Hypercholesterolemia Increases the Production of Leukotriene B4 in Neutrophils by Enhancing the Nuclear Localization of 5-Lipoxygenase

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Xiao-Feng Lai

2014-11-01

Full Text Available Aims: Neutrophils can synthesize leukotriene B4 (LTB4 by activating the 5-lipoxygenase (5-LOsignaling pathway. LTB4 is a pro-inflammatory mediator associated with the etiology and progression of atherosclerosis. It can increase function and number of neutrophils in an autocrine manner. Since hypercholesterolemia is associated with an increase in the number and function of neutrophils, we hypothesized that this effect could be mediated through increased production of LTB4 in neutrophils. Methods/Results: Hypercholesterolemia was modeled in Wistar rats by feeding them with a high cholesterol diet. The induction of hypercholesterolemia caused an increase in the plasma levels of LTB4, following lipopolysaccharide stimulation. This effect was recapitulated in vitro, both in the presence and absence of stimulation with the activator of 5-LO, A23187. Neutrophils in hypercholesterolemia rats expressed similar total levels of 5-LO as control rats, but displayed increased nuclear localization of 5-LO, as well as elevated levels of phosphorylated 5-LO and ERK1/2. In vitro, MβCD/cholesterol complexes enriched cholesterol in neutrophils, resulted in similar changes in 5-LO/LTB4. In addition, these alterations could be inhibited with the ERK inhibitor PD98059. Conclusion: Hypercholesterolemia increases LTB4 production in neutrophils by increasing the nuclear localization of 5-LO, which is the result of its phosphorylation by activated ERK1/2.

Leukotriene-B4 concentrations in exhaled breath condensate and lung function after thirty minutes of breathing technically dried compressed air.

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Neubauer, Birger; Struck, Niclas; Mutzbauer, Till S; Schotte, Ulrich; Langfeldt, Norbert; Tetzlaff, Kay

2002-01-01

In previous studies it had been shown that leukotriene-B4 [LTB4] concentrations in the exhaled breath mirror the inflammatory activity of the airways if the respiratory tract has been exposed to occupational hazards. In diving the respiratory tract is exposed to cold and dry air and the nasopharynx, as the site of breathing-gas warming and humidification, is bypassed. The aim of the present study was to obtain LTB4-concentrations in the exhaled breath and spirometric data of 17 healthy subjects before and after thirty minutes of technically dried air breathing at normobar ambient pressure. The exhaled breath was collected non-invasively, via a permanently cooled expiration tube. The condensate was measured by a standard enzyme immunoassay for LTB4. Lung function values (FVC, FEV1, MEF 25, MEF 50) were simultaneously obtained by spirometry. The measured pre- and post-exposure LTB4- concentrations as well as the lung function values were in the normal range. The present data gave no evidence for any inflammatory activity in the subjects' airways after thirty minutes breathing technically dried air.

Carbon monoxide inhibits omega-oxidation of leukotriene B4 by human polymorphonuclear leukocytes: evidence that catabolism of leukotriene B4 is mediated by a cytochrome P-450 enzyme.

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Shak, S; Goldstein, I M

1984-09-17

Carbon monoxide significantly inhibits omega-oxidation of exogenous leukotriene B4 to 20-OH-leukotriene B4 and 20-COOH-leukotriene B4 by unstimulated polymorphonuclear leukocytes as well as omega-oxidation of leukotriene B4 that is generated when cells are stimulated with the calcium ionophore, A23187. Inhibition of omega-oxidation by carbon monoxide is concentration-dependent, completely reversible, and specific. Carbon monoxide does not affect synthesis of leukotriene B4 by stimulated polymorphonuclear leukocytes or other cell functions (i.e., degranulation, superoxide anion generation). These findings suggest that a cytochrome P-450 enzyme in human polymorphonuclear leukocytes is responsible for catabolizing leukotriene B4 by omega-oxidation.

Leukotriene B4-Neutrophil Elastase Axis Drives Neutrophil Reverse Transendothelial Cell Migration In Vivo.

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Colom, Bartomeu; Bodkin, Jennifer V; Beyrau, Martina; Woodfin, Abigail; Ody, Christiane; Rourke, Claire; Chavakis, Triantafyllos; Brohi, Karim; Imhof, Beat A; Nourshargh, Sussan

2015-06-16

Breaching endothelial cells (ECs) is a decisive step in the migration of leukocytes from the vascular lumen to the extravascular tissue, but fundamental aspects of this response remain largely unknown. We have previously shown that neutrophils can exhibit abluminal-to-luminal migration through EC junctions within mouse cremasteric venules and that this response is elicited following reduced expression and/or functionality of the EC junctional adhesion molecule-C (JAM-C). Here we demonstrate that the lipid chemoattractant leukotriene B4 (LTB4) was efficacious at causing loss of venular JAM-C and promoting neutrophil reverse transendothelial cell migration (rTEM) in vivo. Local proteolytic cleavage of EC JAM-C by neutrophil elastase (NE) drove this cascade of events as supported by presentation of NE to JAM-C via the neutrophil adhesion molecule Mac-1. The results identify local LTB4-NE axis as a promoter of neutrophil rTEM and provide evidence that this pathway can propagate a local sterile inflammatory response to become systemic. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Resveratrol, a Red Wine Polyphenol, Suppresses Pancreatic Cancer by Inhibiting Leukotriene A4 Hydrolase

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Oi, Naomi; Jeong, Chul-Ho; Nadas, Janos; Cho, Yong-Yeon; Pugliese, Angelo; Bode, Ann M.; Dong, Zigang

2016-01-01

The anticancer effects of red wine have attracted considerable attention. Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is a well-known polyphenolic compound of red wine with cancer chemopreventive activity. However, the basis for this activity is unclear. We studied leukotriene A4 hydrolase (LTA4H) as a relevant target in pancreatic cancer. LTA4H knockdown limited the formation of leukotriene B4 (LTB4), the enzymatic product of LTA4H, and suppressed anchorage-independent growth of pancreatic cancer cells. An in silico shape similarity algorithm predicted that LTA4H might be a potential target of resveratrol. In support of this idea, we found that resveratrol directly bound to LTA4H in vitro and in cells and suppressed proliferation and anchorage-independent growth of pancreatic cancer by inhibiting LTB4 production and expression of the LTB4 receptor 1 (BLT1). Notably, resveratrol exerted relatively stronger inhibitory effects than bestatin, an established inhibitor of LTA4H activity, and the inhibitory effects of resveratrol were reduced in cells where LTA4H was suppressed by shRNA-mediated knockdown. Importantly, resveratrol inhibited tumor formation in a xenograft mouse model of human pancreatic cancer by inhibiting LTA4H activity. Our findings identify LTA4H as a functionally important target for mediating the anticancer properties of resveratrol. PMID:20952510

Distinct cellular sources of hepoxilin A3 and leukotriene B4 are used to coordinate bacterial-induced neutrophil transepithelial migration.

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Pazos, Michael A; Pirzai, Waheed; Yonker, Lael M; Morisseau, Christophe; Gronert, Karsten; Hurley, Bryan P

2015-02-01

Neutrophilic infiltration is a leading contributor to pathology in a number of pulmonary disease states, including cystic fibrosis. Hepoxilin A3 (HXA3) is a chemotactic eicosanoid shown to mediate the transepithelial passage of neutrophils in response to infection in several model systems and at multiple mucosal surfaces. Another well-known eicosanoid mediating general neutrophil chemotaxis is leukotriene B4 (LTB4). We sought to distinguish the roles of each eicosanoid in the context of infection of lung epithelial monolayers by Pseudomonas aeruginosa. Using human and mouse in vitro transwell model systems, we used a combination of biosynthetic inhibitors, receptor antagonists, as well as mutant sources of neutrophils to assess the contribution of each chemoattractant in driving neutrophil transepithelial migration. We found that following chemotaxis to epithelial-derived HXA3 signals, neutrophil-derived LTB4 is required to amplify the magnitude of neutrophil migration. LTB4 signaling is not required for migration to HXA3 signals, but LTB4 generation by migrated neutrophils plays a significant role in augmenting the initial HXA3-mediated migration. We conclude that HXA3 and LTB4 serve independent roles to collectively coordinate an effective neutrophilic transepithelial migratory response. Copyright © 2015 by The American Association of Immunologists, Inc.

Leukotriene B4 induces EMT and vimentin expression in PANC-1 pancreatic cancer cells: Involvement of BLT2 via ERK2 activation.

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Kim, You Ri; Park, Mi Kyung; Kang, Gyeong Jin; Kim, Hyun Ji; Kim, Eun Ji; Byun, Hyun Jung; Lee, Moo-Yeol; Lee, Chang Hoon

2016-12-01

Leukotriene B 4 (LTB 4 ) is a leukocyte chemoattractant and plays a major role controlling inflammatory responses including pancreatitis. LTB 4 is known to be correlated with cancer progression. LTB 4 induces keratin phosphorylation and reorganization by activating extracellular regulated kinase (ERK) in PANC-1 pancreatic cancer cell lines. However, the role of LTB 4 in epithelial mesenchymal transition (EMT) and vimentin expression in pancreatic cancer cells is unknown. We examined whether LTB 4 induces EMT and vimentin expression by Western blot, si-RNA, and RT-PCR. LTB 4 induced morphological change, decreased E-cadherin expression and increased N-cadherin and vimentin expression. LTB4 increased migration and invasion of PANC-1 cancer cells. LTB 4 dose-dependently upregulated expression of vimentin in PANC-1 cancer cells. LTB 4 -induced vimentin expression was suppressed by LY255283 (BLT2 antagonist). Comp A, a BLT2 agonist, further increased vimentin expression. Gene silencing of BLT2 suppressed LTB 4 -or Comp A-induced vimentin expression in PANC-1 cells. The MEK inhibitor, PD98059 suppressed Comp A-induced vimentin expression. Comp A or transfection of plasmid containing BLT2 cDNA (pC BLT2 ) activated ERK, and BLT2 gene silencing suppressed Comp A-induced ERK activation. ERK2 siRNA abrogated Comp A-induced vimentin expression and ERK2 overexpression enhanced vimentin expression. One of well-known cause of ras mutation, cigarette smoke extracts increased BLT2 expression in PANC-1 cancer cells. Taken together, these results suggest that BLT2 is involved in LTB 4 -induced vimentin expression through ERK2 in PANC-1 cells. Copyright © 2016 Elsevier Ltd. All rights reserved.

