides (OATPs) to the cellular uptake of flavopiridol was investigated in OATP1B1-, OATP1B3- and OATP2B1-expressing Chinese hamster ovary (CHO) cells. Uptake of flavopiridol into these cells showed typical Michaelis-Menten kinetics with much higher transport capacity for OATP1B3 compared to OATP1B1 and OATP2B1 (Vmax/Km, 33.9 vs. 8.84 and 2.41 µl/mg/min, respectively). The predominant role of OATPs was further supported by a dramatic inhibition of flavopiridol uptake in the presence of the OATP substrate rifampicin. Uptake of flavopiridol by OATPs also seems to be an important determinant in breast cancer cells. The much higher mRNA level for OATP1B1 found in wild-type compared to ZR-75-1 OATP1B1 knockdown cells correlated with higher flavopiridol initial uptake leading to 4.6-fold decreased IC50 values in the cytotoxicity assay (IC50, 1.45 vs. 6.64 µM). Cell cycle profile also showed a clear incidence for a stronger cell cycle arrest in the G2/M phase for ZR-75-1 wild-type cells compared to OATP1B1 knockdown cells, further indicating an active uptake via OATP1B1. In conclusion, our results revealed OATP1B1, OATP1B3 and OATP2B1 as uptake transporters for flavopiridol in cancer cells, which may also apply in patients during cancer therapy.

  1. Data of evolutionary structure change: 1CG5B-1LJWB [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1CG5B-1LJWB 1CG5 1LJW B B VKLSEDQEHYIKGVWKDVDHKQITAKALERVFVVYPWTT...line>ILE CA 224 GLY CA 259 1LJW B 1LJWB GDLSTPDAVMGNPK ... CA 298 ASP CA 280 THR CA 322 1LJW... B 1LJWB ELHCDKLHVDP

  2. 26 CFR 49.4262(b)-1 - Exclusion of certain travel.

    Science.gov (United States)

    2010-04-01

    ... 26 Internal Revenue 16 2010-04-01 2010-04-01 true Exclusion of certain travel. 49.4262(b)-1 Section 49.4262(b)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) MISCELLANEOUS EXCISE TAXES FACILITIES AND SERVICES EXCISE TAXES Transportation of Persons § 49.4262(b)-1 Exclusion of certain travel. (a) In general....

  3. Data of evolutionary structure change: 1AC6B-1TVDB [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1AC6B-1TVDB 1AC6 1TVD B B DSVTQTEGQVALSEEDFLTIHCNYSASG-YPALFWYVQYPGEGPQFLFRASRDKEK...N--KLTFGAGTKLTIKP DKVTQSSPDQTVASGSEVVLLCTYDTVYSNPDLFWYRIRPDYSFQFVFYGD-DSRSEGADFTQGRFSVK...HILTQKAFHLVISPVRTEDSATYYCAFTLPPPTDKLIFGKGTRVTVEP EEE EEE EEEEEEEE - EEEEEEE EEE EEEEE----... 1TVD B 1TVDB 1TVD B 1TVDB

  4. Data of evolutionary structure change: 1CG5B-1HBRB [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1CG5B-1HBRB 1CG5 1HBR B B VKLSEDQEHYIKGVWKDVDHKQITAKALERVFVVYPWTT...>GLY CA 259 VAL CA 324 1HBR B... 1HBRB NLSSPTAILGNPMV HHH...ne> ASP CA 280 THR CA 322 1HBR B 1HBRB ELHCDKLHVDP

  5. Data of evolutionary structure change: 1CG5B-1NIHB [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1CG5B-1NIHB 1CG5 1NIH B B VKLSEDQEHYIKGVWKDVDHKQITAKALERVFVVYPWTT...>ILE CA 224 GLY CA 259 1NIH B... 1NIHB GDLSTPDAVMGNPK HHH...e>ASP CA 280 THR CA 322 1NIH ...B 1NIHB ELHCDKLHVDP HIIIII

  6. Preparation of materials for an intercomparison of methods for aflatoxin B1 in peanut meal

    NARCIS (Netherlands)

    Egmond; H.P.van; Sizoo; E.A.; Paulsch; W.E.

    1986-01-01

    T.b.v. de 2e BCR "Intercomparison of methods for aflatoxin B1 in peanut meal", werden geampulleerde aflatoxine B1 standaardoplossingen (concentratie 10 ug/ml in chloroform) bereid en gedistribueerd aan deelnemers. De aangegeven concentratie van aflatoxine B1 in de standaardoplossing

  7. Novel Roles for Kv7 Channels in Shaping Histamine-Induced Contractions and Bradykinin-Dependent Relaxations in Pig Coronary Arteries

    Science.gov (United States)

    Chen, Xingjuan; Li, Wennan; Hiett, S. Christopher; Obukhov, Alexander G.

    2016-01-01

    Voltage-gated Kv7 channels are inhibited by agonists of Gq-protein-coupled receptors, such as histamine. Recent works have provided evidence that inhibition of vascular Kv7 channels may trigger vessel contractions. In this study, we investigated how Kv7 activity modulates the histamine-induced contractions in “healthy” and metabolic syndrome (MetS) pig right coronary arteries (CAs). We performed isometric tension and immunohistochemical studies with domestic, lean Ossabaw, and MetS Ossabaw pig CAs. We found that neither the Kv7.2/Kv7.4/Kv7.5 activator ML213 nor the general Kv7 inhibitor XE991 altered the tension of CA rings under preload, indicating that vascular Kv7 channels are likely inactive in the preloaded rings. Conversely, ML213 potently dilated histamine-pre-contracted CAs, suggesting that Kv7 channels are activated during histamine applications and yet partially inhibited by histamine. Immunohistochemistry analysis revealed strong Kv7.4 immunostaining in the medial and intimal layers of the CA wall, whereas Kv7.5 immunostaining intensity was strong in the intimal but weak in the medial layers. The medial Kv7 immunostaining was significantly weaker in MetS Ossabaw CAs as compared to lean Ossabaw or domestic CAs. Consistently, histamine-pre-contracted MetS Ossabaw CAs exhibited attenuated ML213-dependent dilations. In domestic pig CAs, where medial Kv7 immunostaining intensity was stronger, histamine-induced contractions spontaneously decayed to ~31% of the peak amplitude within 4 minutes. Oppositely, in Ossabaw CAs, where Kv7 immunostaining intensity was weaker, the histamine-induced contractions were more sustained. XE991 pretreatment significantly slowed the decay rate of histamine-induced contractions in domestic CAs, supporting the hypothesis that increased Kv7 activity correlates with a faster rate of histamine-induced contraction decay. Alternatively, XE991 significantly decreased the amplitude of bradykinin-dependent dilations in pre

  8. Rapakinin, an anti-hypertensive peptide derived from rapeseed protein, dilates mesenteric artery of spontaneously hypertensive rats via the prostaglandin IP receptor followed by CCK(1) receptor.

    Science.gov (United States)

    Yamada, Yuko; Iwasaki, Masashi; Usui, Hachiro; Ohinata, Kousaku; Marczak, Ewa D; Lipkowski, Andrzej W; Yoshikawa, Masaaki

    2010-05-01

    The anti-hypertensive peptide Arg-Ile-Tyr, which was isolated based on its inhibitory activity (IC(50)=28microM) for angiotensin I-converting enzyme (ACE) from the subtilisin digest of rapeseed protein, exhibited vasorelaxing activity (EC(50)=5.1microM) in an endothelium-dependent manner in the mesenteric artery of spontaneously hypertensive rats (SHRs). We named the peptide rapakinin. ACE inhibitors are reported to induce nitric oxide (NO)-dependent vasorelaxation by elevating the endogenous bradykinin level; however, the vasorelaxation induced by 10microM of rapakinin was blocked only insignificantly by HOE140 or N(G)-nitro-l-arginine methyl ester (l-NAME), antagonists of bradykinin B(2) receptor and an inhibitor of NO synthase, respectively. On the other hand, the vasorelaxation induced by 10microM rapakinin was significantly blocked by indomethacin and CAY10441, a cyclooxygenase (COX) inhibitor and an antagonist of the IP receptor, respectively. The vasorelaxing activity of rapakinin was also blocked by lorglumide, an antagonist of the cholecystokinin (CCK) CCK(1) receptor, although rapakinin has no affinity for the IP and CCK(1) receptors. The vasorelaxation induced by 10microM iloprost, an IP receptor agonist, was also blocked by lorglumide, suggesting that CCK-CCK(1) receptor system is activated downstream of the PGI(2)-IP receptor system. The anti-hypertensive activity of rapakinin after oral administration in SHRs was also blocked by CAY10441 and lorglumide. These results suggest that the anti-hypertensive activity of rapakinin might be mediated mainly by the PGI(2)-IP receptor, followed by CCK-CCK(1) receptor-dependent vasorelaxation. Copyright (c) 2010 Elsevier Inc. All rights reserved.

  9. Insulin stimulates transport of organic anion compounds mediated by organic anion transporting polypeptide 2B1 in the human intestinal cell line Caco-2.

    Science.gov (United States)

    Kobayashi, Taku; Koizumi, Takahiro; Kobayashi, Masaki; Ogura, Jiro; Horiuchi, Yuichi; Kimura, Yuki; Kondo, Ayuko; Furugen, Ayako; Narumi, Katsuya; Takahashi, Natsuko; Iseki, Ken

    2017-04-01

    Organic anion transporting polypeptide 2B1 (OATP2B1) is the major uptake transporter in the intestine, and transports various clinically used therapeutic agents. Insulin acts through the insulin receptor in targeted cells, and Rab8A is one of the insulin signaling pathways. The small intestine in humans also expresses insulin receptor and Rab8A. It has been reported that insulin stimulates peptide transporter 1 (PEPT1) expression at the apical membrane and increases uptake of PEPT1 substrates in small intestine epithelial model cells (Caco-2 cells). However, the effect of insulin on OATP2B1 in the small intestine has not been fully investigated. We found that Rab8A was associated with OATP2B1-mediated estrone-3-sulfate (E3S) uptake. Insulin stimulated the uptake of E3S by Caco-2 cells and the enhancement was sustained for 120 min. The Vmax value of E3S uptake significantly increased upon insulin exposure. Caco-2 cells treated with insulin showed increased OATP2B1 expression at the cell surface. The apical-to-basal transport of E3S was also increased by insulin. The increase of E3S transport was inhibited by the cold condition (4 °C) or the OATP2B1 inhibitor, taurocholate. These results indicate that insulin acts on the small intestine to increase OATP2B1-mediated absorption. Copyright © 2016 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

  10. Effect of vitamin B1 and mixtures of B1 with other vitamins on cytostatic efficiency of sanazole under irradiation. A study in vitro

    Science.gov (United States)

    Heinrich, Edith; Getoff, Nikola

    2003-06-01

    Experiments in vitro, using bacteria Escherichia coli (AB 1157) as a biological model, showed that the cytostatic efficiency of sanazole (AK-2123, a nitrotriazole-type radiosensitizer) in radiation treatment can be strongly influenced by the presence of various vitamins. In airfree media the sanazole action is increased by a factor of 2.5 in the presence of vitamin (vit.) B1, vit. C E-acetate and β-carotene, whereas vit. B1 used individually possesses a 2.7-times higher cytostatic activity than sanazole itself. In media containing air the highest increase of sanazole action is observed in the presence of vit. B1 and C, whereas the individual use of vit. B1 shows a radiation protection effect. In media saturated with N 2O the addition of the vit. B1 and C causes a 1.8-times larger sanazole activity, but the application of vit. B1 alone brings about a very high radiation protection. From studies of vit. B1-radiolysis it can be concluded that OH radicals are the major primary transients leading to substrate degradation. The results are of interest for the radiation therapy of cancer.

  11. CYP1B1 expression, a potential risk factor for breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Goth-Goldstein, Regine; Erdmann, Christine A.; Russell, Marion

    2001-05-31

    CYP1B1 expression in non-tumor breast tissue from breast cancer patients and cancer-free individuals was determined to test the hypothesis that high CYP1B1 expression is a risk factor for breast cancer. Large interindividual variations in CYP1B1 expression were found with CYP1B1 levels notably higher in breast cancer patients than cancer-free individuals. The results indicate that CYP1B1 might play a role in breast cancer either through increased PAH activation or through metabolism of endogenous estrogen to a carcinogenic derivative.

  12. Expression of the retinoic acid catabolic enzyme CYP26B1 in the human brain to maintain signaling homeostasis.

    Science.gov (United States)

    Stoney, Patrick N; Fragoso, Yara D; Saeed, Reem Bu; Ashton, Anna; Goodman, Timothy; Simons, Claire; Gomaa, Mohamed S; Sementilli, Angelo; Sementilli, Leonardo; Ross, Alexander W; Morgan, Peter J; McCaffery, Peter J

    2016-07-01

    Retinoic acid (RA) is a potent regulator of gene transcription via its activation of a set of nuclear receptors controlling transcriptional activation. Precise maintenance of where and when RA is generated is essential and achieved by local expression of synthetic and catabolic enzymes. The catabolic enzymes Cyp26a1 and Cyp26b1 have been studied in detail in the embryo, where they limit gradients of RA that form patterns of gene expression, crucial for morphogenesis. This paracrine role of RA has been assumed to occur in most tissues and that the RA synthetic enzymes release RA at a site distant from the catabolic enzymes. In contrast to the embryonic CNS, relatively little is known about RA metabolism in the adult brain. This study investigated the distribution of Cyp26a1 and Cyp26b1 transcripts in the rat brain, identifying several novel regions of expression, including the cerebral cortex for both enzymes and striatum for Cyp26b1. In vivo use of a new and potent inhibitor of the Cyp26 enzymes, ser 2-7, demonstrated a function for endogenous Cyp26 in the brain and that hippocampal RA levels can be raised by ser 2-7, altering the effect of RA on differential patterning of cell proliferation in the hippocampal region of neurogenesis, the subgranular zone. The expression of CYP26A1 and CYP26B1 was also investigated in the adult human brain and colocalization of CYP26A1 and the RA synthetic enzyme RALDH2 indicated a different, autocrine role for RA in human hippocampal neurons. Studies with the SH-SY5Y human neuroblastoma cell line implied that the co-expression of RA synthetic and catabolic enzymes maintains retinoid homeostasis within neurons. This presents a novel view of RA in human neurons as part of an autocrine, intracellular signaling system.

  13. NF-kappa B1 is required for optimal CD4+ Th1 cell development and resistance to Leishmania major.

    Science.gov (United States)

    Artis, David; Speirs, Kendra; Joyce, Karen; Goldschmidt, Michael; Caamaño, Jorge; Hunter, Christopher A; Scott, Phillip

    2003-02-15

    The NF-kappaB family of transcription factors regulates the expression of a wide range of immune response genes involved in immunity to pathogens. However, the need for individual family members in regulating innate and adaptive immune responses in vivo has yet to be clearly defined. We investigated the role of NF-kappaB1 in the induction of protective IL-12-dependent Th1 cell responses following infection with the intracellular protozoan parasite Leishmania major. Whereas wild-type C57BL/6 mice controlled parasite replication, NF-kappaB1 knockout (KO) mice were susceptible to infection, developing chronic unresolving lesions associated with persistent parasites. There was a profound defect in Ag-specific CD4(+) T cell proliferation and IFN-gamma production in infected KO mice, although innate responses-including IL-12 production and control of intracellular parasite replication by macrophages-were intact. In vitro polyclonal stimulation of purified naive KO T cells revealed an intrinsic defect in CD4(+) T cell proliferation associated with reduced IL-2 receptor expression, but operating independently of APC function and IL-2 production. Critically, the frequency of proliferating KO CD4(+) T cells secreting IFN-gamma matched that of wild-type cells, suggesting that NF-kappaB1 was not required for efficient transcription of the IFN-gamma gene. Taken together, these results identify a novel role for NF-kappaB1 in CD4(+) T cell proliferation and the development of Th1 cell responses required for protective immunity against intracellular pathogens.

  14. Effects of polymorphisms of the SLCO2B1 transporter gene on the pharmacokinetics of montelukast in humans.

    Science.gov (United States)

    Kim, Kyoung-Ah; Lee, Hye-Mi; Joo, Hyun-Jin; Park, In-Bae; Park, Ji-Young

    2013-11-01

    Montelukast, a leukotriene receptor antagonist, is a substrate of organic anion transporting OATP2B1 encoded by the SLCO2B1. We evaluated the effects of six non-synonymous (c.1175C>T, c.1457C>T, c.43C>T, c.935G>A, c.601G>A, and c.644A>T) polymorphisms and one promoter (g.-282G>A) polymorphism on the pharmacokinetics of montelukast. A single dose of 10 mg montelukast was administered in 24 healthy subjects. Its levels were measured up to 24 hours and a pharmacokinetic analysis was performed based on the SLCO2B1 polymorphisms. We did not encounter subjects with c.1175C>T, c.43C>T, or c.644A>T polymorphisms. The remaining SLCO2B1 polymorphisms did not affect plasma levels of montelukast, and pharmacokinetic parameters of montelukast did not differ among genotype groups. Oral clearance results were as follows: (1) 3.3 L/h for c.935GG, 3.0 L/h for c.935GA, and 3.5 L/h for c.935AA; (2) 3.4 L/h for c.1457CC, 2.9 L/h for c.1457CT, and 3.2 L/h for c.1457TT; (3) 3.2 L/h for c.601GG, 3.4 L/h for c.601GA, and 3.4 L/h for c.601AA; (4) 3.2 L/h for g.-282GG, 3.4 L/h for g.-282GA, and 3.2 L/h for g.-282AA. The findings suggest that SLCO2B1 polymorphisms do not affect the pharmacokinetics of montelukast and that SLCO2B1 polymorphisms appear to be a minor determinant of inter-individual variability of montelukast. © 2013, The American College of Clinical Pharmacology.

  15. The effects of anti-hypertensive drugs and the mechanism of hypertension in vascular smooth muscle cell-specific ATP2B1 knockout mice.

    Science.gov (United States)

    Okuyama, Yuki; Hirawa, Nobuhito; Fujita, Megumi; Fujiwara, Akira; Ehara, Yosuke; Yatsu, Keisuke; Sumida, Koichiro; Kagimoto, Minako; Katsumata, Mari; Kobayashi, Yusuke; Saka, Sanae; Umemura, Satoshi; Tamura, Kouichi

    2018-02-01

    ATP2B1 is a gene associated with hypertension. We reported previously that mice lacking ATP2B1 in vascular smooth muscle cells (VSMC ATP2B1 KO mice) exhibited high blood pressure and increased intracellular calcium concentration. The present study was designed to investigate whether lack of the ATP2B1 gene causes a higher response to calcium channel blockers (CCBs) than to other types of anti-hypertensive drugs. Both VSMC ATP2B1 KO and control mice were administered anti-hypertensive drugs while monitoring blood pressure shifts. We also examined the association of nitric oxide synthase (NOS) activity in those mice to investigate whether another mechanism of hypertension existed. VSMC ATP2B1 KO mice exhibited significantly greater anti-hypertensive effects with a single injection of nicardipine, but the effects of an angiotensin II receptor blocker (ARB), an α-blocker and amlodipine on blood pressure were all similar to control mice. However, long-term treatment with amlodipine, but not an ARB, significantly decreased the blood pressure of KO mice compared with control mice. Both mRNA and protein expression levels of the L-type calcium channel were significantly upregulated in KO VSMCs. There were no alterations in neural NOS protein expression of VSMCs or in urinary NO production between the two groups. VSMC ATP2B1 KO mice had a higher response to CCBs for blood pressure-lowering effects than other anti-hypertensive drugs. These results mean that increased intracellular calcium concentration in VSMCs due to lack of ATP2B1 and subsequent activation of L-type calcium channels mainly affects blood pressure and suggests increased susceptibility to CCBs in this type of hypertension.

  16. NOAA Climate Data Record (CDR) of Gridded Satellite Data from ISCCP B1 (GridSat-B1) Infrared Channel Brightness Temperature, Version 2

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The Gridded Satellite (GridSat-B1) data provides a uniform set of quality controlled geostationary satellite observations for the visible, infrared window and...

  17. Metabolism of aflatoxin B1 and identification of the major aflatoxin B1-DNA adducts formed in cultured human bronchus and colon

    DEFF Research Database (Denmark)

    1979-01-01

    Aflatoxin B1 and benzo(a)pyrene were activated by both cultured human bronchus and human colon as measured by binding to cellular DNA and protein. The binding of aflatoxin B1 to DNA was dose dependent, and the level of binding was higher in cultured human bronchus than it was in the colon. When...... compared to aflatoxin B1, the binding level of benzo(a)pyrene to both bronchial and colonic DNA was generally higher. The major adducts formed in both tissues by the interaction of aflatoxin B1 and DNA were chromatographically identical to 2,3-dihydro-2-(N7-guanyl)-3-hydroxyaflatoxin B1 (Structure 1...... in these two peaks, and the ratio of radioactivity between the peaks was nearly 1. In colonic DNA, the ratio between Structures 1 and 11 was approximately 2. These observations add aflatoxin B1 to the list of chemical procarcinogens metabolized by cultured human tissues and in which the carcinogen-DNA adducts...

  18. A modified multi-echo AFI for simultaneous B1(+) magnitude and phase mapping.

    Science.gov (United States)

    Choi, Narae; Lee, Joonsung; Kim, Min-Oh; Shin, Jaewook; Kim, Dong-Hyun

    2014-05-01

    To simultaneously acquire the B1(+) magnitude and B1(+) phase, a modified multi-echo actual flip-angle imaging (AFI) sequence is proposed. A multi-echo gradient echo sequence was integrated into every even TR of AFI to measure both magnitude and phase of B1(+). In addition, to increase the signal-to-noise ratio of the B1(+) phase, a double-angle multi-echo AFI sequence, in which the flip-angle of the RF pulses is α at the odd TR and 2α at the even TR is proposed. Images were simulated to evaluate the performance of this method under various imaging and physical parameters. The performance was compared to the spin echo based B1(+) mapping method in phantom and in vivo studies. In the simulation, the estimation error decreased as TR1/T1 decreased and TR2/TR1 increased. For double-angle AFI, flip-angle ranges that could estimate B1(+) magnitude and phase better than the original AFI were identified. Using the proposed method, B1(+) phase estimation was similar to spin echo phase. In the phantom study, correlation coefficient between the estimated B1(+) phases using the spin echo and the proposed method was 0.9998. The results show that the B1(+) magnitude and B1(+) phase can be simultaneously acquired and accurately estimated using the proposed double-angle AFI method. Copyright © 2014 Elsevier Inc. All rights reserved.

  19. Overexpression of SULT2B1b Promotes Angiogenesis in Human Gastric Cancer

    Directory of Open Access Journals (Sweden)

    Wen Chen

    2016-03-01

    Full Text Available Background/Aims: Overexpression of cytosolic sulfotransferase 2B1b (SULT2B1b has been commonly found in colorectal and hepatocellular carcinoma, suggesting that SULT2B1b might act as a potential oncogenic protein. However, its clinical significance and biological role in gastric cancer progression remain largely unknown. Methods: Expressions of SULT2B1b in clinical gastric cancer (GC samples were examined using qRT-PCR and Western blot. Results: SULT2B1b was markedly overexpressed in human GC samples, and positively correlated with vessel density and associated with poor clinical features. We also demonstrated that overexpression of SULT2B1b resulted in increased tumor angiogenesis and tumor growth in mouse GC models. In addition, ablation of SULT2B1b in human GC cells lines BGC823 and MKN45 decreased the capability of the cells to recruit endothelial cells. Moreover, depletion of SULT2B1b in GC cells reduced VEGF-A expression by downregulating SP1 and AP2. Conclusion: Our results suggested that the SULT2B1b-mediated angiogenic pathway could serve as biomarkers for GC diagnosis and prognosis, and suppressing SULT2B1b-mediated angiogenic signaling might be a promising strategy for developing novel GC treatment.

  20. NIa-pro of Papaya ringspot virus interacts with papaya methionine sulfoxide reductase B1.

    Science.gov (United States)

    Gao, Le; Shen, Wentao; Yan, Pu; Tuo, Decai; Li, Xiaoying; Zhou, Peng

    2012-12-05

    A chloroplast-localized papaya methionine sulfoxide reductase B1 (PaMsrB1) interacting with Papaya ringspot virus (PRSV) NIa-Pro was identified using a Sos recruitment two-hybrid system (SRS). SRS analysis of several deletion mutants of PRSV NIa-Pro and PaMsrB1 demonstrated that the C-terminal (residues 133-239) fragment of PRSV NIa-Pro and residues 112-175 of PaMsrB1 were necessary for this interaction between PRSV NIa-Pro and PaMsrB1. MsrB1 can repair Met-oxidized proteins damaged by reactive oxygen species (ROS). We confirmed that PRSV infection leads to ROS accumulation and a slight upregulation of level PaMsrB1 mRNA in papaya. This interaction between PaMsrB1 with PRSV NIa-Pro may disturb the import of PaMsrB1 into the chloroplasts. These results suggest that this specific interaction could interfere with PaMsrB1 into the chloroplasts to scavenge ROS caused by PRSV infection. This may be a novel mechanism of PRSV towards the host defense. Copyright © 2012 Elsevier Inc. All rights reserved.

  1. Modulating role of Semecarpus anacardium L. nut milk extract on aflatoxin B(1) biotransformation.

    Science.gov (United States)

    Premalatha, B; Sachdanandam, P

    2000-01-01

    As part of a substantial effort to curtail the adverse health effects posed by aflatoxin B(1), studies have been conducted to elucidate the possible mechanism for the anticarcinogenic action of Semecarpus anacardium nut extract against aflatoxin B(1)-induced hepatocellular carcinoma. Rats are monitored for levels of urinary, serum and liver biomarkers, namely, unmetabolised aflatoxin B(1), and its metabolites aflatoxin M(1), and aflatoxin Q(1), over the course of 2 weeks with nut extract therapy following a single-exposure to aflatoxin B(1). Due to the administration of nut extract, the excretion of unmetabolised aflatoxin B(1) was increased in day 1 urine when compared with rats without drug treatment. In serum and liver which were collected on day 16 and the rest of periodical urine samples showed aflatoxin B(1) and its metabolites in undetectable levels. The nut extract administration induced cytochrome P(450), glutathione, and glutathione-S-transferase levels in liver homogenates of aflatoxin B(1)-treated rats. These data seem to indicate that anticarcinogenic action by Semecarpus anacardium nut extract is possibly via suppression of aflatoxin B(1)activation and through interaction with microsomal-activating components. Previous evidence from this laboratory about the potency of Semecarpus anacardium nut extract against aflatoxin B(1)-induced hepatocellular carcinoma together with the present results suggest that extremely effective therapeutic protection can be achieved by this drug against aflatoxin B(1)-mediated ill effects. Copyright 2000 Academic Press.

  2. Cell stress promotes the association of phosphorylated HspB1 with F-actin.

    Directory of Open Access Journals (Sweden)

    Joseph P Clarke

    Full Text Available Previous studies have suggested that the small heat shock protein, HspB1, has a direct influence on the dynamics of cytoskeletal elements, in particular, filamentous actin (F-actin polymerization. In this study we have assessed the influence of HspB1 phosphorylation on its interaction(s with F-actin. We first determined the distribution of endogenous non-phosphorylated HspB1, phosphorylated HspB1 and F-actin in neuroendocrine PC12 cells by immunocytochemistry and confocal microscopy. We then investigated a potential direct interaction between HspB1 with F-actin by precipitating F-actin directly with biotinylated phalloidin followed by Western analyses; the reverse immunoprecipitation of HspB1 was also carried out. The phosphorylation influence of HspB1 in this interaction was investigated by using pharmacologic inhibition of p38 MAPK. In control cells, HspB1 interacts with F-actin as a predominantly non-phosphorylated protein, but subsequent to stress there is a redistribution of HspB1 to the cytoskeletal fraction and a significantly increased association of pHspB1 with F-actin. Our data demonstrate HspB1 is found in a complex with F-actin both in phosphorylated and non-phosphorylated forms, with an increased association of pHspB1 with F-actin after heat stress. Overall, our study combines both cellular and biochemical approaches to show cellular localization and direct demonstration of an interaction between endogenous HspB1 and F-actin using methodolgy that specifically isolates F-actin.

  3. Flavonoids exhibit diverse effects on CYP11B1 expression and cortisol synthesis

    Energy Technology Data Exchange (ETDEWEB)

    Cheng, Li-Chuan; Li, Lih-Ann, E-mail: lihann@nhri.org.tw

    2012-02-01

    CYP11B1 catalyzes the final step of cortisol biosynthesis. The effects of flavonoids on transcriptional expression and enzyme activity of CYP11B1 were investigated using the human adrenocortical H295R cell model. All tested nonhydroxylated flavones including 3′,4′-dimethoxyflavone, α-naphthoflavone, and β-naphthoflavone upregulated CYP11B1 expression and cortisol production, whereas apigenin and quercetin exhibited potent cytotoxicity and CYP11B1 repression at high concentrations. Nonhydroxylated flavones stimulated CYP11B1-catalyzed cortisol formation at transcriptional level. Resveratrol increased endogenous and substrate-supported cortisol production like nonhydroxylated flavones tested, but it had no effect on CYP11B1 gene expression and enzyme activity. Resveratrol appeared to alter cortisol biosynthesis at an earlier step. The Ad5 element situated in the − 121/− 106 region was required for basal and flavone-induced CYP11B1 expression. Overexpression of COUP-TFI did not improve the responsiveness of Ad5 to nonhydroxylated flavones. Although COUP-TFI overexpression increased CYP11B1 and CYP11B2 promoter activation, its effect was not mediated through the common Ad5 element. Treating cells with PD98059 (a flavone-type MEK1 inhibitor) increased CYP11B1 promoter activity, but not involving ERK signaling because phosphorylation of ERK1/2 remained unvarying throughout the course of treatment. Likewise, AhR was not responsible for the CYP11B1-modulating effects of flavonoids because inconsistency with their effects on AhR activation. 3′,4′-dimethoxyflavone and 8-Br-cAMP additively activated CYP11B1 promoter activity. H-89 reduced 3′,4′-dimethoxyflavone-induced CYP11B1 promoter activation but to a lesser extent as compared to its inhibition on cAMP-induced transactivation. Our data suggest that constant exposure to nonhydroxylated flavones raises a potential risk of high basal and cAMP-induced cortisol synthesis in consequence of increased CYP11B1

  4. Anti-migraine effect of Areca Catechu L. nut extract in bradykinin-induced plasma protein extravasation and vocalization in rats.