Leukotriene B4-Neutrophil Elastase Axis Drives Neutrophil Reverse Transendothelial Cell Migration In Vivo

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Colom, Bartomeu; Bodkin, Jennifer V.; Beyrau, Martina; Woodfin, Abigail; Ody, Christiane; Rourke, Claire; Chavakis, Triantafyllos; Brohi, Karim; Imhof, Beat A.; Nourshargh, Sussan

2015-01-01

Summary Breaching endothelial cells (ECs) is a decisive step in the migration of leukocytes from the vascular lumen to the extravascular tissue, but fundamental aspects of this response remain largely unknown. We have previously shown that neutrophils can exhibit abluminal-to-luminal migration through EC junctions within mouse cremasteric venules and that this response is elicited following reduced expression and/or functionality of the EC junctional adhesion molecule-C (JAM-C). Here we demonstrate that the lipid chemoattractant leukotriene B4 (LTB4) was efficacious at causing loss of venular JAM-C and promoting neutrophil reverse transendothelial cell migration (rTEM) in vivo. Local proteolytic cleavage of EC JAM-C by neutrophil elastase (NE) drove this cascade of events as supported by presentation of NE to JAM-C via the neutrophil adhesion molecule Mac-1. The results identify local LTB4-NE axis as a promoter of neutrophil rTEM and provide evidence that this pathway can propagate a local sterile inflammatory response to become systemic. PMID:26047922

Esculetin reduces leukotriene B4 level in plasma of rats with adjuvant-induced arthritis

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Przemysław Rzodkiewicz

2016-10-01

Full Text Available Objectives : Esculetin (6,7-dihydroxycoumarin is a natural coumarin with anti-oxidant, anti-inflammatory and anti-nociceptive activity. It acts as a potent inhibitor of lipoxygenases (5-LOX and 12-LOX and decreases the production of matrix metalloproteinases (MMP-1, MMP-3 and MMP-9. Because both inhibition of lipoxygenases and inhibition of matrix metalloproteinases are effective strategies in the treatment of rheumatoid arthritis, we investigated whether esculetin may be effective in adjuvant-induced arthritis in rats. Material and methods : The study was performed on male Lewis rats, in the adjuvant-induced arthritis model. Rats were divided into two groups: control (treated with 1% methylcellulose and experimental (treated with esculetin – 10 mg/kg ip.. The tested compound was administered for 5 consecutive days starting on the 21st day after induction of arthritis. Each group consisted of 7 animals. After 5 days of treatment, rats were anesthetized. The concentration of leukotriene B4 (LTB4 in plasma was determined by a competitive enzyme immunoassay. Results : The LTB4 level in plasma of rats with adjuvant-induced arthritis is increased in comparison to rats without inflammation (362 ±34 vs. 274 ±15 pg/ml, p < 0.01, respectively. Five-day treatment with esculetin in adjuvant-induced arthritis rats decreases the LTB4 level to a level comparable with rats without inflammation (284 ±23 pg/ml, p < 0.01. Conclusions : LTB4 is the most potent chemotactic agent influencing neutrophil migration into the joint. It is known that its level in serum of patients with active rheumatoid arthritis is increased and correlates with disease severity. Some other lipoxygenase inhibitors have already been tested as potential drug candidates in clinical and preclinical trials for rheumatoid arthritis (Zileuton, PF-4191834. Because esculetin decreases the LTB4 level in plasma of rats in adjuvant-induced arthritis, it may also be considered as an attractive

The Role of PPAR Receptors and Leukotriene B4 Receptors in Mediating the Effects of LY293111 in Pancreatic Cancer

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Thomas E. Adrian

2008-01-01

Full Text Available Pancreatic cancer is a devastating disease in which current therapies are inadequate. Separate lines of research have identified the 5-lipoxygenase/leukotriene B4 receptor pathway and the PPAR pathway as potential targets for prevention or treatment of this disease. LY293111 was originally designed as a potent leukotriene B4 receptor antagonist for treatment of inflammatory conditions. LY293111 was also known to have inhibitory effects on 5-lipoxygenase, which is upstream of the production of leukotrienes. LY293111 was shown to have potent anticancer effects in pancreatic cancer and several other solid malignancies, where it caused cell cycle arrest and marked apoptosis. Subsequently, it came to light that LY293111 exhibited PPAR agonist activity in addition to its effects on the 5-lipoxygenase pathway. This raises the question of which of the two targets is of greatest importance with regard to the anticancer effects of this agent. The evidence to date is not conclusive, but suggests that the effects of LY293111 may be mediated by both LTB4 receptors and PPAR.

Plant Natural Products Calycosin and Gallic Acid Synergistically Attenuate Neutrophil Infiltration and Subsequent Injury in Isoproterenol-Induced Myocardial Infarction: A Possible Role for Leukotriene B4 12-Hydroxydehydrogenase?

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Cheng, Yuanyuan; Tse, Hung Fat; Le, X. Chris; Rong, Jianhui

2015-01-01

Leukotriene B4 12-hydroxydehydrogenase (LTB4DH) catalyzes the oxidation of proinflammatory LTB4 into less bioactive 12-oxo-LTB4. We recently discovered that LTB4DH was induced by two different natural products in combination. We previously isolated gallic acid from Radix Paeoniae through a bioactivity-guided fractionation procedure. The purpose of this study is to test the hypothesis that LTB4DH inducers may suppress neutrophil-mediated inflammation in myocardial infarction. We first isolated the active compound(s) from another plant, Radix Astragali, by the similar strategy. By evaluating LTB4DH induction, we identified calycosin and formononetin from Radix Astragali by HPLC-ESI-MS technique. We confirmed that gallic acid and commercial calycosin or formononetin could synergistically induce LTB4DH expression in HepG2 cells and human neutrophils. Moreover, calycosin and gallic acid attenuated the effects of LTB4 on the survival and chemotaxis of neutrophil cell culture. We further demonstrated that calycosin and gallic acid synergistically suppressed neutrophil infiltration and protected cardiac integrity in the isoproterenol-induced mice model of myocardial infarction. Calycosin and gallic acid dramatically suppressed isoproterenol-induced increase in myeloperoxidase (MPO) activity and malondialdehyde (MDA) level. Collectively, our results suggest that LTB4DH inducers (i.e., calycosin and gallic acid) may be a novel combined therapy for the treatment of neutrophil-mediated myocardial injury. PMID:26265982

Modulation of the heterogeneous membrane potential response of neutrophils to N-formyl-methionyl-leucyl-phenylalanine (FMLP) by leukotriene B4: evidence for cell recruitment

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Fletcher, M.P.

1986-01-01

Individual human neutrophils (PMN) isolated by Hypaque-Ficoll gradient sedimentation, dextran sedimentation, or buffy coat preparation were assessed for the effects of leukotriene B4 (5S,12R dihydroxy 6,14-cis-8, 10 trans eicosatetraenoic acid (LTB4)-pretreatment on N-formylmethionyl-leucyl-phenylalanine (FMLP)-mediated membrane potential or oxidative responses by using flow cytometry and a lipophilic probe of membrane potential (di-pentyl-oxacarbocyanine, di-O-C(5)3), or the nitroblue tetrazolium dye (NBT) reduction test, respectively. Although exposure to LTB4 (10(-7) M) had no effect on the membrane potential of resting PMN and little effect on oxidant production, pretreating PMN with LTB4 followed by FMLP (10(-6) M) demonstrated a significant enhancement in the proportion of depolarizing PMN over that seen with FMLP alone (p = 0.0014, N = 9). This recruitment of previously unresponsive cells by LTB4 was dose and time dependent, with the maximal relative increase in the proportion of depolarizing cells occurring at LTB4 concentrations of 10(-8) to 10(-7) M and within 1 min of LTB4 addition. The recruitment effect persisted despite vigorous washing of the cells. LTB4 also increased the proportion of NBT-positive PMN in response to FMLP. Although LTB4 alone did not depolarize PMN it did induce a light scatter shift indicative of cell activation. 3 H-FMLP binding studied at 0 degree C comparing buffer and LTB4-treated PMN indicated no significant change in the number or affinity of FMLP binding. The data provide evidence for the recruitment of a greater proportion of cells into a FMLP-responsive state as a mechanism for the enhanced functional response of PMN pretreated with LTB4, as well as for a dissociation of the membrane potential and light scattering responses of cells to this pro-inflammatory LT

Prostaglandin E2/leukotriene B4 balance induced by Lutzomyia longipalpis saliva favors Leishmania infantum infection.

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Araújo-Santos, Théo; Prates, Deboraci Brito; França-Costa, Jaqueline; Luz, Nívea F; Andrade, Bruno B; Miranda, José Carlos; Brodskyn, Claudia I; Barral, Aldina; Bozza, Patrícia T; Borges, Valéria Matos

2014-12-20

Eicosanoids and sand fly saliva have a critical role in the Leishmania infection. Here, we evaluated the effect of Lutzomyia longipalpis salivary gland sonicate (SGS) on neutrophil and monocyte recruitment and activation of eicosanoid production in a murine model of inflammation. C57BL/6 mice were inoculated intraperitonealy with Lutzomyia longipalpis SGS or Leishmania infantum or both, followed by analyses of cell recruitment, parasite load and eicosanoid production. Intraperitoneal injection of Lutzomyia longipalpis SGS together with Leishmania infantum induced an early increased parasite viability in monocytes and neutrophils. L. longipalpis SGS increased prostaglandin E2 (PGE2), but reduced leukotriene B4 (LTB4) production ex vivo in peritoneal leukocytes. In addition, the pharmacological inhibition of cyclooxygenase 2 (COX-2) with NS-398 decreased parasite viability inside macrophages during Leishmania infection in the presence of L. longipalpis SGS arguing that PGE2 production is associated with diminished parasite killing. These findings indicate that L. longipalpis SGS is a critical factor driving immune evasion of Leishmania through modulation of PGE2/LTB4 axis, which may represent an important mechanism on establishment of the infection.

Selectivity of recombinant human leukotriene D(4), leukotriene B(4), and lipoxin A(4) receptors with aspirin-triggered 15-epi-LXA(4) and regulation of vascular and inflammatory responses.

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Gronert, K; Martinsson-Niskanen, T; Ravasi, S; Chiang, N; Serhan, C N

2001-01-01

Aspirin-triggered lipoxin A(4) (ATL, 15-epi-LXA(4)) and leukotriene D(4) (LTD(4)) possess opposing vascular actions mediated via receptors distinct from the LXA(4) receptor (ALX) that is involved in leukocyte trafficking. Here, we identified these receptors by nucleotide sequencing and demonstrate that LTD(4) receptor (CysLT(1)) is induced in human vascular endothelia by interleukin-1beta. Recombinant CysLT(1) receptor gave stereospecific binding with both [(3)H]-LTD(4) and a novel labeled mimetic of ATL ([(3)H]-ATLa) that was displaced with LTD(4) and ATLa ( approximately IC(50) 0.2 to 0.9 nmol/L), but not with a bioinactive ATL isomer. The clinically used CysLT(1) receptor antagonist, Singulair, showed a lower rank order for competition with [(3)H]-ATLa (IC(50) approximately 8.3 nmol/L). In contrast, LTD(4) was an ineffective competitive ligand for recombinant ALX receptor with [(3)H]-ATLa, and ATLa did not compete for [(3)H]-LTB(4) binding with recombinant LTB(4) receptor. Endogenous murine CysLT(1) receptors also gave specific [(3)H]-ATLa binding that was displaced with essentially equal affinity by LTD(4) or ATLa. Systemic ATLa proved to be a potent inhibitor (>50%) of CysLT(1)-mediated vascular leakage in murine skin (200 microg/kg) in addition to its ability to block polymorphonuclear leukocyte recruitment to dorsal air pouch (4 microg/kg). These results indicate that ATL and LTD(4) bind and compete with equal affinity at CysLT(1), providing a molecular basis for aspirin-triggered LXs serving as a local damper of both vascular CysLT(1) signals as well as ALX receptor-regulated polymorphonuclear leukocyte traffic.