    Science.gov (United States)

    Bhandare, Amol M; Vyawahare, Neeraj S; Kshirsagar, Ajay D

    2015-08-02

    Areca catechu Linn. (Arecaceae) nut is a popular folk remedy for the treatment of migraine in Kerala and Tamil Nadu states of India. This study was designed to investigate the effect of hydroalcoholic extract of A. catechu L. nut (ANE) treatment on migraine pain in rat models to strengthen its use as an anti-migraine therapy. Bradykinin (0.1 μmol/kg) injection in to left femoral vein of rat produced PPE which was measured with luminescence spectrometer. Vocalizations were produced in rats with 10 μg of bradykinin infusion into common carotid artery. Phonogram was recorded before, during and for 5min after bradykinin injection and sumatriptan was used as a standard anti-migraine drug. In both models, the ANE was orally administered at doses of 250 and 500 mg/kg, 60 min before bradykinin infusion. The PPE was reduced in both ANE treated groups of rats. The percent fluorescein was significantly increased in positive control group (97.00±1.7%; p<0.0001) compared to negative control (63.87±1.2%). With ANE treatments (250 and 500 mg/kg) PPE was significantly decreased to 88.88±1.4% (p<0.01) and 83.55±0.1% (p<0.0001) compared to positive control group, respectively. On the other hand in the model of vocalization, with 250 and 500 mg/kg ANE treatment, vocalization was significantly reduced to 33.33% and 16.66%, respectively, compared to saline treated rats. The reduction in vocalization is comparable to the reference drug sumatriptan. The findings provide the strong evidence for anti-migraine potential of ANE in rat models of migraine. In summary, therapeutic intervention with ANE treatment could be a promising strategy for prevention of migraine. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  5. ErbB1-4-dependent EGF/neuregulin signals and their cross talk in the central nervous system: pathological implications in schizophrenia and Parkinson’s disease

    Directory of Open Access Journals (Sweden)

    Yuriko eIwakura

    2013-02-01

    Full Text Available Ligands for ErbB1-4 receptor tyrosine kinases, such as epidermal growth factor (EGF and neuregulins, regulate brain development and function. Thus, abnormalities in their signaling are implicated in the etiology or pathology of schizophrenia and Parkinson’s disease. Among the ErbB receptors, ErbB1 and ErbB4 are expressed in dopamine and GABA neurons, while ErbB1, 2, and/or 3 are mainly present in oligodendrocytes, astrocytes and their precursors. Thus, deficits in ErbB signaling might contribute to schizophrenia neuropathology stemming from these cell types. By incorporating the latest cancer molecular biology as well as our recent progress, we discuss signal cross talk between the ErbB1-4 subunits and their neurobiological functions in each cell type. The potential contribution of virus-derived cytokines (virokines that mimic EGF and neuregulin-1 in brain diseases are also discussed.

  6. Transcriptomic Characterization of SF3B1 Mutation Reveals Its Pleiotropic Effects in Chronic Lymphocytic Leukemia.

    Science.gov (United States)

    Wang, Lili; Brooks, Angela N; Fan, Jean; Wan, Youzhong; Gambe, Rutendo; Li, Shuqiang; Hergert, Sarah; Yin, Shanye; Freeman, Samuel S; Levin, Joshua Z; Fan, Lin; Seiler, Michael; Buonamici, Silvia; Smith, Peter G; Chau, Kevin F; Cibulskis, Carrie L; Zhang, Wandi; Rassenti, Laura Z; Ghia, Emanuela M; Kipps, Thomas J; Fernandes, Stacey; Bloch, Donald B; Kotliar, Dylan; Landau, Dan A; Shukla, Sachet A; Aster, Jon C; Reed, Robin; DeLuca, David S; Brown, Jennifer R; Neuberg, Donna; Getz, Gad; Livak, Kenneth J; Meyerson, Matthew M; Kharchenko, Peter V; Wu, Catherine J

    2016-11-14

    Mutations in SF3B1, which encodes a spliceosome component, are associated with poor outcome in chronic lymphocytic leukemia (CLL), but how these contribute to CLL progression remains poorly understood. We undertook a transcriptomic characterization of primary human CLL cells to identify transcripts and pathways affected by SF3B1 mutation. Splicing alterations, identified in the analysis of bulk cells, were confirmed in single SF3B1-mutated CLL cells and also found in cell lines ectopically expressing mutant SF3B1. SF3B1 mutation was found to dysregulate multiple cellular functions including DNA damage response, telomere maintenance, and Notch signaling (mediated through KLF8 upregulation, increased TERC and TERT expression, or altered splicing of DVL2 transcript, respectively). SF3B1 mutation leads to diverse changes in CLL-related pathways. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. Simultaneous T(1) and B(1) (+) mapping using reference region variable flip angle imaging.

    Science.gov (United States)

    Sung, Kyunghyun; Saranathan, Manojkumar; Daniel, Bruce L; Hargreaves, Brian A

    2013-10-01

    To present a new method that can simultaneously and efficiently measure T1 and B1 (+) maps using reference region variable flip angle (RR-VFA) imaging. Assuming T1 relaxation time in a reference region such as fat is well characterized, and the reference region sufficiently covers smoothly varying B1 (+) field inhomogeneity, B1 (+) maps can be measured from VFA images, conventionally used for T1 measurements. Fat-only images from two-point Dixon acquisitions were used to compute B1 (+) maps, and the B1 (+) maps were compared with ones using the double-angle method (DAM) in 22 breast MRI patients at 3T. Additionally, high spatial resolution VFA images were acquired to show T1 measurements with and without the RR-VFA B1 (+) correction in six patients. RR-VFA is able to generate reliable B1 (+) maps, similar to those using the conventional DAM. This simultaneous T1 and B1 (+) mapping can also be used to reduce T1 estimation errors, where T1 maps have more uniform fibroglandular tissue T1 and better depiction of heterogeneous T1 of breast masses. A new method that can measure both T1 and B1 (+) maps based on Dixon VFA images is described, offering improved T1 quantification with no scan time penalty. Copyright © 2013 Wiley Periodicals, Inc.

  8. Simultaneous T1 and B1+ Mapping using Reference Region Variable Flip Angle Imaging

    Science.gov (United States)

    Sung, Kyunghyun; Saranathan, Manojkumar; Daniel, Bruce L.; Hargreaves, Brian A.

    2013-01-01

    Purpose To present a new method that can simultaneously and efficiently measure T1 and B1+ maps using reference region variable flip angle (RR-VFA) imaging. Methods Assuming T1 relaxation time in a reference region such as fat is well characterized, and the reference region sufficiently covers smoothly varying B1+ field inhomogeneity, B1+ maps can be measured from VFA images, conventionally used for T1 measurements. Fat-only images from 2-point Dixon acquisitions were used to compute B1+ maps, and the B1+ maps were compared with ones using the double angle method (DAM) in 22 breast MRI patients at 3T. Additionally, high spatial resolution VFA images were acquired to show T1 measurements with and without the RR-VFA B1+ correction in six patients. Results RR-VFA is able to generate reliable B1+ maps, similar those using the conventional DAM. This simultaneous T1 and B1+ mapping can also be used to reduce T1 estimation errors, where T1 maps have more uniform fibroglandular tissue T1 and better depiction of heterogeneous T1 of breast masses. Conclusion A new method that can measure both T1 and B1+ maps based on Dixon VFA images is described, offering improved T1 quantification with no scan time penalty. PMID:23943610

  9. Macrophage Liver Kinase B1 Inhibits Foam Cell Formation and Atherosclerosis.

    Science.gov (United States)

    Liu, Zhaoyu; Zhu, Huaiping; Dai, Xiaoyan; Wang, Cheng; Ding, Ye; Song, Ping; Zou, Ming-Hui

    2017-10-13

    LKB1 (liver kinase B1) is a serine/threonine kinase and tumor suppressor, which regulates the homeostasis of hematopoietic cells and immune responses. Macrophages transform into foam cells upon taking-in lipids. No role for LKB1 in foam cell formation has previously been reported. We sought to establish the role of LKB1 in atherosclerotic foam cell formation. LKB1 expression was examined in human carotid atherosclerotic plaques and in western diet-fed atherosclerosis-prone Ldlr -/- and ApoE -/- mice. LKB1 expression was markedly reduced in human plaques when compared with nonatherosclerotic vessels. Consistently, time-dependent reduction of LKB1 levels occurred in atherosclerotic lesions in western diet-fed Ldlr -/- and ApoE -/- mice. Exposure of macrophages to oxidized low-density lipoprotein downregulated LKB1 in vitro. Furthermore, LKB1 deficiency in macrophages significantly increased the expression of SRA (scavenger receptor A), modified low-density lipoprotein uptake and foam cell formation, all of which were abolished by blocking SRA. Further, we found LKB1 phosphorylates SRA resulting in its lysosome degradation. To further investigate the role of macrophage LKB1 in vivo, ApoE -/- LKB1 fl/fl LysM cre and ApoE -/- LKB1 fl/fl mice were fed with western diet for 16 weeks. Compared with ApoE -/- LKB1 fl/fl wild-type control, ApoE -/- LKB1 fl/fl LysM cre mice developed more atherosclerotic lesions in whole aorta and aortic root area, with markedly increased SRA expression in aortic root lesions. We conclude that macrophage LKB1 reduction caused by oxidized low-density lipoprotein promotes foam cell formation and the progression of atherosclerosis. © 2017 American Heart Association, Inc.

  10. Biased G protein-coupled receptor agonism mediates Neu1 sialidase and matrix metalloproteinase-9 crosstalk to induce transactivation of insulin receptor signaling.

    Science.gov (United States)

    Haxho, Fiona; Haq, Sabah; Szewczuk, Myron R

    2017-12-24

    G protein-coupled receptors (GPCR) can participate in a number of signaling pathways, and this property led to the concept of biased GPCR agonism. Agonists, antagonists and allosteric modulators can bind to GPCRs in different ways, creating unique conformations that differentially modulate signaling through one or more G proteins. A unique neuromedin B (NMBR) GPCR-signaling platform controlling mammalian neuraminidase-1 (Neu1) and matrix metalloproteinase-9 (MMP9) crosstalk has been reported in the activation of the insulin receptor (IR) through the modification of the IR glycosylation. Here, we propose that there exists a biased GPCR agonism as small diffusible molecules in the activation of Neu1-mediated insulin receptor signaling. GPCR agonists bombesin, bradykinin, angiotensin I and angiotensin II significantly and dose-dependently induce Neu1 sialidase activity and IR activation in human IR-expressing rat hepatoma cell lines (HTC-IR), in the absence of insulin. Furthermore, the GPCR agonist-induced Neu1 sialidase activity could be specifically blocked by the NMBR inhibitor, BIM-23127. Protein expression analyses showed that these GPCR agonists significantly induced phosphorylation of IRβ and insulin receptor substrate-1 (IRS1). Among these, angiotensin II was the most potent GPCR agonist capable of promoting IRβ phosphorylation in HTC-IR cells. Interestingly, treatment with BIM-23127 and Neu1 inhibitor oseltamivir phosphate were able to block GPCR agonist-induced IR activation in HTC cells in vitro. Additionally, we found that angiotensin II receptor (type I) exists in a multimeric receptor complex with Neu1, IRβ and NMBR in naïve (unstimulated) and stimulated HTC-IR cells with insulin, bradykinin, angiotensin I and angiotensin II. This complex suggests a molecular link regulating the interaction and signaling mechanism between these molecules on the cell surface. These findings uncover a biased GPCR agonist-induced IR transactivation signaling axis

  11. Qualitative and quantitative re-evaluation of epidermal growth factor-ErbB1 action on developing midbrain dopaminergic neurons in vivo and in vitro: target-derived neurotrophic signaling (Part 1).

    Science.gov (United States)

    Iwakura, Yuriko; Zheng, Yingjun; Sibilia, Maria; Abe, Yuichi; Piao, Ying-Shan; Yokomaku, Daisaku; Wang, Ran; Ishizuka, Yuta; Takei, Nobuyuki; Nawa, Hiroyuki

    2011-07-01

    Although epidermal growth factor (EGF) receptor (ErbB1) is implicated in Parkinson's disease and schizophrenia, the neurotrophic action of ErbB1 ligands on nigral dopaminergic neurons remains controversial. Here, we ascertained colocalization of ErbB1 and tyrosine hydroxylase (TH) immunoreactivity and then characterized the neurotrophic effects of ErbB1 ligands on this cell population. In mesencephalic culture, EGF and glial-derived neurotrophic factor (GDNF) similarly promoted survival and neurite elongation of dopaminergic neurons and dopamine uptake. The EGF-promoted dopamine uptake was not inhibited by GDNF-neutralizing antibody or TrkB-Fc, whereas EGF-neutralizing antibody fully blocked the neurotrophic activity of the conditioned medium that was prepared from EGF-stimulated mesencephalic cultures. The neurotrophic action of EGF was abolished by ErbB1 inhibitors and genetic disruption of erbB1 in culture. In vivo administration of ErbB1 inhibitors to rat neonates diminished TH and dopamine transporter (DAT) levels in the striatum and globus pallidus but not in the frontal cortex. In parallel, there was a reduction in the density of dopaminergic varicosities exhibiting intense TH immunoreactivity. In agreement, postnatal erbB1-deficient mice exhibited similar decreases in TH levels. Although neurotrophic supports to dopaminergic neurons are redundant, these results confirm that ErbB1 ligands contribute to the phenotypic and functional development of nigral dopaminergic neurons. © 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.

  12. Molecular basis for amino acid sensing by family C G-protein-coupled receptors

    DEFF Research Database (Denmark)

    Wellendorph, Petrine; Bräuner-Osborne, Hans

    2009-01-01

    Family C of human G-protein-coupled receptors (GPCRs) is constituted by eight metabotropic glutamate receptors, two gamma-aminobutyric acid type B (GABA(B1-2)) subunits forming the heterodimeric GABA(B) receptor, the calcium-sensing receptor, three taste1 receptors (T1R1-3), a promiscuous L...

  13. Inhibition of NF-kB 1 (NF-kBp50 by RNA interference in chicken macrophage HD11 cell line challenged with Salmonella enteritidis

    Directory of Open Access Journals (Sweden)

    Hsin-I Chiang

    2009-01-01

    Full Text Available The NF-kB pathway plays an important role in regulating the immunity response in animals. In this study, small interfering RNAs (siRNA were used to specifically inhibit NF-kB 1 expression and to elucidate the role of NF-kB in the signal transduction pathway of the Salmonella challenge in the chicken HD11 cell line. The cells were transfected with either NF-kB 1 siRNA, glyceraldehyde 3-phosphate dehydrogenase siRNA (positive control or the negative control siRNA for 24 h, followed by Salmonella enteritidis (SE challenge or non-challenge for 1 h and 4 h. Eight candidate genes related to the signal pathway of SE challenge were selected to examine the effect of NF-kB 1 inhibition on their expressions by mRNA quantification. The results showed that, with a 36% inhibition of NF-kB 1 expression, gene expression of both Toll-like receptor (TLR 4 and interleukin (IL-6 was consistently and significantly increased at both 1 h and 4 h following SE challenge, whereas the gene expression of MyD88 and IL-1β was increased at 1 h and 4 h, respectively. These findings suggest a likely inhibitory regulation by NF-kB 1, and could lay the foundation for studying the gene network of the innate immune response of SE infection in chickens.

  14. Essential role of the transcription factor Bhlhe41 in regulating the development, self-renewal and BCR repertoire of B-1a cells

    Science.gov (United States)

    Kreslavsky, Taras; Vilagos, Bojan; Tagoh, Hiromi; Kostanova Poliakova, Daniela; Schwickert, Tanja; Wöhner, Miriam; Jaritz, Markus; Weiss, Siegfried; Taneja, Reshma; Rossner, Moritz J.; Busslinger, Meinrad

    2017-01-01

    Innate-like B-1a cells provide a first line of defense against pathogens, yet little is known about their transcriptional control. Here we identified an essential role of the transcription factor Bhlhe41, with a lesser contribution of Bhlhe40, in controlling late stages of B-1a cell differentiation. Bhlhe41–/–Bhlhe40–/– B-1a cells were severely reduced as compared to their wild-type counterparts. Mutant B-1a cells exhibited an abnormal cell-surface phenotype and altered B-cell receptor (BCR) repertoire exemplified by loss of the phosphatidylcholine-specific VH12/Vκ4 BCR. Expression of a pre-rearranged VH12/Vκ4 BCR failed to rescue the mutant phenotype and revealed enhanced proliferation accompanied with increased cell death. Bhlhe41 directly repressed the expression of cell cycle regulators and inhibitors of BCR signaling, while enabling pro-survival cytokine signaling. Thus, Bhlhe41 controls the development, BCR repertoire and self-renewal of B-1a cells. PMID:28250425

  15. Organic anion transporting polypeptides OATP1B1 and OATP1B3 and their genetic variants influence the pharmacokinetics and pharmacodynamics of raloxifene

    Science.gov (United States)

    2012-01-01

    Background Raloxifene, a selective estrogen receptor modulator, exhibits quite large and unexplained interindividual variability in pharmacokinetics and pharmacodynamics. The aim of this study was to determine the role of organic-anion transporting polypeptides OATP1B1 and OATP1B3 and their genetic variants in the pharmacokinetics and pharmacodynamics of raloxifene. Methods To test the role of OATP1B1 and OATP1B3 transporters on hepatic uptake of raloxifene and its metabolites an in vitro model of Chinese Hamster Ovary cells expressing OATP1B1 or OATP1B3 was employed. The influence of OATP1B1 and OATP1B3 genetic variants on in vivo pharmacokinetics and pharmacodynamics was evaluated in 53 osteoporotic postmenopausal women treated with raloxifene. Results Our in vitro results showed that raloxifene and two of the three metabolites, raloxifene-4'-β-glucuronide (M2) and raloxifene-6,4'-diglucuronide (M3), interact with OATP1B1 and OATP1B3. Higher M3 and total raloxifene serum concentrations in patients correlated with lower serum levels of bone resorption marker, serum C-terminal telopeptide fragments of type I collagen, indicating a higher antiresorptive effect of raloxifene. Higher concentrations of M2 correlated with higher increase of lumbar spine bone mineral density supporting the raloxifene vertebral fracture specific protection effect. Finally, raloxifene, M3 and total raloxifene serum concentrations were significantly higher in patients with SLCO1B1 c.388A > G polymorphism and *1b haplotype implicating a considerable genetic effect on pharmacokinetics and pharmacodynamics of raloxifene. Conclusions These findings indicate that SLCO1B1 c.388A > G polymorphism could play an important role in pharmacokinetics and pharmacodynamics of raloxifene. PMID:22533838

  16. Organic anion transporting polypeptides OATP1B1 and OATP1B3 and their genetic variants influence the pharmacokinetics and pharmacodynamics of raloxifene

    Directory of Open Access Journals (Sweden)

    Trdan Lušin Tina

    2012-04-01

    Full Text Available Abstract Background Raloxifene, a selective estrogen receptor modulator, exhibits quite large and unexplained interindividual variability in pharmacokinetics and pharmacodynamics. The aim of this study was to determine the role of organic-anion transporting polypeptides OATP1B1 and OATP1B3 and their genetic variants in the pharmacokinetics and pharmacodynamics of raloxifene. Methods To test the role of OATP1B1 and OATP1B3 transporters on hepatic uptake of raloxifene and its metabolites an in vitro model of Chinese Hamster Ovary cells expressing OATP1B1 or OATP1B3 was employed. The influence of OATP1B1 and OATP1B3 genetic variants on in vivo pharmacokinetics and pharmacodynamics was evaluated in 53 osteoporotic postmenopausal women treated with raloxifene. Results Our in vitro results showed that raloxifene and two of the three metabolites, raloxifene-4'-β-glucuronide (M2 and raloxifene-6,4'-diglucuronide (M3, interact with OATP1B1 and OATP1B3. Higher M3 and total raloxifene serum concentrations in patients correlated with lower serum levels of bone resorption marker, serum C-terminal telopeptide fragments of type I collagen, indicating a higher antiresorptive effect of raloxifene. Higher concentrations of M2 correlated with higher increase of lumbar spine bone mineral density supporting the raloxifene vertebral fracture specific protection effect. Finally, raloxifene, M3 and total raloxifene serum concentrations were significantly higher in patients with SLCO1B1 c.388A > G polymorphism and *1b haplotype implicating a considerable genetic effect on pharmacokinetics and pharmacodynamics of raloxifene. Conclusions These findings indicate that SLCO1B1 c.388A > G polymorphism could play an important role in pharmacokinetics and pharmacodynamics of raloxifene.

  17. Global gene profiling of aging lungs in Atp8b1 mutant mice.

    Science.gov (United States)

    Soundararajan, Ramani; Stearns, Timothy M; Czachor, Alexander; Fukumoto, Jutaro; Turn, Christina; Westermann-Clark, Emma; Breitzig, Mason; Tan, Lee; Lockey, Richard F; King, Benjamin L; Kolliputi, Narasaiah

    2016-09-29

    Recent studies implicate cardiolipin oxidation in several age-related diseases. Atp8b1 encoding Type 4 P-type ATPases is a cardiolipin transporter. Mutation in Atp8b1 gene or inflammation of the lungs impairs the capacity of Atp8b1 to clear cardiolipin from lung fluid. However, the link between Atp8b1 mutation and age-related gene alteration is unknown. Therefore, we investigated how Atp8b1 mutation alters age-related genes. We performed Affymetrix gene profiling of lungs isolated from young (7-9 wks, n=6) and aged (14 months, 14 M, n=6) C57BL/6 and Atp8b1 mutant mice. In addition, Ingenuity Pathway Analysis (IPA) was performed. Differentially expressed genes were validated by quantitative real-time PCR (qRT-PCR). Global transcriptome analysis revealed 532 differentially expressed genes in Atp8b1 lungs, 157 differentially expressed genes in C57BL/6 lungs, and 37 overlapping genes. IPA of age-related genes in Atp8b1 lungs showed enrichment of Xenobiotic metabolism and Nrf2-mediated signaling pathways. The increase in Adamts2 and Mmp13 transcripts in aged Atp8b1 lungs was validated by qRT-PCR. Similarly, the decrease in Col1a1 and increase in Cxcr6 transcripts was confirmed in both Atp8b1 mutant and C57BL/6 lungs. Based on transcriptome profiling, our study indicates that Atp8b1 mutant mice may be susceptible to age-related lung diseases.

  18. Upregulation of CYP1B1 expression by inflammatory cytokines is mediated by the p38 MAP kinase signal transduction pathway.

    Science.gov (United States)

    Smerdová, Lenka; Šmerdová, Jana; Kabátková, Markéta; Kohoutek, Jiří; Blažek, Dalibor; Machala, Miroslav; Vondráček, Jan

    2014-11-01

    Cytochrome P450 1B1 (CYP1B1) is an enzyme that has a unique tumor-specific pattern of expression and is capable of bioactivating a wide range of carcinogenic compounds. We have reported previously that coordinated upregulation of CYP1B1 by inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and the aryl hydrocarbon receptor ligands, may increase bioactivation of promutagens, such as benzo[a]pyrene (BaP) in epithelial cells. Here, we extend those studies by describing a novel mechanism participating in the regulation of CYP1B1 expression, which involves activation of the p38 mitogen-activated protein kinase (p38) and mitogen- and stress-activated protein kinase 1 (MSK1). Using inhibitors of p38 and MSKs, as well as mouse embryonic cells derived from p38α-deficient and MSK1/2 double knockout mice, we show here that TNF-α potentiates CYP1B1 upregulation via the p38/MSK1 kinase cascade. Effects of this inflammatory cytokine on CYP1B1 expression further involve the positive transcription elongation factor b (P-TEFb). The inhibition of the P-TEFb subunit, cyclin-dependent kinase 9 (CDK9), which phosphorylates RNA polymerase II (RNAPII), prevented the enhanced CYP1B1 induction by a combination of BaP and inflammatory cytokine. Furthermore, using chromatin immunoprecipitation assays, we found that cotreatment of epithelial cells with TNF-α and BaP resulted in enhanced recruitment of both CDK9 and RNAPII to the Cyp1b1 gene promoter. Overall, these results have implications concerning the contribution of inflammatory factors to carcinogenesis, since enhanced CYP1B1 induction during inflammation may alter metabolism of exogenous carcinogens, as well as endogenous CYP1B1 substrates playing role in tumor development. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  19. Flavopiridol pharmacogenetics: clinical and functional evidence for the role of SLCO1B1/OATP1B1 in flavopiridol disposition.

    Directory of Open Access Journals (Sweden)

    Wenjun Ni

    2010-11-01

    Full Text Available Flavopiridol is a cyclin-dependent kinase inhibitor in phase II clinical development for treatment of various forms of cancer. When administered with a pharmacokinetically (PK-directed dosing schedule, flavopiridol exhibited striking activity in patients with refractory chronic lymphocytic leukemia. This study aimed to evaluate pharmacogenetic factors associated with inter-individual variability in pharmacokinetics and outcomes associated with flavopiridol therapy.Thirty-five patients who received single-agent flavopiridol via the PK-directed schedule were genotyped for 189 polymorphisms in genes encoding 56 drug metabolizing enzymes and transporters. Genotypes were evaluated in univariate and multivariate analyses as covariates in a population PK model. Transport of flavopiridol and its glucuronide metabolite was evaluated in uptake assays in HEK-293 and MDCK-II cells transiently transfected with SLCO1B1. Polymorphisms in ABCC2, ABCG2, UGT1A1, UGT1A9, and SLCO1B1 were found to significantly correlate with flavopiridol PK in univariate analysis. Transport assay results indicated both flavopiridol and flavopiridol-glucuronide are substrates of the SLCO1B1/OATP1B1 transporter. Covariates incorporated into the final population PK model included bilirubin, SLCO1B1 rs11045819 and ABCC2 rs8187710. Associations were also observed between genotype and response. To validate these findings, a second set of data with 51 patients was evaluated, and overall trends for associations between PK and PGx were found to be consistent.Polymorphisms in transport genes were found to be associated with flavopiridol disposition and outcomes. Observed clinical associations with SLCO1B1 were functionally validated indicating for the first time its relevance as a transporter of flavopiridol and its glucuronide metabolite. A second 51-patient dataset indicated similar trends between genotype in the SLCO1B1 and other candidate genes, thus providing support for these findings

  20. Flavopiridol pharmacogenetics: clinical and functional evidence for the role of SLCO1B1/OATP1B1 in flavopiridol disposition.

    Science.gov (United States)

    Ni, Wenjun; Ji, Jia; Dai, Zunyan; Papp, Audrey; Johnson, Amy J; Ahn, Sunjoo; Farley, Katherine L; Lin, Thomas S; Dalton, James T; Li, Xiaobai; Jarjoura, David; Byrd, John C; Sadee, Wolfgang; Grever, Michael R; Phelps, Mitch A

    2010-11-01

    Flavopiridol is a cyclin-dependent kinase inhibitor in phase II clinical development for treatment of various forms of cancer. When administered with a pharmacokinetically (PK)-directed dosing schedule, flavopiridol exhibited striking activity in patients with refractory chronic lymphocytic leukemia. This study aimed to evaluate pharmacogenetic factors associated with inter-individual variability in pharmacokinetics and outcomes associated with flavopiridol therapy. Thirty-five patients who received single-agent flavopiridol via the PK-directed schedule were genotyped for 189 polymorphisms in genes encoding 56 drug metabolizing enzymes and transporters. Genotypes were evaluated in univariate and multivariate analyses as covariates in a population PK model. Transport of flavopiridol and its glucuronide metabolite was evaluated in uptake assays in HEK-293 and MDCK-II cells transiently transfected with SLCO1B1. Polymorphisms in ABCC2, ABCG2, UGT1A1, UGT1A9, and SLCO1B1 were found to significantly correlate with flavopiridol PK in univariate analysis. Transport assay results indicated both flavopiridol and flavopiridol-glucuronide are substrates of the SLCO1B1/OATP1B1 transporter. Covariates incorporated into the final population PK model included bilirubin, SLCO1B1 rs11045819 and ABCC2 rs8187710. Associations were also observed between genotype and response. To validate these findings, a second set of data with 51 patients was evaluated, and overall trends for associations between PK and PGx were found to be consistent. Polymorphisms in transport genes were found to be associated with flavopiridol disposition and outcomes. Observed clinical associations with SLCO1B1 were functionally validated indicating for the first time its relevance as a transporter of flavopiridol and its glucuronide metabolite. A second 51-patient dataset indicated similar trends between genotype in the SLCO1B1 and other candidate genes, thus providing support for these findings. Further study

  1. 26 CFR 1.6050B-1 - Information returns by person making unemployment compensation payments.

    Science.gov (United States)

    2010-04-01

    ... unemployment compensation payments. 1.6050B-1 Section 1.6050B-1 Internal Revenue INTERNAL REVENUE SERVICE... Information returns by person making unemployment compensation payments. For taxable years beginning after December 31, 1978, every person who makes payments of unemployment compensation (as defined in section 85...

  2. Immunosuppressive effects of fumonisin B1 in the Trichinella spiralis model

    NARCIS (Netherlands)

    Nijs M de; Egmond HP van; Jong WH de; Loveren H van; LPI; ARO; MGB

    2002-01-01

    Fumonisine B1 is een mycotoxine geproduceerd door Fusarium moniliforme en wordt vooral gevonden in mais. Fumonisine B1 veroorzaakt oesophaguskanker in de mens, longoedeem in het varken en leuko-encephalomalacie in het paard. Effecten van dit mycotoxine op het immuunsysteem werden waargenomen in

  3. A subset of AID-dependent B-1a cells initiates hypersensitivity and pneumococcal pneumonia resistance

    NARCIS (Netherlands)

    Askenase, Phillip W; Bryniarski, Krzysztof; Paliwal, Vipin; Redegeld, Frank; Groot Kormelink, Thomas; Kerfoot, Steven; Hutchinson, Andrew T; van Loveren, Henk; Campos, Regis; Itakura, Atsuko; Majewska-Szczepanik, Monika; Yamamoto, Natsuo; Nazimek, Katarzyn; Szczepanik, Marian; Ptak, Wold

    2015-01-01

    We propose that there is a special B-1a B cell subset ("sB-1a" cells) that mediates linked processes very early after immunization to initiate cutaneous contact sensitivity (CS), delayed-type hypersensitivity (DTH), and immune resistance to pneumococcal pneumonia. Our published data indicate that in

  4. 26 CFR 1.669(b)-1A - Tax on distribution.

    Science.gov (United States)

    2010-04-01

    ... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Tax on distribution. 1.669(b)-1A Section 1.669(b... (CONTINUED) INCOME TAXES Treatment of Excess Distributions of Trusts Applicable to Taxable Years Beginning Before January 1, 1969 § 1.669(b)-1A Tax on distribution. (a) In general. The partial tax imposed on the...

  5. 26 CFR 1.668(b)-1A - Tax on distribution.

    Science.gov (United States)

    2010-04-01

    ... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Tax on distribution. 1.668(b)-1A Section 1.668(b... (CONTINUED) INCOME TAXES Treatment of Excess Distributions of Trusts Applicable to Taxable Years Beginning Before January 1, 1969 § 1.668(b)-1A Tax on distribution. (a) In general. The partial tax imposed on the...

  6. DREAM - A Novel Approach for Robust, Ultra-Fast, Multi-Slice B1 Mapping

    NARCIS (Netherlands)

    Nehrke, K.; Boernert, P.

    2012-01-01

    Fast and robust in vivo B1 mapping is an essential prerequisite forquantitative MRI or multi-element transmit applications like RF-shimming or accelerated multi-dimensional RF pulses. However, especially at higher field strength, the acquisition speed of current B1-mapping approaches is

  7. 26 CFR 1.802(b)-1 - Tax on life insurance companies.

    Science.gov (United States)

    2010-04-01

    ... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Tax on life insurance companies. 1.802(b)-1...) INCOME TAX (CONTINUED) INCOME TAXES Life Insurance Companies § 1.802(b)-1 Tax on life insurance companies... August 16, 1954, section 802(b) imposes a tax on the 1954 life insurance company taxable income of all...

  8. Role of CYP1B1 in PAH-DNA Adduct Formation and Breast Cancer Risk

    National Research Council Canada - National Science Library

    Goth-Goldstein, Regine

    2002-01-01

    ...) to reactive intermediates appears to be the cytochrome P45O enzyme CYPlB1. High CYPlB1 enzyme levels may result in increased formation of PAH-DNA adducts in breast tissue and lead to subsequent development of breast cancer...

  9. 26 CFR 31.3302(b)-1 - Additional credit against tax.

    Science.gov (United States)

    2010-04-01

    ... 26 Internal Revenue 15 2010-04-01 2010-04-01 false Additional credit against tax. 31.3302(b)-1...) EMPLOYMENT TAXES AND COLLECTION OF INCOME TAX AT SOURCE EMPLOYMENT TAXES AND COLLECTION OF INCOME TAX AT SOURCE Federal Unemployment Tax Act (Chapter 23, Internal Revenue Code of 1954) § 31.3302(b)-1 Additional...

  10. Literatuuronderzoek naar HPLC-methoden voor de bepaling van vitamine B1 en B2

    NARCIS (Netherlands)

    Hollman, P.

    1986-01-01

    Analyses van vitamine B1 en B2 worden door de afdeling Additieven/Micronutrienten veelvuldig uitgevoerd in zeer diverse produkten. Dit stelt hoge eisen aan de selektiviteit van de gebruikte methoden. Onlangs werd dan ook HPLC geïntroduceerd voor de analyse van vitamine B1 en B2. Op basis van een

  11. 75 FR 13451 - Airworthiness Directives; Turbomeca Arriel 2B1 Turboshaft Engines

    Science.gov (United States)

    2010-03-22

    ... 2B1 Turboshaft Engines AGENCY: Federal Aviation Administration (FAA), DOT. ACTION: Notice of proposed... Arriel 2B1 turboshaft engines. This proposed AD results from mandatory continuing airworthiness...-2251. FOR FURTHER INFORMATION CONTACT: Kevin Dickert, Aerospace Engineer, Engine Certification Office...

  12. Evaluation of new methods of analysis for the determination of aflatoxin B1 in feeding stuffs

    NARCIS (Netherlands)

    Egmond; H.P.van; Sizoo; E.A.; Paulsch; W.E.

    1985-01-01

    Vier methoden van onderzoek, voorgesteld binnen de EG om de bestaande officiele methode van onderzoek van het bepalen van aflatoxine B1 in voedermiddelen te vervangen, zijn vergeleken voor wat betreft hun geschiktheid om aflatoxine B1 in citrushoudende veevoeders te bepalen. Gebleken is dat de

  13. Production of milk-clotting enzyme by Bacillus subtilis B1 from wheat ...

    African Journals Online (AJOL)

    Three strains, Bacillus subtilis B1, B. subtilis B18 and Bacillus thuringiensis B12, were screened from wheat bran to produce milk-clotting enzyme. Among them, B. subtilis B1 exhibited considerable milkclotting activity with low proteolytic activity. After response surface methodology optimization, milkclotting activity was ...

  14. 26 CFR 1.1402(b)-1 - Self-employment income.

    Science.gov (United States)

    2010-04-01

    ... remuneration paid to an employee for services covered by: (a) An agreement entered into pursuant to section 218... 26 Internal Revenue 12 2010-04-01 2010-04-01 false Self-employment income. 1.1402(b)-1 Section 1.1402(b)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX...

  15. 22 CFR 9b.1 - Press access to the Department of State.

    Science.gov (United States)

    2010-04-01

    ..., concessionaries, barber shop, dry cleaners and the Foreign Affairs Recreation Association offices for the purposes... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Press access to the Department of State. 9b.1 Section 9b.1 Foreign Relations DEPARTMENT OF STATE GENERAL REGULATIONS GOVERNING DEPARTMENT OF STATE PRESS...

  16. Immunosuppressive effects of fumonisin B1 in the Trichinella spiralis model

    NARCIS (Netherlands)

    Nijs M de; Egmond HP van; Jong WH de; Loveren H van; LPI; ARO; MGB

    Fumonisin B1 is a mycotoxin produced by Fusarium moniliforme and is found mainly in maize. Fumonisin B1 has been associated with human esophageal cancer, lung edema in pigs and leuko-encephalomalacia in equine species. Adverse effects of this mycotoxin on the immune system can be expected but were

  17. 26 CFR 1.662(b)-1 - Character of amounts; when no charitable contributions are made.

    Science.gov (United States)

    2010-04-01

    ... income as the total of each class bears to the total distributable net income of the estate or trust... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Character of amounts; when no charitable contributions are made. 1.662(b)-1 Section 1.662(b)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF...

  18. Long-term exposure to IL-1beta enhances Toll-IL-1 receptor-mediated inflammatory signaling in murine airway hyperresponsiveness

    DEFF Research Database (Denmark)

    Zhang, Yaping; Xu, Cang-Bao; Cardell, Lars-Olaf

    2009-01-01

    -time PCR-based cDNA array. The key gene expressions that were altered were verified by immunohistochemistry using confocal microscopy. Tracheal ring segment contractile responsiveness to the inflammatory mediator bradykinin was monitored using a sensitive myograph system. The results showed that after...... array, a sensitive and powerful tool, consisting of 84 genes related to Toll-IL-1 receptor signal pathways. Murine tracheal segments were organ cultured for four days in the presence and absence of IL-1beta. The Toll-IL-1 receptor-mediated inflammatory signal gene profile was studied using the real...

  19. The occurrence of fumonisin B1 in maize-containing foods in The Netherlands.

    Science.gov (United States)

    de Nijs, M; Sizoo, E A; Vermunt, A E; Notermans, S H; van Egmond, H P

    1998-01-01

    Seventy-eight maize-containing foods obtained from retail stores in The Netherlands were analysed for fumonisin B1 contamination. Thirty-six per cent of the samples were contaminated with fumonisin B1 in the range of 8 micrograms kg-1 (limit of detection) to 1430 micrograms/kg-1. Forty-six per cent of the minimally treated maize samples (n = 39; maize for bread production, maize for popcorn, maize flour and polenta) were contaminated with fumonisin B1 in the range of 8-380 micrograms kg-1. Twenty-six per cent of the maize-containing processed foods (n = 39; tostada, canned maize, maize starch, maize bread, popped maize, flour mixes, maize chips and cornflakes) were contaminated with fumonisin B1 in the range of 8-1430 micrograms/kg-1. This survey shows that maize-containing foods in The Netherlands frequently can be contaminated with fumonisin B1.

  20. Goniodysgenesis variability and activity of CYP1B1 genotypes in primary congenital glaucoma.

    Directory of Open Access Journals (Sweden)

    María T García-Antón

    Full Text Available Mutations in the CYP1B1 gene are currently the main known genetic cause of primary congenital glaucoma (PCG, a leading cause of blindness in children. Here, we analyze for the first time the CYP1B1 genotype activity and the microscopic and clinical phenotypes in human PCG. Surgical pieces from trabeculectomy from patients with PCG (n = 5 and sclerocorneal rims (n = 3 from cadaver donors were processed for transmission electron microscopy. Patients were classified into three groups depending on goniodysgenesis severity, which was influenced by CYP1B1 enzymatic activity. The main histological changes observed in the outflow pathway of patients with PCG and mutations in CYP1B1 were: i underdeveloped collector channels and the Schlemm's canal; ii abnormal insertion of the ciliary muscle; iii death of the trabecular endothelial cells. Our findings could be useful in improving treatment strategy of PCG associated with CYP1B1 mutations.

  1. Sulfolobus Replication Factor C stimulates the activity of DNA Polymerase B1

    DEFF Research Database (Denmark)

    Xing, Xuanxuan; Zhang, Likui; Guo, Li

    2014-01-01

    Replication factor C (RFC) is known to function in loading proliferating cell nuclear antigen (PCNA) onto primed DNA, allowing PCNA to tether DNA polymerase for highly processive DNA synthesis in eukaryotic and archaeal replication. In this report, we show that an RFC complex from...... with the ability of RFC to facilitate DNA binding by PolB1 through protein-protein interaction. These results suggest that Sulfolobus RFC may play a role in recruiting DNA polymerase for efficient primer extension, in addition to clamp loading, during DNA replication....... the hyperthermophilic archaea of the genus Sulfolobus physically interacts with DNA polymerase B1 (PolB1) and enhances both the polymerase and 3'-5' exonuclease activities of PolB1 in an ATP-independent manner. Stimulation of the PolB1 activity by RFC is independent of the ability of RFC to bind DNA but is consistent...

  2. CYP1B1 Mutations in Individuals With Primary Congenital Glaucoma and Residing in Denmark

    DEFF Research Database (Denmark)

    Grønskov, Karen; Redó-Riveiro, Alba; Sandfeld, Lisbeth

    2016-01-01

    in Denmark. The study included 37 unrelated individuals with PCG. Individuals were investigated for CYP1B1 mutations by Sanger sequencing of polymerase chain reaction products using BigDye terminators and capillary electrophoresis. A total of 12 mutations were identified and 5 of these were novel. Six were......Primary congenital glaucoma (PCG OMIM 231300) can be caused by pathogenic sequence variations in cytochrome P450, subfamily 1, polypeptide 1 (CYP1B1). The purpose of this study was to investigate the contribution of sequence variations in CYP1B1 in a cohort of individuals with PCG residing...... was homozygous and 1 was apparently homozygous. Three individuals were heterozygous for sequence variations in CYP1B1 thought to be pathogenic-one of these was p.(Tyr81Asn). Several known sequence variations with presumably no functional effect were found in the cohort. In this study, we identified 12 CYP1B1...

  3. OCT4B1 Regulates the Cellular Stress Response of Human Dental Pulp Cells with Inflammation

    Directory of Open Access Journals (Sweden)

    Lu Liu

    2017-01-01

    Full Text Available Introduction. Infection and apoptosis are combined triggers for inflammation in dental tissues. Octamer-binding transcription factor 4-B1 (OCT4B1, a novel spliced variant of OCT4 family, could respond to the cellular stress and possess antiapoptotic property. However, its specific role in dental pulpitis remains unknown. Methods. To investigate the effect of OCT4B1 on inflammation of dental pulp cells (DPCs, its expression in inflamed dental pulp tissues and DPCs was examined by in situ hybridization, real-time PCR, and FISH assay. OCT4B1 overexpressed DPCs model was established, confirmed by western blot and immunofluorescence staining, and then stimulated with Lipopolysaccharide (LPS. Apoptotic rate was determined by Hoechst/PI staining and FACS. Cell survival rate was calculated by CCK8 assay. Results. In situ hybridization, real-time PCR, and FISH assay revealed that OCT4B1 was extensively expressed in inflamed dental pulp tissues and DPCs with LPS stimulation. Western blot and immunofluorescence staining showed the expression of OCT4B1 and OCT4B increased after OCT4B1 transfection. Hoechst/PI staining and FACS demonstrated that less red/blue fluorescence was detected and apoptotic percentage decreased (3.45% after transfection. CCK8 demonstrated that the survival rate of pCDH-OCT4B1-flag cells increased. Conclusions. OCT4B1 plays an essential role in inflammation and apoptosis of DPCs. OCT4B might operate synergistically with OCT4B1 to reduce apoptosis.

  4. SF3B1-initiating mutations in MDS-RSs target lymphomyeloid hematopoietic stem cells.

    Science.gov (United States)

    Mortera-Blanco, Teresa; Dimitriou, Marios; Woll, Petter S; Karimi, Mohsen; Elvarsdottir, Edda; Conte, Simona; Tobiasson, Magnus; Jansson, Monika; Douagi, Iyadh; Moarii, Matahi; Saft, Leonie; Papaemmanuil, Elli; Jacobsen, Sten Eirik W; Hellström-Lindberg, Eva

    2017-08-17

    Mutations in the RNA splicing gene SF3B1 are found in >80% of patients with myelodysplastic syndrome with ring sideroblasts (MDS-RS). We investigated the origin of SF3B1 mutations within the bone marrow hematopoietic stem and progenitor cell compartments in patients with MDS-RS. Screening for recurrently mutated genes in the mononuclear cell fraction revealed mutations in SF3B1 in 39 of 40 cases (97.5%), combined with TET2 and DNMT3A in 11 (28%) and 6 (15%) patients, respectively. All recurrent mutations identified in mononuclear cells could be tracked back to the phenotypically defined hematopoietic stem cell (HSC) compartment in all investigated patients and were also present in downstream myeloid and erythroid progenitor cells. While in agreement with previous studies, little or no evidence for clonal (SF3B1 mutation) involvement could be found in mature B cells, consistent involvement at the pro-B-cell progenitor stage was established, providing definitive evidence for SF3B1 mutations targeting lymphomyeloid HSCs and compatible with mutated SF3B1 negatively affecting lymphoid development. Assessment of stem cell function in vitro as well as in vivo established that only HSCs and not investigated progenitor populations could propagate the SF3B1 mutated clone. Upon transplantation into immune-deficient mice, SF3B1 mutated MDS-RS HSCs differentiated into characteristic ring sideroblasts, the hallmark of MDS-RS. Our findings provide evidence of a multipotent lymphomyeloid HSC origin of SF3B1 mutations in MDS-RS patients and provide a novel in vivo platform for mechanistically and therapeutically exploring SF3B1 mutated MDS-RS. © 2017 by The American Society of Hematology.

  5. CYP1B1 Cytopathy: Uncommon Phenotype of a Homozygous CYP1B1 Deletion as Internal Corneal Ulcer of Von Hippel.

    Science.gov (United States)

    Oliva-Biénzobas, Valeria; Navas, Alejandro; C Astiazarán, Mirena; Chacón-Camacho, Oscar Francisco; A Bermúdez-Magner, Jose; Takane, Mariana; Graue-Hernández, Enrique; Zenteno, Juan Carlos

    2017-10-01

    To report a mutation of CYP1B1 in a newborn with a rare phenotype without the classic features of anterior segment dysgenesis or congenital glaucoma. The newborn presented with diffuse corneal edema and bilaterally elevated intraocular pressure (IOP). Ophthalmological examination, ultrasound, and ultrasound biomicroscopy were performed; congenital infections were ruled out. Genetic analysis was performed. The patient underwent penetrating keratoplasty and goniotomy in a single surgical time. The button was subjected to histopathological examination. The patient is the first child of young, healthy, consanguineous parents. Ophthalmological examination revealed visual acuity of light perception and increased IOP in both eyes. CYP1B1 gene analysis demonstrated homozygosity for a 1-bp deletion in exon 2 (c.830delT). IOP was normalized, and the corneal button was clear after surgical treatment. Histopathological analysis revealed loss of the Bowman membrane in the central cornea, fibrosis of the stroma, absence of endothelial cells, and loss of Descemet membrane centrally. We present an uncommon mutation and clinical description of CYP1B1. This report and further studies could provide us better understanding of the mutational spectrum of CYP1B1.

  6. Impact of angiotensin and endothelin converting enzymes and related bradykinin on renal functions in L-NAME hypertensive rats

    Science.gov (United States)

    Omar, Ali Zainal; Maulood, Ismail M.

    2017-09-01

    The renin-angiotensin system (RAS), one of the most important hormonal systems, controls the kidney functions by regulating fluid volume, and electrolyte balance. The current study included the effects of kinin-kallikrein system (KKS) and its interaction with both angiotensin converting enzyme (ACE) and endothelin converting enzyme (ECE) on some of kidney function test parameters. In the present experiment, rats were divided into six groups, the first group was infused with normal saline, the second group was L-NG-Nitroarginine methyl ester (L-NAME) treated rats, third group was bradykinin (BK), forth group was captopril (ACEi), fifth group was phosphoramidon (ECEi), sixth group was a combination of BK with phosphoramidon. L-NAME was intravenously infused for one hour to develop systematic hypertension in male rats. After one hour of infusion, the results showed that L-NAME significantly increased serum creatinine. While, it decreased glomerular filtration rate (GFR), and K+ excretion rate. Moreover, BK increased packed cell volume PCV%, serum creatinine and K+ ion concentration. While, it reduced GFR, serum Ca+2 ion concentration, K+ and Na+ excretion rates. On the other hand, captopril infusion showed its effect by reduction in GFR, serum Ca+2 ion and electrolyte excretion rates. Phosphoramidon an ECEi dramatically reduced serum Ca+2 ion, but it increased pH, GFR and Ca+2 excretion rate. The results suggested that BK and Captopril each alone severely reduces GFR value. Interestingly, inhibition of ET-1 production via phosphoramidon could markedly elevate GFR values.

  7. A bradykinin potentiating peptide from Egyptian cobra venom strongly affects rat atrium contractile force and cellular calcium regulation.

    Science.gov (United States)

    El-Saadani, Muhammad A M; El-Sayed, Muhammad F

    2003-12-01

    Peptide fractions were isolated from venoms of the Egyptian snake Naja haje haje (cobra BPP) and the scorpions Buthus occitanus (BPP(B)) and Leirus quenquestriatus (BPP(L)). The pharmacological effects of these peptides were bioassayed and showed bradykinin potentiating activities. Amino acid analysis revealed that 14 amino acids contribute to the structure of BPP(B) and 16 for BPP(L), while cobra BPP was composed of 15 amino acids. Treatment of rat atrial preparations with 50 microg/ml of cobra BPP caused a significant reduction (Pcobra BPP in a way that restored the atrial force development. Na(+)-channel blockers did not change the force development at 5 mM Ca(2+). Experiments with (45)Ca revealed that Ca(2+) uptake of cobra BPP treated atria was 0.52+/-0.07 microM/g wet mass and the force at the end of the uptake period was 55.0+/-2.0%. The corresponding values for non-treated preparations were 0.56+/-0.04 microM/g and 92.0%+/-3.0%, respectively. Our results revealed that cobra BPP did not exhibit any effect on Ca(2+) uptake by rat atrial preparations, but strongly affected cellular Ca(2+) regulation.

  8. Interaction between bradykinin potentiating nonapeptide (BPP9a) and {beta}-cyclodextrin: A structural and thermodynamic study

    Energy Technology Data Exchange (ETDEWEB)

    Lula, Ivana; De Sousa, Frederico B. [Departamento de Quimica, Instituto de Ciencias Exatas, Universidade Federal de Minas Gerais, Av. Antonio Carlos, 6627, 31270-901, Belo Horizonte, MG (Brazil); Denadai, Angelo M.L. [Centro Federal de Educacao Tecnologica de Minas Gerais, CEFET-MG, Campus VII, 35.183-006, Timoteo, MG (Brazil); Ferreira de Lima, Guilherme; Duarte, Helio Anderson [Departamento de Quimica, Instituto de Ciencias Exatas, Universidade Federal de Minas Gerais, Av. Antonio Carlos, 6627, 31270-901, Belo Horizonte, MG (Brazil); Mares Guia, Thiago R. dos [Departamento de Bioquimica e Imunologia, ICB, Universidade Federal de Minas Gerais, 31270-901, Belo Horizonte, MG (Brazil); Faljoni-Alario, Adelaide [Departamento de Bioquimica, Instituto de Quimica, Universidade de Sao Paulo, 05508-900, Sao Paulo, SP (Brazil); Santoro, Marcelo M. [Departamento de Bioquimica e Imunologia, ICB, Universidade Federal de Minas Gerais, 31270-901, Belo Horizonte, MG (Brazil); Camargo, Antonio C.M. de [Center for Applied Toxinology CAT-CEPID, Laboratorio Especial de Toxicologia Aplicada, Instituto Butantan, 05503-900, Sao Paulo, SP (Brazil); Santos, Robson A.S. dos [Departamento de Fisiologia e Biofisica, ICB, Universidade Federal de Minas Gerais, 31270-901, Belo Horizonte, MG (Brazil); and others

    2012-02-01

    Herein, we demonstrate the physical and chemical characterizations of the supramolecular complex formed between {beta}-cyclodextrin ({beta}CD) and bradykinin potentiating nonapeptide (BPP9a), an endogenous toxin found in Bothrops jararaca. Circular dichroism results indicate a conformational change in the BPP9a secondary structure upon its complexation with {beta}CD. Nuclear magnetic resonance results, mainly from NOESY experiments, and theoretical calculations showed a favorable interaction between the tryptophan residue of BPP9a and the {beta}CD cavity. Thermodynamic inclusion parameters were investigated by isothermal titration calorimetry, demonstrating that {beta}CD/BPP9a complex formation is an exothermic process that results in a reduction in entropy. Additionally, in vitro degradation study of BPP9a against trypsin (37 Degree-Sign C, pH 7.2) showed higher stability of peptide in presence of {beta}CD. This {beta}CD/BPP9a complex, which presents new chemical properties arising from the peptide inclusion process, may be useful as an antihypertensive drug in oral pharmaceutical formulations. Highlights: Black-Right-Pointing-Pointer Cd and NMR showed evidences for the existence of more than one structure in solution. Black-Right-Pointing-Pointer Complexation with {beta}CD reduces the conformational rigidity of the peptide. Black-Right-Pointing-Pointer {beta}CD cavity recognize Trp and/or Pro segments of BPP9a. Black-Right-Pointing-Pointer Interactions involving disaggregation of BPP9a assemblies and binding with {beta}CD.

  9. Effect of bradykinin on TGF-β1-induced retinal pigment epithelial cell proliferation and extracellular matrix secretion.

    Science.gov (United States)

    Cai, Wenting; Wei, Qingquan; Liu, Qingyu; Ren, Chengda; Liu, Junling; Zhang, Ruiling; He, Mengmei; Wang, Qianyi; Du, Yaru; Yu, Jing

    2016-11-10

    To evaluate the effect of bradykinin (BK) on TGF-β1-induced retinal pigment epithelial (RPE) cell proliferation and extracellular matrix secretion and to elucidate the relationship between BK and the Erk/Akt signaling pathway. The effects of BK on TGF-β1-induced RPE cell proliferation were examined via CCK-8 assay. Cell culture supernatant collagen I concentrations were measured via ELISA. Fibronectin (Fn), matrix metalloproteinase-2 (MMP-2) and MMP-9 mRNA and protein expression levels were measured via q-PCR and Western blotting, respectively. Changes in Akt/Erk phosphorylation induced by BK and HOE-140 were evaluated via Western blotting. TGF-β1 stimulated ARPE-19 cell proliferation, which was inhibited by BK, whose effects were inhibited by HOE-140. BK inhibited TGF-β1-induced collagen I, Fn and MMP-2 secretion in RPE cells, and these effects were inhibited by HOE-140. BK also inhibited TGF-β1-induced Akt phosphorylation in RPE cells, and these effects were blocked by HOE-140. BK had no significant effect on Erk-mediated signaling. The findings from this study indicate that BK could be novel therapeutic targets for the treatment of PVR.

  10. OATP1B1 Polymorphism as a Determinant of Erythromycin Disposition

    Science.gov (United States)

    Lancaster, CS; Bruun, GH; Peer, CJ; Mikkelsen, TS; Corydon, TJ; Gibson, AA; Hu, S; Orwick, SJ; Mathijssen, RHJ; Figg, WD; Baker, SD; Sparreboom, A

    2012-01-01

    Previous studies have demonstrated that the pharmacokinetic profile of erythromycin, a probe for CYP3A4 activity, is affected by inhibitors or inducers of hepatic solute carriers. We hypothesized that these interactions are mediated by OATP1B1 (gene symbol, SLCO1B1), a polypeptide expressed on the basolateral surface of hepatocytes. Using stably transfected Flp-In T-REx 293 cells, erythromycin was found to be a substrate for OATP1B1*1A (wildtype) with a Km of ~13 µM, and its transport was reduced by ~50% in cells expressing OATP1B1*5 (V174A). Deficiency of the ortholog transporter Oatp1b2 in mice was associated with a 52% decrease in the metabolic rate of erythromycin (P = 0.000043). In line with these observations, in humans, the c.521T>C variant in SLCO1B1 (rs4149056), encoding OATP1B1*5, was associated with a genotype-dosage dependent decline in erythromycin metabolism (P = 0.0072). These results suggest that impaired OATP1B1 function can alter erythromycin metabolism independently of changes in CYP3A4 activity. PMID:22990751

  11. Tensor-polarized structure function b1 in the standard convolution description of the deuteron

    Science.gov (United States)

    Cosyn, W.; Dong, Yu-Bing; Kumano, S.; Sargsian, M.

    2017-04-01

    Tensor-polarized structure functions of a spin-1 hadron are additional observables, which do not exist for the spin-1 /2 nucleon. They could probe novel aspects of the internal hadron structure. Twist-2 tensor-polarized structure functions are b1 and b2, and they are related by the Callan-Gross-like relation in the Bjorken scaling limit. In this work, we theoretically calculate b1 in the standard convolution description for the deuteron. Two different theoretical models, a basic convolution description and a virtual nucleon approximation, are used for calculating b1, and their results are compared with the HERMES measurement. We found large differences between our theoretical results and the data. Although there is still room to improve by considering higher-twist effects and in the experimental extraction of b1 from the spin asymmetry Az z, there is a possibility that the large differences require physics beyond the standard deuteron model for their interpretation. Future b1 studies could shed light on a new field of hadron physics. In particular, detailed experimental studies of b1 will start soon at the Thomas Jefferson National Accelerator Facility. In addition, there are possibilities to investigate tensor-polarized parton distribution functions and b1 at Fermi National Accelerator Laboratory and a future electron-ion collider. Therefore, further theoretical studies are needed for understanding the tensor structure of the spin-1 deuteron, including a new mechanism to explain the large differences between the current data and our theoretical results.

  12. OATP1B1 polymorphism as a determinant of erythromycin disposition.

    Science.gov (United States)

    Lancaster, C S; Bruun, G H; Peer, C J; Mikkelsen, T S; Corydon, T J; Gibson, A A; Hu, S; Orwick, S J; Mathijssen, R H J; Figg, W D; Baker, S D; Sparreboom, A

    2012-11-01

    Previous studies have demonstrated that the pharmacokinetic profile of erythromycin, a probe for CYP3A4 activity, is affected by inhibitors or inducers of hepatic solute carriers. We hypothesized that these interactions are mediated by OATP1B1 (gene symbol, SLCO1B1), a polypeptide expressed on the basolateral surface of hepatocytes. Using stably transfected Flp-In T-Rex293 cells, erythromycin was found to be a substrate for OATP1B1*1A (wild type) with a Michaelis-Menten constant of ~13 µmol/l, and that its transport was reduced by ~50% in cells expressing OATP1B1*5 (V174A). Deficiency of the ortholog transporter Oatp1b2 in mice was associated with a 52% decrease in the metabolic rate of erythromycin (P = 0.000043). In line with these observations, in humans the c.521T>C variant in SLCO1B1 (rs4149056), encoding OATP1B1*5, was associated with a decline in erythromycin metabolism (P = 0.0072). These results suggest that impairment of OATP1B1 function can alter erythromycin metabolism, independent of changes in CYP3A4 activity.

  13. Detoxification of aflatoxin B1 and patulin by Enterococcus faecium strains.

    Science.gov (United States)

    Topcu, Ali; Bulat, Tugba; Wishah, Refaat; Boyaci, Ismail H

    2010-05-15

    Aim of the present study was to investigate the detoxification of aflatoxin B(1) and patulin from aqueous solution by probiotic culture of Enterococcus faecium M74 and commercial culture of E. faecium EF031. The effect of the bacterial viability, incubation time and pH of the medium on the binding ability was tested. Also, binding stability was determined by washing the bacteria-mycotoxin complexes with phosphate buffer saline. Both M74 and EF031 strains have the ability to remove aflatoxin B(1) and patulin. While M74 removes 19.3 to 30.5% of aflatoxin B(1) and 15.8 to 41.6% of patulin, EF031 removes 23.4 to 37.5% of aflatoxin B(1) and 19.5 to 45.3% of patulin throughout a 48 h incubation period. The removal of aflatoxin B(1) and patulin was highest at pH 7.0 and 4.0, respectively. The stability of the aflatoxin B(1) and patulin complexes formed with the bacterial strains was found to be high. The viability of the bacteria did not have any significant effect on the detoxification of aflatoxin B(1) and patulin. Detoxification properties of E. faecium could represent new strategies for a possible application in the human diet and animal feed. 2010 Elsevier B.V. All rights reserved.

  14. Vasoinhibins Prevent Bradykinin-Stimulated Endothelial Cell Proliferation by Inactivating eNOS via Reduction of both Intracellular Ca2+ Levels and eNOS Phosphorylation at Ser1179

    Science.gov (United States)

    Thebault, Stéphanie; González, Carmen; García, Celina; Zamarripa, David Arredondo; Nava, Gabriel; Vaca, Luis; López-Casillas, Fernando; de la Escalera, Gonzalo Martínez; Clapp, Carmen

    2011-01-01

    Vasoinhibins, a family of antiangiogenic peptides derived from prolactin proteolysis, inhibit the vascular effects of several proangiogenic factors, including bradykinin (BK). Here, we report that vasoinhibins block the BK-induced proliferation of bovine umbilical vein endothelial cells. This effect is mediated by the inactivation of endothelial nitric oxide synthase (eNOS), as the NO donor DETA-NONOate reverted vasoinhibin action. It is an experimentally proven fact that the elevation of intracellular Ca2+ levels ([Ca2+]i) upon BK stimulation activates eNOS, and vasoinhibins blocked the BK-mediated activation of phospholipase C and the formation of inositol 1,4,5-triphosphate leading to a reduced release of Ca2+ from intracellular stores. The [Ca2+]i rise evoked by BK also involves the influx of extracellular Ca2+ via canonical transient receptor potential (TRPC) channels. Vasoinhibins likely interfere with TRPC-mediated Ca2+ entry since La3+, which is an enhancer of TRPC4 and TRPC5 channel activity, prevented vasoinhibins from blocking the stimulation by BK of endothelial cell NO production and proliferation, and vasoinhibins reduced the BK-induced increase of TRPC5 mRNA expression. Finally, vasoinhibins prevented the BK-induced phosphorylation of eNOS at Ser1179, a post-translational modification that facilitates Ca2+-calmodulin activation of eNOS. Together, our data show that vasoinhibins, by lowering NO production through the inhibition of both [Ca2+]i mobilization and eNOS phosphorylation, prevent the BK-induced stimulation of endothelial cell proliferation. Thus, vasoinhibins help to regulate BK effects on angiogenesis and vascular homeostasis.

  15. Vasoinhibins Prevent Bradykinin-Stimulated Endothelial Cell Proliferation by Inactivating eNOS via Reduction of both Intracellular Ca2+ Levels and eNOS Phosphorylation at Ser1179

    Directory of Open Access Journals (Sweden)

    Carmen Clapp

    2011-07-01

    Full Text Available Vasoinhibins, a family of antiangiogenic peptides derived from prolactin proteolysis, inhibit the vascular effects of several proangiogenic factors, including bradykinin (BK. Here, we report that vasoinhibins block the BK-induced proliferation of bovine umbilical vein endothelial cells. This effect is mediated by the inactivation of endothelial nitric oxide synthase (eNOS, as the NO donor DETA-NONOate reverted vasoinhibin action. It is an experimentally proven fact that the elevation of intracellular Ca2+ levels ([Ca2+]i upon BK stimulation activates eNOS, and vasoinhibins blocked the BK-mediated activation of phospholipase C and the formation of inositol 1,4,5-triphosphate leading to a reduced release of Ca2+ from intracellular stores. The [Ca2+]i rise evoked by BK also involves the influx of extracellular Ca2+ via canonical transient receptor potential (TRPC channels. Vasoinhibins likely interfere with TRPC-mediated Ca2+ entry since La3+, which is an enhancer of TRPC4 and TRPC5 channel activity, prevented vasoinhibins from blocking the stimulation by BK of endothelial cell NO production and proliferation, and vasoinhibins reduced the BK-induced increase of TRPC5 mRNA expression. Finally, vasoinhibins prevented the BK-induced phosphorylation of eNOS at Ser1179, a post-translational modification that facilitates Ca2+-calmodulin activation of eNOS. Together, our data show that vasoinhibins, by lowering NO production through the inhibition of both [Ca2+]i mobilization and eNOS phosphorylation, prevent the BK-induced stimulation of endothelial cell proliferation. Thus, vasoinhibins help to regulate BK effects on angiogenesis and vascular homeostasis.