Evidence for eosinophil recruitment, leukotriene B4 production and mast cell hyperplasia following Toxocara canis infection in rats

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D. Carlos

2011-04-01

Full Text Available It is well known that eosinophilia is a key pathogenetic component of toxocariasis. The objective of the present study was to determine if there is an association between peritoneal and blood eosinophil influx, mast cell hyperplasia and leukotriene B4 (LTB4 production after Toxocara canis infection. Oral inoculation of 56-day-old Wistar rats (N = 5-7 per group with 1000 embryonated eggs containing third-stage (L3 T. canis larvae led to a robust accumulation of total leukocytes in blood beginning on day 3 and peaking on day 18, mainly characterized by eosinophils and accompanied by higher serum LTB4 levels. At that time, we also noted increased eosinophil numbers in the peritoneal cavity. In addition, we observed increased peritoneal mast cell number in the peritoneal cavity, which correlated with the time course of eosinophilia during toxocariasis. We also demonstrated that mast cell hyperplasia in the intestines and lungs began soon after the T. canis larvae migrated to these compartments, reaching maximal levels on day 24, which correlated with the complete elimination of the parasite. Therefore, mast cells appear to be involved in peritoneal and blood eosinophil infiltration through an LTB4-dependent mechanism following T. canis infection in rats. Our data also demonstrate a tight association between larval migratory stages and intestinal and pulmonary mast cell hyperplasia in the toxocariasis model.

Leukotriene B4 receptors on guinea pig alveolar eosinophils

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Maghni, K.; de Brum-Fernandes, A.J.; Foeldes-Filep, E.G.; Gaudry, M.; Borgeat, P.; Sirois, P.

1991-01-01

The existence of receptors for LTB4 on highly purified guinea pig alveolar eosinophils was investigated. Massive infiltration of eosinophils in alveolar spaces was induced in guinea pigs by i.v. injections of Sephadex beads G50 (16 mg/kg). Alveolar eosinophils (50 x 10(6) cells) were purified to approximately 98% by Percoll continuous density gradient centrifugation. The binding studies indicated that alveolar eosinophils bind LTB4 in a saturable, reversible and specific manner. Scatchard analysis indicated the existence of high-affinity binding sites (Kd1 = 1.00 ± 0.22 nM; Bmax1 = 966 ± 266 sites/cell) and low-affinity binding sites (Kd2 = 62.5 ± 8.9 nM; Bmax2 = 5557 ± 757 sites/cell). The metabolism of LTB4 by alveolar eosinophils in binding conditions was assessed by RP-HPLC and no significant degradation of [3H]LTB4 was observed. LTB4 dose-dependently stimulated eosinophil migration in both chemokinesis and chemotaxis assays with an EC50 value of 1.30 ± 0.14 and 18.14 ± 1.57 nM, respectively. LTB4 caused a dose-dependent increase in the production of superoxide anion with an apparent EC50 value of 50 x 10(-9) M in the authors experimental conditions. LTB4 also induced a dose-dependent increase in the generation of TxA2 with an EC50 value of 46.2 x 10(-9) M. Taken together, their results demonstrated that guinea pig alveolar eosinophils express two classes of specific receptors for LTB4. The high-affinity binding sites seem associated to chemokinesis and chemotaxis whereas the low-affinity binding sites seem associated to superoxide anion production and generation of TxA2. The existence of LTB4 receptors in eosinophils could explain the presence of these cells in hypersensitivity reactions

MAC-1 Glycoprotein Family mediates adherence of neutrophils to endothelial cells stimulated by leukotriene B/sub 4/ and platelet activating factor

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Tonnesen, M.G.; Anderson, D.C.; Springer, T.A.; Knedler, A.; Avdi, N.; Henson, P.M.

1986-03-01

The process of neutrophil (N) adhesion to and migration through endothelium (EC), an early event in the induction of the acute inflammatory response, has been attributed to the generation of extravascular chemoattractant peptides and lipids. Although both leukotriene B/sub 4/ (LTB/sub 4/) and platelet activating factor (PAF) enhance N adherence to EC, the mechanisms involved in this interaction are still not completely understood. Since the MAC-1 Glycoprotein (GP) Family has recently been shown to be required for a variety of adherence-dependent functions of stimulated N, the authors questioned whether these adherence-associated GP might be involved in N adherence to EC stimulated by LTB/sub 4/ or PAF. Using a microtiter adherence assay with /sup 111/In labeled N, they assessed the ability of N from patients with MAC-1, LFA-1 Deficiency to adhere to monolayers of human omental microvascular or umbilical vein EC as well as to serum-coated plastic. Patient N exhibited markedly diminished adherence in response to LTB/sub 4/ or PAF compared to normal controls. LTB/sub 4/ and PAF enhanced expression of the MAC-1 GP Family on the surface of normal N as determined by flow cytofluorimetry using a monoclonal antibody (TS1/18) to the GP common beta subunit. In addition TS1/18 (20 ..mu..g/ml) completely inhibited N adherence stimulated by either LTB/sub 4/ (10/sup -8/M) or PAF(10/sup -11/M). Thus, the MAC-1 GP Family appears to be important in chemotactic factor regulation of N adherence to EC.

A new method to evaluate anti-allergic effect of food component by measuring leukotriene B4 from a mouse mast cell line.

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Takasugi, Mikako; Muta, Emi; Yamada, Koji; Arai, Hirofumi

2018-02-01

Leukotrienes (LTs), chemical mediators produced by mast cells, play an important role in allergic symptoms such as food allergies and hay fever. We tried to construct an evaluation method for the anti-LTB 4 activity of chemical substances using a mast cell line, PB-3c. PB-3c pre-cultured with or without arachidonic acid (AA) was stimulated by calcium ionophore (A23187) for 20 min, and LTB 4 production by the cells was determined by HPLC with UV detection. LTB 4 was not detected when PB-3c was pre-cultured without AA. On the other hand, LTB 4 production by PB-3c pre-cultured with AA was detectable by HPLC, and the optimal conditions of PB-3c for LTB 4 detection were to utilize the cells pre-cultured with 50 µM AA for 48 h. MK-886 (5-lipoxygenase inhibitor) completely inhibited LTB 4 production, but AACOCF 3 (phospholipase A 2 inhibitor) slightly increased LTB 4 production, suggesting that LTB 4 was generated from exogenous free AA through 5-lipoxygenase pathway. We applied this technique to the evaluation of the anti-LTB 4 activity of food components. PB-3c pre-cultured with 50 µM AA for 48 h was stimulated with A23187 in the presence of 50 µM soybean isoflavones (daidzin, genistin, daidzein, and genistein), equol, quercetin, or kaempferol. Genistein, equol, quercetin, and kaempferol strongly inhibited LTB 4 production without cytotoxicity. These results suggest that a new assay system using PB-3c is convenient to evaluate LTB 4 inhibition activity by food components. This method could be utilized for elucidation of the mechanisms of LTB 4 release suppression by food components such as flavonoids and the structure-activity relationship.

Ir-LBP, an ixodes ricinus tick salivary LTB4-binding lipocalin, interferes with host neutrophil function.

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Jérôme Beaufays

Full Text Available BACKGROUND: During their blood meal, ticks secrete a wide variety of proteins that can interfere with their host's defense mechanisms. Among these proteins, lipocalins play a major role in the modulation of the inflammatory response. METHODOLOGY/PRINCIPAL FINDINGS: We previously identified 14 new lipocalin genes in the tick Ixodes ricinus. One of them codes for a protein that specifically binds leukotriene B4 with a very high affinity (Kd: +/-1 nM, similar to that of the neutrophil transmembrane receptor BLT1. By in silico approaches, we modeled the 3D structure of the protein and the binding of LTB4 into the ligand pocket. This protein, called Ir-LBP, inhibits neutrophil chemotaxis in vitro and delays LTB4-induced apoptosis. Ir-LBP also inhibits the host inflammatory response in vivo by decreasing the number and activation of neutrophils located at the tick bite site. Thus, Ir-LBP participates in the tick's ability to interfere with proper neutrophil function in inflammation. CONCLUSIONS/SIGNIFICANCE: These elements suggest that Ir-LBP is a "scavenger" of LTB4, which, in combination with other factors, such as histamine-binding proteins or proteins inhibiting the classical or alternative complement pathways, permits the tick to properly manage its blood meal. Moreover, with regard to its properties, Ir-LBP could possibly be used as a therapeutic tool for illnesses associated with an increased LTB4 production.

Leukotriene B4 catabolism: quantitation of leukotriene B4 and its omega-oxidation products by reversed-phase high-performance liquid chromatography.

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Shak, S

1987-01-01

LTB4 and its omega-oxidation products may be rapidly, sensitively, and specifically quantitated by the methods of solid-phase extraction and reversed-phase high-performance liquid chromatography (HPLC), which are described in this chapter. Although other techniques, such as radioimmunoassay or gas chromatography-mass spectrometry, may be utilized for quantitative analysis of the lipoxygenase products of arachidonic acid, only the technique of reversed-phase HPLC can quantitate as many as 10 metabolites in a single analysis, without prior derivatization. In this chapter, we also reviewed the chromatographic theory which we utilized in order to optimize reversed-phase HPLC analysis of LTB4 and its omega-oxidation products. With this information and a gradient HPLC system, it is possible for any investigator to develop a powerful assay for the potent inflammatory mediator, LTB4, or for any other lipoxygenase product of arachidonic acid.

Leukotrienes and leukotriene modifiers in pediatric allergic diseases

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Ehab

... 12(1):3-12. 3. Leukotrienes and leukotriene modifiers in pediatric allergic diseases ... childhood allergic diseases. This review ... produce cysteinyl-LTs and LTB4 spontaneously in vitro.8. Although nonleukocyte cells generally do not have sufficient 5-LO and FLAP to synthesize .... uninterrupted sleep in these patients.55.

The leukotriene B{sub 4} receptor, BLT1, is required for the induction of experimental autoimmune encephalomyelitis

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Kihara, Yasuyuki, E-mail: kihara-yasuyuki@umin.net [Department of Biochemistry and Molecular Biology, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan); Yokomizo, Takehiko [Department of Medical Biochemistry, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582 (Japan); Core Research for Embryonic Science and Technology (CREST), Japan Science and Technology Agency (Japan); Kunita, Akiko; Morishita, Yasuyuki; Fukayama, Masashi [Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033 (Japan); Ishii, Satoshi; Shimizu, Takao [Department of Biochemistry and Molecular Biology, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)

2010-04-09

Leukotriene B{sub 4} (LTB{sub 4}) is a potent chemoattractant and activator of neutrophils, macrophages and T cells. These cells are a key component of inflammation and all express BLT1, a high affinity G-protein-coupled receptor for LTB{sub 4}. However, little is known about the neuroimmune functions of BLT1. In this study, we describe a distinct role for BLT1 in the pathology of experimental autoimmune encephalomyelitis (EAE) and T{sub H}1/T{sub H}17 immune responses. BLT1 mRNA was highly upregulated in the spinal cord of EAE mice, especially during the induction phase. BLT1{sup -/-} mice had delayed onset and less severe symptoms of EAE than BLT1{sup +/+} mice. Additionally, inflammatory cells were recruited to the spinal cord of asymptomatic BLT1{sup +/+}, but not BLT1{sup -/-} mice before the onset of disease. Ex vivo studies showed that both the proliferation and the production of IFN-{gamma}, TNF-{alpha}, IL-17 and IL-6 were impaired in BLT1{sup -/-} cells, as compared with BLT1{sup +/+} cells. Thus, we suggest that BLT1 exacerbates EAE by regulating the migration of inflammatory cells and T{sub H}1/T{sub H}17 immune responses. Our findings provide a novel therapeutic option for the treatment of multiple sclerosis and other T{sub H}17-mediated diseases.