  16. Protein kinase C affects the internalization and recycling of organic anion transporting polypeptide 1B1.

    Science.gov (United States)

    Hong, Mei; Hong, Weifang; Ni, Chunxu; Huang, Jiujiu; Zhou, Chao

    2015-10-01

    Organic anion-transporting polypeptides are members of the solute carrier (SLC) family and key determinants for the transmembrane transport of a wide variety of compounds. OATP1B1 is predominantly expressed at the basolateral membrane of human hepatocytes and play an important role in drug clearance from the body. It has been demonstrated to be responsible for the hepatic uptake of various drugs. Computer-based hydropathy analysis predicted several putative phosphorylation sites at the amino and carboxyl termini and at intracellular loop 3 of OATP family members. Therefore, their transport functions may be regulated by phosphorylation. Previous studies have demonstrated that uptake function of OATP2B1 and OATP1A2 is regulated by protein kinase C (PKC). In the present study, we treated HEK293 cells stably expressing OATP1B1 with different PKC modulators and measured their transport activity for prototypic substrate estrone-3-sulfate. It was found that OATP1B1 uptake function was reduced upon PKC activation. Further studies indicated that PKC may affect OATP1B1 activity through regulation of the cell surface protein level. Moreover, we found out that PKC activator phorbol 12-myristate 13-acetate (PMA) not only affects the internalization of OATP1B1 but its recycling as well. Immunocytochemistry analysis revealed that internalized OATP1B1 co-localized with early and recycling endosomal markers and the co-localization of OATP1B1 with recycling endosome is dependent on PKC activation. Taken together, our present study demonstrated that PKC regulates the function of OATP1B1 by affecting internalization and recycling of the transporter protein. Copyright © 2015 Elsevier B.V. All rights reserved.

  17. Contribution of CYP1B1 mutations and founder effect to primary congenital glaucoma in Mexico.

    Science.gov (United States)

    Zenteno, Juan Carlos; Hernandez-Merino, Elena; Mejia-Lopez, Herlinda; Matías-Florentino, Margarita; Michel, Norma; Elizondo-Olascoaga, Celia; Korder-Ortega, Vincent; Casab-Rueda, Homero; Garcia-Ortiz, Jose Elias

    2008-01-01

    The frequency of primary congenital glaucoma (PCG)-causing CYP1B1 mutations varies importantly among distinct populations, ranging from 20% in Indonesians and Japanese to about 100% among the Saudi Arabians and Slovakian Gypsies. Thus, the molecular characterization of large groups of PCG from different ethnic backgrounds is important to establish the actual CYP1B1 contribution in specific populations. In this work, the molecular analysis of the CYP1B1 gene in a group of Mexican PCG patients is reported. Thirty unrelated Mexican patients fulfilling the clinical criteria for PCG were included. Two cases were familial and with proven consanguinity, originating from distinct regions of the country. Polymerase chain reaction amplification and direct automated sequencing of the CYP1B1 coding region was performed in each participating subject. An identical pathogenic CYP1B1 mutation was demonstrated in 2 unrelated PCG subjects. The mutation consisted of a homozygous G to A transition at nucleotide position 1505 in exon 3, which predicted a substitution of glutamic acid for lysine at residue 387 of the protein (E387K). In the remaining 28 PCG subjects, no deleterious mutations were identified. Both subjects with the E387K mutation shared a same haplotype for 5 CYP1B1 intragenic single nucleotide polymorphisms, indicating a common origin of the allele. Mexican patients with PCG are rarely (less than 10%) due to CYP1B1 mutations. Available data indicate that most of the non-Brazilian Latin American PCG patients investigated to date are not due to CYP1B1 defects. Populations with low incidence of CYP1B1 mutations are appropriate candidates for the identification of novel PCG-causing genes.

  18. Aflatoxin B1 adsorption by the natural aluminosilicates - concentrate of montmorillonite and zeolite

    Directory of Open Access Journals (Sweden)

    Marković Marija A.

    2016-01-01

    Full Text Available Aflatoxin B1 adsorption by the concentrate of bentonite clay - montmorillonite and the natural zeolite - clinoptilolite and was investigated at the initial toxin concentration 4 ppm, with different amonunts of solid phase in suspension (10, 5, 2 and 1 mg/10 mL and different pH values - 3, 7 and 9. Results indicated that for both minerals, decreasing the amount of solid phase in suspension, decrease the amount of active sites relevant for adsorption of aflatoxin B1. Thus, for concentrate of montnorillonite, at the lowest level of solid phase in suspension (1 mg/10 mL, aflatoxin B1 adsorption indexes were 97% at pH 3, 88% at pH 7 and 82% at pH 9, while for the natural zeolite, adsorption of toxin was 9% at pH 3 and 7% at pH 7 and 9. Since inorganic cations in minerals are mainly responsible for aflatoxin B1 adsorption, even the natural zeolite - clinoptilite has much higher cation exchange capacity (the content of inorganic exchangeable cations compared to the concentrate of montmorillonite, adsorption of aflatoxin B1 by this mineral is much lower. Comparing the molecular dimensions of aflatoxin B1 molecule with the dimension of channels of clinoptilolite and interlamellar space of montmorillonite it is obvious that this toxin is adsorbed only at the external surface of clinoptilolite while in the montmorillonite all active sites are equally available for its adsorption. Thus, the concentrate of montmorillonite posess by higher adsorption capacity for aflatoxin B1. Results presented in this paper confirmed the fact the differences in the structure of minerals led to their different efficiency for adsorption of aflatoxin B1. Mineralogical and chemical composition, determination of cation exchange capacity, etc., are very important parameters influencing the effectiveness of minerals as aflatoxin B1 adsorbents. [Projekat Ministarstva nauke Republike Srbije, br. 451-03-2802-IP Tip1/142, br. 172018 i br. 34013

  19. Spliceosomal component Sf3b1 is essential for hematopoietic differentiation in zebrafish.

    Science.gov (United States)

    De La Garza, Adriana; Cameron, Rosannah C; Nik, Sara; Payne, Sara G; Bowman, Teresa V

    2016-09-01

    SF3B1 (Splicing factor 3b, subunit 1) is one of the most commonly mutated factors in myelodysplastic syndrome (MDS). Although the genetic correlation between SF3B1 mutations and MDS etiology are quite strong, no in vivo model currently exists to explore how SF3B1 loss alters blood cell development. Using zebrafish mutants, we show here that proper function of Sf3b1 is required for all hematopoietic lineages. As in MDS patients, zebrafish sf3b1 mutants develop a macrocytic-anemia-like phenotype due to a block in maturation at a late progenitor stage. The mutant embryos also develop neutropenia, because their primitive myeloid cells fail to mature and turn on differentiation markers such as l-plastin and myeloperoxidase. In contrast, production of definitive hematopoietic stem and progenitor cells (HSPCs) from hemogenic endothelial cells within the dorsal aorta is greatly diminished, whereas arterial endothelial cells are correctly fated. Notch signaling, imperative for the endothelial-to-hematopoietic transition, is also normal, indicating that HSPC induction is blocked in sf3b1 mutants downstream or independent of Notch signaling. The data demonstrate that Sf3b1 function is necessary during key differentiation fate decisions in multiple blood cell types. Zebrafish sf3b1 mutants offer a novel animal model with which to explore the role of splicing in hematopoietic development and provide an excellent in vivo system with which to delve into the question of why and how Sf3b1 dysfunction is detrimental to hematopoietic differentiation, which could improve MDS diagnosis and treatment. Copyright © 2016 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.

  20. MicroRNA-223 is a novel negative regulator of HSP90B1 in CLL.

    Science.gov (United States)

    Rodríguez-Vicente, Ana E; Quwaider, Dalia; Benito, Rocío; Misiewicz-Krzeminska, Irena; Hernández-Sánchez, María; de Coca, Alfonso García; Fisac, Rosa; Alonso, José-María; Zato, Carolina; de Paz, Juan Francisco; García, Juan Luis; Sarasquete, Ma Eugenia; Hernández, José Ángel; Corchado, Juan M; González, Marcos; Gutiérrez, Norma C; Hernández-Rivas, Jesús-María

    2015-04-08

    MicroRNAs are known to inhibit gene expression by binding to the 3'UTR of the target transcript. Downregulation of miR-223 has been recently reported to have prognostic significance in CLL. However, there is no evidence of the pathogenetic mechanism of this miRNA in CLL patients. By applying next-generation sequencing techniques we have detected a common polymorphism (rs2307842), in 24% of CLL patients, which disrupts the binding site for miR-223 in HSP90B1 3'UTR. We investigated whether miR-223 directly targets HSP90B1 through luciferase assays and ectopic expression of miR-223. Quantitative real-time polymerase chain reaction and western blot were used to determine HSP90B1 expression in CLL patients. The relationship between rs2307842 status, HSP90B1 expression and clinico-biological data were assessed. HSP90B1 is a direct target for miR-223 by interaction with the putative miR-223 binding site. The analysis in paired samples (CD19+ fraction cell and non-CD19+ fraction cell) showed that the presence of rs2307842 and IGHV unmutated genes determined HSP90B1 overexpression in B lymphocytes from CLL patients. These results were confirmed at the protein level by western blot. Of note, HSP90B1 overexpression was independently predictive of shorter time to the first therapy in CLL patients. By contrast, the presence of rs2307842 was not related to the outcome. HSP90B1 is a direct target gene of miR-223. Our results provide a plausible explanation of why CLL patients harboring miR-223 downregulation are associated with a poor outcome, pointing out HSP90B1 as a new pathogenic mechanism in CLL and a promising therapeutic target.

  1. Distal renal tubular acidosis with nerve deafness secondary to ATP6B1 gene mutation

    Directory of Open Access Journals (Sweden)

    Parvathina Sriram Naveen

    2015-01-01

    Full Text Available Autosomal recessive distal renal tubular acidosis (dRTA is associated with mutation in the ATP6B1 gene encoding the B1 subunit of H + -ATPase, one of the key membrane transporters for net acid excretion of α-intercalated cells of medullary collecting ducts. Sensori-neural deafness frequently accompanies this type of dRTA. We herewith describe a patient who had distinct features of dRTA with bilateral sensori-neural hearing loss and ATP6B1 mutation. This is a rare entity.

  2. CYP1B1 expression in ovarian cancer in the laying hen Gallusdomesticus.

    Science.gov (United States)

    Zhuge, Yan; Lagman, Jo Ann J; Ansenberger, Kristine; Mahon, Cassandra J; Daikoku, Takiko; Dey, Sudhansu K; Bahr, Janice M; Hales, Dale B

    2009-01-01

    Ovarian carcinoma is the most lethal gynecological malignancy. The genetic and molecular mechanisms that cause it still remain largely unknown. CYP1B1 is a cytochrome P450 enzyme that catalyzes the conversion of estrogens to genotoxic catechol estrogens which may cause DNA mutations and initiate ovarian epithelial cancer. Our objectives were to evaluate CYP1B1 expression, distribution and localization in the hen ovary and to determine if there is an increased CYP1B1 expression associated with, and possibly involved in the initiation of ovarian cancer. Two groups of hens were used: 1. young (50 weeks of age; devoid of cancer) and 2. old (165 weeks of age; divided into two groups: age-matched normal and ovarian cancer). CYP1B1 mRNA and protein expression were analyzed in cancerous ovaries, ovaries of age-matched normal and/or young hens by quantitative real-time PCR (qRT-PCR), in situ hybridization (ISH) and immunohistochemistry (IHC). RNA was extracted from tissue preserved in RNAlater for qRT-PCR. Tissue frozen in liquid nitrogen was used for ISH. Tissue fixed in neutral buffered formalin was subjected to IHC. Higher expression of CYP1B1 mRNA was observed in cancerous ovaries as compared to ovaries of young and age-matched normal hens by qRT-PCR. ISH and IHC confirmed that the expression of CYP1B1 was much higher in ovarian tumors compared to ovaries of age-matched normal hens. CYP1B1 mRNA and protein were distributed extensively throughout the carcinoma, while primarily localized to the granulosa layer surrounding the follicle in age-matched normal hens. IHC also showed nuclear localization of CYP1B1. Highly expressed CYP1B1 was found in POF-3 from young and age-matched normal hens as compared to POF-1 and POF-2 by qRT-PCR. No significant difference was found in the expression of CYP1B1 between the distal (site of rupture) and the proximal (site of attachment to the ovary) of POF-1 from young and age-matched normal hens. High expression of CYP1B1 in the hen ovary

  3. Combined Pharmacophore Modeling, 3D-QSAR, Homology Modeling and Docking Studies on CYP11B1 Inhibitors

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    Rui Yu

    2015-01-01

    Full Text Available The mitochondrial cytochrome P450 enzymes inhibitor steroid 11β-hydroxylase (CYP11B1 can decrease the production of cortisol. Therefore, these inhibitors have an effect in the treatment of Cushing’s syndrome. A pharmacophore model generated by Genetic Algorithm with Linear Assignment for Hypermolecular Alignment of Datasets (GALAHAD was used to align the compounds and perform comparative molecular field analysis (CoMFA with Q2 = 0.658, R2 = 0.959. The pharmacophore model contained six hydrophobic regions and one acceptor atom, and electropositive and bulky substituents would be tolerated at the A and B sites, respectively. A three-dimensional quantitative structure-activity relationship (3D-QSAR study based on the alignment with the atom root mean square (RMS was applied using comparative molecular field analysis (CoMFA with Q2 = 0.666, R2 = 0.978, and comparative molecular similarity indices analysis (CoMSIA with Q2 = 0.721, R2 = 0.972. These results proved that all the models have good predictability of the bioactivities of inhibitors. Furthermore, the QSAR models indicated that a hydrogen bond acceptor substituent would be disfavored at the A and B groups, while hydrophobic groups would be favored at the B site. The three-dimensional (3D model of the CYP11B1 was generated based on the crystal structure of the CYP11B2 (PDB code 4DVQ. In order to probe the ligand-binding modes, Surflex-dock was employed to dock CYP11B1 inhibitory compounds into the active site of the receptor. The docking result showed that the imidazolidine ring of CYP11B1 inhibitors form H bonds with the amino group of residue Arg155 and Arg519, which suggested that an electronegative substituent at these positions could enhance the activities of compounds. All the models generated by GALAHAD QSAR and Docking methods provide guidance about how to design novel and potential drugs for Cushing’s syndrome treatment.

  4. Chiral resolution and binding study of 1,3,4,14b-tetrahydro-2,10-dimethyl-2H,10H-pyrazino[2,1-d]pyrrolo[1,2-b] [1,2,5]benzotriazepine (10-methyl-10-azaaptazepine) and 2-methyl-1,3,4,14b-tetrahydro-2H-pyrazino[2,1-d]pyrrolo[1,2-b] [1,2,5]benzothiadiazepine 10,10-dioxide (tiaaptazepine).

    Science.gov (United States)

    De Martino, Gabriella; La Regina, Giuseppe; La Torre, Francesco; Cirilli, Roberto; Mereghetti, Ilario; Cagnotto, Alfredo; Artico, Marino; Silvestri, Romano

    2005-01-01

    The affinities of the enantiomers of 1,3,4,14b-tetrahydro-2,10-dimethyl-2H,10H-pyrazino[2,1-d]pyrrolo[1,2-b] [1,2,5]benzotriazepine (10-methyl-10-azaaptazepine, 5) and 2-methyl-1,3,4,14b-tetrahydro-2H-pyrazino[2,1-d]pyrrolo[1,2-b] [1,2,5]benzothiadiazepine 10,10-dioxide (tiaaptazepine, 6) were evaluated in receptor binding assays. Compound (+)-(S)-5, the most significant tested enantiomer, showed good affinities for 5-HT1A, 5-HT2A 5-HT2C and alpha2NA receptors, moderate affinities for DA1, DA3r and 5-HT3 receptors and it was devoid of affinity for DA2, alpha(1NA) and muscarinic receptors. Compound (+)-(S)-5 showed an interesting pharmacological profile different from those of the reference compounds mirtazepine, mianserin and 6-methoxymianserin.

  5. Organic anion transporter 1B1 (SLCO1B1) polymorphism and gallstone formation: High incidence of Exon4 CA genotype in female patients in North India.

    Science.gov (United States)

    Srivastava, Anshika; Srivastava, Anvesha; Srivastava, Neena; Choudhuri, Gourdas; Mittal, Balraj

    2011-01-01

      Gallstone disease is an important cause of abdominal morbidity Organic anion transport protein 1B1 (OATP1B1) (encoded by SLCO1B1) is a major transporter protein for bile salt uptake in enterohepatic circulation of bile salts. Disturbance in this pathway can decrease relative concentration of bile salts in gallbladder and may lead to formation of gallstones. We investigated role of SLCO1B1 polymorphisms [(Exon4 C > A (Pro155Thr; rs11045819) and Ex6 + 40T > C (Val174Ala; rs4149056)] in conferring interindividual susceptibility to gallstone disease.   A total of 173 healthy controls and 226 gallstone patients (USG positive) were recruited. Genotyping was done by using standard polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method.   The observed control frequencies of both polymorphisms of SLCO1B1 gene [(Exon4 C > A (Pro155Thr; rs11045819) and Ex6 + 40T > C (Val174Ala; rs4149056)] were in agreement with Hardy-Weinberg equilibrium. The frequency CA genotype and A allele of Exon4 C > A polymorphism was higher in gallstones patients (12.4% and 6.2%) as compared to controls (5.2% and 2.6%) which was statistically significant [(P = 0.029; OR = 2.31; 95% CI = 1.1-5.0); (P = 0.034; OR = 2.22; 95% CI = 1.1-4.8)], respectively). However, distribution of genotypes and alleles of Ex6 + 40T > C polymorphism was almost similar between gallstone patients and controls. Haplotype analysis showed frequency of A,T haplotype consisting of was significantly higher in gallstone patients as compared to controls and was imposing risk for the disease (P = 0.036; OR = 2.34; 95% CI = 1.0-5.1).   These results suggest that SLCO1B1 Exon4 C > A polymorphism confers increased risk for gallstone disease in North Indian population. © 2010 The Japan Society of Hepatology.

  6. Plexin-B1 activates NF-κB and IL-8 to promote a pro-angiogenic response in endothelial cells.

    Directory of Open Access Journals (Sweden)

    Ying-Hua Yang

    Full Text Available BACKGROUND: The semaphorins and their receptors, the plexins, are proteins related to c-Met and the scatter factors that have been implicated in an expanding signal transduction network involving co-receptors, RhoA and Ras activation and deactivation, and phosphorylation events. Our previous work has demonstrated that Semaphorin 4D (Sema4D acts through its receptor, Plexin-B1, on endothelial cells to promote angiogenesis in a RhoA and Akt-dependent manner. Since NF-κB has been linked to promotion of angiogenesis and can be activated by Akt in some contexts, we wanted to examine NF-κB in Sema4D treated cells to determine if there was biological significance for the pro-angiogenic phenotype observed in endothelium. METHODS/PRINCIPAL FINDINGS: Using RNA interference techniques, gel shifts and NF-κB reporter assays, we demonstrated NF-κB translocation to the nucleus in Sema4D treated endothelial cells occurring downstream of Plexin-B1. This response was necessary for endothelial cell migration and capillary tube formation and protected endothelial cells against apoptosis as well, but had no effect on cell proliferation. We dissected Plexin-B1 signaling with chimeric receptor constructs and discovered that the ability to activate NF-κB was dependent upon Plexin-B1 acting through Rho and Akt, but did not involve its role as a Ras inhibitor. Indeed, inhibition of Rho by C3 toxin and Akt by LY294002 blocked Sema4D-mediated endothelial cell migration and tubulogenesis. We also observed that Sema4D treatment of endothelial cells induced production of the NF-κB downstream target IL-8, a response necessary for angiogenesis. Finally, we could show through co-immunofluorescence for p65 and CD31 that Sema4D produced by tumor xenografts in nude mice activated NF-κB in vessels of the tumor stroma. CONCLUSION/SIGNIFICANCE: These findings provide evidence that Sema4D/Plexin-B1-mediated NF-κB activation and IL-8 production is critical in the generation a

  7. Drug-drug interactions between rosuvastatin and oral antidiabetic drugs occurring at the level of oatp1b1s

    NARCIS (Netherlands)

    Steeg, E. van de; Greupink, R.; Schreurs, M.; Nooijen, I.H.G.; Verhoeck, K.C.M.; Hanemaaijer, R.; Ripken, D.; Monshouwer, M.; Vlaming, M.L.H.; DeGroot, J.; Verwei, M.; Russel, F.G.M.; Huisman, M.T.; Wortelboer, H.M.

    2013-01-01

    Organic anion-transporting polypeptide 1B1 (OATP1B1) is an important hepatic uptake transporter, of which the polymorphic variant OATP1B1*15 (Asn130Asp and Val174Ala) has been associated with decreased transport activity. Rosuvastatin is an OATP1B1 substrate and often concomitantly prescribed with

  8. Dioxin exposure reduces the steroidogenic capacity of mouse antral follicles mainly at the level of HSD17B1 without altering atresia

    Energy Technology Data Exchange (ETDEWEB)

    Karman, Bethany N., E-mail: bklement@illinois.edu; Basavarajappa, Mallikarjuna S., E-mail: mbshivapur@gmail.com; Hannon, Patrick, E-mail: phannon2@illinois.edu; Flaws, Jodi A., E-mail: jflaws@illinois.edu

    2012-10-01

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent ovarian toxicant. Previously, we demonstrated that in vitro TCDD (1 nM) exposure decreases production/secretion of the sex steroid hormones progesterone (P4), androstenedione (A4), testosterone (T), and 17β-estradiol (E2) in mouse antral follicles. The purpose of this study was to determine the mechanism by which TCDD inhibits steroidogenesis. Specifically, we examined the effects of TCDD on the steroidogenic enzymes, atresia, and the aryl hydrocarbon receptor (AHR) protein. TCDD exposure for 48 h increased levels of A4, without changing HSD3B1 protein, HSD17B1 protein, estrone (E1), T or E2 levels. Further, TCDD did not alter atresia ratings compared to vehicle at 48 h. TCDD, however, did down regulate the AHR protein at 48 h. TCDD exposure for 96 h decreased transcript levels for Cyp11a1, Cyp17a1, Hsd17b1, and Cyp19a1, but increased Hsd3b1 transcript. TCDD exposure particularly lowered both Hsd17b1 transcript and HSD17B1 protein. However, TCDD exposure did not affect levels of E1 in the media nor atresia ratings at 96 h. TCDD, however, decreased levels of the proapoptotic factor Bax. Collectively, these data suggest that TCDD exposure causes a major block in the steroidogenic enzyme conversion of A4 to T and E1 to E2 and that it regulates apoptotic pathways, favoring survival over death in antral follicles. Finally, the down‐regulation of the AHR protein in TCDD exposed follicles persisted at 96 h, indicating that the activation and proteasomal degradation of this receptor likely plays a central role in the impaired steroidogenic capacity and altered apoptotic pathway of exposed antral follicles. -- Highlights: ► TCDD disrupts steroidogenic enzymes in mouse antral follicles. ► TCDD particularly affects the HSD17B1 enzyme in mouse antral follicles. ► TCDD does not affect atresia ratings in mouse antral follicles. ► TCDD decreases levels of the proapoptitic factor Bax in mouse antral follicles.

  9. Growth inhibitory effects of the dual ErbB1/ErbB2 tyrosine kinase inhibitor PKI-166 on human prostate cancer xenografts.

    Science.gov (United States)

    Mellinghoff, Ingo K; Tran, Chris; Sawyers, Charles L

    2002-09-15

    Experiments with human prostate cancer cell lines have shown that forced overexpression of the ErbB2-receptor tyrosine kinase (RTK) promotes androgen-independent growth and increases androgen receptor-transcriptional activity in a ligand-independent fashion. To investigate the relationship between ErbB-RTK signaling and androgen in genetically unmanipulated human prostate cancer, we performed biochemical and biological studies with the dual ErbB1/ErbB2 RTK inhibitor PKI-166 using human prostate cancer xenograft models with isogenic sublines reflecting the transition from androgen-dependent to androgen-independent growth. In the presence of low androgen concentrations, PKI-166 showed profound growth-inhibitory effects on tumor growth, which could be partially reversed by androgen add-back. At physiological androgen concentrations, androgen withdrawal greatly enhanced the ability of PKI-166 to retard tumor growth. The level of extracellular signal-regulated kinase activation correlated with the response to PKI-166 treatment, whereas the expression levels of ErbB1 and ErbB2 did not. These results suggest that ErbB1/ErbB2 RTKs play an important role in the biology of androgen-independent prostate cancer and provide a rationale for clinical evaluation of inhibitors targeted to this pathway.

  10. Observation and Properties of L=1 B_1 and B_2* Mesons

    CERN Document Server

    Abazov, V M; Abolins, M; Acharya, B S; Adams, M; Adams, T; Aguiló, E; Ahn, S H; Ahsan, M; Alexeev, G D; Alkhazov, G; Alton, A; Alverson, G; Alves, G A; Anastasoaie, M; Ancu, L S; Andeen, T; Anderson, S; Andrieu, B; Anzelc, M S; Arnoud, Y; Arov, M; Arthaud, M; Askew, A; Åsman, B; Assis-Jesus, A C S; Atramentov, O; Autermann, C; Avila, C; Ay, C; Badaud, F; Baden, A; Bagby, L; Baldin, B; Bandurin, D V; Banerjee, S; Banerjee, P; Barberis, E; Barfuss, A F; Bargassa, P; Baringer, P; Barreto, J; Bartlett, J F; Bassler, U; Bauer, D; Beale, S; Bean, A; Begalli, M; Begel, M; Belanger-Champagne, C; Bellantoni, L; Bellavance, A; Benítez, J A; Beri, S B; Bernardi, G; Bernhard, R; Berntzon, L; Bertram, I; Besançon, M; Beuselinck, R; Bezzubov, V A; Bhat, P C; Bhatnagar, V; Biscarat, C; Blazey, G; Blekman, F; Blessing, S; Bloch, D; Bloom, K; Böhnlein, A; Boline, D; Bolton, T A; Borissov, G; Bos, K; Bose, T; Brandt, A; Brock, R; Brooijmans, G; Bross, A; Brown, D; Buchanan, N J; Buchholz, D; Bühler, M; Büscher, V; Burdin, S; Burke, S; Burnett, T H; Buszello, C P; Butler, J M; Calfayan, P; Calvet, S; Cammin, J; Caron, S; Carvalho, W; Casey, B C K; Cason, N M; Castilla-Valdez, H; Chakrabarti, S; Chakraborty, D; Chan, K M; Chan, K; Chandra, A; Charles, F; Cheu, E; Chevallier, F; Cho, D K; Choi, S; Choudhary, B; Christofek, L; Christoudias, T; Cihangir, S; Claes, D; Clément, C; Clement, B; Coadou, Y; Cooke, M; Cooper, W E; Corcoran, M; Couderc, F; Cousinou, M C; Crepe-Renaudin, S; Cutts, D; Cwiok, M; Da Motta, H; Das, A; Davies, G; De, K; De Jong, S J; de Jong, P; De La Cruz-Burelo, E; De Oliveira Martins, C; Degenhardt, J D; Déliot, F; Demarteau, M; Demina, R; Denisov, D; Denisov, S P; Desai, S; Diehl, H T; Diesburg, M; Dominguez, A; Dong, H; Dudko, L V; Duflot, L; Dugad, S R; Duggan, D; Duperrin, A; Dyer, J; Dyshkant, A; Eads, M; Edmunds, D; Ellison, J; Elvira, V D; Enari, Y; Eno, S; Ermolov, P; Evans, H; Evdokimov, A; Evdokimov, V N; Ferapontov, A V; Ferbel, T; Fiedler, F; Filthaut, F; Fisher, W; Fisk, H E; Ford, M; Fortner, M; Fox, H; Fu, S; Fuess, S; Gadfort, T; Galea, C F; Gallas, E; Galyaev, E; García, C; García-Bellido, A; Gavrilov, V; Gay, P; Geist, W; Gelé, D; Gerber, C E; Gershtein, Yu; Gillberg, D; Ginther, G; Gollub, N; Gómez, B; Goussiou, A; Grannis, P D; Greenlee, H; Greenwood, Z D; Gregores, E M; Grenier, G; Gris, P; Grivaz, J F; Grohsjean, A; Grünendahl, S; Grünewald, M W; Guo, J; Guo, F; Gutíerrez, P; Gutíerrez, G; Haas, A; Hadley, N J; Haefner, P; Hagopian, S; Haley, J; Hall, I; Hall, R E; Han, L; Hanagaki, K; Hansson, P; Harder, K; Harel, A; Harrington, R; Hauptman, J M; Hauser, R; Hays, J; Hebbeker, T; Hedin, D; Hegeman, J G; Heinmiller, J M; Heinson, A P; Heintz, U; Hensel, C; Herner, K; Hesketh, G; Hildreth, M D; Hirosky, R; Hobbs, J D; Hoeneisen, B; Hoeth, H; Hohlfeld, M; Hong, S J; Hooper, R; Hossain, S; Houben, P; Hu, Y; Hubacek, Z; Hynek, V; Iashvili, I; Illingworth, R; Ito, A S; Jabeen, S; Jaffré, M; Jain, S; Jakobs, K; Jarvis, C; Jesik, R; Johns, K; Johnson, C; Johnson, M; Jonckheere, A; Jonsson, P; Juste, A; Käfer, D; Kahn, S; Kajfasz, E; Kalinin, A M; Kalk, J R; Kalk, J M; Kappler, S; Karmanov, D; Kasper, J; Kasper, P; Katsanos, I; Kau, D; Kaur, R; Kaushik, V; Kehoe, R; Kermiche, S; Khalatyan, N; Khanov, A; Kharchilava, A I; Kharzheev, Yu M; Khatidze, D; Kim, H; Kim, T J; Kirby, M H; Kirsch, M; Klima, B; Kohli, J M; Konrath, J P; Kopal, M; Korablev, V M; Kothari, B; Kozelov, A V; Krop, D; Kryemadhi, A; Kühl, T; Kumar, A; Kunori, S; Kupco, A; Kurca, T; Kvita, J; Lacroix, F; Lam, D; Lammers, S; Landsberg, G L; Lazoflores, J; Lebrun, P; Lee, W M; Leflat, A; Lehner, F; Lellouch, J; Lesne, V; Lévêque, J; Lewis, P; Li, J; Li, Q Z; Li, L; Lietti, S M; Lima, J G R; Lincoln, D; Linnemann, J; Lipaev, V V; Lipton, R; Liu, Y; Liu, Z; Lobo, L; Lobodenko, A; Lokajícek, M; Lounis, A; Love, P; Lubatti, H J; Lyon, A L; Maciel, A K A; Mackin, D; Madaras, R J; Mättig, P; Magass, C; Magerkurth, A; Makovec, N; Mal, P K; Malbouisson, H B; Malik, S; Malyshev, V L; Mao, H S; Maravin, Y; Martin, B; McCarthy, R; Melnitchouk, A; Mendes, A; Mendoza, L; Mercadante, P G; Merkin, M; Merritt, K W; Meyer, J; Meyer, A; Michaut, M; Millet, T; Mitrevski, J; Molina, J; Mommsen, R K; Mondal, N K; Moore, R W; Moulik, T; Muanza, G S; Mulders, M; Mulhearn, M; Mundal, O; Mundim, L; Nagy, E; Naimuddin, M; Narain, M; Naumann, N A; Neal, H A; Negret, J P; Neustroev, P; Nilsen, H; Nomerotski, A; Novaes, S F; Nunnemann, T; O'Dell, V; O'Neil, D C; Obrant, G; Ochando, C; Onoprienko, D; Oshima, N; Osta, J; Otec, R; Oteroy-Garzon, G J; Owen, M; Padley, P; Pangilinan, M; Parashar, N; Park, S J; Park, S K; Parsons, J; Partridge, R; Parua, N; Patwa, A; Pawloski, G; Penning, B; Perea, P M; Peters, K; Peters, Y; Petroff, P; Petteni, M; Piegaia, R; Piper, J; Pleier, M A; Podesta-Lerma, P L M; Podstavkov, V M; Pogorelov, Y; Pol, M E; Polozov, P; Pompo, A; Pope, B G; Popov, A V; Potter, C; Prado da Silva, W L; Prosper, H B; Protopopescu, S D; Qian, J; Quadt, A; Quinn, B; Rakitine, A; Rangel, M S; Rani, K J; Ranjan, K; Ratoff, P N; Renkel, P; Reucroft, S; Rich, P; Rijssenbeek, M; Ripp-Baudot, I; Rizatdinova, F K; Robinson, S; Rodrigues, R F; Royon, C; Rubinov, P; Ruchti, R; Safronov, G; Sajot, G; Sánchez-Hernández, A; Sanders, M P; Santoro, A F S; Savage, G; Sawyer, L; Scanlon, T; Schaile, A D; Schamberger, R D; Scheglov, Y; Schellman, H; Schieferdecker, P; Schliephake, T; Schmitt, C; Schwanenberger, C; Schwartzman, A; Schwienhorst, R; Sekaric, J; Sen-Gupta, S; Severini, H; Shabalina, E; Shamim, M; Shary, V; Shchukin, A A; Shivpuri, R K; Shpakov, D; Siccardi, V; Simák, V; Sirotenko, V I; Skubic, P L; Slattery, P F; Smirnov, D; Smith, R P; Snow, J; Snow, G R; Snyder, S; Söldner-Rembold, S; Sonnenschein, L; Sopczak, A; Sosebee, M; Soustruznik, K; Souza, M; Spurlock, B; Stark, J; Steele, J; Stolin, V; Stone, A; Stoyanova, D A; Strandberg, J; Strandberg, S; Strang, M A; Strauss, M; Strauss, E; Ströhmer, R; Strom, D; Strovink, M; Stutte, L; Sumowidagdo, S; Svoisky, P; Sznajder, A; Talby, M; Tamburello, P; Tanasijczuk, A; Taylor, W; Telford, P; Temple, J; Tiller, B; Tissandier, F; Titov, M; Tokmenin, V V; Tomoto, M; Toole, T; Torchiani, I; Trefzger, T; Tsybychev, D; Tuchming, B; Tully, C; Tuts, P M; Unalan, R; Uvarov, S; Uvarov, L; Uzunyan, S; Vachon, B; Van den Berg, P J; van Eijk, B; Van Kooten, R; Van Leeuwen, W M; Varelas, N; Varnes, E W; Vartapetian, A H; Vasilyev, I A; Vaupel, M; Verdier, P; Vertogradov, L S; Verzocchi, M; Villeneuve-Séguier, F; Vint, P; Vokac, P; Von Törne, E; Voutilainen, M; Vreeswijk, M; Wagner, R; Wahl, H D; Wang, L; Wang, M H L; Warchol, J; Watts, G; Wayne, M; Weber, M; Weber, G; Weerts, H; Wenger, A; Wermes, N; Wetstein, M; White, A; Wicke, D; Wilson, G W; Williams, M R J; Wimpenny, S J; Wobisch, M; Wood, D R; Wyatt, T R; Xie, Y; Yacoob, S; Yamada, R; Yan, M; Yasuda, T; Yatsunenko, Y A; Yip, K; Yoo, H D; Youn, S W; Yu, J; Yu, C; Yurkewicz, A; Zatserklyaniy, A; Zeitnitz, C; Zhang, D; Zhao, T; Zhou, B; Zhu, J; Zielinski, M; Zieminska, D; Zieminski, A; Zivkovic, L; Zutshi, V; Zverev, E G

    2007-01-01

    Excited B mesons B_1 and B_2* are observed directly for the first time as two separate states in fully reconstructed decays to B+(*) pi-. The mass of B_1 is measured to be (5720.6 +- 2.4 +- 1.4) MeV/c^2 and the mass difference DeltaM between B_2* and B_1 is (26.2 +- 3.1 +- 0.9) MeV/c^2, giving the mass of the B_2* as (5746.8 +- 2.4 +- 1.7) MeV/c^2. The production rate for B_1 and B_2* mesons is determined to be a fraction (13.9 +- 1.9 +- 3.2)% of the production rate of the B+ meson.

  11. Data of evolutionary structure change: 1DC3B-1VSVC [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1DC3B-1VSVC 1DC3 1VSV B C TIKVGINGFGRIGRIVFRAAQKRSDIEIVAINDL-LDAD...SNASCTTNCLAPLAKVINDNFGIIEGLMTTVHATTATQKTVDGPS--HKDWRGGRGASQNIIPSSTGAAKAVGKVLPELNGKLTGMAFRVPTPNVSVVDLTVRLEKAA...GRCAGNNIIPASTGAAKAVGKVIPALNGKLTGMAIRVPTPDVSVVDLTCKLAKPASIEEIYQAVKEASNGPMKGIMGYTSD... 243 ALA CA 310 ASP CA 265 TYR CA 267 1VSV... C 1VSVC

  12. Data of evolutionary structure change: 1DC6B-1VSVD [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1DC6B-1VSVD 1DC6 1VSV B D TIKVGINGFGRIGRIVFRAAQKRSDIEIVAINDLL-DAD...SNASCTTNCLAPLAKVINDNFGIIEGLMTTVHATTATQKTVDGPS--HKDWRGGRGASQNIIPSSTGAAKAVGKVLPELNGKLTGMAFRVPTPNVSVVDLTVRLEKAA...GRCAGNNIIPASTGAAKAVGKVIPALNGKLTGMAIRVPTPDVSVVDLTCKLAKPASIEEIYQAVKEASNGPMKGIMGYTSD...> 1VSV D 1VSV...ine>VAL CA 453 SER CA 511 1VSV

  13. Data of evolutionary structure change: 1CB4B-1FUNF [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1CB4B-1FUNF 1CB4 1FUN B F ATKAVCVLKGDGPVQGTIHFEAKG--DTVVVTGSITGLT...VIGIAK ATKAVAVLKGDGPVQGIINFEQKESNGPVKVWGSIKGLTEGLHGFHVHEFGDNTAGCTSAGPHFNPLSRKHGGPKDEERHVGDLGNVT...E EEEEEEEE GGG EEEEE EEEEEEE EEEEE HHHH EEEEEEE EVID> 01FUN F 1FUNF FEQKESNGPVKV

  14. Data of evolutionary structure change: 1AC6B-1TVDA [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1AC6B-1TVDA 1AC6 1TVD B A DSVTQTEGQVALSEEDFLTIHCNYSASG-YPALFWYVQYPGEGPQFLFRASRDKEK...N--KLTFGAGTKLTIKP DKVTQSSPDQTVASGSEVVLLCTYDTVYSNPDLFWYRIRPD-----YSFQF---VFYGDDSRSEGADFT...RFSVKHILTQKAFHLVISPVRTEDSATYYCAFTLPPPTDKLIFGKGTRVTVEP EEE EEE EEEEEEEE - EEEEEEE EEE EEEEE-----------... 1TVD A 1TVDA

  15. Bioimprinting as a tool for the detection of aflatoxin B1 using a capacitive biosensor

    Directory of Open Access Journals (Sweden)

    Alvaro V. Gutierrez R.

    2016-09-01

    Full Text Available A strategy for the detection of aflatoxin B1 using a capacitive biosensor has been studied. The use of proteins for the generation of sites with high specificity against aflatoxin B1 are produced via bioimprinting. This technique has become a tool for the detection of aflatoxin B1 using a capacitive biosensor. The results demonstrate the ability to generate specific interactions with aflatoxin B1 with a linear relation between signals registered and log concentration of the target aflatoxin in the concentration range of 3.2 × 10−6 to 3.2 × 10−9 M when using ovalbumin as framework for the bioimprinting.

  16. Data of evolutionary structure change: 1BZ7B-1LMKC [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1BZ7B-1LMKC 1BZ7 1LMK B C DVQLVESGGGLVQPGGSRKLSCAASGFTFSNFGMHWVRQAPEKGLEWVAYISSGGS...QTYICNVN------HKPSNTKVDK -VQLQQSGTELMKPGRSLKISCKTTGYIFSNYWIEWVKQRPGHGLEWIGKILPGGGSNTYND... 1LMK C 1LMKC 1 1LMK C 1LMKC 2 1LMK C 1LMKC

  17. Data of evolutionary structure change: 1LA6B-1MKOC [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1LA6B-1MKOC 1LA6 1MKO B C VEWTDKERSIISDIFSHMD--YDDIGPKALSRCLVVYPWTQRYFI-----MSNANV...AAHGIKVLHGLDRGMKNMDNIADAYTDLSTLHSEKLHVDPDNFKLLSDCITIVLAAKMGHAFTAETQGAFQKFLAAVVSALGK--- ... 1MKO C 1MKOC 1MKO C 1MKOC

  18. Data of evolutionary structure change: 1AJ8B-1VGMA [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1AJ8B-1VGMA 1AJ8 1VGM B A --LAKGLEDVYIDQTNICYIDGKEGKLYYRGYSVEELAELSTFEEVVYLLWWGKLP...KYASKLGD-----KKLFEIAERLERLVEEYLSKKGISINVDYWSGLVFYGMKIPIELYTTIFAMGRIAGWTAHLAEYVSH-NRIIRPRLQYVGEIGKKYLPIELR...EELIHLMLYGELPNRQQLNQIKGIINESFEVPEQVISTIFSMPRNCDAIGMMETAFGILASIY---DPKWNRATNKELAVQIIAKTATITANIYRAKEGL... 1VGM A 1VGMA 1VGM A 1VGMA

  19. Fast B1 mapping based on interleaved-three-flip-angle (ITFA) excitation.

    Science.gov (United States)

    Kang, Lae Hoon; Kim, Dong Eun; Lee, Soo Yeol

    2013-11-01

    Fast B1 mapping based on short-TR sequences is prone to T1-induced errors. The purpose of this study is to develop a novel fast B1 mapping method that is less prone to T1-induced errors. The authors acquired three gradient echoes by applying three RF pulses of different flip angles in an interleaved manner. The new method, named interleaved-three-flip-angle (ITFA) method, employs a short TR for fast scan. Since the pixel intensity of the gradient echo images is dependent on both B1 and T1, the authors could compute a B1 map from the three gradient echo images with excluding the T1-effects. The authors simulated the proposed B1 mapping method for various T1 values, and they found optimal flip angles for ITFA experiments for a given repetition time. To evaluate the B1 mapping performance, the authors made a human-brain-mimicking phantom that had six compartments with different T1 and T2. The authors performed B1 mapping experiments at 3T on the phantom and a volunteer using the ITFA method, the actual flip angle imaging (AFI) method, and the double angle method (DAM), and then, the authors compared the B1 mapping results. Using a birdcage coil as a transceiver at 3T, the authors performed ITFA scans of the phantom and a volunteer with TR of 60 ms and the nominal flips angles of (25°, 70°, 80°). The authors also performed AFI scans with TR1/TR2 of 30/150 ms and the nominal flip angle of 60°. In both the phantom and human head imaging performed with the same scan times for ITFA and AFI, ITFA showed smaller average B1 errors than AFI when they were compared to DAM. ITFA excitations made it possible to reduce the T1-effects on B1 mapping of the human-brain-mimicking phantom and the human brain at 3T. The authors expect the ITFA method can be used for B1 shimming once the optimal flip angles have been predetermined for the target imaging region and for the preferred TR.

  20. Role of CYP1B1 in PAH-DNA adduct formation and breast cancer risk

    Energy Technology Data Exchange (ETDEWEB)

    Goth-Goldstein, Regine; Russell, Marion L.; Muller, A.P.; Caleffi, M.; Eschiletti, J.; Graudenz, M.; Sohn, Michael D.

    2010-04-01

    This study investigated the hypothesis that increased exposure to polycyclic aromatic hydrocarbons (PAHs) increases breast cancer risk. PAHs are products of incomplete burning of organic matter and are present in cigarette smoke, ambient air, drinking water, and diet. PAHs require metabolic transformation to bind to DNA, causing DNA adducts, which can lead to mutations and are thought to be an important pre-cancer marker. In breast tissue, PAHs appear to be metabolized to their cancer-causing form primarily by the cytochrome P450 enzyme CYP1B1. Because the genotoxic impact of PAH depends on their metabolism, we hypothesized that high CYP1B1 enzyme levels result in increased formation of PAH-DNA adducts in breast tissue, leading to increased development of breast cancer. We have investigated molecular mechanisms of the relationship between PAH exposure, CYP1B1 expression and breast cancer risk in a clinic-based case-control study. We collected histologically normal breast tissue from 56 women (43 cases and 13 controls) undergoing breast surgery and analyzed these specimens for CYP1B1 genotype, PAH-DNA adducts and CYP1B1 gene expression. We did not detect any difference in aromatic DNA adduct levels of cases and controls, only between smokers and non-smokers. CYP1B1 transcript levels were slightly lower in controls than cases, but the difference was not statistically significant. We found no correlation between the levels of CYP1B1 expression and DNA adducts. If CYP1B1 has any role in breast cancer etiology it might be through its metabolism of estrogen rather than its metabolism of PAHs. However, due to the lack of statistical power these results should be interpreted with caution.

  1. A survey of aflatoxin B-1 in maize and awareness of aflatoxins in Vietnam

    OpenAIRE

    Lee, H S; Nguyen-Viet, H.; Lindahl, Johanna; Thanh, H. M.; Khanh, T. N.; Hien, L. T. T.; Grace, D.

    2017-01-01

    Vietnam is a tropical country with high temperature and precipitation, which may provide good conditions for fungal growth. A few limited studies have been conducted to evaluate the level of aflatoxin B1 in maize in Vietnam. In addition, no studies have been conducted to evaluate the perception and knowledge of aflatoxins in Vietnam. Therefore, the main objective of this study was to determine the levels of aflatoxin B1 for human and animal consumption in maize and evaluate perceptions and kn...

  2. Effect of superoxide and inflammatory factor on aflatoxin B1 triggered hepatocellular carcinoma

    OpenAIRE

    Qin, Huimin; Li, Hongtao; Zhou, Xiaolin; Peng, Chen; Tan, Honghu; WANG, MINXIN

    2016-01-01

    Presently, there have been a lot of documents confirmed that aflatoxin B1 could promote the incident rate of hepato-cellular carcinoma, but the specific mechanism is not completely clear. Some evidences showed that it might relate to oxidative stress and inflammatory reaction. So the rat hepato-cellular carcinoma model was applied in this study for being discussed. Aflatoxin B1 was applied for inducing the rats to produce hepato-cellular carcinoma model to evaluate the expression of histopath...

  3. Cloning and tissue expression of cytochrome P450 1B1 and 1C1 ...

    African Journals Online (AJOL)

    Cytochrome P450 1 (CYP1) is widely used as an indicator of exposure to environmental contaminants. In the study, two full-length complementary DNAs encode for CYP1B1 and CYP1C1 were cloned from medaka liver exposed to 500 ppb β-naphthoflavone for 24 h. CYP1B1, having 1984 bp, contains an open reading ...

  4. The Potent of Aspergillus parasiticus to Produce Aflatoxin B1 on the Maize Flour During Storage

    Directory of Open Access Journals (Sweden)

    Agus Selamat Duniaji

    2016-03-01

    Full Text Available Aflatoxin B1 contamination caused by Aspergillus parasiticus and Aspergiluus Aspergillus flavus is a great concern in maize production worldwide. A. parasiticus infection and aflatoxin B1 contamination are usually found in maize and their processed during storage, distribution and processing. Aflatoxin B1 contamination in food and feed can cause the cancer diseases in animal and human. This research was aimed to determinate the potency of A. parasiticus to produce aflatoxin B1 in maize during storage 0, 5, 10 and 15 days. The research methods was using Completed Random Design (CRD with three replicated. The research was investigation of a number of colony A. parasiticus in Petato Dextro Agar (PDA and Aflatoxin B1 content by using Enzym Linked Immunosorbant Assay (ELISA. Result of research showed that A.parasiticus were susceptible to grow in maize flour and produce aflatoxin B1 during storage. The population of A. parasiticus in maize flour were  9.5 x 105 d in primary storage (0 days that was the total colony were increasing  .7 x 106 (storage 5 days, 2.5 x 107 (storage 10 days and 1.5 x 108 cfu/g with storage 15 days A. parasiticus was a potent to produce aflatoxin B1 in myzena flour with total of aflatoxin B1 is  66.50 ppb of mayzena flour during storage 5 days , 46.40 ppb with 10 days storage, 57.00 ppb during storage 15 days and was not found in 0 days.

  5. Biosynthetic relationship among aflatoxins B1, B2, M1, and M2.

    OpenAIRE

    Dutton, M F; Ehrlich, K.; Bennett, J W

    1985-01-01

    Aflatoxins are a family of toxic, acetate-derived decaketides that arise biosynthetically through polyhydroxyanthraquinone intermediates. Most studies have assumed that aflatoxin B1 is the biosynthetic precursor of the other aflatoxins. We used a strain of Aspergillus flavus which accumulates aflatoxin B2 to investigate the later stages of aflatoxin biosynthesis. This strain produced aflatoxins B2 and M2 but no detectable aflatoxin B1 when grown over 12 days in a low-salt, defined growth medi...

  6. Determination of Aflatoxin B1 in Smokeless Tobacco Products by Use of UHPLC-MS/MS.

    Science.gov (United States)

    Zitomer, Nicholas; Rybak, Michael E; Li, Zhong; Walters, Matthew J; Holman, Matthew R

    2015-10-21

    This work developed a UHPLC-MS/MS method for the detection and quantitation of aflatoxins in smokeless tobacco products, which was then used to determine aflatoxin B1 concentrations in 32 smokeless tobacco products commercially available in the United States. Smokeless tobacco products were dried, milled, and amended with (13)C17-labeled internal standards, extracted in water/methanol solution in the presence of a surfactant, isolated through use of immunoaffinity column chromatography, and reconstituted in mobile phase prior to UHPLC-MS/MS analysis. The method was capable of baseline separation of aflatoxins B1, B2, G1, and G2 in a 2.5 min run by use of a fused core C18 column and a water/methanol gradient. MS/MS transition (m/z) 313.3 → 241.2 was used for aflatoxin B1 quantitation, with 313.3 → 285.1 used for confirmation. The limit of detection (LOD) for aflatoxin B1 was 0.007 parts per billion (ppb). Method imprecision for aflatoxin B1 (expressed as coefficient of variation) ranged from 5.5 to 9.4%. Spike recoveries were 105-111%. Aflatoxin B1 concentrations in the smokeless tobacco products analyzed ranged from B1 was most frequently detected in dry snuffs and chews, whereas all moist snuff products tested were below LOD. The amounts of aflatoxin B1 detected were low relative to the 20 ppb regulatory limit established by the U.S. Food and Drug Administration for foods and feeds.

  7. Stability of aflatoxin B1 in animal feed candidate reference materials

    NARCIS (Netherlands)

    Roos, A.H.; Mazijk, van R.J.; Tuinstra, L.G.M.T.; Huf, F.A.

    1991-01-01

    Two candidate reference materials animal feed were stored at a temperature of -18°C, 4 C, 20°C and 37°C. The stability of aflatoxin B1 was studied duringa period of two years. A significant decrease in the aflatoxin B1 content was measured in the samples stared at 20°C and 37°C. In the samples

  8. Transcriptional regulation of male-sterility in 7B-1 male-sterile tomato mutant.

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    Vahid Omidvar

    Full Text Available The 7B-1 tomato (Solanum lycopersicum L. cv Rutgers is a male-sterile mutant with enhanced tolerance to abiotic stress, which makes it a potential candidate for hybrid seed breeding and stress engineering. To underline the molecular mechanism regulating the male-sterility in 7B-1, transcriptomic profiles of the 7B-1 male-sterile and wild type (WT anthers were studied using mRNA sequencing (RNA-Seq. In total, 768 differentially expressed genes (DEGs were identified, including 132 up-regulated and 636 down-regulated transcripts. Gene ontology (GO enrichment analysis of DEGs suggested a general impact of the 7B-1 mutation on metabolic processes, such as proteolysis and carbohydrate catabolic process. Sixteen candidates with key roles in regulation of anther development were subjected to further analysis using qRT-PCR and in situ hybridization. Cytological studies showed several defects associated with anther development in the 7B-1 mutant, including unsynchronized anther maturation, dysfunctional meiosis, arrested microspores, defect in callose degradation and abnormal tapetum development. TUNEL assay showed a defect in programmed cell death (PCD of tapetal cells in 7B-1 anthers. The present study provides insights into the transcriptome of the 7B-1 mutant. We identified several genes with altered expression level in 7B-1 (including beta-1,3 glucanase, GA2oxs, cystatin, cysteine protease, pectinesterase, TA29, and actin that could potentially regulate anther developmental processes, such as meiosis, tapetum development, and cell-wall formation/degradation.

  9. LytB1 and LytB2 of Mycobacterium tuberculosis Are Not Genetically Redundant.

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    Amanda Claire Brown

    Full Text Available Mycobacterium tuberculosis synthesises isoprenoid precursors via the MEP/DOXP pathway and at least five enzymes in the pathway (Dxs1, Dxr/IspC, IspD, IspF, and GcpE/IspG are required for growth in vitro. We investigated the role of LytB (IspH in M. tuberculosis; M. tuberculosis is unusual in that it has two homologs-LytB1 and LytB2. We were unable to delete the lytB2 gene unless we provided an additional copy elsewhere, demonstrating that this is the essential homolog. We expressed lytB1 from the lytB2 promoter and confirmed that this could not complement for loss of function of lytB2, despite LytB1 possessing all the previously described conserved critical residues. Interestingly the sole LytB homolog of Mycobacterium smegmatis was able to compensate for loss of LytB2 in M. tuberculosis. We tested translational fusions of LytB1 and LytB2 for functionality in M. tuberculosis, but only a fusion with 90% N-terminal LytB2 and 10% C-terminal LytB1 was functional. In order to identify the key difference between the two proteins, site directed mutagenesis was used to change LytB2 residues into their counterparts in LytB1. None of these amino acid substitutions was essential for function and all lytB2 mutant alleles were functional. In contrast, mutation of the key residues for [Fe4S4] cluster formation, as well as a catalytic residue in LytB1 did not result in functional complementation. Thus, although LytB1 and LytB2 are not genetically redundant, this is not dependent on small amino acid changes, but is likely to be a result of major overall structural differences.

  10. Effect of Heating Processes and Home Cooking Methods of Rice on Concentration of Aflatoxin B1

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    B Hajimohammadi

    2016-09-01

    Full Text Available Introduction: Mycotoxin contamination of crops for human and animal health has been facing a serious concern. Aflatoxin B1 is the most toxic types of aflatoxins in foodssuch as rice. The aim of this study was to investigate the Effect of heating processes and home cooking methods of rice on concentration of aflatoxin B1. methods: The heating processes of 20 and 120 minutes and rinse in three types of roasted rice, boiled and water cooked was studied in naturally contaminated with aflatoxin  B1 and the amount by high performance liquid chromatography (HPLC measured. Results: In the cases of 20 minutes and 120 minutes, the mean concentration of aflatoxin  B1 heats rice decreased as much as 16.6% and 81.7%. Although this reduction was not statistically significant heating at 20 minutes but at 120 minutes with heating was significant(P<0/05. The decrease in the average concentration of aflatoxin  B1in boiled, water cooked and roasted rice to order 60.2%, 85.5% and 87.6% indicated that this reduction was not statistically significant in the boiled cooking, but the cooking utensils and this reduction was not statistically with fried rice (P<0/05 was significant. Conclusion: The results show that the processes of heat and cook the rice variety could reduce the risks of aflatoxin  B1 in rice consumed by man.

  11. Differential requirements for VirB1 and VirB2 during Brucella abortus infection.

    Science.gov (United States)

    den Hartigh, Andreas B; Sun, Yao-Hui; Sondervan, David; Heuvelmans, Niki; Reinders, Marjolein O; Ficht, Thomas A; Tsolis, Renée M

    2004-09-01

    The Brucella abortus virB operon, encoding a type IV secretion system (T4SS), is required for intracellular replication and persistent infection in the mouse model. The products of the first two genes of the virB operon, virB1 and virB2, are predicted to be localized at the bacterial surface, where they could potentially interact with host cells. Studies to date have focused on characterization of transposon mutations in these genes, which are expected to exert polar effects on downstream genes in the operon. In order to determine whether VirB1 and VirB2 are required for the function of the T4SS apparatus, we constructed and characterized nonpolar deletion mutations of virB1 and virB2. Both mutants were shown to be nonpolar, as demonstrated by their ability to express the downstream gene virB5 during stationary phase of growth in vitro. Both VirB1 and VirB2 were essential for intracellular replication in J774 macrophages. The nonpolar virB2 mutant was unable to cause persistent infection in the mouse model, demonstrating the essential role of VirB2 in the function of the T4SS apparatus during infection. In contrast, the nonpolar virB1 mutant persisted at wild-type levels, showing that the function of VirB1 is dispensable in the mouse model of persistent infection.

  12. DjhnRNPA2/B1-like gene is required for planarian regeneration and tissue homeostasis.

    Science.gov (United States)

    Dong, Zimei; Yang, Tong; Yang, Yibo; Dou, He; Chen, Guangwen

    2017-10-30

    The hnRNPs play important roles in physiological processes in eukaryotic organisms by regulation of pre-mRNA after transcription, including pre-mRNA splicing, mRNA stability, DNA replication and repair and telomere maintenance and so on. However, it remains unclear about the specific functions of these genes. In this study, the full-length cDNA sequence of hnRNPA2/B1-like was first cloned from Dugesia japonica, and its roles were investigated by WISH and RNAi. The results showed that: (1) DjhnRNPA2/B1-like was highly conserved during animal evolution; (2) DjhnRNPA2/B1-like mRNA was mainly distributed each side of the body in intact worms and regenerative blastemas, and its expression levels were up-regulated on days 0 and 5 after amputation; (3) the intact and regenerating worms gradually lysed or lost regeneration capacity after DjhnRNPA2/B1-like RNAi; and (4) DjhnRNPA2/B1-like expression is induced by temperature and heavy metal ion stress. The data suggests that DjhnRNPA2/B1-like is a multiple functional gene, it plays important roles in regeneration and homeostatic maintenance and it is also involved in stress responses in planarians. Our work provides basic data for the study of regenerative mechanism and stress responses in freshwater planarians. Copyright © 2017. Published by Elsevier B.V.

  13. Cleavage of kininogen and subsequent bradykinin release by the complement component: mannose-binding lectin-associated serine protease (MASP-1.

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    József Dobó

    Full Text Available Bradykinin (BK, generated from high-molecular-weight kininogen (HK is the major mediator of swelling attacks in hereditary angioedema (HAE, a disease associated with C1-inhibitor deficiency. Plasma kallikrein, activated by factor XIIa, is responsible for most of HK cleavage. However other proteases, which activate during episodes of angioedema, might also contribute to BK production. The lectin pathway of the complement system activates after infection and oxidative stress on endothelial cells generating active serine proteases: MASP-1 and MASP-2. Our aim was to study whether activated MASPs are able to digest HK to release BK. Initially we were trying to find potential new substrates of MASP-1 in human plasma by differential gel electrophoresis, and we identified kininogen cleavage products by this proteomic approach. As a control, MASP-2 was included in the study in addition to MASP-1 and kallikrein. The proteolytic cleavage of HK by MASPs was followed by SDS-PAGE, and BK release was detected by HPLC. We showed that MASP-1 was able to cleave HK resulting in BK production. MASP-2 could also cleave HK but could not release BK. The cleavage pattern of MASPs is similar but not strictly identical to that of kallikrein. The catalytic efficiency of HK cleavage by a recombinant version of MASP-1 and MASP-2 was about 4.0×10(2 and 2.7×10(2 M(-1 s(-1, respectively. C1-inhibitor, the major inhibitor of factor XIIa and kallikrein, also prevented the cleavage of HK by MASPs. In all, a new factor XII- and kallikrein-independent mechanism of bradykinin production by MASP-1 was demonstrated, which may contribute to the pro-inflammatory effect of the lectin pathway of complement and to the elevated bradykinin levels in HAE patients.