Leukotriene B₄-leukotriene B₄ receptor axis promotes oxazolone-induced contact dermatitis by directing skin homing of neutrophils and CD8⁺ T cells.

Science.gov (United States)

Lv, Jiaoyan; Zou, Linlin; Zhao, Lina; Yang, Wei; Xiong, Yingluo; Li, Bingji; He, Rui

2015-09-01

Leukotriene B4 (LTB4 ) is a lipid mediator that is rapidly generated in inflammatory sites, and its functional receptor, BLT1, is mostly expressed on immune cells. Contact dermatitis is a common inflammatory skin disease characterized by skin oedema and abundant inflammatory infiltrates, primarily including neutrophils and CD8(+) T cells. The role of the LTB4 -BLT1 axis in contact dermatitis remains largely unknown. In this study, we found up-regulated gene expression of 5-lipoxygenase and leukotriene A4 hydrolase, two critical enzymes for LTB4 synthesis, BLT1 and elevated LTB4 levels in skin lesions of oxazolone (OXA)-induced contact dermatitis. BLT1 deficiency or blockade of LTB4 and BLT1 by the antagonists, bestatin and U-75302, respectively, in the elicitation phase caused significant decreases in ear swelling and skin-infiltrating neutrophils and CD8(+) T cells, which was accompanied by significantly reduced skin expression of CXCL1, CXCL2, interferon-γ and interleukin-1β. Furthermore, neutrophil depletion during the elicitation phase of OXA-induced contact dermatitis also caused significant decreases in ear swelling and CD8(+) T-cell infiltration accompanied by significantly decreased LTB4 synthesis and gene expression of CXCL2, interferon-γ and interleukin-1β. Importantly, subcutaneous injection of exogenous LTB4 restored the skin infiltration of CD8(+) T cells in neutrophil-depleted mice following OXA challenge. Collectively, our results demonstrate that the LTB4 -BLT1 axis contributes to OXA-induced contact dermatitis by mediating skin recruitment of neutrophils, which are a major source of LTB4 that sequentially direct CD8(+) T-cell homing to OXA-challenged skin. Hence, LTB4 and BLT1 could be potential therapeutic targets for the treatment of contact dermatitis. © 2015 John Wiley & Sons Ltd.

Development of 125I-leukotriene B4 radio-immunoassay and its clinical applications

International Nuclear Information System (INIS)

Wang Zhaoyue; He Yang; Chen Dechun; Ruan Changgeng

1992-11-01

LTB 4 was extracted from porcine blood with the help of HPLC. The antiserum was raised by immunizing rabbits with LTB 4 which has been conjugated with bovine serum albumin by mixed anhydride method method. The titer of the anti-body was 1:7000 and the affinity coefficient was 2.1 x 10 9 L/M. Its cross reactions with LTA 4 , LTC 4 , LTD 4 and other arachidonic acid metabolites were 0.4 ∼ 6.4%.The 125 I-histamine-LTB 4 was prepared by using chloramine T procedure. The minimum detectable limit was 25 pg/tube. The recovery rate was 84.2 ∼ 113%. The intra- and inter-assay coefficient of variation were 5.2% and 9.7% respectively. The amount of LTB 4 produced by normal human PMNL which were stimulated by ionophore A23187 and arachidonic acid was 695.5 ± 329.7 pg/10 6 cells. PMNL of patients with various acute leukemias and CML generated an increased quantities of LTB 4 , TXB 2 and 6-keto-PGF 1α . LTB 4 produced by PMNL also showed an increasing tendency in both cerebral thrombosis and acute myocardial infarction, but was not altered in cerebral hemorrhage of non-infarction coronary disease

Zyflamend reduces LTB4 formation and prevents oral carcinogenesis in a 7,12-dimethylbenz[alpha]anthracene (DMBA)-induced hamster cheek pouch model.

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Yang, Peiying; Sun, Zheng; Chan, Diana; Cartwright, Carrie A; Vijjeswarapu, Mary; Ding, Jibin; Chen, Xiaoxin; Newman, Robert A

2008-11-01

Aberrant arachidonic acid metabolism, especially altered cyclooxygenase and 5-lipoxygenase (LOX) activities, has been associated with chronic inflammation as well as carcinogenesis in human oral cavity tissues. Here, we examined the effect of Zyflamend, a product containing 10 concentrated herbal extracts, on development of 7,12-dimethylbenz[alpha]anthracene (DMBA)-induced inflammation and oral squamous cell carcinoma (SCC). A hamster cheek pouch model was used in which 0.5% DMBA was applied topically onto the left cheek pouch of male Syrian golden hamsters either three times per week for 3 weeks (short term) or 6 weeks (long term). Zyflamend was then applied topically at one of three different doses (25, 50 and 100 microl) onto the left cheek pouch three times for 1 week (short-term study) or chronically for 18 weeks. Zyflamend significantly reduced infiltration of inflammatory cells, incidence of hyperplasia and dysplastic lesions, bromodeoxyuridine-labeling index as well as number of SCC in a concentration-dependent manner. Application of Zyflamend (100 microl) reduced formation of leukotriene B(4) (LTB(4)) by 50% compared with DMBA-treated tissues. The reduction of LTB(4) was concentration dependent. The effect of Zyflamend on inhibition of LTB(4) formation was further confirmed with in vitro cell-based assay. Adding LTB(4) to RBL-1 cells, a rat leukemia cell line expressing high levels of 5-LOX and LTA(4) hydrolase, partially blocked antiproliferative effect of Zyflamend. This study demonstrates that Zyflamend inhibited LTB(4) formation and modulated adverse histopathological changes in the DMBA-induced hamster cheek pouch model. The study suggests that Zyflamend might prevent oral carcinogenesis at the post-initiation stage.

Breath condensate levels of 8-isoprostane and leukotriene B4 after ozone inhalation are greater in sensitive versus nonsensitive subjects.

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Alfaro, Mario F; Walby, William F; Adams, William C; Schelegle, Edward S

2007-01-01

Ozone (O3) inhalation induces pulmonary function decrements and inflammation. The present study was designed to determine if a relationship exists between O3 induced pulmonary function changes and the presence of inflammatory markers as measured in exhaled breath condensates (EBCs) obtained from O3-sensitive and nonsensitive human subjects. Eight healthy adult volunteers (4 males/4 females, age 18 to 30 years) were studied, characterized as to their ozone sensitivity and placed into 2 groups (sensitive and nonsensitive) with each group having 2 males and 2 females. Subjects completed a 20-minute EBC collection and pulmonary function test (PFT) prior to a single 60-minute bout of cycle ergometer exercise (V(E) = 50-55 L/min) while breathing filtered air (FA) or 0.35 ppm O3. Subjective symptom scores (SSSs) were collected at 6, 20, 40, and 60 minutes during exposure. An immediate postexposure PFT was performed followed by an EBC collection. Subjective symptom scores, EBCs, and PFTs were collected at 1, 4 and 8 hours post exposure. EBCs were analyzed for prostaglandin E2 (PGE2), leukotriene B4 (LTB4), 8-isoprostane, and total nitric oxide (NO) metabolites (nitrate + nitrite content). Sensitive subjects, breathing O3, had significantly greater functional decrements in PFTs, increased SSSs, and increased rapid shallow breathing as well as elevated levels of 8-isoprostane and LTB4 in EBCs compared to those breathing FA. In addition, there were significant increases in nitrate + nitrite content in both sensitive and nonsensitive subjects breathing O3 compared to FA. These results indicate that sensitive subjects have elevated arachidonic acid metabolites in EBCs compared to nonsensitive subjects after O3 inhalation.

A specific assay for leukotriene B4 in human whole blood

DEFF Research Database (Denmark)

Fogh, J; Poulsen, L K; Bisgaard, H

1992-01-01

between standard and sample dilution curves. Purification was, therefore, extended by combinations of the following steps: 1) protein precipitation, 2) lipid extractions, and 3) high-performance liquid chromatography (HPLC). One of two commercially available LTB4 standards was found to contain multiple...... components, several of which were immunoreactive in RIA. Even for the standard containing pure LTB4, interference was demonstrated by lack of parallelism between sample and standard dilution curves. Testing eight combinations of varying purification steps, we found that only a three-step purification...

Characterization of arachidonate 5-lipoxygenase and leukotriene A4 synthetase from RBL-1 cells

International Nuclear Information System (INIS)

Cook, M.; Hogaboom, G.K.; Sarau, H.M.; Foley, J.J.; Crooke, S.T.

1986-01-01

5-lipoxygenase (LO) and leukotriene (LT) A4 synthetase from RBL-1 high speed (105,000 x g for 60 min) supernatants were partially purified by protein-high performance liquid chromatography (HPLC) and characterized in detail. The partially purified preparation contained only 5-LO and LTA4 synthetase and was isolated from 12-LO, peroxidase and LTA4 hydrolase activities. Reaction products were separated by reversed phase HPLC and quantitated by absorption spectrophotometry and radiochemical detection. The enzyme preparation rapidly converted [ 14 C]arachidonate to [ 14 C]5-hydroperoxyeicosatetraenoic acid (HPETE) and [ 14 C]5,12-dihydroperoxyeicosatetraenoic acids (diHETEs). The 5,12-diHETEs were primarily non-enzymatic breakdown products of LTA4 (e.g., 6-trans-LTB4 and 6-trans-12-epi-LTB4). Both the 5-LO and LTA4 synthetase activities were Ca 2+- and ATP-dependent. For both enzyme activities, the CA 2+ stimulation required the presence of ATP. The fatty acid hydroperoxides, 5-,12-, and 15-HPETE, both stimulated ([ 3 μM]) 5-LO and LTA4 synthetase activities. The rapid isolation and subsequent characterization of 5-LO and LTA4 synthetase provide the bases for the further understanding of the role of the LO pathway in biological processes

Impact of arachidonic versus eicosapentaenoic acid on exotonin-induced lung vascular leakage: relation to 4-series versus 5-series leukotriene generation.