  14. Incidência de fumonisina B1, aflatoxinas B1, B2, G1 e G2, ocratoxina A e zearalenona em produtos de milho Occurrence of fumonisin B1, aflatoxins B1, B2, G1, and G2, ochratoxin A and zearalenone in corn products

    Directory of Open Access Journals (Sweden)

    Luciane Mie Kawashima

    2006-09-01

    Full Text Available Levantamentos de ocorrência de micotoxinas em alimentos foram realizados nas últimas duas décadas nas regiões Sudeste e Sul do Brasil. Levantamentos em alimentos comercializados em outras regiões têm-se limitado a aflatoxinas em amendoim e castanhas do Brasil. O presente trabalho pesquisou a presença de fumonisina B1, aflatoxinas B1, B2, G1 e G2, ocratoxina A e zearalenona em 74 amostras de produtos a base de milho adquiridas no comércio da cidade de Recife, PE, durante o período de 1999 a 2001. Fumonisina B1 foi determinada por cromatografia líquida de alta eficiência com detecção por fluorescência e as demais toxinas foram determinadas por cromatografia em camada delgada. Fumonisina B1 foi encontrada em 94,6% das amostras em concentrações variando de 20 a 8600 µg/kg. Apenas 5 amostras continham aflatoxina B1 e o teor máximo encontrado foi 20 µg/kg. Duas amostras ultrapassaram o limite de 20 µg/kg para a somatória das aflatoxinas B1, B2, G1 e G2 (farinha de milho pré-cozida com 21,5 µg/kg e quirera (xerém com 23,3 µg/kg. As aflatoxinas G1 e G2, ocratoxina A e zearalenona não foram detectadas em nenhuma das amostras. Todas as amostras contaminadas com aflatoxinas também apresentaram fumonisina B1.Research concerning the presence of mycotoxin in food has been conducted in the Southwest and South regions of Brazil over the last two decades. Research in other regions has been limited to aflatoxin in peanuts and Brazil nuts. The aim of this work is to study the presence of fumonisin B1, aflatoxins B1, B2, G1, and G2, ochratoxin A and zearalenone in 74 samples of corn products acquired in shops and food markets in the city of Recife (PE from 1999 to 2001. Fumonisin B1 was determined by high performance liquid chromatography and fluorescence was detected. The other toxins were determined by thin layer chromatography. Fumonisin B1 was found in 94.6% of the samples in levels from 20 to 8600 µg/kg. Only 5 samples contained

  15. SR-B1-targeted nanodelivery of anti-cancer agents: a promising new approach to treat triple-negative breast cancer

    Directory of Open Access Journals (Sweden)

    Johnson R

    2017-06-01

    Full Text Available Rebecca Johnson,1 Nirupama Sabnis,2 Xiangle Sun,1 Ruhani Ahluwalia,3 Andras G Lacko2,4 1Institute of Molecular Medicine, 2Institute for Cardiovascular and Metabolic Diseases, University of North Texas Health Science Center, 3Harmony School of Innovation, 4Department of Pediatrics, University of North Texas Health Science Center, Fort Worth, TX, USA Abstract: Patients with triple-negative breast cancer (TNBC have a considerably less favorable prognosis than those with hormone-positive breast cancers. TNBC patients do not respond to current endocrine treatment and have a 5-year survival prognosis of <30%. The research presented here is intended to fill a void toward the much needed development of improved treatment strategies for metastatic TNBC. The overall goal of this research was to evaluate the effectiveness of reconstituted high-density lipoprotein (rHDL nanoparticles (NPs as delivery agents for anti-TNBC drugs. Using lapatinib and valrubicin as components of the rHDL/drug complexes resulted in a significantly better performance of the NP-transported drugs compared with their free (unencapsulated counterparts. The enhancement of the therapeutic effect and the protection of normal cells (cardiomyocytes achieved via the rHDL NPs were likely due to the overexpression of the high-density lipoprotein (HDL (scavenger receptor class B type 1 [SR-B1] receptor by the TNBC cells. Keywords: breast cancer, TNBC, rHDL nanoparticles, SR-B1 receptors, targeted drug delivery, lapatinib, valrubicin

  16. Mutations in SULT2B1 Cause Autosomal-Recessive Congenital Ichthyosis in Humans.

    Science.gov (United States)

    Heinz, Lisa; Kim, Gwang-Jin; Marrakchi, Slaheddine; Christiansen, Julie; Turki, Hamida; Rauschendorf, Marc-Alexander; Lathrop, Mark; Hausser, Ingrid; Zimmer, Andreas D; Fischer, Judith

    2017-06-01

    Ichthyoses are a clinically and genetically heterogeneous group of genodermatoses associated with abnormal scaling of the skin over the whole body. Mutations in nine genes are known to cause non-syndromic forms of autosomal-recessive congenital ichthyosis (ARCI). However, not all genetic causes for ARCI have been discovered to date. Using whole-exome sequencing (WES) and multigene panel screening, we identified 6 ARCI-affected individuals from three unrelated families with mutations in Sulfotransferase family 2B member 1 (SULT2B1), showing their causative association with ARCI. Cytosolic sulfotransferases form a large family of enzymes that are involved in the synthesis and metabolism of several steroids in humans. We identified four distinct mutations including missense, nonsense, and splice site mutations. We demonstrated the loss of SULT2B1 expression at RNA and protein levels in keratinocytes from individuals with ARCI by functional analyses. Furthermore, we succeeded in reconstructing the morphologic skin alterations in a 3D organotypic tissue culture model with SULT2B1-deficient keratinocytes and fibroblasts. By thin layer chromatography (TLC) of extracts from these organotypic cultures, we could show the absence of cholesterol sulfate, the metabolite of SULT2B1, and an increased level of cholesterol, indicating a disturbed cholesterol metabolism of the skin upon loss-of-function mutation in SULT2B1. In conclusion, our study reveals an essential role for SULT2B1 in the proper development of healthy human skin. Mutation in SULT2B1 leads to an ARCI phenotype via increased proliferation of human keratinocytes, thickening of epithelial layers, and altered epidermal cholesterol metabolism. Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  17. B-1 cells modulate the murine macrophage response to Leishmania major infection.

    Science.gov (United States)

    Arcanjo, Angelica F; Nunes, Marise P; Silva-Junior, Elias B; Leandro, Monique; da Rocha, Juliana Dutra Barbosa; Morrot, Alexandre; Decote-Ricardo, Debora; Freire-de-Lima, Celio Geraldo

    2017-05-26

    To investigate the modulatory effect of B-1 cells on murine peritoneal macrophages infected with Leishmania major (L. major) in vitro. Peritoneal macrophages obtained from BALB/c and BALB/c XID mice were infected with L. major and cultured in the presence or absence of B-1 cells obtained from wild-type BALB/c mice. Intracellular amastigotes were counted, and interleukin-10 (IL-10) production was quantified in the cellular supernatants using an enzyme-linked immunosorbent assay. The levels of the lipid mediator prostaglandin E2 (PGE2) were determined using a PGE2 enzyme immunoassay kit (Cayman Chemical, Ann Arbor, MI), and the number of lipid bodies was quantified in the cytoplasm of infected macrophages in the presence and absence of B-1 cells. Culturing the cells with selective PGE2-neutralizing drugs inhibited PGE2 production and confirmed the role of this lipid mediator in IL-10 production. In contrast, we demonstrated that B-1 cells derived from IL-10 KO mice did not favor the intracellular growth of L. major. We report that B-1 cells promote the growth of L. major amastigotes inside peritoneal murine macrophages. We demonstrated that the modulatory effect was independent of physical contact between the cells, suggesting that soluble factor(s) were released into the cultures. We demonstrated in our co-culture system that B-1 cells trigger IL-10 production by L. major-infected macrophages. Furthermore, the increased secretion of IL-10 was attributed to the presence of the lipid mediator PGE2 in supernatants of L. major-infected macrophages. The presence of B-1 cells also favors the production of lipid bodies by infected macrophages. In contrast, we failed to obtain the same effect on parasite replication inside L. major-infected macrophages when the B-1 cells were isolated from IL-10 knockout mice. Our results show that elevated levels of PGE2 and IL-10 produced by B-1 cells increase L. major growth, as indicated by the number of parasites in cell cultures.

  18. SLCO1B1 *15 haplotype is associated with rifampin-induced liver injury.

    Science.gov (United States)

    Li, Ling-Min; Chen, Lei; Deng, Guo-Hong; Tan, Wen-Ting; Dan, Yun-Jie; Wang, Rong-Quan; Chen, Wen-Sheng

    2012-07-01

    The organic anion transporting polypeptide 1B1 (OATP1B1, encoded by SLCO1B1) plays an important role in the transport of endogenous and xenobiotic compounds, such as bile acids and rifampin. In this study, the association between OATP1B1 polymorphisms and rifampin hepatotoxicity was investigated using integrated population genetic analysis and functional studies. A total of 273 unrelated patients treated with rifampin were recruited. The allele frequencies were examined in patients with drug (rifampin)-induced liver injury (DILI) (n = 118) and without (non-DILI) (n = 155). Functional analyses were conducted to determine whether the inhibition of bile acids by rifampin was associated with OATP1B1 variants. In the present study, 24 single nucleotide polymorphisms (SNPs) in OATP1B1 were detected in a Chinese population, with two of them causing an amino acid change (rs2306283 and rs4149056). The haplotypes constructed by these two SNPs were OATP1B1 *1a, *1b, *5 and *15, with their respective frequencies being 23.44, 66.30, 0.73 and 9.52% in a total of 273 individuals. The logistic regression analysis indicated that the *15 haplotype was associated with susceptibility to DILI (p = 0.03, OR = 2.04, 95% CI 1.05-3.96). The frequency of the *15 haplotype in DILI patients was significantly higher than that in non-DILI patients (p = 0.03). In the subgroup analysis, the *15 haplotype was associated with susceptibility to cholestatic/mixed injury (p = 0.03, OR = 2.31, 95% CI 1.06-5.02). Functional assessment of the OATP1B1 *15 haplotype revealed that the activity of bile acid uptake was markedly reduced compared to the three other haplotypes. In the inhibition study, the inhibition by rifampin in the *15 haplotype was greater compared to that in the other haplotypes. These results suggest that the OATP1B1 *15 haplotype is an important predisposing factor for rifampin-induced liver injury.

  19. B1 SOX coordinate cell specification with patterning and morphogenesis in the early zebrafish embryo.

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    Yuichi Okuda

    2010-05-01

    Full Text Available The B1 SOX transcription factors SOX1/2/3/19 have been implicated in various processes of early embryogenesis. However, their regulatory functions in stages from the blastula to early neurula remain largely unknown, primarily because loss-of-function studies have not been informative to date. In our present study, we systematically knocked down the B1 sox genes in zebrafish. Only the quadruple knockdown of the four B1 sox genes sox2/3/19a/19b resulted in very severe developmental abnormalities, confirming that the B1 sox genes are functionally redundant. We characterized the sox2/3/19a/19b quadruple knockdown embryos in detail by examining the changes in gene expression through in situ hybridization, RT-PCR, and microarray analyses. Importantly, these phenotypic analyses revealed that the B1 SOX proteins regulate the following distinct processes: (1 early dorsoventral patterning by controlling bmp2b/7; (2 gastrulation movements via the regulation of pcdh18a/18b and wnt11, a non-canonical Wnt ligand gene; (3 neural differentiation by regulating the Hes-class bHLH gene her3 and the proneural-class bHLH genes neurog1 (positively and ascl1a (negatively, and regional transcription factor genes, e.g., hesx1, zic1, and rx3; and (4 neural patterning by regulating signaling pathway genes, cyp26a1 in RA signaling, oep in Nodal signaling, shh, and mdkb. Chromatin immunoprecipitation analysis of the her3, hesx1, neurog1, pcdh18a, and cyp26a1 genes further suggests a direct regulation of these genes by B1 SOX. We also found an interesting overlap between the early phenotypes of the B1 sox quadruple knockdown embryos and the maternal-zygotic spg embryos that are devoid of pou5f1 activity. These findings indicate that the B1 SOX proteins control a wide range of developmental regulators in the early embryo through partnering in part with Pou5f1 and possibly with other factors, and suggest that the B1 sox functions are central to coordinating cell fate

  20. Prenatal exposure to aflatoxin B1: developmental, behavioral, and reproductive alterations in male rats

    Science.gov (United States)

    Supriya, Ch.; Reddy, P. Sreenivasula

    2015-06-01

    Previous studies have shown that aflatoxin B1 (AfB1) inhibits androgen biosynthesis as a result of its ability to form a high-affinity complex with the steroidogenic acute regulatory protein. The results of the present study demonstrate the postnatal effects of in utero exposure to AfB1 in the rat. Pregnant Wistar rats were given 10, 20, or 50 μg AfB1/kg body weight daily from gestation day (GD) 12 to GD 19. At parturition, newborns were observed for clinical signs and survival. All animals were born alive and initially appeared to be active. Male pups from control and AfB1-exposed animals were weaned and maintained up to postnatal day (PD) 100. Litter size, birth weight, sex ratio, survival rate, and crown-rump length of the pups were significantly decreased in AfB1-exposed rats when compared to controls. Elapsed time (days) for testes to descend into the scrotal sac was significantly delayed in experimental pups when compared to control pups. Behavioral observations such as cliff avoidance, negative geotaxis, surface rightening activity, ascending wire mesh, open field behavior, and exploratory and locomotory activities were significantly impaired in experimental pups. Body weights and the indices of testis, cauda epididymis, prostate, seminal vesicles, and liver were significantly reduced on PD 100 in male rats exposed to AfB1 during embryonic development when compared with controls. Significant reduction in the testicular daily sperm production, epididymal sperm count, and number of viable, motile, and hypo-osmotic tail coiled sperm was observed in experimental rats. The levels of serum testosterone and activity levels of testicular hydroxysteroid dehydrogenases were significantly decreased in a dose-dependent manner with a significant increase in the serum follicle-stimulating hormone and luteinizing hormone in experimental rats. Deterioration in the testicular and cauda epididymal architecture was observed in experimental rats. The results of fertility

  1. Installation restoration program. Operable Unit B1 remedial investigation/feasibility study. Appendices. Final report

    Energy Technology Data Exchange (ETDEWEB)

    1993-06-30

    This document presents the results from the remedial investigation and feasibility study for Operable Unit (OU) B1 at McClellan AFB, Sacramento, CA. Operable Unit B1 includes the Defense Reutilization and Marketing Office (DRMO) storage lot and Civil Engineering storage lot at McClellan AFB. The main chemicals of concern are PCBs, dioxins, and furans which may have leaked from transformers stored at OU B1 or were constituents of waste oil applied to soils to control dust. Sections 1.0 through 4.0 of the report present results from the RI, the potential for contaminant migration/transport from OU B1 and the current and future risks associated with OU B1. The FS begins in Section 5.0 identifying the remedial action objectives, in Sections 6.0 and 7.0, technologies are screened and potential remedial alternatives are developed. The final six remedial alternatives are analyzed and compared to each other using the criteria established in the NCP in Section 8.0.

  2. Impact of aflatoxin B1 on the pharmacokinetic disposition of enrofloxacin in broiler chickens.

    Science.gov (United States)

    Kalpana, Starling; Srinivasa Rao, G; Malik, Jitendra K

    2015-09-01

    The potential impact of subchronic exposure of aflatoxin B1 was investigated on the pharmacokinetic disposition of enrofloxacin in broiler chickens. Broiler chickens given either normal or aflatoxin B1 (750μg/kg diet) supplemented diet for 6 weeks received a single oral dose of enrofloxacin (10mg/kg body wt). Blood samples were drawn from the brachial vein at predetermined time intervals after drug administration. Enrofloxacin plasma concentrations analyzed by RP-HPLC were significantly lower in aflatoxin B1-exposed broiler chickens at 0.167, 0.5 and 1.0h after drug administration. In aflatoxin B1-exposed broiler chickens, the absorption rate constant (ka) of enrofloxacin (0.20±0.05h(-1)) was significantly decreased as compared to the unexposed birds (0.98±0.31h(-1)). The values of [Formula: see text] , tmax and AUC0-∞ of enrofloxacin were nonsignificantly increased by 17%, 26% and 17% in aflatoxin-exposed broiler chickens, respectively. Subchronic aflatoxin B1 exposure markedly decreased the initial absorption of enrofloxacin without significantly influencing other pharmacokinetic parameters in broiler chickens. Copyright © 2015 Elsevier B.V. All rights reserved.

  3. Fetal Lymphoid Progenitors Become Restricted to B-1 Fates Coincident with IL-7Rα Expression.

    Science.gov (United States)

    Iida, Ryuji; Shinoda, Kaori; Hayano, Yuki; Nagai, Yoshinori; Takatsu, Kiyoshi; Kouro, Taku

    2016-01-01

    B-1 cells represent a sub-fraction of B lymphocytes that participate in T cell-independent antibody production and contribute to innate immunity. While the production of B-1 cells is favored during the fetal waves of lymphopoiesis, it has been unclear when and how that differentiation option is specified. To clarify this, lymphoid and hematopoietic progenitors of fetal liver (FL) and adult bone marrow (ABM) were examined for the B cell differentiation potential. Mouse common lymphoid progenitors (CLPs) and more primitive KSL fraction of FL and ABM were transferred to SCID mice and donor-derived B cell subsets were analyzed 4 weeks later. CLPs were also cultured on ST2 stromal cells for 6 days prior to transplantation. While Lin- IL-7Rα+ CLPs from ABM differentiated to B-1, B-2 and marginal zone B (MZB) cells, equivalent cells from d15 FL differentiated mostly to B-1a cells. We found that fetal CLPs had less ability to colonize the bone marrow than adult CLPs. However, the fetal/adult difference was already present when progenitors were cultured in an identical condition before transplantation. More primitive KSL fraction of FL could generate the same broad spectrum of B cells typical of adults, including splenic MZB cells. In conclusion, we argue that FL and ABM-CLPs are intrinsically different regarding B-1/B-2 fates and the difference is acquired just before or coincident with the acquisition of IL-7Rα expression.

  4. B1 and T1 mapping of the breast with a reference tissue method.

    Science.gov (United States)

    Pineda, Federico D; Medved, Milica; Fan, Xiaobing; Karczmar, Gregory S

    2016-04-01

    To develop a method for mapping the B1 field using a reference signal from a tissue with known T1. Flip angle correction factors were calculated in a region with a known "gold standard" T1; by comparing T1 values from a variable flip angle (VFA) sequence to the "gold standard" and correcting the value of the Ernst angle. The resulting partial B1 map was interpolated for all other regions. In the breast, fat is an ideal reference tissue because its T1 is spatially homogeneous and interpatient variability is low. This method was tested with scans of phantoms and patients (n = 4) on a 3T magnet. The performance of the method was evaluated by comparing the results of VFA T1 mapping with and without B1 correction to inversion recovery (IR) T1 maps. Phantom data determined that a linear inverse distance weighted interpolation accurately recovered the full B1 map. Use of interpolated maps to correct the VFA data in vivo, reduced the average difference in the T1 of parenchyma between VFA and IR results from 58% to 8%. This proof-of-principle study showed that it is possible to recover a full and accurate map of the B1 field in the breast by using a reference tissue (fat) with an accurately measured T1. © 2015 Wiley Periodicals, Inc.

  5. Fetal Lymphoid Progenitors Become Restricted to B-1 Fates Coincident with IL-7Rα Expression.

    Directory of Open Access Journals (Sweden)

    Ryuji Iida

    Full Text Available B-1 cells represent a sub-fraction of B lymphocytes that participate in T cell-independent antibody production and contribute to innate immunity. While the production of B-1 cells is favored during the fetal waves of lymphopoiesis, it has been unclear when and how that differentiation option is specified. To clarify this, lymphoid and hematopoietic progenitors of fetal liver (FL and adult bone marrow (ABM were examined for the B cell differentiation potential. Mouse common lymphoid progenitors (CLPs and more primitive KSL fraction of FL and ABM were transferred to SCID mice and donor-derived B cell subsets were analyzed 4 weeks later. CLPs were also cultured on ST2 stromal cells for 6 days prior to transplantation. While Lin- IL-7Rα+ CLPs from ABM differentiated to B-1, B-2 and marginal zone B (MZB cells, equivalent cells from d15 FL differentiated mostly to B-1a cells. We found that fetal CLPs had less ability to colonize the bone marrow than adult CLPs. However, the fetal/adult difference was already present when progenitors were cultured in an identical condition before transplantation. More primitive KSL fraction of FL could generate the same broad spectrum of B cells typical of adults, including splenic MZB cells. In conclusion, we argue that FL and ABM-CLPs are intrinsically different regarding B-1/B-2 fates and the difference is acquired just before or coincident with the acquisition of IL-7Rα expression.

  6. Rapid pretreatment and detection of trace aflatoxin B1 in traditional soybean sauce.

    Science.gov (United States)

    Xie, Fang; Lai, WeiHua; Saini, Jasdeep; Shan, Shan; Cui, Xi; Liu, DaoFeng

    2014-05-01

    Soybean sauce, a traditional fermented food in China, has different levels of aflatoxin B1 pollution. Two kinds of direct and indirect immunomagnetic bead methods for the pretreatment of aflatoxin B1 were evaluated in this work. A method was established to detect aflatoxin B1 in soybean sauce using an immunomagnetic bead system for pretreatment and ELISA for quantification. The pretreatment method of immunomagnetic beads performed better compared with the conventional extraction and immunoaffinity column method. ELISA exhibited a good linear relationship at an aflatoxin B1 concentration of 0.05-0.3μg/kg (r(2)=0.9842). The average recoveries across spike levels varied from 0.5 to 7μg/kg were 83.6-104% with a relative standard deviation between 4.2% and 11.7%. With the advantages of rapid detection, easy operation, simple equipment, sensitivity, accuracy, and high recovery; this method can be well applied in the trace determination of aflatoxin B1 in soybean sauce samples. Copyright © 2013 Elsevier Ltd. All rights reserved.

  7. Predicting the orientation of protein G B1 on hydrophobic surfaces using Monte Carlo simulations.

    Science.gov (United States)

    Harrison, Elisa T; Weidner, Tobias; Castner, David G; Interlandi, Gianluca

    2016-12-06

    A Monte Carlo algorithm was developed to predict the most likely orientations of protein G B1, an immunoglobulin G (IgG) antibody-binding domain of protein G, adsorbed onto a hydrophobic surface. At each Monte Carlo step, the protein was rotated and translated as a rigid body. The assumption about rigidity was supported by quartz crystal microbalance with dissipation monitoring experiments, which indicated that protein G B1 adsorbed on a polystyrene surface with its native structure conserved and showed that its IgG antibody-binding activity was retained. The Monte Carlo simulations predicted that protein G B1 is likely adsorbed onto a hydrophobic surface in two different orientations, characterized as two mutually exclusive sets of amino acids contacting the surface. This was consistent with sum frequency generation (SFG) vibrational spectroscopy results. In fact, theoretical SFG spectra calculated from an equal combination of the two predicted orientations exhibited reasonable agreement with measured spectra of protein G B1 on polystyrene surfaces. Also, in explicit solvent molecular dynamics simulations, protein G B1 maintained its predicted orientation in three out of four runs. This work shows that using a Monte Carlo approach can provide an accurate estimate of a protein orientation on a hydrophobic surface, which complements experimental surface analysis techniques and provides an initial system to study the interaction between a protein and a surface in molecular dynamics simulations.

  8. Inherited variation in OATP1B1 is associated with treatment outcome in acute myeloid leukemia.

    Science.gov (United States)

    Drenberg, C D; Paugh, S W; Pounds, S B; Shi, L; Orwick, S J; Li, L; Hu, S; Gibson, A A; Ribeiro, R C; Rubnitz, J E; Evans, W E; Sparreboom, A; Baker, S D

    2016-06-01

    Using broad interrogation of clinically relevant drug absorption, distribution, metabolism, and excretion (ADME) genes on the DMET platform, we identified a genetic variant in SLCO1B1 (rs2291075; c.597C>T), encoding the transporter OATP1B1, associated with event-free (P = 0.006, hazard ratio = 1.74) and overall survival (P = 0.012, hazard ratio = 1.85) in children with de novo acute myeloid leukemia (AML). Lack of SLCO1B1 expression in leukemic blasts suggested the association might be due to an inherited rather than a somatic effect. rs2291075 was in strong linkage with known functional variants rs2306283 (c.388A>G) and rs4149056 (c.521T>C). Functional studies in vitro determined that four AML-directed chemotherapeutics (cytarabine, daunorubicin, etoposide, and mitoxantrone) are substrates for OATP1B1 and the mouse ortholog Oatp1b2. In vivo pharmacokinetic studies using Oatp1b2-deficient mice further confirmed our results. Collectively, these findings demonstrate an important role for OATP1B1 in the systemic pharmacokinetics of multiple drugs used in the treatment of AML and suggest that inherited variability in host transporter function influences the effectiveness of therapy. © 2015 The American Society for Clinical Pharmacology and Therapeutics.

  9. PENGARUH KADAR THIAMINE (VITAMIN B1 TERHADAP PERTUMBUHAN JAMUR TIRAM PUTIH (Pleurotus ostreatus

    Directory of Open Access Journals (Sweden)

    Munir Munir

    2016-08-01

    Full Text Available Indonesia is one of the centers of biodiversity in particular areas of food, which one of them is from a species of white oyster mushroom (Pleurotus ostreatus. To improve the effectiveness and efficiency of production time associated with fulfilling the request of the oyster mushroom (Pleurotus ostreatus is high in the market, the utilization of thiamine (vitamin B1 need to be investigated. This study aims to determine the levels of thiamine (vitamin B1, which is best used in the growth of oyster mushroom (Pleurotus ostreatus. This study used quantitative experiments and research design complete randomized design with four treatments and six times as many repetitions as well as research along with the observations made on 21 June to 11 July 2015 (in 20 days in the House of White Oyster Mushroom Production Nurseries, Ogan Komering Ulu Timur (OKUT. As for the levels of thiamine (vitamin B1 used in this study use the unit ppm (parts per million, namely: B0 (control, B1 (0.1 ppm, B2 (0.2 ppm, B3 (0.3 ppm. Parameters measured were the growth of oyster mushroom (Pleurotus ostreatus which include emerging buds time (day, the time of harvest (days, weight (grams, wide hood (cm, and stem length (cm. Conclusions from the study and based on data analysis (ANOVA and F test showed that administration of thiamine (vitamin B1 does not provide an effective influence on the growth of oyster mushroom (Pleurotus ostreatus.

  10. Association of cytochrome P450 1B1 haplotypes with head and neck cancer risk.

    Science.gov (United States)

    Katiyar, Tridiv; Maurya, Shailendra S; Hasan, Feza; Singh, Arvind P; Khan, Anwar J; Hadi, Rahat; Singh, Sudhir; Bhatt, Madan L B; Parmar, Devendra

    2017-07-01

    Genetic polymorphisms have been reported in several cytochrome P450 (CYP) genes, including CYP1B1 which metabolically activates procarcinogens present in tobacco to carcinogenic intermediates. This study used a case-control approach in North Indian population to determine associations between genetic variants in CYP1B1 and risk of Head and Neck Squamous Cell Carcinoma (HNSCC). We examined the genotype and haplotype frequencies at various single-nucleotide polymorphisms (SNPs), including SNPs previously reported in the promoter region and intron 1 of CYP1B1 in Caucasians. Using cycle sequencing, 9 SNPs were identified in the promoter region, intron 1, and exons 2 and 3. Haplotype analysis revealed that 5 SNPs (those in the promoter region, intron, and Arg48Gly and Ala119Ser in exon 2) were in strong linkage disequilibrium (LD). Cases with the T-A-T-G-T haplotype were significantly associated with increased risk of HNSCC. Interestingly, qRT-PCR studies revealed a significant increase in mRNA expression of CYP1B1 in peripheral blood isolated from cases with the T-A-T-G-T haplotype compared with cases with the C-G-C-C-G haplotype, and in cases compared to controls for both main haplotypes. The data thus provide evidence that CYP1B1 haplotypes could be more effective in predicting HNSCC risk. Environ. Mol. Mutagen. 58:443-450, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  11. Application of a fuzzy neural network model in predicting polycyclic aromatic hydrocarbon-mediated perturbations of the Cyp1b1 transcriptional regulatory network in mouse skin

    Energy Technology Data Exchange (ETDEWEB)

    Larkin, Andrew [Department of Environmental and Molecular Toxicology, Oregon State University (United States); Department of Statistics, Oregon State University (United States); Superfund Research Center, Oregon State University (United States); Siddens, Lisbeth K. [Department of Environmental and Molecular Toxicology, Oregon State University (United States); Superfund Research Center, Oregon State University (United States); Krueger, Sharon K. [Superfund Research Center, Oregon State University (United States); Linus Pauling Institute, Oregon State University (United States); Tilton, Susan C.; Waters, Katrina M. [Superfund Research Center, Oregon State University (United States); Computational Biology and Bioinformatics Group, Pacific Northwest National Laboratory, Richland, WA 99352 (United States); Williams, David E., E-mail: david.williams@oregonstate.edu [Department of Environmental and Molecular Toxicology, Oregon State University (United States); Superfund Research Center, Oregon State University (United States); Linus Pauling Institute, Oregon State University (United States); Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331 (United States); Baird, William M. [Department of Environmental and Molecular Toxicology, Oregon State University (United States); Superfund Research Center, Oregon State University (United States); Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331 (United States)

    2013-03-01

    Polycyclic aromatic hydrocarbons (PAHs) are present in the environment as complex mixtures with components that have diverse carcinogenic potencies and mostly unknown interactive effects. Non-additive PAH interactions have been observed in regulation of cytochrome P450 (CYP) gene expression in the CYP1 family. To better understand and predict biological effects of complex mixtures, such as environmental PAHs, an 11 gene input-1 gene output fuzzy neural network (FNN) was developed for predicting PAH-mediated perturbations of dermal Cyp1b1 transcription in mice. Input values were generalized using fuzzy logic into low, medium, and high fuzzy subsets, and sorted using k-means clustering to create Mamdani logic functions for predicting Cyp1b1 mRNA expression. Model testing was performed with data from microarray analysis of skin samples from FVB/N mice treated with toluene (vehicle control), dibenzo[def,p]chrysene (DBC), benzo[a]pyrene (BaP), or 1 of 3 combinations of diesel particulate extract (DPE), coal tar extract (CTE) and cigarette smoke condensate (CSC) using leave-one-out cross-validation. Predictions were within 1 log{sub 2} fold change unit of microarray data, with the exception of the DBC treatment group, where the unexpected down-regulation of Cyp1b1 expression was predicted but did not reach statistical significance on the microarrays. Adding CTE to DPE was predicted to increase Cyp1b1 expression, whereas adding CSC to CTE and DPE was predicted to have no effect, in agreement with microarray results. The aryl hydrocarbon receptor repressor (Ahrr) was determined to be the most significant input variable for model predictions using back-propagation and normalization of FNN weights. - Highlights: ► Tested a model to predict PAH mixture-mediated changes in Cyp1b1 expression ► Quantitative predictions in agreement with microarrays for Cyp1b1 induction ► Unexpected difference in expression between DBC and other treatments predicted ► Model predictions

  12. No Effect of SLCO1B1 and CYP3A4/5 Polymorphisms on the Pharmacokinetics and Pharmacodynamics of Ticagrelor in Healthy Chinese Male Subjects.

    Science.gov (United States)

    Li, Mupeng; Hu, Yaodong; Li, Huilan; Wen, Zhipeng; Hu, Xiaolei; Zhang, Daoyu; Zhang, Yanjiao; Xiao, Jian; Tang, Jie; Chen, Xiaoping

    2017-01-01

    Ticagrelor is a direct-acting P2Y12 receptor antagonist. It is rapidly absorbed and partly metabolized to the active metabolite AR-C124910XX by CYP3A4 and CYP3A5. Three genetic loci (SLCO1B1, CYP3A4, and UGT2B7) were reported to affect ticagrelor pharmacokinetics. This study aimed to investigate the possible effects of SLCO1B1 and CYP3A4/5 genetic polymorphisms on the pharmacokinetics and pharmacodynamics of ticagrelor in healthy Chinese male volunteers. Eighteen healthy male volunteers who participated in pharmacogenetics study of ticagrelor were genotyped for SLCO1B1 rs113681054, SLCO1B1*5 (rs4149056), CYP3A4*1G (rs2242480), and CYP3A5*3 (rs776746). All subjects received a single 180 mg loading dose of ticagrelor and then series blood samples were collected from 0 to 48 h. Plasma concentrations of ticagrelor and AR-C124910XX were determined by the high performance liquid chromatography-tandem mass spectrometry method. Inhibition in platelet aggregation (IPA) was assessed and the area under the time-effect curve (AUEC) for the IPA was calculated as pharmacodynamic parameters. No significant difference in ticagrelor pharmacokinetics among genotypes of the two genes was observed. The AUEC did not differ significantly among genotypes of candidate single nucleotide polymorphisms (SNPs). Our data suggest that common genetic variants in SLCO1B1 and CYP3A4/5 may have no effect on the pharmacokinetics and pharmacodynamics of ticagrelor in healthy Chinese volunteers.