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Grimminger, F; Wahn, H; Mayer, K; Kiss, L; Walmrath, D; Seeger, W

1997-02-01

Escherichia coli hemolysin (HlyA) is a proteinaceous pore-forming exotoxin that is implicated as a significant pathogenicity factor in extraintestinal E. coli infections including sepsis. In perfused rabbit lungs, subcytolytic concentrations of the toxin evoke thromboxane-mediated vasoconstriction and prostanoid-independent protracted vascular permeability increase (11). In the present study, the influence of submicromolar concentrations of free arachidonic acid (AA) and eicosapentaenoic acid (EPA) on the HlyA-induced leakage response was investigated. HlyA at concentration from 0.02 to 0.06 hemolytic units/ml provoked a dose-dependent, severalfold increase in the capillary filtration coefficient (Kfc), accompanied by the release of leukotriene(LT)B4, LTC4, and LTE4 into the recirculating buffer fluid. Simultaneous application of 100 nmol/L AA markedly augmented the HlyA-elicited leakage response, concomitant with an amplification of LTB4 release and a change in the kinetics of cysteinyl-LT generation. In contrast, 50 to 200 nmol/L EPA suppressed in a dose-dependent manner the HlyA-induced increase in Kfc values. This was accompanied by a blockage of 4-series LT generation and a dose-dependent appearance of LTB5, LTC5, and LTE5. In addition, EPA fully antagonized the AA-induced amplification of the HlyA-provoked Kfc increase, again accompanied by a shift from 4-series to 5-series LT generation. We conclude that the vascular leakage provoked by HlyA in rabbit lungs is differentially influenced by free AA versus free EPA, related to the generation of 4- versus 5-series leukotrienes. The composition of lipid emulsions used for parenteral nutrition may thus influence inflammatory capillary leakage.

Stereoselective semi-hydrogenation and deuteration of a diacetylenic precursor of leukotriene B4 methyl ester

International Nuclear Information System (INIS)

Pontikis, R.; Le Merrer, Y.; Depezay, J.-C.; Petillot, Y.; Rousseau, B.; Beaucourt, J.P.

1990-01-01

[6,7,14,15- 2 H4]-Leukotriene B4 methyl ester was prepared by reduction with deuterium gas of a suitable precursor (deuterium incorporation > 90%). Several catalytic semi-hydrogenations were affected in order to determine the best conditions for the labeling step. (author)

Sesquiterpene glucosides from anti-leukotriene B4 release fraction of Taraxacum officinale.

Science.gov (United States)

Kashiwada, Y; Takanaka, K; Tsukada, H; Miwa, Y; Taga, T; Tanaka, S; Ikeshiro, Y

2001-01-01

Chemical examination of the MeOH extract of the root of Taraxacum officinale, which exhibited inhibitory activity on the formation of leukotriene B4 from activated human neutrophils, has resulted in the isolation of 14-O-beta-D-glucosyl-11,13-dihydro-taraxinic acid (1) and 14-O-beta-D-glucosyl-taraxinic acid (2). The absolute stereostructure of 1 has been established by X-ray chrystallographic examination.

Stereoselective semi-hydrogenation and deuteration of a diacetylenic precursor of leukotriene B sub 4 methyl ester

Energy Technology Data Exchange (ETDEWEB)

Pontikis, R.; Le Merrer, Y.; Depezay, J.-C. (U.D.C. CNRS-INSERM (URA 400), 75, Paris (France). Lab. de Chimie et Biochimie Pharamacologiques et Toxicologiques); Petillot, Y.; Rousseau, B.; Beaucourt, J.P. (CEA Centre d' Etudes Nucleaires de Saclay, 91 - Gif-sur-Yvette (France). Service des Molecules Marquees)

1990-10-01

(6,7,14,15-{sup 2}H4)-Leukotriene B4 methyl ester was prepared by reduction with deuterium gas of a suitable precursor (deuterium incorporation > 90%). Several catalytic semi-hydrogenations were affected in order to determine the best conditions for the labeling step. (author).

LTB4 stimulates growth of human pancreatic cancer cells via MAPK and PI-3 kinase pathways

International Nuclear Information System (INIS)

Tong, W.-G.; Ding, X.-Z.; Talamonti, Mark S.; Bell, Richard H.; Adrian, Thomas E.

2005-01-01

We have previously shown the importance of LTB4 in human pancreatic cancer. LTB4 receptor antagonists block growth and induce apoptosis in pancreatic cancer cells both in vitro and in vivo. Therefore, we investigated the effect of LTB4 on proliferation of human pancreatic cancer cells and the mechanisms involved. LTB4 stimulated DNA synthesis and proliferation of both PANC-1 and AsPC-1 human pancreatic cancer cells, as measured by thymidine incorporation and cell number. LTB4 stimulated rapid and transient activation of MEK and ERK1/2 kinases. The MEK inhibitors, PD98059 and U0126, blocked LTB4-stimulated ERK1/2 activation and cell proliferation. LTB4 also stimulated phosphorylation of p38 MAPK; however, the p38 MAPK inhibitor, SB203580, failed to block LTB4-stimulated growth. The activity of JNK/SAPK was not affected by LTB4 treatment. Phosphorylation of Akt was also induced by LTB4 and this effect was blocked by the PI-3 kinase inhibitor wortmannin, which also partially blocked LTB4-stimulated cell proliferation. In conclusion, LTB4 stimulates proliferation of human pancreatic cancer cells through MEK/ERK and PI-3 kinase/Akt pathways, while p38 MPAK and JNK/SAPK are not involved

Measurement of tumor necrosis factor-α, leukotriene B4, and interleukin 8 in the exhaled breath condensate in patients with acute exacerbations of chronic obstructive pulmonary disease

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Fanny WS Ko

2008-12-01

Full Text Available Fanny WS Ko1, Ting-Fan Leung2, Gary WK Wong2, Jenny Ngai1, Kin W To1, Susanna Ng1, David SC Hui11Department of Medicine and Therapeutics; 2Department of Pediatrics, The Chinese University of Hong Kong, Hong KongBackground: Assessment of airway inflammation in the clinical course of acute exacerbations of chronic obstructive pulmonary disease (AECOPD may advance our understanding of the pathogenesis and treatment.Objectives: To assess airway inflammation in patients during the course of AECOPD by serial analyses of their exhaled breath condensates (EBC.Methods: Twenty-six patients with AECOPD (22 males, mean[SD] percentage predicted forced expiratory volume in one second (FEV1 44.8 [14.3], 11 with stable COPD, and 14 age and sex-matched healthy controls were studied. Patients with AECOPD were treated with systemic steroid and antibiotic for 7 days. EBC was collected from each patient with AECOPD on Day 5, 14, 30, and 60 post-hospitalization using EcoScreen (VIASYS Healthcare, USA during tidal breathing over 10 minutes. Concentrations of tumor necrosis factor-α (TNF-α, leukotriene B4 (LTB4, and interleukin-8 (IL-8 were measured by enzyme-linked immunosorbent assay.Results: The median (IQR of TNF-α level on Day 5 was 5.08 (3.80–6 .32 pg/ml, which was lower than on Day 14 (5.84 [4.91–9.14] pg/ml, p = 0.017, Day 30 (6.14 [3.82–7.67] pg/ml, p = 0.045, and Day 60 (5.60 [4.53–8.80] pg/ml, p = 0.009. On Day 60, subjects receiving inhaled corticosteroid (ICS had a lower level of TNF-α than those who were not (4.82 [4.06–5.65] vs 7.66 [5.48–10.9] pg/ml, p = 0.02. EBC LTB4 level did not change significantly during recovery from AECOPD whereas IL-8 was mostly undetectable.Conclusions: EBC TNF-α level was low in patients receiving systemic steroid and antibiotic therapy for AECOPD. These findings suggest a potential role for serial EBC TNF-α for noninvasive monitoring of disease activity.Keywords: COPD, exacerbation, exhaled breath

Blockade of leukotriene production by a single oral dose of MK-0591 in active ulcerative colitis

DEFF Research Database (Denmark)

Hillingsø, Jens; Kjeldsen, J; Laursen, L S

1995-01-01

dialysis fluid, ex vivo biosynthesis of LTB4 in whole blood, and urinary excretion of leukotriene E4 (LTE4) from 16 patients with mild to moderately active distally located ulcerative colitis were measured by use of radioimmunoassays in a double-blind, placebo-controlled parallel-design study before...... was unchanged. In whole blood, MK-0591 decreased ex vivo biosynthesis of LTB4 (p LTE4 was reduced by more than 85% (p

Endogenous leukotriene D4 formation during anaphylactic shock in the guinea pig

International Nuclear Information System (INIS)

Keppler, A.; Oerning, L.; Bernstroem, K.; Hammarstroem, S.

1987-01-01

Experiments on the metabolism and excretion of i.v. administered selectively labeled [ 3 H 8 ]leukotriene C 4 in bile duct-cannulated guinea pigs indicated predominantly biliary excretion of tritium. The major leukotriene metabolite in bile was identified as leukotriene D 4 . By monitoring leukotriene excretion radioimmunochromatographically, it was shown that guinea pigs suffering from anaphylactic shock produce leukotriene D 4 endogenously. Immunological challenge of animals sensitized to ovalbumin was accompanied by an increase of biliary leukotriene D 4 concentrations from 10 +/- 1 to 86 +/- 10 nM. When considering that bile flow was decreased to about half after challenge, the excretion rate of leukotriene D 4 in bile increased from 0.88 +/- 0.16 before 3.18 +/- 0.38 pmol x min -1 x kg -1 after challenge. It is concluded that systemic anaphylaxis in the guinea pig is associated with endogenous generation of leukotriene C 4

Leveraging model-based study designs and serial micro-sampling techniques to understand the oral pharmacokinetics of the potent LTB4 inhibitor, CP-105696, for mouse pharmacology studies.

Science.gov (United States)

Spilker, Mary E; Chung, Heekyung; Visswanathan, Ravi; Bagrodia, Shubha; Gernhardt, Steven; Fantin, Valeria R; Ellies, Lesley G

2017-07-01

1. Leukotriene B4 (LTB4) is a proinflammatory mediator important in the progression of a number of inflammatory diseases. Preclinical models can explore the role of LTB4 in pathophysiology using tool compounds, such as CP-105696, that modulate its activity. To support preclinical pharmacology studies, micro-sampling techniques and mathematical modeling were used to determine the pharmacokinetics of CP-105696 in mice within the context of systemic inflammation induced by a high-fat diet (HFD). 2. Following oral administration of doses > 35 mg/kg, CP-105696 kinetics can be described by a one-compartment model with first order absorption. The compound's half-life is 44-62 h with an apparent volume of distribution of 0.51-0.72 L/kg. Exposures in animals fed an HFD are within 2-fold of those fed a normal chow diet. Daily dosing at 100 mg/kg was not tolerated and resulted in a >20% weight loss in the mice. 3. CP-105696's long half-life has the potential to support a twice weekly dosing schedule. Given that most chronic inflammatory diseases will require long-term therapies, these results are useful in determining the optimal dosing schedules for preclinical studies using CP-105696.

Influence of standard and novel LTB4 analogs on human neutrophil chemotaxis measured by the multiwell cap assay.