  13. A novel CYP1B1 mutation with congenital glaucoma and total aniridia.

    Science.gov (United States)

    Alzuhairy, Sultan; Abu-Amero, Khaled K; Al-Shahwan, Sami; Edward, Deepak P

    2015-03-01

    Primary congenital glaucoma is a common disorder in the Middle East mainly caused by mutations in the the CYP1Bl gene. We report a family with three siblings that presented with recalcitrant childhood glaucoma, aniridia in two siblings with a novel CYP1B1 gene mutation. Review of pedigree, clinical history and clinical course of the family. Genetic testing in the affected family members. Three sisters presented with clinical findings of severe congenital glaucoma and a positive family history. Clinical examination of two of sisters revealed corneal scarring, bilateral aniridia with severe glaucoma that required multiple surgical procedures to control intraocular pressure. The third sibling presented with garden-variety primary congenital glaucoma. Genetic analysis revealed a novel CYP1B1 gene mutation (g.8291 C > T; p.S485F). CYP1B1 mutation related congenital glaucoma can present with an extreme form of anterior segment dysgenesis that includes recalcitrant glaucoma, corneal opacification and aniridia.

  14. Factor XII-independent activation of the bradykinin-forming cascade: Implications for the pathogenesis of hereditary angioedema types I and II.

    Science.gov (United States)

    Joseph, Kusumam; Tholanikunnel, Baby G; Bygum, Anette; Ghebrehiwet, Berhane; Kaplan, Allen P

    2013-08-01

    We have previously reported that prekallikrein expresses an active site when it is bound to high-molecular-weight kininogen (HK) and can digest HK to produce bradykinin. The reaction is stoichiometric and inhibited by C1 inhibitor (C1-INH) or corn trypsin inhibitor. Addition of heat shock protein 90 leads to conversion of prekallikrein to kallikrein in a zinc-dependent reaction. Our goal was to determine whether these reactions are demonstrable in plasma and distinguish them from activation through factor XII. Plasma was incubated in polystyrene plates and assayed for kallikrein formation. C1-INH was removed from factor XII-deficient plasma by means of immunoadsorption. We demonstrate that prekallikrein-HK will activate to kallikrein in phosphate-containing buffers and that the rate is further accelerated on addition of heat shock protein 90. Prolonged incubation of plasma deficient in both factor XII and C1-INH led to conversion of prekallikrein to kallikrein and cleavage of HK, as was seen in plasma from patients with hereditary angioedema but not plasma from healthy subjects. These results indicate that C1-INH stabilizes the prekallikrein-HK complex to prevent HK cleavage either by prekallikrein or by prekallikrein-HK autoactivation to generate kallikrein. In patients with hereditary angioedema, kallikrein and bradykinin formation can occur without invoking factor XII activation, although the kallikrein formed can rapidly activate factor XII if it is surface bound. Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

  15. Effects of histamine, 5-hydroxytryptamine and bradykinin on the vascular system of isolated lungs of the guinea-pig and the influence of phenylbutazone on these effects

    Science.gov (United States)

    Aarsen, P. N.; Zeegers, A.

    1972-01-01

    1. In isolated lungs of the guinea-pig perfused through the pulmonary artery repeated doses of histamine progressively increased pulmonary arterial pressure and reduced fluctuations in tracheal pressure. Phenylbutazone almost completely abolished the effect of histamine on the arterial pressure and suppressed the progression of the effect on tracheal pressure. 2. The effects of 5-hydroxytryptamine and bradykinin did not show such progression. 3. The fractions of radioactivity remaining in the lungs after doses of 14C-histamine did not differ significantly after successive doses. The outflow of radioactivity from previously loaded lungs was greatly increased by histamine, bradykinin and 5-hydroxytryptamine. This increase was not affected by papaverine. 4. Successive doses of histamine, but not 5-hydroxytryptamine, produced a progressive increase in weight of the lungs and this effect was accompanied by a progressive increase in arterial pressure. Both effects were strongly suppressed by phenylbutazone. 5. It is concluded that repeated administration of histamine causes an accumulation of fluid in the lungs probably mainly in the interstitial spaces, which results in an inhibition of the tracheal pressure fluctuations. Phenylbutazone prevents this effect by suppressing the vasoconstrictor action of histamine without affecting the increased vascular permeability. PMID:4403102

  16. Gender and age-dependent differences in the bradykinin-degradation within the pericardial fluid of patients with coronary artery disease.

    Science.gov (United States)

    Bechtloff, Roland; Goette, Andreas; Bukowska, Alicja; Kähne, Thilo; Peters, Brigitte; Huth, Christof; Wolke, Carmen; Lendeckel, Uwe

    2011-01-21

    Cardiovascular diseases (CVD) and, in particular, coronary artery disease (CAD) are the leading causes of death in developed countries, especially in the elderly population. Males exhibit a higher risk for cardiovascular events than women. The pericardial fluid (PF) is in direct contact with the epicardial sections of the coronary arteries and the perimyocardium. A systematic analysis of gender-specific or age-related differences in angiotensin-related pathways like bradykinin metabolism however, has not been performed in the PF so far. Therefore, the amounts of angiotensin-converting enzyme (ACE) and the rate of the degradation of bradykinin (BK) and the amounts/activity of major BK-degrading enzymes, aminopeptidase N (APN) and dipeptidyl-aminopeptidase IV (DPIV), were assessed in the pericardial fluid (PF) of 44 patients undergoing coronary artery bypass grafting. We found BK being degraded within the PF. Interestingly, there was an age-dependent decrease in the amounts of ACE protein in women. In elderly women, ACE/APN and ACE/DPIV ratios were substantially reduced to 41.4% or 29.4% respectively (pgender-dependent differences in BK metabolism within the PF in patients with coronary artery disease. The present finding that the expression of ACE is lowest in elderly women, despite the presence of similar BK degradation, might help to explain the potentially reduced therapeutic effects of ACE inhibitors in elderly women. Copyright © 2009 Elsevier Ireland Ltd. All rights reserved.

  17. SF3B1 mutations constitute a novel therapeutic target in breast cancer.

    Science.gov (United States)

    Maguire, Sarah L; Leonidou, Andri; Wai, Patty; Marchiò, Caterina; Ng, Charlotte Ky; Sapino, Anna; Salomon, Anne-Vincent; Reis-Filho, Jorge S; Weigelt, Britta; Natrajan, Rachael C

    2015-03-01

    Mutations in genes encoding proteins involved in RNA splicing have been found to occur at relatively high frequencies in several tumour types including myelodysplastic syndromes, chronic lymphocytic leukaemia, uveal melanoma, and pancreatic cancer, and at lower frequencies in breast cancer. To investigate whether dysfunction in RNA splicing is implicated in the pathogenesis of breast cancer, we performed a re-analysis of published exome and whole genome sequencing data. This analysis revealed that mutations in spliceosomal component genes occurred in 5.6% of unselected breast cancers, including hotspot mutations in the SF3B1 gene, which were found in 1.8% of unselected breast cancers. SF3B1 mutations were significantly associated with ER-positive disease, AKT1 mutations, and distinct copy number alterations. Additional profiling of hotspot mutations in a panel of special histological subtypes of breast cancer showed that 16% and 6% of papillary and mucinous carcinomas of the breast harboured the SF3B1 K700E mutation. RNA sequencing identified differentially spliced events expressed in tumours with SF3B1 mutations including the protein coding genes TMEM14C, RPL31, DYNL11, UQCC, and ABCC5, and the long non-coding RNA CRNDE. Moreover, SF3B1 mutant cell lines were found to be sensitive to the SF3b complex inhibitor spliceostatin A and treatment resulted in perturbation of the splicing signature. Albeit rare, SF3B1 mutations result in alternative splicing events, and may constitute drivers and a novel therapeutic target in a subset of breast cancers. © 2014 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

  18. Cdc2/cyclin B1 regulates centrosomal Nlp proteolysis and subcellular localization.

    Science.gov (United States)

    Zhao, Xuelian; Jin, Shunqian; Song, Yongmei; Zhan, Qimin

    2010-11-01

    The formation of proper mitotic spindles is required for appropriate chromosome segregation during cell division. Aberrant spindle formation often causes aneuploidy and results in tumorigenesis. However, the underlying mechanism of regulating spindle formation and chromosome separation remains to be further defined. Centrosomal Nlp (ninein-like protein) is a recently characterized BRCA1-regulated centrosomal protein and plays an important role in centrosome maturation and spindle formation. In this study, we show that Nlp can be phosphorylated by cell cycle protein kinase Cdc2/cyclin B1. The phosphorylation sites of Nlp are mapped at Ser185 and Ser589. Interestingly, the Cdc2/cyclin B1 phosphorylation site Ser185 of Nlp is required for its recognition by PLK1, which enable Nlp depart from centrosomes to allow the establishment of a mitotic scaffold at the onset of mitosis . PLK1 fails to dissociate the Nlp mutant lacking Ser185 from centrosome, suggesting that Cdc2/cyclin B1 might serve as a primary kinase of PLK1 in regulating Nlp subcellular localization. However, the phosphorylation at the site Ser589 by Cdc2/cyclin B1 plays an important role in Nlp protein stability probably due to its effect on protein degradation. Furthermore, we show that deregulated expression or subcellular localization of Nlp lead to multinuclei in cells, indicating that scheduled levels of Nlp and proper subcellular localization of Nlp are critical for successful completion of normal cell mitosis, These findings demonstrate that Cdc2/cyclin B1 is a key regulator in maintaining appropriate degradation and subcellular localization of Nlp, providing novel insights into understanding on the role of Cdc2/cyclin B1 in mitotic progression.

  19. Patterns of cyclin A and B1 immunostaining in papillary thyroid carcinoma.

    Science.gov (United States)

    Cyniak-Magierska, Anna; Stasiak, Magdalena; Naze, Maciej; Dedecjus, Marek; Brzeziński, Jan; Lewiński, Andrzej

    2015-01-01

    Cyclin A, encoded by CCNA (cyclin A) gene with locus in chromosome 4q27, and cyclin B1, encoded by CCNB1 (cyclin B1) gene with locus in chromosome 5q12, are proteins that play a key role in the passage through the restriction point in G2 phase of the cell cycle. The aim of the study was to analyse immunohistochemically the expression of cyclins A and B1 in different variants of papillary thyroid carcinoma (PTC). The immunostaining patterns of the proteins in question in the tissue of 40 resected PTC (20 cases of classic variant of PTC, 9 cases of PTC follicular variant and 11 cases of other non-classic variants of PTC) were investigated. On analyzing cyclin A and B1 expression, positive staining in 90% cases of PTC were observed. The study revealed a significant difference in expression of cyclins A and B1 between classic and non-classic variants of PTC. The expression of both examined cyclins was weaker in the classic variant of PTC. In the group of follicular variant of PTC, the expression of cyclins was of medium intensity and in the group of other non-classic variants of PTC, the expression was clearly higher. The results of the presented study suggest that cyclins A and B1 expression may have a characteristic pattern of immunostaining for particular variants of PTC. If the obtained results are confirmed in a larger group of patients, the diagnostic panel constructed of the antibodies against these proteins may increase the diagnostic accuracy in PTC cases.

  20. Results from the photoemission spectroscopy beamline 2B1 at Pohang Light Source

    CERN Document Server

    Chung, Y H; Kim, D Y; Kim, H J; Kim, J M; Kim, T S; Ro, C; Raza, H; Thornton, G; Kim, B S; Kim, K J; Kang, T H

    1999-01-01

    The results of photoemission spectroscopy using molybdenum and tantalum samples have been obtained from the new beamline 2B1 at Pohang Light Source. Beamline 2B1 is based on a spherical grating monochromator (SGM) which is equipped with five gratings. The photon energy range from 184 to 1100 eV was covered in this work using two gratings (Gratings 4 and 5). The photon energy resolution has been deduced from Ta Fermi-level spectra and 3d spectra of Mo.

  1. [Studies on the state of vitamins B1, B2 and B6 in Down's syndrome].

    Science.gov (United States)

    Schmid, F; Christeller, S; Rehm, W

    1975-09-11

    In 110 children-between 0-16 years of age-, 90 children with Down-syndrome and 20 controls the following metabolic parameter were analyzed: ETK (vitamin-B1-activating coefficient), EGR (vitamin B2), P-5'-P, EGOT (vitamin B6), GOT, GPT, pH, K, Na, Ca, Cl, uric-acid (HS). Among some important correlations between the different parameters it could be demonstrated-for the first time to our knowledge-that in Mongoloids a disturbance of the vitamin-B1-metabolism exists, certified by the so-called transketolase-test.

  2. Sampling and Analysis Instruction for Borehole Sampling at 118-B-1 Burial Ground

    Energy Technology Data Exchange (ETDEWEB)

    W. S. Thompson

    2007-04-02

    The Washington Closure Hanford (WCH) Field Remediation Project has removed all of the disposed materials and contaminated soil from the 118-B-1 Burial Ground with the exception of tritium-contaminated soil that is believed to extend from the bottom of the present excavation to groundwater and is believed to contribute to tritium contamination observed at down-gradient monitoring Well 199-B8-6. This sampling and analysis instruction (SAI) provides the requirements for sample collection and laboratory analysis for characterization of the vertical distribution of tritium contamination in the vadose zone soil below the 118-B-1 Burial Ground remedial action excavation.

  3. Fate of Fumonisin B1 in Naturally Contaminated Corn during Ethanol Fermentation

    OpenAIRE

    Bothast, R J; Bennett, G. A.; VanCauwenberge, J E; Richard, J. L.

    1992-01-01

    Two lots of corn naturally contaminated with fumonisin B1 (15 and 36 ppm) and a control lot (no fumonisin B1 detected) were used as substrates for ethanol production in replicate 8.5-liter yeast fermentations. Ethanol yields were 8.8% for both the control and low-fumonisin corn, while the high-fumonisin corn contained less starch and produced 7.2% ethanol. Little degradation of fumonisin occurred during fermentation, and most was recovered in the distillers' grains, thin stillage, and distill...

  4. Cdc20 hypomorphic mice fail to counteract de novo synthesis of cyclin B1 in mitosis.

    NARCIS (Netherlands)

    Malureanu, L.; Jeganathan, K.B.; Jin, F.; Baker, D.J.; Ree, J.H.; Gullon, O.; Chen, Z.; Henley, J.R.; Deursen, J.M.A. van

    2010-01-01

    Cdc20 is an activator of the anaphase-promoting complex/cyclosome that initiates anaphase onset by ordering the destruction of cyclin B1 and securin in metaphase. To study the physiological significance of Cdc20 in higher eukaryotes, we generated hypomorphic mice that express small amounts of this

  5. Design and verification of the Risø-B1 airfoil family for wind turbines

    DEFF Research Database (Denmark)

    Fuglsang, P.; Bak, C.; Gaunaa, M.

    2004-01-01

    wind tunnel, Denmark, at a Reynolds number of 1.6x10(6). For both airfoils the predicted target characteristics were met. Results for Risø-B1-18 showed a maximum lift coefficient of 1.64. A standard case of zigzag tape leading edge roughness caused a drop in maximum lift of only 3.7%. Cases of more...... severe roughness caused reductions in maximum lift between 12% and 27%. Results for the Risø-B1-24 airfoil showed a maximum lift coefficient of 1.62. The standard case leading edge roughness caused a drop in maximum lift of 7.4%. Vortex generators and Gurney flaps in combination could increase maximum...... were designed to have high maximum lift and high design lift to allow a slender flexible blade while maintaining high aerodynamic efficiency. The design was carried out with a Risø in-house multi disciplinary optimization tool. Wind tunnel testing was done for Risø-B1-18 and Risø-B1-24 in the VELUX...

  6. The vitamin B1 metabolism of Staphylococcus aureus is controlled at enzymatic and transcriptional levels

    NARCIS (Netherlands)

    Müller, Ingrid B; Bergmann, Bärbel; Groves, Matthew R; Couto, Isabel; Amaral, Leonard; Begley, Tadhg P; Walter, Rolf D; Wrenger, Carsten

    2009-01-01

    Vitamin B1 is in its active form thiamine pyrophosphate (TPP), an essential cofactor for several key enzymes in the carbohydrate metabolism. Mammals must salvage this crucial nutrient from their diet in order to complement the deficiency of de novo synthesis. In the human pathogenic bacterium

  7. 26 CFR 31.3306(b)(1)-1 - $3,000 limitation.

    Science.gov (United States)

    2010-04-01

    ... SOURCE Federal Unemployment Tax Act (Chapter 23, Internal Revenue Code of 1954) § 31.3306(b)(1)-1 $3,000... employer is immaterial. The acquisition may occur as a consequence of the incorporation of a business by a...

  8. Inhibition of apoptic cell death induced by Pseudomonas syringae pv. Tabaci and mycotoxin fumonisin B1

    NARCIS (Netherlands)

    Iakimova, E.T.; Batchvorova, R.; Kapchina, V.; Popov, T.; Atanassov, A.; Woltering, E.J.

    2004-01-01

    The impact of programmed cell death (PCD) inhibitors on lesion formation and biochemical events in transgenic (ttr line) and non-transgenic (Nevrokop 1164) tobacco infected with Pseudomonas syringae pv. tabaci was tested. Programmed cell death in tomato cell culture was induced by Fumonisin B1 (FUM)

  9. Data of evolutionary structure change: 1DC3B-1CERP [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1DC3B-1CERP 1DC3 1CER B P TIKVGINGFGRIGRIVFRAAQKRSDIEIVAINDLLDADYMAYMLKYDSTHGRFDGT...1CER P 1CERP EAYDPSRHHIIS...1CER P 1CERP LHSRG-VEVAL ...1CER P 1CERP LDLPH-KDLRR ...1CER P 1CERP TKALG-NMVKV

  10. Data of evolutionary structure change: 1DC6B-1CERP [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1DC6B-1CERP 1DC6 1CER B P TIKVGINGFGRIGRIVFRAAQKRSDIEIVAINDLLDADYMAYMLKYDSTHGRFDGT...1CER P 1CERP EAYDPSRHHIIS...1CER P 1CERP LHSRG-VEVAL ...1CER P 1CERP LDLPH-KDLRR ...1CER P 1CERP TKALG-NMVKV

  11. ATP8B1 and ATP11C: Two Lipid Flippases Important for Hepatocyte Function

    NARCIS (Netherlands)

    Naik, Jyoti; de Waart, Dirk R.; Utsunomiya, Karina; Duijst, Suzanne; Mok, Kam Ho; Oude Elferink, Ronald P. J.; Bosma, Piter J.; Paulusma, Coen C.

    2015-01-01

    P4 ATPases are lipid flippases and transport phospholipids from the exoplasmic to the cytosolic leaflet of biological membranes. Lipid flipping is important for the biogenesis of transport vesicles. Recently it was shown that loss of the P4 ATPases ATP8B1 and ATP11C are associated with severe

  12. Preparation of B1-(Cr,Ga)N thin films by pulsed laser deposition

    Science.gov (United States)

    Mizuno, Yusei; Nakayama, Tadachika; Suematsu, Hisayuki; Suzuki, Tsuneo

    2018-02-01

    Cr–Ga–N thin films were prepared on (100)-oriented MgO single-crystal substrates by pulsed laser deposition at various substrate temperatures. An ablation plasma, generated by irradiating a Cr–10 at. % Ga alloy target with a Nd:YAG laser, was applied to the substrates to deposit the Cr–Ga–N thin films. Rutherford backscattering spectroscopy revealed that the ratio of the amount of Ga to the amount of Cr plus Ga (hereafter Cr+Ga) in all Cr–Ga–N thin films was approximately 10 at. %. X-ray diffraction and microstructural observation indicated that Cr–Ga–N thin films deposited at substrate temperatures (T sub) above 773 K contained two crystal phases: B1 (NaCl type)-CrN and B4 (würtzite type)-GaN. By contrast, Cr–Ga–N thin films deposited at a T sub of 673 K grew epitaxially and were composed of a single B1-(Cr,Ga)N phase, synthesized by substituting some of the Cr atoms in B1-CrN with Ga atoms. The epitaxial B1-(Cr,Ga)N thin films showed a higher hardness than epitaxial CrN films.

  13. Data of evolutionary structure change: 1CF5B-1RTCA [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1CF5B-1RTCA 1CF5 1RTC B A --------DVNFDLSTATAKTYTKFIEDFRATL-PFSHK...A 211 1RTC A 1RTCA...ain> 1RTC A 1RTCA SALYYYSTGGTQLPT...pdbChain> 1RTCA MRTRIRYNRRSA HHHHHH 1RTCA AYFFH-PDNQE

  14. Selection and application of strand displacement probes for a fumonisin B1 aptamer

    Science.gov (United States)

    Fumonisin B1 (FB1) is a toxin produced by Fusarium moniliforme, mainly on contaminated maize and maize products. In this study a solid surface chain displacement strategy was used to isolate oligonucleotide displacement probes for a FB1 aptamer. The probes were used as the basis for the development ...

  15. 10522 ASSESSMENT OF AFLATOXINS B1, B2, G1 AND G2 ...

    African Journals Online (AJOL)

    user

    2013-04-13

    Apr 13, 2013 ... Aflatoxins belong to a group of naturally occurring toxins which contaminate foodstuffs under favourable conditions. Aspergillus flavus and Aspergillus parasiticus produce aflatoxins; the four major aflatoxins which contaminate foodstuffs are B1, B2,. G1 and G2. Maize, groundnuts, rice, wheat and other ...

  16. Genome sequence of the Bacteroides fragilis phage ATCC 51477-B1.

    Science.gov (United States)

    Hawkins, Shawn A; Layton, Alice C; Ripp, Steven; Williams, Dan; Sayler, Gary S

    2008-08-18

    The genome of a fecal pollution indicator phage, Bacteroides fragilis ATCC 51477-B1, was sequenced and consisted of 44,929 bases with a G+C content of 38.7%. Forty-six putative open reading frames were identified and genes were organized into functional clusters for host specificity, lysis, replication and regulation, and packaging and structural proteins.

  17. 17 CFR 270.5b-1 - Definition of “total assets.”

    Science.gov (United States)

    2010-04-01

    ... (CONTINUED) RULES AND REGULATIONS, INVESTMENT COMPANY ACT OF 1940 § 270.5b-1 Definition of “total assets.” The term total assets, when used in computing values for the purposes of sections 5 and 12 of the Act, shall mean the gross assets of the company with respect to which the computation is made, taken as of...

  18. A patient with a rare leukodystrophy related to lamin B1 duplication.

    LENUS (Irish Health Repository)

    Molloy, A

    2012-06-01

    The hereditary leukodystrophies are rare disorders caused by molecular abnormalities leading to destruction of or failure of development of central white matter. For almost 30 years there has been increasing recognition of later onset Autosomal Dominant Leukodystrophy (ADLD). We report the first genetically confirmed case of lamin B1 duplication causing ADLD from Ireland.

  19. 17 CFR 270.34b-1 - Sales literature deemed to be misleading.

    Science.gov (United States)

    2010-04-01

    ... 17 Commodity and Securities Exchanges 3 2010-04-01 2010-04-01 false Sales literature deemed to be... (CONTINUED) RULES AND REGULATIONS, INVESTMENT COMPANY ACT OF 1940 § 270.34b-1 Sales literature deemed to be misleading. Any advertisement, pamphlet, circular, form letter, or other sales literature addressed to or...

  20. Data of evolutionary structure change: 1AR4B-1UNFX [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1AR4B-1UNFX 1AR4 1UNF B X ---AVYTLPELPYDYSALEPYISGEIMELHHDKHHKAYV...EEEEEEEEGGG EEEEEEE EEE EEE HHHH HHHHHHHHHH EEHHHHHHHHHHHHHH EVID> 1UNF X 1UNFX VNPL....9240429401397705 5.314901828765869 EVID>...ine>TRP CA 396 ASP CA 314 ASP CA 367 1UNF

  1. Comparative docking studies of CYP1b1 and its PCG-associated ...

    Indian Academy of Sciences (India)

    PRAKASH KUMAR

    to be involved in the metabolism of the endogenous steroid oestradiol (E2), the metabolites of which have ... Further, hydroxylation of E2 is considered to be the characteristic reaction catalysed by CYP1b1 (Murray et ..... of side-chains of aromatic amino acids, which stack with the ligand molecules. The hydrophobic nature of ...

  2. Mineralogy and Petrology of EK-459-5-1, A Type B1 CAI from Allende

    Science.gov (United States)

    Jeffcoat, C. R.; Kerekgyarto, A. G.; Lapen, T. J.; Andreasen, R.; Righter, M.; Ross, D. K.

    2015-01-01

    Calcium-aluminum-rich inclusions (CAIs) are a type of coarse-grained clast composed of Ca-, Al-, and Mg-rich silicates and oxides found in chondrite meteorites. Type B (CAIs) are exclusively found in the CV chondrite meteorites and are the most well studied type of inclusion found in chondritic meteorites. Type B1 CAIs are distinguished by a nearly monomineralic rim of melilite that surrounds an interior predominantly composed of melilite, fassaite (Ti and Al-rich clinopyroxene), anorthite, and spinel with varying amounts of other minor primary and secondary phases. The formation of Type B CAIs has received considerable attention in the course of CAI research and quantitative models, experimental results and observations from Type B inclusions remain largely in disagreement. Recent experimental results and quantitative models have shown that the formation of B1 mantles could have occurred by the evaporative loss of Si and Mg during the crystallization of these objects. However, comparative studies suggest that the lower bulk SiO2 compositions in B1s result in more prior melilite crystallization before the onset of fassaite and anorthite crystallization leading to the formation of thick melilite rich rims in B1 inclusions. Detailed petrographic and cosmochemical studies of these inclusions will further our understanding of these complex objects.

  3. Data of evolutionary structure change: 1CG5B-1HBRD [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1CG5B-1HBRD 1CG5 1HBR B D VKLSEDQEHYIKGVWKDVDHKQITAKALERVFVVYPWTT...e>GLY CA 259 VAL CA 324 1HBR ...D 1HBRD NLSSPTAILGNPMV HH...e> ASP CA 280 THR CA 322 1HBR D 1HBRD ELHCDKLHVDP

  4. Data of evolutionary structure change: 1CG5B-1NIHA [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1CG5B-1NIHA 1CG5 1NIH B A VKLSEDQEHYIKGVWKDV--DHKQITAKALERVFVVYPW...GLN CA 334 ILE CA 384 1NIH A 1NIHA AWGKVGAHAGEY HHHHHGG...line> ALA CA 307 ASN CA 225 1NIH... A 1NIHA KTYFPHFDLSHG<

  5. Determining the frequencies of B1, B2, B3 and E alleles of the ...

    African Journals Online (AJOL)

    The aim of the study was to determine the frequencies of B1, B2, B3 and E alleles of the CSN1S1 gene and their effects on milk yield and composition in the Saanen goat breed. Milk samples were collected to identify milk composition with Fourier transform ınfrared (FTIR) spectroscopy. The polymerase chain ...

  6. Biosynthetic relationship among aflatoxins B1, B2, M1, and M2.

    Science.gov (United States)

    Dutton, M F; Ehrlich, K; Bennett, J W

    1985-01-01

    Aflatoxins are a family of toxic, acetate-derived decaketides that arise biosynthetically through polyhydroxyanthraquinone intermediates. Most studies have assumed that aflatoxin B1 is the biosynthetic precursor of the other aflatoxins. We used a strain of Aspergillus flavus which accumulates aflatoxin B2 to investigate the later stages of aflatoxin biosynthesis. This strain produced aflatoxins B2 and M2 but no detectable aflatoxin B1 when grown over 12 days in a low-salt, defined growth medium containing asparagine. Addition of dichlorvos to this growth medium inhibited aflatoxin production with concomitant accumulation of versiconal hemiacetal acetate. When mycelial pellets were grown for 24, 48, and 72 h in growth medium and then transferred to a replacement medium, only aflatoxin B2 and M2 were recovered after 96 h of incubation. Addition of sterigmatocystin to the replacement medium led to the recovery of higher levels of aflatoxins B2 and M2 than were detected in control cultures, as well as to the formation of aflatoxins B1 and M1 and O-methylsterigmatocystin. These results support the hypothesis that aflatoxins B1 and B2 can arise independently via a branched pathway. PMID:3925881

  7. Biosynthetic relationship among aflatoxins B1, B2, M1, and M2.

    Science.gov (United States)

    Dutton, M F; Ehrlich, K; Bennett, J W

    1985-06-01

    Aflatoxins are a family of toxic, acetate-derived decaketides that arise biosynthetically through polyhydroxyanthraquinone intermediates. Most studies have assumed that aflatoxin B1 is the biosynthetic precursor of the other aflatoxins. We used a strain of Aspergillus flavus which accumulates aflatoxin B2 to investigate the later stages of aflatoxin biosynthesis. This strain produced aflatoxins B2 and M2 but no detectable aflatoxin B1 when grown over 12 days in a low-salt, defined growth medium containing asparagine. Addition of dichlorvos to this growth medium inhibited aflatoxin production with concomitant accumulation of versiconal hemiacetal acetate. When mycelial pellets were grown for 24, 48, and 72 h in growth medium and then transferred to a replacement medium, only aflatoxin B2 and M2 were recovered after 96 h of incubation. Addition of sterigmatocystin to the replacement medium led to the recovery of higher levels of aflatoxins B2 and M2 than were detected in control cultures, as well as to the formation of aflatoxins B1 and M1 and O-methylsterigmatocystin. These results support the hypothesis that aflatoxins B1 and B2 can arise independently via a branched pathway.

  8. Modelling approach to limit aflatoxin B1 contamination in dairy cattle compound feed

    NARCIS (Netherlands)

    Bouzembrak, Y.; Fels-Klerx, van der H.J.

    2016-01-01

    Feeding dairy cattle with safe compound feed helps farmers to ensure food safety. However, several ingredients often used in compound feed production can be contaminated with aflatoxin B1 (AFB1), which may result into milk contaminated with aflatoxin M1. Given the number of ingredients and their

  9. EC-collaborative study on the determination of aflatoxin B1 in animal feeding stuffs

    NARCIS (Netherlands)

    Egmond HP van; Heisterkamp SH; Paulsch WE

    1989-01-01

    Een gemeenschappelijk onderzoek werd georganiseerd om een methode te testen, die binnen de EEG kandidaat staat als officiele methode voor het bepalen van aflatoxine B1 in samengestelde diervoeders. Aan het onderzoek namen 25 laboratoria uit 11 EG-landen deel. Met de methode, gebaseerd op

  10. Screening of self-assembled monolayer for aflatoxin B1 detection using immune-capacitive sensor.

    Science.gov (United States)

    Gutierrez R, Alvaro V; Hedström, Martin; Mattiasson, Bo

    2015-12-01

    A capacitive biosensor was used for detection of aflatoxin B1. Two different methods for cleaning gold electrodes were evaluated using cyclic voltammetry in the presence of ferricyanide as redox couple. The methods involve use of a sequence of cleaning steps avoiding the use of Piranha solution and plasma cleaner. Anti-aflatoxin B1 was immobilized on self-assembled monolayers (SAM). The immune-capacitive biosensor is able to detect aflatoxin B1 concentrations in a linear range of 3.2 × 10-12 M to 3.2 × 10-9 M when thiourea was used to form the SAM; 3.2 × 10-9 M to 3.2 × 10-7 M when thioctic acid was used. When the gold surface was isolated with tyramine-electropolymerization linear ranges of 3.2 × 10-13 M to 3.2 × 10-7 M and 3.2 × 10-9 M to 3.2 × 10-7 M where obtained, respectively. The results obtained show the difference in linear range, limit of detection, and limit of quantification when different self-assembled monolayers are used for aflatoxin B1 detection.