Science.gov (United States)

Psychoyos, S; Uziel-Fusi, S; Bhagwat, S; Morrissey, M M

1989-11-30

Standard and novel LTB4 analogs were tested for neutrophil chemoattractant activity using the multiwell cap assay (Evans et al. (1986) Biosc. Rep. 6, 1041). The assay uses disposable equipment and measures chemotaxis by the number of cells able to migrate across the full thickness of cellulose nitrate filters. Under standard conditions (90 min incubation at 37 degrees C in buffer containing 2% bovine albumin), LTB4 and 6-cis-LTB1 had EC50 values of 3.5 and 15,000 nM, respectively. 20-hydroxy-LTB4 was equipotent with LTB4 and exhibited a similar biphasic chemotactic response, however, only one third of the number of cells migrated through the filter. 20-carboxy-LTB4 was inactive up to 1,000 nM. 5-desoxy-((6,7)-cis-cyclopropyl)-LTB2, (6,7)-benzo-LTB2 and 5-desoxy-(8,10)-LTB2 had EC50 values of 11,300, 50,000 and 84,000 nM, respectively. Checkerboard analysis indicated a chemokinetic component of 42% for LTB4 at a concentration causing peak chemotaxis. Reduction of albumin in the buffer to 0.5% increased the apparent potencies of LTB4 and 6-cis-LTB1 five-fold. Since LTB4 is a mediator of inflammation, various anti-inflammatory agents were tested at peak concentrations observed in vivo for in vitro inhibition of LTB4-stimulated chemotaxis in the presence of 0.5% albumin. Under the conditions of the assay, chloroquine diphosphate, dexamethasone, indomethacin, penicillamine, piroxicam and diclofenac sodium were inactive; gold sodium thiomalate was inhibitory (IC50 = 20 microM).

Leukotrienes B4, C4, D4 and E4 in the Exhaled Breath Condensate (EBC), Blood and Urine in Patients with Pneumoconiosis

Czech Academy of Sciences Publication Activity Database

Pelclová, D.; Fenclová, Z.; Vlčková, Š.; Lebedová, J.; Syslová, K.; Pecha, O.; Běláček, J.; Navrátil, Tomáš; Kuzma, Marek; Kačer, P.

2012-01-01

Roč. 50, č. 4 (2012), s. 299-306 ISSN 0019-8366 Institutional support: RVO:61388955 ; RVO:61388971 Keywords : leukotrienes * Lung fibrosis * exhaled breath condensate Subject RIV: CG - Electrochemistry Impact factor: 0.870, year: 2012

Pharmacological modulation of human platelet leukotriene C4-synthase.

Science.gov (United States)

Sala, A; Folco, G; Henson, P M; Murphy, R C

1997-03-21

The aim of this study was to test if human platelet leukotriene C4-synthase (LTC4-S) is pharmacologically different from cloned and expressed LTC4-S and, in light of the significant homologies between 5-lipoxygenase activating protein (FLAP) and LTC4-S, if different potencies of leukotriene synthesis inhibitors acting through binding with FLAP (FLAP inhibitors) reflect in different potencies as LTC4-S inhibitors. Leukotriene C4 (LTC4) synthesis by washed human platelets supplemented with synthetic leukotriene A4 (LTA4) was studied in the absence and presence of two different, structurally unrelated FLAP inhibitors (MK-886 and BAY-X1005) as well as a direct 5-lipoxygenase inhibitor (zileuton). LTC4 production was analyzed by RP-HPLC coupled to diode array detection. We report that human platelet LTC4-S was inhibited by MK-886 and BAY-X1005 (IC50 of 4.7 microM and 91.2 microM, respectively), but not by zileuton (inactive up to 300 microM); all 3 compounds were able to inhibit 5-lipoxygenase metabolite biosynthesis in intact human polymorphonuclear leukocytes (IC50 of 0.044 microM, 0.85 microM, and 1.5 microM, respectively). Platelet LTC4-S does not appear pharmacologically different from expression cloned LTC4-S. LTC4-S inhibition by FLAP inhibitors is in agreement with the significant homology reported for expression-cloned LTC4-S with FLAP, Furthermore, functional homology of the binding sites for inhibitors on LTC4-S and FLAP is suggested by the conservation of the relative potencies of MK-886 and BAY-X1005 vs FLAP-dependent 5-lipoxygenase activity and LTC4-S inhibition: MK-886 was 19.3-fold more potent than BAY-X1005 as FLAP inhibitor and 19.6-fold more potent than BAY-X1005 as LTC4-S inhibitor.

Inhibitory activity of tryptanthrin on prostaglandin and leukotriene synthesis.

Science.gov (United States)

Danz, Henning; Stoyanova, Stefka; Thomet, Olivier A R; Simon, Hans-Uwe; Dannhardt, Gerd; Ulbrich, Holger; Hamburger, Matthias

2002-10-01

The indolo[2,1- b]quinazoline alkaloid tryptanthrin has previously been identified as the cyclooxygenase-2 (COX-2) inhibitory principle in the extract ZE550 prepared from the medicinal plant Isatis tinctoria (Brassicaceae). We here investigated the potential inhibitory activity of tryptanthrin and ZE550 on COX-2, COX-1 in cellular and cell-free systems. A certain degree of selectivity towards COX-2 was observed when COX-1-dependent formation of thromboxane B(2) (TxB(2)) in HEL cells and COX-2-dependent formation of 6-ketoprostaglandin F(1alpha) (6-keto-PGF(1alpha)) in Mono Mac 6 and RAW 264.7 cells were compared. Preferential inhibition of COX-2 by two orders of magnitude was found in phorbol myristate acetate (PMA) activated bovine aortic coronary endothelial cells (BAECs). Assays with purified COX isoenzymes from sheep confirmed the high selectivity towards COX-2. The leukotriene B(4) (LTB(4)) release from calcium ionophore-stimulated human granulocytes (neutrophils) was used as a model to determine 5-lipoxygenase (5-LOX) activity. Tryptanthrin and the extract ZE550 inhibited LTB(4) release in a dose dependent manner and with a potency comparable to that of the clinically used 5-LOX inhibitor zileuton.

Susceptibility to endotoxin induced uveitis is not reduced in mice deficient in BLT1, the high affinity leukotriene B4 receptor

OpenAIRE

Smith, J R; Subbarao, K; Franc, D T; Haribabu, B; Rosenbaum, J T

2004-01-01

Aim: To investigate the role of arachidonic acid derived chemotactic factor, LTB4, in the development of endotoxin induced uveitis (EIU), using mice deficient in the BLT1 gene which encodes the high affinity LTB4 receptor.

COMPARISON OF SELECTIVE AND NON SELECTIVE CYCLO-OXYGENASE 2 INHIBITORS IN EXPERIMENTAL COLITIS EXACERBATION: role of leukotriene B4 and superoxide dismutase

Directory of Open Access Journals (Sweden)

José Wander BREGANÓ

2014-09-01

Full Text Available Context Nonsteroidal anti-inflammatory drugs are considered one of the most important causes of reactivation of inflammatory bowel disease. With regard to selective cyclo-oxygenase 2 inhibitors, the results are controversial in experimental colitis as well as in human studies. Objectives The aim this study is to compare nonsteroidal anti-inflammatory drugs effects, selective and non selective cyclo-oxygenase 2 inhibitors, in experimental colitis and contribute to the understanding of the mechanisms which nonsteroidal anti-inflammatory drugs provoke colitis exacerbation. Methods Six groups of rats: without colitis, with colitis, and colitis treated with celecoxib, ketoprofen, indometacin or diclofenac. Survival rates, hemoglobin, plasmatic albumin, colonic tissue of interleukin-1ß, interleukin-6, tumor necrosis factor alpha, prostaglandin E2, catalase, superoxide dismutase, thiobarbituric acid-reactive substances, chemiluminescence induced by tert-butil hydroperoxides, and tissue and plasmatic leukotriene B4 were determined. Results The groups treated with diclofenac or indometacin presented lower survival rates, hemoglobin and albumin, higher tissue and plasmatic leukotriene B4 and tissue superoxide dismutase than the group treated with celecoxib. Ketoprofen presented an intermediary behavior between diclofenac/indometacin and celecoxib, concerning to survival rate and albumin. The groups without colitis, with colitis and with colitis treated with celecoxib showed leukotriene B4 and superoxide dismutase lower levels than the groups treated with nonselective cyclo-oxygenase 2 inhibitors. Conclusions Diclofenac and indometacin presented the highest degree of induced colitis exacerbation with nonsteroidal anti-inflammatory drugs, celecoxib did not show colitis exacerbation, and ketoprofen presented an intermediary behavior between diclofenac/indometacin and celecoxib. These results suggest that leukotriene B4 and superoxide dismutase can be

The effect of n-3 fatty acids and coenzyme Q10 supplementation on neutrophil leukotrienes, mediators of inflammation resolution and myeloperoxidase in chronic kidney disease.

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Barden, Anne E; Shinde, Sujata; Burke, Valerie; Puddey, Ian B; Beilin, Lawrence J; Irish, Ashley B; Watts, Gerald F; Mori, Trevor A

2018-03-22

Neutrophils release leukotriene (LT)B 4 and myeloperoxidase (MPO) that may be important mediators of chronic inflammation in chronic kidney disease (CKD). The n-3 fatty acids (n-3 FA) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have the potential to attenuate inflammation through production of LTB 5 and the Specialized Proresolving Lipid Mediators (SPM) that promote the resolution of inflammation. In animal models, coenzyme Q10 (CoQ) also attenuates inflammation by reducing MPO and LTB 4 . This study evaluated the independent and combined effects of n-3 FA and CoQ supplementation on neutrophil leukotrienes, the pro-inflammatory eicosanoid 5-hydroxyeicosatetraenoic acid (5-HETE), SPM, and plasma MPO, in patients with CKD. In a double-blind, placebo-controlled intervention of factorial design, 85 patients with CKD were randomized to either n-3 FA (4 g), CoQ (200 mg), both supplements, or control (4 g olive oil), daily for 8 weeks. Plasma MPO and calcium ionophore-stimulated neutrophil release of LTs, 5-HETE and SPM were measured at baseline and after 8 weeks. Seventy four patients completed the intervention. n-3 FA, but not CoQ, significantly increased neutrophil LTB 5 (P n-3 FA or CoQ. Plasma MPO was significantly reduced with n-3 FA alone (P = 0.013) but not when given in combination with CoQ. n-3 FA supplementation in patients with CKD leads to increased neutrophil release of LTB 5 and several SPM, as well as a reduction in plasma MPO that may have important implications for limiting chronic inflammation. Copyright © 2018 Elsevier Inc. All rights reserved.

An aspirin-triggered lipoxin A4 stable analog displays a unique topical anti-inflammatory profile.

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Schottelius, Arndt J; Giesen, Claudia; Asadullah, Khusru; Fierro, Iolanda M; Colgan, Sean P; Bauman, John; Guilford, William; Perez, Hector D; Parkinson, John F

2002-12-15

Lipoxins and 15-epi-lipoxins are counter-regulatory lipid mediators that modulate leukocyte trafficking and promote the resolution of inflammation. To assess the potential of lipoxins as novel anti-inflammatory agents, a stable 15-epi-lipoxin A(4) analog, 15-epi-16-p-fluorophenoxy-lipoxin A(4) methyl ester (ATLa), was synthesized by total organic synthesis and examined for efficacy relative to a potent leukotriene B(4) (LTB(4)) receptor antagonist (LTB(4)R-Ant) and the clinically used topical glucocorticoid methylprednisolone aceponate. In vitro, ATLa was 100-fold more potent than LTB(4)R-Ant for inhibiting neutrophil chemotaxis and trans-epithelial cell migration induced by fMLP, but was approximately 10-fold less potent than the LTB(4)R-Ant in blocking responses to LTB(4). A broad panel of cutaneous inflammation models that display pathological aspects of psoriasis, atopic dermatitis, and allergic contact dermatitis was used to directly compare the topical efficacy of ATLa with that of LTB(4)R-Ant and methylprednisolone aceponate. ATLa was efficacious in all models tested: LTB(4)/Iloprost-, calcium ionophore-, croton oil-, and mezerein-induced inflammation and trimellitic anhydride-induced allergic delayed-type hypersensitivity. ATLa was efficacious in mouse and guinea pig skin inflammation models, exhibiting dose-dependent effects on edema, neutrophil or eosinophil infiltration, and epidermal hyperproliferation. We conclude that the LXA(4) and aspirin-triggered LXA(4) pathways play key anti-inflammatory roles in vivo. Moreover, these results suggest that ATLa and related LXA(4) analogs may have broad therapeutic potential in inflammatory disorders and could provide an alternative to corticosteroids in certain clinical settings.

Increase in salivary cysteinyl-leukotriene concentration in patients with aspirin-intolerant asthma.

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Ono, Emiko; Taniguchi, Masami; Higashi, Noritaka; Mita, Haruhisa; Yamaguchi, Hiromichi; Tatsuno, Sayaka; Fukutomi, Yuma; Tanimoto, Hidenori; Sekiya, Kiyoshi; Oshikata, Chiyako; Tsuburai, Takahiro; Tsurikisawa, Naomi; Otomo, Mamoru; Maeda, Yuji; Hasegawa, Maki; Miyazaki, Eishi; Kumamoto, Toshihide; Akiyama, Kazuo

2011-03-01

Cysteinyl-leukotrienes (CysLTs; LTC4, LTD4, and LTE4) play a considerable role in the pathophysiology of aspirin-intolerant asthma (AIA). Saliva has recently been validated as novel, simple, and noninvasive method for investigating inflammation in patients with asthma. The aim of this study is to clarify the molecular species of CysLT in saliva and to evaluate the CysLT and LTB4 concentrations in saliva in AIA patients. We also examined how the CysLT concentration in saliva reflects that of their corresponding urinary metabolite. We preformed an analytical cross-sectional study. CysLT and LTB4 concentrations in saliva were quantified by enzyme immunoassay (EIA) following purification by high-performance liquid chromatography (HPLC). 1. When analyzed by EIA in combination with HPLC, saliva was found to consist of LTC4, LTD4 and LTE4 in similar amounts. 2. In saliva analysis among the three groups (AIA patients, aspirin-tolerant asthma [ATA] patients, and healthy subjects), both the concentrations of CysLTs and LTB4 were significantly higher in AIA patients than in ATA patients and healthy subjects. 3. We found significant correlations between CysLT concentration and LTB4 concentration in saliva in each group. 4. No significant correlation was found between the concentration of LTE4 in urine and that of CysLTs in saliva. In this study, we found higher concentrations of CysLTs and LTB4 in saliva from AIA patients than in saliva from ATA patients, suggesting that the quantification of CysLT and LTB4 concentrations in saliva may be another diagnostic strategy for AIA.

Bone infected/inflamed conditions: Clinical experience with RP517, a Tc99m-leukotriene B4 receptor antagonist

International Nuclear Information System (INIS)

Soroa, V.; Nicolini, J.; Camin, L.; Ughetti, R.; Velasquez, M.

2003-01-01

Full text: Objectives: Tc 99m- RP517- is a receptor antagonist of Leukotriene B4 (LTB4) labelling predominantly neutrophils, in whole blood. The aim of this clinical trial was to obtain the best acquisition protocol and performance of this agent in detecting bone, joint and soft tissue infected / inflamed pathologies. Methods: RP517 was labelled with 15-20 mCi (555-740MBq) Tc99m per doses. Twenty-six patients studied (F 14, M 12) with range ages 19- 93, suspected of bone, joint and soft tissue infection (25) and one with fever of unknown origin (FUO). Laboratory data, anatomical images and one other scintiscan (MDP, Ga-67 or Tc99m- ciprofloxacin) were evaluated. Acquisition protocol: flow, 30 min, 1, 2, 3, 4 - 24h planar or Spect images as required. Results documented with histology, cultures or clinical follow up. Scans were classified as positive when abnormal uptake persisted in the 24h images or negative when positivity faded, or not detected in later images. Results: Labeling efficiency 86-90%. No adverse reactions encountered. Image protocol modified to a flow, 30 min, 4 and 24h images. Ten-fifteen % of in vivo leucocyte labelling at 1h. Early bile and intestinal excretion did not improve with cleansing enemas or food restrain. Late bone marrow activity is less visible than with in vitro leucocyte labeling. Only 16 patients had proven biopsies and cultures with coincident images in 8 True Positive; other 6 cases were True Negative, 2 False Negative (with positive Ga-67 and Tc99m-ciprofloxacin) and no False Positive. Sensitivity 80%, Specificity 100%. Conclusions: A kit should be produced in order to make it easily available. Pharmaceutically manipulation altering the excretion route could validate studies in abdominal infections and FUO that are now disesteemed. Protocol images must include 24h scans. Advantage of RP517 is the lack of cell labeling manipulation. Larger series must be studied to obtain statistics on joint bone and soft tissue infection

Leucocyte labeling: Preliminary clinical evaluation of RP517, the 99mTc-Leukotriene B4 receptor antagonist for infection/inflammation

International Nuclear Information System (INIS)

Soroa, V.E.; Velasquez, M.H.; Nicolini, J.; Ughetti, R.; Camin, L.

2002-01-01

99mTc- Leukotriene B4 (LTB4) is a receptor antagonist RP517 that labels predominantly neutrophils, in whole blood. This new radiopharmaceutical has been developed for imaging infection and inflammation. Aim: We conducted this clinical trial to obtain the best protocol imaging and the efficacy of this novel agent in the detection of suspected infected/inflamed patients. Materials and Methods: RP517 was labelled with 15-20 mCi (555-740 MBq) 99mTc for each patient, with a labeling efficiency of 86-95%. Nine patients studied (F 3, M 6) with ages 45-83, suspected of bone, joint and soft tissue infection (8) and one with fever of unknown origin (FUO). Laboratory, anatomical images and one other scintiscan (MDP, Gallium or 99mTc-ciprofloxacin) were used for evaluation. Acquisition protocol: flow, 30 min, 1, 2, 3, 4 - 24h planar or SPECT images if required. Results were compared to histology, cultures, the clinical derivation and follow up. Scans were classified as positive if abnormal uptake persisted through the 24h images or negative when absent pathological uptake or when positivity faded in later images. Results: No adverse reaction encountered. Image protocol modified to a flow, 30 min, 4 and 24h acquisitions. Early bladder excretion and intestinal activity requires previous cleansing enemas and food restrain. Late bone marrow activity is less visible than with in vitro leucocyte labeling. Coincident images were obtained in 3 True Positive, in 5 True Negative except in a hip prosthesis where Gallium and 99mTc-ciprofloxacin showed positivity and RP517 was False negative. Conclusions: A kit should be produced in order to make it available for Nuclear Medicine Departments. Known advantages of RP517 is the lack of in vitro cell labeling manipulation. We do not recommend investigation of FUO or abdominal pathologies. A larger series must be studied in order to be able to obtain statistics on joint bone and soft tissue infection/inflammation where this compound seems to be

CYP4F18-Deficient Neutrophils Exhibit Increased Chemotaxis to Complement Component C5a

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Rachel Vaivoda

2015-01-01

Full Text Available CYP4Fs were first identified as enzymes that catalyze hydroxylation of leukotriene B4 (LTB4. CYP4F18 has an unusual expression in neutrophils and was predicted to play a role in regulating LTB4-dependent inflammation. We compared chemotaxis of wild-type and Cyp4f18 knockout neutrophils using an in vitro assay. There was no significant difference in the chemotactic response to LTB4, but the response to complement component C5a increased 1.9–2.25-fold in knockout cells compared to wild-type (P < 0.01. This increase was still observed when neutrophils were treated with inhibitors of eicosanoid synthesis. There were no changes in expression of other CYP4 enzymes in knockout neutrophils that might compensate for loss of CYP4F18 or lead to differences in activity. A mouse model of dextran sodium sulfate colitis was used to investigate the consequences of increased C5a-dependent chemotaxis in vivo, but there was no significant difference in weight loss, disease activity, or colonic tissue myeloperoxidase between wild-type and Cyp4f18 knockout mice. This study demonstrates the limitations of inferring CYP4F function based on an ability to use LTB4 as a substrate, points to expanding roles for CYP4F enzymes in immune regulation, and underscores the in vivo challenges of CYP knockout studies.

Leukotriene E4 induces airflow obstruction and mast cell activation through the cysteinyl leukotriene type 1 receptor.

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Lazarinis, Nikolaos; Bood, Johan; Gomez, Cristina; Kolmert, Johan; Lantz, Ann-Sofie; Gyllfors, Pär; Davis, Andy; Wheelock, Craig E; Dahlén, Sven-Erik; Dahlén, Barbro

2018-03-05

Leukotriene (LT) E 4 is the final active metabolite among the cysteinyl leukotrienes (CysLTs). Animal studies have identified a distinct LTE 4 receptor, suggesting that current cysteinyl leukotriene type 1 (CysLT 1 ) receptor antagonists can provide incomplete inhibition of CysLT responses. We tested this hypothesis by assessing the influence of the CysLT 1 antagonist montelukast on responses induced by means of inhalation of LTE 4 in asthmatic patients. Fourteen patients with mild intermittent asthma and 2 patients with aspirin-exacerbated respiratory disease received 20 mg of montelukast twice daily and placebo for 5 to 7 days in a randomized, double-blind, crossover study (NCT01841164). The PD 20 value was determined at the end of each treatment period based on an increasing dose challenge. Measurements included lipid mediators in urine and sputum cells 4 hours after LTE 4 challenge. Montelukast completely blocked LTE 4 -induced bronchoconstriction. Despite tolerating an at least 10 times higher dose of LTE 4 after montelukast, there was no difference in the percentage of eosinophils in sputum. Urinary excretion of all major lipid mediators increased after LTE 4 inhalation. Montelukast blocked release of the mast cell product prostaglandin (PG) D 2 , as well as release of PGF 2α and thromboxane (Tx) A 2 , but not increased excretion of PGE 2 and its metabolites or isoprostanes. LTE 4 induces airflow obstruction and mast cell activation through the CysLT 1 receptor. Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Characterization of guinea pig myocardial leukotriene C4 binding sites. Regulation by cations and sulfhydryl-directed reagents

International Nuclear Information System (INIS)

Hogaboom, G.K.; Mong, S.; Stadel, J.M.; Crooke, S.T.