  11. Effect of fumonisin B1 on rat hepatic P450 system

    NARCIS (Netherlands)

    Spotti, M.; Maas, R.F.M.; Nijs, C.M. de; Fink-Gremmels, J.

    2000-01-01

    The effects of the mycotoxin fumonisin B1 (FB1) on the hepatic cytochrome P450 system were investigated in male rats dosed daily by oral gavage with 3 mg FB1 per kg body weight for 9 consecutive days. FB1 treatment resulted in a reduced weight gain. At the same time, CYP2E activity was increased,

  12. ATP8B1 deficiency; Pathophysiology and treatment of a cholestatic syndrome with extrahepatic symptoms

    NARCIS (Netherlands)

    Stapelbroek, J.M.

    2009-01-01

    ATP8B1 deficiency is a severe and clinically highly variable hereditary disorder that is primarily characterized by intrahepatic cholestasis. It generally presents as a permanent disorder, progressive familial intrahepatic cholestasis type 1 (PFIC1), or with intermittent cholestasis (benign

  13. CYP1B1 and myocilin gene mutations in Egyptian patients with ...

    African Journals Online (AJOL)

    Mahmoud R. Fassad

    2016-08-09

    Aug 9, 2016 ... CYP1B1 and myocilin gene mutations in Egyptian patients with primary congenital glaucoma. Mahmoud R. Fassad a. , Asmaa K. Amin a. , Heba A. Morsy a. , Noha M. Issa a. ,. Nader H. Bayoumi b. , Sahar A. El Shafei a. , Soha F. Kholeif a,. * a Department of Human Genetics, Medical Research Institute, ...

  14. CYP1B1 and myocilin gene mutations in Egyptian patients with ...

    African Journals Online (AJOL)

    Purpose: Primary congenital glaucoma (PCG) accounts for 26–29% of childhood blindness in Egypt. The identification of disease causing mutations has not been extensively investigated. We aimed to examine the frequency of CYP1B1 and MYOC mutations in PCG Egyptian patients, and study a possible ...

  15. CYP1B1 and myocilin gene mutations in Egyptian patients with ...

    African Journals Online (AJOL)

    Mahmoud R. Fassad

    2016-08-09

    Aug 9, 2016 ... Abstract Purpose: Primary congenital glaucoma (PCG) accounts for 26–29% of childhood blind- ness in Egypt. The identification of disease causing mutations has not been extensively investigated. We aimed to examine the frequency of CYP1B1 and MYOC mutations in PCG Egyptian patients, and study a ...

  16. Polymorphisms in sh2b1 and spns1 loci are associated with ...

    Indian Academy of Sciences (India)

    Dag Hammarskjölds väg 20, 751 85, Uppsala, Sweden. [Västermark Å., Jacobsson J. A., Johansson Å., Fredriksson R., Gyllensten U. and Schiöth H. B. 2012 Polymorphisms in sh2b1 and spns1 loci are associated with triglyceride levels in a healthy population in northern Sweden. J. Genet. 91, 237–240]. Introduction.

  17. Picking the Bone: The B-1 Bomber as a Platform for Innovation

    Science.gov (United States)

    2010-06-01

    first combat sorties into Kosovo against the Novi Sad petroleum production facility at Pancevo, northeast of Belgrade.92 The target needed to be...particular mission, B-1s were tasked to strike Novi Sad , two aircraft were flying in formation when they made one pass over the target, each dropping 84

  18. 26 CFR 1.170A-9 - Definition of section 170(b)(1)(A) organization.

    Science.gov (United States)

    2010-04-01

    ... curriculum and normally has a regularly enrolled body of pupils or students in attendance at the place where... for scholarships, libraries and student loans. (ii) To qualify under section 170(b)(1)(A)(iv), the... calendar year in which the contribution is made such organization must be committed to spend such...

  19. 26 CFR 1.666(b)-1A - Total taxes deemed distributed.

    Science.gov (United States)

    2010-04-01

    ... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Total taxes deemed distributed. 1.666(b)-1A... taxable year and the amount is not less than the undistributed net income for such preceding taxable year... net income” (as defined in § 1.665(d)-1A(b)) for such preceding taxable year is also deemed...

  20. Data of evolutionary structure change: 1AO5B-1ELCA [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1AO5B-1ELCA 1AO5 1ELC B A VVGGFNCEKNSQPWQVAVYYQ----KEHICGGVLLDRNW...TPTWQKPDDLQCVFITLLPNENCAKV--YLQKVTDVMLCAGEMGGGKDTCRDDSGGPLICD----GILQGTTSYGPV-PCGKPGVPAIYTNLIKFNSWIKDTMMKNA TRP CA 491 1ELC A 1ELCA...hain> 1ELC A 1ELCA PLHCLVNGQYAVHG... PRO CA 225 1ELC A 1ELCA

  1. Evaluation of vitamin B1 status of alcoholic subjects in Abidjan (Côte ...

    African Journals Online (AJOL)

    Given the clinical importance of free thiamine and its esters on the essential human organs, their determination seems necessary to appreciate vitamin B1 status ... free thiamine and its phosphate esters: thiamine monophosphate and thiamine diphosphate by reverse phase liquid chromatography and fluorimetric detection.

  2. Most harmful algal bloom species are vitamin B1 and B12 auxotrophs.

    Science.gov (United States)

    Tang, Ying Zhong; Koch, Florian; Gobler, Christopher J

    2010-11-30

    Eutrophication can play a central role in promoting harmful algal blooms (HABs), and therefore many HAB studies to date have focused on macronutrients (N, P, Si). Although a majority of algal species require exogenous B vitamins (i.e., auxotrophic for B vitamins), the possible importance of organic micronutrients such as B vitamins (B(1), B(7), B(12)) in regulating HABs has rarely been considered. Prior investigations of vitamins and algae have examined a relatively small number of dinoflagellates (n = 26) and a paucity of HAB species (n = 4). In the present study, the vitamin B(1), B(7), and B(12) requirements of 41 strains of 27 HAB species (19 dinoflagellates) were investigated. All but one species (two strains) of harmful algae surveyed required vitamin B(12), 20 of 27 species required B(1), and 10 of 27 species required B(7), all proportions higher than the previously reported for non-HAB species. Half-saturation (K(s)) constants of several HAB species for B(1) and B(12) were higher than those previously reported for other phytoplankton and similar to vitamin concentrations reported in estuaries. Cellular quotas for vitamins suggest that, in some cases, HAB demands for vitamins may exhaust standing stocks of vitamins in hours to days. The sum of these findings demonstrates the potentially significant ecological role of B-vitamins in regulating the dynamics of HABs.

  3. Genetic variation in the HSD17B1 gene and risk of prostate cancer.

    Directory of Open Access Journals (Sweden)

    Peter Kraft

    2005-11-01

    Full Text Available Steroid hormones are believed to play an important role in prostate carcinogenesis, but epidemiological evidence linking prostate cancer and steroid hormone genes has been inconclusive, in part due to small sample sizes or incomplete characterization of genetic variation at the locus of interest. Here we report on the results of a comprehensive study of the association between HSD17B1 and prostate cancer by the Breast and Prostate Cancer Cohort Consortium, a large collaborative study. HSD17B1 encodes 17beta-hydroxysteroid dehydrogenase 1, an enzyme that converts dihydroepiandrosterone to the testosterone precursor Delta5-androsterone-3beta,17beta-diol and converts estrone to estradiol. The Breast and Prostate Cancer Cohort Consortium researchers systematically characterized variation in HSD17B1 by targeted resequencing and dense genotyping; selected haplotype-tagging single nucleotide polymorphisms (htSNPs that efficiently predict common variants in U.S. and European whites, Latinos, Japanese Americans, and Native Hawaiians; and genotyped these htSNPs in 8,290 prostate cancer cases and 9,367 study-, age-, and ethnicity-matched controls. We found no evidence that HSD17B1 htSNPs (including the nonsynonymous coding SNP S312G or htSNP haplotypes were associated with risk of prostate cancer or tumor stage in the pooled multiethnic sample or in U.S. and European whites. Analyses stratified by age, body mass index, and family history of disease found no subgroup-specific associations between these HSD17B1 htSNPs and prostate cancer. We found significant evidence of heterogeneity in associations between HSD17B1 haplotypes and prostate cancer across ethnicity: one haplotype had a significant (p < 0.002 inverse association with risk of prostate cancer in Latinos and Japanese Americans but showed no evidence of association in African Americans, Native Hawaiians, or whites. However, the smaller numbers of Latinos and Japanese Americans in this study makes

  4. Residues of aflatoxins B1 and M1 in different biological matrices of swine orally administered aflatoxin B1 and Saccharomyces cerevisiae

    Directory of Open Access Journals (Sweden)

    L. Rizzi

    2010-01-01

    Full Text Available Mycotoxins are acutely toxic, carcinogenic, mutagenic, and oestrogenic secondary metabolites produced by moulds, mostly of the genera Aspergillus, Penicillum and Fusarium. Aflatoxins (AFs are dangerous molecules to animals and humans produced mostly by Aspergillus flavus and A. parasiticus (Marin et al., 2002. Aflatoxin B1 (AFB1 is the most potent of all aflatoxins and is of great concern because of its adverse effects to the health of humans and domestic animals, including also teratogenic and immunosuppressive effects (Eaton and Callagher, 1994. Aflatoxin M1 (AFM1 is a hydroxilated metabolite of AFB1 characterized by a rapid elimination through the milk and the urine, and by a lower toxicity than its parent compound.

  5. The Crystal Structure of Cytochrome P450 4B1 (CYP4B1) Monooxygenase Complexed with Octane Discloses Several Structural Adaptations for ω-Hydroxylation*♦

    Science.gov (United States)

    Hsu, Mei-Hui; Baer, Brian R.; Rettie, Allan E.

    2017-01-01

    P450 family 4 fatty acid ω-hydroxylases preferentially oxygenate primary C–H bonds over adjacent, energetically favored secondary C–H bonds, but the mechanism explaining this intriguing preference is unclear. To this end, the structure of rabbit P450 4B1 complexed with its substrate octane was determined by X-ray crystallography to define features of the active site that contribute to a preference for ω-hydroxylation. The structure indicated that octane is bound in a narrow active-site cavity that limits access of the secondary C–H bond to the reactive intermediate. A highly conserved sequence motif on helix I contributes to positioning the terminal carbon of octane for ω-hydroxylation. Glu-310 of this motif auto-catalytically forms an ester bond with the heme 5-methyl, and the immobilized Glu-310 contributes to substrate positioning. The preference for ω-hydroxylation was decreased in an E310A mutant having a shorter side chain, but the overall rates of metabolism were retained. E310D and E310Q substitutions having longer side chains exhibit lower overall rates, likely due to higher conformational entropy for these residues, but they retained high preferences for octane ω-hydroxylation. Sequence comparisons indicated that active-site residues constraining octane for ω-hydroxylation are conserved in family 4 P450s. Moreover, the heme 7-propionate is positioned in the active site and provides additional restraints on substrate binding. In conclusion, P450 4B1 exhibits structural adaptations for ω-hydroxylation that include changes in the conformation of the heme and changes in a highly conserved helix I motif that is associated with selective oxygenation of unactivated primary C–H bonds. PMID:28167536

  6. The Crystal Structure of Cytochrome P450 4B1 (CYP4B1) Monooxygenase Complexed with Octane Discloses Several Structural Adaptations for ω-Hydroxylation.

    Science.gov (United States)

    Hsu, Mei-Hui; Baer, Brian R; Rettie, Allan E; Johnson, Eric F

    2017-03-31

    P450 family 4 fatty acid ω-hydroxylases preferentially oxygenate primary C-H bonds over adjacent, energetically favored secondary C-H bonds, but the mechanism explaining this intriguing preference is unclear. To this end, the structure of rabbit P450 4B1 complexed with its substrate octane was determined by X-ray crystallography to define features of the active site that contribute to a preference for ω-hydroxylation. The structure indicated that octane is bound in a narrow active-site cavity that limits access of the secondary C-H bond to the reactive intermediate. A highly conserved sequence motif on helix I contributes to positioning the terminal carbon of octane for ω-hydroxylation. Glu-310 of this motif auto-catalytically forms an ester bond with the heme 5-methyl, and the immobilized Glu-310 contributes to substrate positioning. The preference for ω-hydroxylation was decreased in an E310A mutant having a shorter side chain, but the overall rates of metabolism were retained. E310D and E310Q substitutions having longer side chains exhibit lower overall rates, likely due to higher conformational entropy for these residues, but they retained high preferences for octane ω-hydroxylation. Sequence comparisons indicated that active-site residues constraining octane for ω-hydroxylation are conserved in family 4 P450s. Moreover, the heme 7-propionate is positioned in the active site and provides additional restraints on substrate binding. In conclusion, P450 4B1 exhibits structural adaptations for ω-hydroxylation that include changes in the conformation of the heme and changes in a highly conserved helix I motif that is associated with selective oxygenation of unactivated primary C-H bonds. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  7. miR-379 regulates cyclin B1 expression and is decreased in breast cancer.

    Directory of Open Access Journals (Sweden)

    Sonja Khan

    Full Text Available MicroRNAs are small non-coding RNA molecules that control gene expression post-transcriptionally, and are known to be altered in many diseases including breast cancer. The aim of this study was to determine the relevance of miR-379 in breast cancer. miR-379 expression was quantified in clinical samples including tissues from breast cancer patients (n=103, healthy controls (n=30 and patients with benign breast disease (n=35. The level of miR-379 and its putative target Cyclin B1 were investigated on all breast tissue specimens by RQ-PCR. Potential relationships with gene expression and patient clinicopathological details were also determined. The effect of miR-379 on Cyclin B1 protein expression and function was investigated using western blot, immunohistochemistry and proliferation assays respectively. Finally, the levels of circulating miR-379 were determined in whole blood from patients with breast cancer (n=40 and healthy controls (n=34. The level of miR-379 expression was significantly decreased in breast cancer (Mean(SEM 1.9 (0.09 Log10 Relative Quantity (RQ compared to normal breast tissues (2.6 (0.16 Log10 RQ, p<0.01. miR-379 was also found to decrease significantly with increasing tumour stage. A significant negative correlation was determined between miR-379 and Cyclin B1 (r=-0.31, p<0.001. Functional assays revealed reduced proliferation (p<0.05 and decreased Cyclin B1 protein levels following transfection of breast cancer cells with miR-379. Circulating miR-379 was not significantly dysregulated in patients with breast cancer compared to healthy controls (p=0.42. This data presents miR-379 as a novel regulator of Cyclin B1 expression, with significant loss of the miRNA observed in breast tumours.

  8. On the Relevance of ln (z0 /z_{0T})= kB^{-1}

    Science.gov (United States)

    Hicks, Bruce B.; Pendergrass, William R.; Baker, Barry D.; Saylor, Rick D.; O'Dell, Debra L.; Eash, Neal S.; McQueen, Jeffrey T.

    2017-11-01

    The assumption that the roughness Reynolds number ( Re_{*}) can be used as a basis for quantifying the boundary-layer property { kB}^{-1} (= ln (z0/z_{0T})) as in some modern numerical models is questioned. While { Re}_{*} is a useful property in studies of pipe flow, it appears to have only marginal applicability in the case of treeless terrain, as studied in the two experimental situations presented here. For both the daytime and night-time cases there appears to be little correlation between { kB}^{-1} and { Re}_{*} . For daytime, the present studies indicate that the assumption { kB}^{-1} ≈ 2 is acceptable, while for night-time, the scatter involved in relating { kB}^{-1} to { Re}_{*} suggests there is little reason to assume a direct relationship. However, while the scatter affecting all of the night-time results is large, there remains a significant correlation between the heat and momentum fluxes upon which an alternative methodology for describing bulk air-surface exchange at night could be constructed. The friction coefficient (Cf ) and the turbulent Stanton number ({ St}_{*}) are discussed as possible alternatives for describing bulk properties of the air layer adjacent to the surface. While describing the surface roughness in terms of the friction coefficient provides an attractive simplification relative to the conventional methodologies based on roughness length and stability considerations, use of the Stanton number shares many of uncertainties that affect { kB}^{-1} . The transitions at dawn and dusk remain demanding situations to address.

  9. Lack of association between SLCO1B1 polymorphisms and clinical myalgia following rosuvastatin therapy.

    Science.gov (United States)

    Danik, Jacqueline S; Chasman, Daniel I; MacFadyen, Jean G; Nyberg, Fredrik; Barratt, Bryan J; Ridker, Paul M

    2013-06-01

    Carriers of the rs4363657C and rs4149056C alleles in SLCO1B1 have increased myopathic complaints when taking simvastatin. Whether rosuvastatin has a similar effect is uncertain. This study assesses whether SLCO1B1 polymorphisms relate to clinical myalgia after rosuvastatin therapy. In the JUPITER trial, participants without prior cardiovascular disease or diabetes who had low-density lipoprotein cholesterol rs4149056 in SLCO1B1, which encodes organic anion-transporting polypeptide OATP1B1, a regulator of hepatic statin uptake, on clinically reported myalgia. Among 4,404 participants allocated to rosuvastatin, clinical myalgia occurred with a rate of 4.1 events per 100 person-years as compared with 3.7 events per 100 person-years among 4,378 participants allocated to placebo (hazard ratio [HR] 1.13, 95% CI 0.98-1.30). Among those on rosuvastatin, there were no differences in the rate of myalgia among those with the rs4363657C (HR 0.95, 95% CI 0.79-1.14 per allele) or the rs4149056C allele (HR 0.95, 95% CI 0.79-1.15 per allele) compared with those without the C allele. Similar null data were observed when the myalgia definition was broadened to include muscle weakness, stiffness, or pain. None of the 3 participants on rosuvastatin or the 3 participants on placebo with frank myopathy had the minor allele at either polymorphism. There appears to be no increased risk of myalgia among users of rosuvastatin who carry the rs4363657C or the rs4149056C allele in SLCO1B1. Copyright © 2013 Mosby, Inc. All rights reserved.

  10. Long-term exposure to IL-1beta enhances Toll-IL-1 receptor-mediated inflammatory signaling in murine airway hyperresponsiveness

    DEFF Research Database (Denmark)

    Zhang, Yaping; Xu, Cang-Bao; Cardell, Lars-Olaf

    2009-01-01

    -1beta (IL-1beta), induce AHR. However, the underlying intracellular signaling mechanisms that lead to AHR remain elusive. In order to see if the Toll-IL-1 receptor-mediated inflammatory signal pathways are involved in the development of AHR, the present study was designed to use a real-time PCR...... mechanisms to the AHR, the anti-inflammatory drug dexamethasone, was used. Dexamethasone not only completely abolished the IL-1beta-induced AHR to bradykinin, but also abrogated the increased mRNA expression for inflammatory mediators, IL-6, IFN-gamma and Cox-2. In conclusion, long-term exposure of murine...

  11. How does angiotensin AT2 receptor activation help neuronal differentiation and improve neuronal pathological situations?

    Science.gov (United States)

    Guimond, Marie-Odile; Gallo-Payet, Nicole

    2012-01-01

    The angiotensin type 2 (AT2) receptor of angiotensin II has long been thought to be limited to few tissues, with the primary effect of counteracting the angiotensin type 1 (AT1) receptor. Functional studies in neuronal cells have demonstrated AT2 receptor capability to modulate neuronal excitability, neurite elongation, and neuronal migration, suggesting that it may be an important regulator of brain functions. The observation that the AT2 receptor was expressed in brain areas implicated in learning and memory led to the hypothesis that it may also be implicated in cognitive functions. However, linking signaling pathways to physiological effects has always proven challenging since information relative to its physiological functions has mainly emerged from indirect observations, either from the blockade of the AT1 receptor or through the use of transgenic animals. From a mechanistic standpoint, the main intracellular pathways linked to AT2 receptor stimulation include modulation of phosphorylation by activation of kinases and phosphatases or the production of nitric oxide and cGMP, some of which are associated with the Gi-coupling protein. The receptor can also interact with other receptors, either G protein-coupled such as bradykinin, or growth factor receptors such as nerve growth factor or platelet-derived growth factor receptors. More recently, new advances have also led to identification of various partner proteins, thus providing new insights into this receptor’s mechanism of action. This review summarizes the recent advances regarding the signaling pathways induced by the AT2 receptor in neuronal cells, and discussed the potential therapeutic relevance of central actions of this enigmatic receptor. In particular, we highlight the possibility that selective AT2 receptor activation by non-peptide and selective agonists could represent new pharmacological tools that may help to improve impaired cognitive performance in Alzheimer’s disease and other

  12. Role of Phosphate Transport System Component PstB1 in Phosphate Internalization by Nostoc punctiforme.

    Science.gov (United States)

    Hudek, L; Premachandra, D; Webster, W A J; Bräu, L

    2016-11-01

    In bacteria, limited phosphate availability promotes the synthesis of active uptake systems, such as the Pst phosphate transport system. To understand the mechanisms that facilitate phosphate accumulation in the cyanobacterium Nostoc punctiforme, phosphate transport systems were identified, revealing a redundancy of Pst phosphate uptake systems that exists across three distinct operons. Four separate PstB system components were identified. pstB1 was determined to be a suitable target for creating phenotypic mutations that could result in the accumulation of excessive levels of phosphate through its overexpression or in a reduction of the capacity to accumulate phosphate through its deletion. Using quantitative real-time PCR (qPCR), it was determined that pstB1 mRNA levels increased significantly over 64 h in cells cultured in 0 mM added phosphate and decreased significantly in cells exposed to high (12.8 mM) phosphate concentrations compared to the level in cells cultured under normal (0.8 mM) conditions. Possible compensation for the loss of PstB1 was observed when pstB2, pstB3, and pstB4 mRNA levels increased, particularly in cells starved of phosphate. The overexpression of pstB1 increased phosphate uptake by N. punctiforme and was shown to functionally complement the loss of PstB in E. coli PstB knockout (PstB-) mutants. The knockout of pstB1 in N. punctiforme did not have a significant effect on cellular phosphate accumulation or growth for the most part, which is attributed to the compensation for the loss of PstB1 by alterations in the pstB2, pstB3, and pstB4 mRNA levels. This study provides novel in vivo evidence that PstB1 plays a functional role in phosphate uptake in N. punctiforme IMPORTANCE: Cyanobacteria have been evolving over 3.5 billion years and have become highly adept at growing under limiting nutrient levels. Phosphate is crucial for the survival and prosperity of all organisms. In bacteria, limited phosphate availability promotes the synthesis

  13. Cell cycle synchronization and BrdU incorporation as a tool to study the possible selective elimination of ErbB1 gene in the micronuclei in A549 cells

    Energy Technology Data Exchange (ETDEWEB)

    Lauand, C.; Niero, E.L.; Dias, V.M.; Machado-Santelli, G.M. [Departamento de Biologia Celular e do Desenvolvimento, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, SP (Brazil)

    2015-03-06

    Lung cancer often exhibits molecular changes, such as the overexpression of the ErbB1 gene that encodes epidermal growth factor receptor (EGFR). ErbB1 amplification and mutation are associated with tumor aggressiveness and low response to therapy. The aim of the present study was to design a schedule to synchronize the cell cycle of A549 cell line (a non-small cell lung cancer) and to analyze the possible association between the micronuclei (MNs) and the extrusion of ErbB1 gene extra-copies. After double blocking, by the process of fetal bovine serum deprivation and vincristine treatment, MNs formation was monitored with 5-bromo-2-deoxyuridine (BrdU) incorporation, which is an S-phase marker. Statistical analyses allowed us to infer that MNs may arise both in mitosis as well as in interphase. The MNs were able to replicate their DNA and this process seemed to be non-synchronous with the main cell nuclei. The presence of ErbB1 gene in the MNs was evaluated by fluorescent in situ hybridization (FISH). ErbB1 sequences were detected in the MNs, but a relation between the MNs formation and extrusion of amplified ErbB1could not be established. The present study sought to elucidate the meaning of MNs formation and its association with the elimination of oncogenes or other amplified sequences from the tumor cells.

  14. Rethinking Molecular Mimicry in Rheumatic Heart Disease andAutoimmune Myocarditis: Laminin, Collagen IV, CAR and B1AR as Initial Targets of Disease

    Directory of Open Access Journals (Sweden)

    Robert eRoot-Bernstein

    2014-08-01

    Full Text Available Rationale: Molecular mimicry theory (MMT suggests that epitope mimicry between pathogens and human proteins can activate autoimmune disease. Group A streptococci (GAS mimics human cardiac myosin in rheumatic heart disease (RHD and coxsackie viruses (CX mimic actin in autoimmune myocarditis (AM. But myosin and actin are immunologically inaccessible and unlikely initial targets. Extracellular cardiac proteins that mimic GAS and CX would be more likely.Objectives: To determine whether extracellular cardiac proteins such as coxsackie and adenovirus receptor (CAR, beta 1 adrenergic receptor (B1AR, CD55/DAF, laminin, and collagen IV mimic GAS, CX and/or cardiac myosin or actin. Methods: BLAST 2.0 and LALIGN searches of the UniProt protein database were employed to identify potential molecular mimics. Quantitative ELISA was used to measure antibody cross-reactivity. Measurements: Similarities were considered to be significant if a sequence contained at least 5 identical amino acids in 10. Antibodies were considered to be cross-reactive if the binding constant had a Kd less than 10-9 M. Main Results: GAS mimics laminin, CAR and myosin. CX mimics actin and collagen IV and B1AR. The similarity search results are mirrored by antibody cross-reactivities. Additionally, antibodies against laminin recognize antibodies against collagen IV; antibodies against actin recognize antibodies against myosin, and antibodies against GAS recognize antibodies against CX. Thus, there is both mimicry of extracellular proteins and antigenic complementarity between GAS-CX in RHD/AM.Conclusions: RHD/AM may be due to combined infections of GAS with CX localize at cardiomyocytes may produce a synergistic, hyperinflammatory response that cross-reacts with laminin, collagen IV, CAR and/or B1AR. Epitope drift shifts the immune response to myosin and actin after cardiomyocytes become damaged.

  15. Rethinking Molecular Mimicry in Rheumatic Heart Disease and Autoimmune Myocarditis: Laminin, Collagen IV, CAR, and B1AR as Initial Targets of Disease.

    Science.gov (United States)

    Root-Bernstein, Robert

    2014-01-01

    Molecular mimicry theory (MMT) suggests that epitope mimicry between pathogens and human proteins can activate autoimmune disease. Group A streptococci (GAS) mimics human cardiac myosin in rheumatic heart disease (RHD) and coxsackie viruses (CX) mimic actin in autoimmune myocarditis (AM). But myosin and actin are immunologically inaccessible and unlikely initial targets. Extracellular cardiac proteins that mimic GAS and CX would be more likely. To determine whether extracellular cardiac proteins such as coxsackie and adenovirus receptor (CAR), beta 1 adrenergic receptor (B1AR), CD55/DAF, laminin, and collagen IV mimic GAS, CX, and/or cardiac myosin or actin. BLAST 2.0 and LALIGN searches of the UniProt protein database were employed to identify potential molecular mimics. Quantitative enzyme-linked immunosorbent assay was used to measure antibody cross-reactivity. Similarities were considered to be significant if a sequence contained at least 5 identical amino acids in 10. Antibodies were considered to be cross-reactive if the binding constant had a K d less than 10(-9) M. Group A streptococci mimics laminin, CAR, and myosin. CX mimics actin and collagen IV and B1AR. The similarity search results are mirrored by antibody cross-reactivities. Additionally, antibodies against laminin recognize antibodies against collagen IV; antibodies against actin recognize antibodies against myosin, and antibodies against GAS recognize antibodies against CX. Thus, there is both mimicry of extracellular proteins and antigenic complementarity between GAS-CX in RHD/AM. Rheumatic heart disease/AM may be due to combined infections of GAS with CX localized at cardiomyocytes that may produce a synergistic, hyperinflammatory response that cross-reacts with laminin, collagen IV, CAR, and/or B1AR. Epitope drift shifts the immune response to myosin and actin after cardiomyocytes become damaged.

  16. Hydroxysteroid sulfotransferase SULT2B1b promotes hepatocellular carcinoma cells proliferation in vitro and in vivo.

    Directory of Open Access Journals (Sweden)

    Xiaoming Yang

    Full Text Available Hydroxysteroid sulfotransferase 2B1b (SULT2B1b is highly selective for the addition of sulfate groups to 3β-hydroxysteroids. Although previous reports have suggested that SULT2B1b is correlated with cell proliferation of hepatocytes, the relationship between SULT2B1b and the malignant phenotype of hepatocarcinoma cells was not clear. In the present study, we found that SULT2B1 was comparatively higher in the human hepatocarcinoma tumorous tissues than their adjacent tissues. Besides, SULT2B1b overexpression promoted the growth of the mouse hepatocarcinoma cell line Hepa1-6, while Lentivirus-mediated SULT2B1b interference inhibited growth as assessed by the CCK-8 assay. Likewise, inhibition of SULT2B1b expression induced cell-cycle arrest and apoptosis in Hepa1-6 cells by upregulating the expression of FAS, downregulating the expression of cyclinB1, BCL2 and MYC in vitro and in vivo at both the transcript and protein levels. Knock-down of SULT2B1b expression significantly suppressed tumor growth in nude mouse xenografts. Moreover, proliferation rates and SULT2B1b expression were highly correlated in the human hepatocarcinoma cell lines Huh-7, Hep3B, SMMC-7721 and BEL-7402 cells. Knock-down of SULT2B1b inhibited cell growth and cyclinB1 levels in human hepatocarcinoma cells and suppressed xenograft growth in vivo. In conclusion, SULT2B1b expression promotes proliferation of hepatocellular carcinoma cells in vitro and in vivo, which may contribute to the progression of HCC.

  17. B-1a transitional cells are phenotypically distinct and are lacking in mice deficient in IκBNS

    Science.gov (United States)

    Pedersen, Gabriel K.; Àdori, Monika; Khoenkhoen, Sharesta; Dosenovic, Pia; Beutler, Bruce; Karlsson Hedestam, Gunilla B.

    2014-01-01

    B-1 cells mediate early protection against infection by responding to T cell-independent (TI) antigens found on the surface of various pathogens. Mice with impaired expression of the atypical IκB protein IκBNS have markedly reduced frequencies of B-1 cells. We used a mouse strain with dysfunctional IκBNS derived from an N-ethyl-N-nitrosourea (ENU) screen, named bumble, to investigate the point in the development of B-1 cells where IκBNS is required. The presence of wild-type (wt) peritoneal cells in mixed wt/bumble chimeras did not rescue the development of bumble B-1 cells, but wt peritoneal cells transferred to bumble mice restored natural IgM levels and response to TI antigens. The bumble and wt mice displayed similar levels of fetal liver B-1 progenitors and splenic neonatal transitional B (TrB) cells, both of which were previously shown to give rise to B-1 cells. Interestingly, we found that a subset of wt neonatal TrB cells expressed common B-1a