1985-01-01

Using [ 3 H]leukotriene C4 (LTC4) and radioligand-binding techniques, specific leukotriene C4 binding sites have been identified in membranes derived from guinea pig ventricular myocardium. High performance liquid chromatography analyses indicated that, in the presence of the gamma-glutamyl transpeptidase inhibitor L-serine-borate (80 mM), less than 2% of membrane-bound [ 3 H]LTC4 was converted at 20 degrees to [ 3 H]leukotriene D4 or [ 3 H]leukotriene E4. The specific binding of 4 nM [ 3 H]LTC4, in the presence of 80 mM L-serine-borate, reached a stable steady state within 15 min at 20 degrees (pH 7.5). A monophasic Scatchard plot of saturation binding data yielded a dissociation constant (Kd) of 27.5 +/- 6.0 nM and a maximum number of binding sites (Bmax) of 19.9 +/- 5.2 pmol/mg of membrane protein. Competition binding studies of [ 3 H]LTC4 with synthetic leukotriene C4, leukotriene D4, and leukotriene E4 and the putative peptidoleukotriene antagonists FPL 55712, SKF 88046, and 4R-hydroxy-5S-1-cysteinylglycine-6Z-nonadecanoic acid revealed an order of potency of leukotriene C4 much greater than 4R-hydroxy-5S-1-cysteinylglycine-6Z-nonadecanoic acid greater than SKF 88046 greater than LTE4 greater than LTD4 greater than FPL 55712. The specific [ 3 H]LTC4 binding was stimulated by the divalent cations Ca2+, Mg2+, and Mn2+ and to a lesser degree by the monovalent cations Na+, K+, Li+, and NH4+. CaCl2 (3 mM) and NaCl (150 mM) stimulated the LTC4 binding by increasing the Bmax to 42.6 +/- 5.9 and 35.0 +/- 2.0 pmol/mg, respectively, but had minimal effects on Kd

Lower leukotriene C4 levels in bronchoalveolar lavage fluid of asthmatic subjects after 2.5 years of inhaled corticosteroid therapy

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Y. Oosterhoff

1995-01-01

Full Text Available Long-term treatment with inhaled corticosteroids has been shown to result in improvement of symptoms and lung function in subjects with asthma. Arachidonic acid (AA metabolites are thought to play a role in the pathophysiology of asthma. It was assessed whether differences could be found in bronchoalveolar lavage (BAL AA metabolite levels between subjects with asthma who were treated for 2.5 years with inhaled bronchodilators alone or in combination with inhaled corticosteroids. Prostaglandin (PGD2, PGF2α, 6-keto-PGF1α, thromboxane B2, leukotriene (LTC4 and LTB4 levels and cell numbers were assessed in BAL fluid from 22 non-smoking asthmatic subjects. They were participating in a randomized, double-blind multicentre drug trial over a period of 2.5 years. Results of the group treated with inhaled corticosteroids (CS+: beclomethasone 200 μg four times daily were compared with the other group (CS− which was treated with either ipratropium bromide (40 μg four times daily or placebo. BAL LTC4 levels of asthmatic subjects were significantly lower after 2.5 years inhaled corticosteroid therapy (CS+, 9(1–17 pg/ml vs. CS−, 16(6-53 pg/ml; p = 0.01. The same trend was observed for the PGD2 levels. The results suggest that inhaled corticosteroids may exert their beneficial effect on lung function via a mechanism in which inhibition of LTC4 synthesis in the airways is involved.

Oenothera paradoxa defatted seeds extract and its bioactive component penta-O-galloyl-β-D-glucose decreased production of reactive oxygen species and inhibited release of leukotriene B4, interleukin-8, elastase, and myeloperoxidase in human neutrophils.

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Kiss, Anna K; Filipek, Agnieszka; Czerwińska, Monika; Naruszewicz, Marek

2010-09-22

In this study, we analyzed ex vivo the effect of an aqueous extract of Oenothera paradoxa defatted seeds on the formation of neutrophil-derived oxidants. For defining active compounds, we also tested lypophilic extract constituents such as gallic acid, (+)-catechin, ellagic acid, and penta-O-galloyl-β-D-glucose and a hydrophilic fraction containing polymeric procyanidins. The anti-inflammatory potential of the extract and compounds was tested by determining the release from activated neutrophils of elastase, myeloperoxidase, interleukin-8 (IL-8), and leukotriene B4 (LTB4), which are considered relevant for the pathogenesis of cardiovascular diseases. The extract of O. paradoxa defatted seeds displays potent antioxidant effects against both 4β-phorbol-12β-myristate-α13-acetate- and formyl-met-leu-phenylalanine-induced reactive oxygen species production in neutrophils with IC50 values around 0.2 μg/mL. All types of polyphenolics present in the extract contributed to the extract antioxidant activity. According to their IC50 values, penta-O-galloyl-β-D-glucose was the more potent constituent of the extract. In cell-free assays, we demonstrated that this effect is partially due to the scavenging of O2- and H2O2 oxygen species. The extract and especially penta-O-galloyl-β-D-glucose significantly inhibit elastase, myeloperoxidase IL-8, and LTB4 release with an IC50 for penta-O-galloyl-β-D-glucose of 17±1, 15±1, 6.5±2.5, and around 20 μM, respectively. The inhibition of penta-O-galloyl-β-D-glucose on reactive oxygen species and especially on O2- production, myeloperoxidase, and chemoattractant release may reduce the interaction of polymorphonuclear leukocyte with the vascular endothelium and by that potentially diminish the risk of progression of atherosclerosis development.

Leukotriene C4 synthase and ischemic cardiovascular disease and obstructive pulmonary disease in 13,000 individuals

DEFF Research Database (Denmark)

Freiberg, Jacob J; Dahl, Morten; Tybjaerg-Hansen, Anne

2009-01-01

Ischemic cardiovascular disease and obstructive pulmonary disease involve inflammation. Leukotrienes may be important pro-inflammatory mediators. We tested the hypothesis that the (-1072)G > A and (-444)A > C promoter polymorphisms of leukotriene C4 synthase confer risk of transient ischemic atta...... with risk of asthma or COPD. Leukotriene C4 synthase promoter genotypes influence risk of TIA and ischemic stroke, but not risk of IHD/coronary atherosclerosis, asthma, or COPD....

Identification of a murine cysteinyl leukotriene receptor by expression in Xenopus laevis oocytes

DEFF Research Database (Denmark)

Mollerup, Jens; Jørgensen, Sune T.; Hougaard, Charlotte

2001-01-01

We report the identification of an EST encoding a murine cysteinyl leukotriene (mCysLT) receptor. LTD4, LTC4 and LTE4 but not LTB4 or various nucleotides activated Ca2+-evoked Cl- currents in mCysLT1 expressing Xenopus laevis oocytes. The response to LTD4 was blocked by MK-571, reduced by pretrea...... by pretreatment with pertussis toxin (PTX), and was partly dependent on extracellular Ca2+. The identified murine CysLT1 receptor differs from the hCysLT1 receptor with regard to PTX sensitivity, receptor-mediated Ca2+ influx, and antagonist sensitivity....

Vascular effects of leukotriene D4 in human skin

DEFF Research Database (Denmark)

Bisgaard, H

1987-01-01

Leukotriene D4 (LTD4) increased the blood flow rate in human skin, equipotent to histamine in the dose range of 3.1-200 pmol. The vasodilatation lasted for up to 60 min, and no late reactions occurred. Indomethacin did not affect the LTD4-induced blood flow rate. H1 and H2 antagonists reduced...... as a mediator of the axon reflex, and show that LTD4 causes a direct vasodilatory effect that is not mediated via histamine or cyclooxygenase products. The laser-Doppler flowmeter was applied for dynamic studies of the vasopressor response in the skin during a Valsalva maneuver, and the relative changes...

In vivo formation of beta-oxidized metabolites of leukotriene E4 in the rat

International Nuclear Information System (INIS)

Perrin, P.; Zirrolli, J.; Stene, D.O.; Lellouche, J.P.; Beaucourt, J.P.; Murphy, R.C.

1989-01-01

Intraperitoneal administration of [ 3 H]-leukotriene E4 in the rat resulted in the appearance of radiolabel in urine and feces. Separation of polar urinary metabolites and chromatographic comparison of synthetic metabolites indicated the in vivo formation of omega-oxidized metabolites of LTE4 with sequential beta-oxidation. Furthermore, the metabolite identified as 16-carboxy-17,18,19,20-tetranor-14,15-dihydro-N-acetyl-LTE4 substantiates the biochemical pathway of beta-oxidation in vivo involving the 2,4-dienoyl CoA reductase as an integral step. These results substantiate beta-oxidation of sulfidopeptide leukotrienes in vivo and these metabolites account for some of the major urinary metabolites of this class of lipid mediator

Immunogenicity of recombinant Lactobacillus casei-expressing F4 (K88) fimbrial adhesin FaeG in conjunction with a heat-labile enterotoxin A (LTAK63) and heat-labile enterotoxin B (LTB) of enterotoxigenic Escherichia coli as an oral adjuvant in mice.

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Yu, M; Qi, R; Chen, C; Yin, J; Ma, S; Shi, W; Wu, Y; Ge, J; Jiang, Y; Tang, L; Xu, Y; Li, Y

2017-02-01

The aims of this study were to develop an effective oral vaccine against enterotoxigenic Escherichia coli (ETEC) infection and to design new and more versatile mucosal adjuvants. Genetically engineered Lactobacillus casei strains expressing F4 (K88) fimbrial adhesin FaeG (rLpPG-2-FaeG) and either co-expressing heat-labile enterotoxin A (LTA) subunit with an amino acid mutation associated with reduced virulence (LTAK63) and a heat-labile enterotoxin B (LTB) subunit of E. coli (rLpPG-2-LTAK63-co-LTB) or fused-expressing LTAK63 and LTB (rLpPG-2-LTAK63-fu-LTB) were constructed. The immunogenicity of rLpPG-2-FaeG in conjunction with rLpPG-2-LTAK63-co-LTB or rLpPG-2-LTAK63-fu-LTB as an orally administered mucosal adjuvant in mice was evaluated. Results showed that the levels of FaeG-specific serum IgG and mucosal sIgA, as well as the proliferation of lymphocytes, were significantly higher in mice orally co-administered rLpPG-2-FaeG and rLpPG-2-LTAK63-fu-LTB compared with those administered rLpPG-2-FaeG alone, and were lower than those co-administered rLpPG-2-FaeG and rLpPG-2-LTAK63-co-LTB. Moreover, effective protection was observed after challenge with F4+ ETEC strain CVCC 230 in mice co-administered rLpPG-2-FaeG and rLpPG-2-LTAK63-co-LTB or rLpPG-2-FaeG and rLpPG-2-LTAK63-fu-LTB group compared with those that received rLpPG-2-FaeG alone. rLpPG-2-FaeG showed greater immunogenicity in combination with LTAK63 and LTB as molecular adjuvants. Recombinant Lactobacillus provides a promising platform for the development of vaccines against F4+ ETEC infection. © 2016 The Society for Applied Microbiology.

Leukotriene formation by purified 5-lipoxygenase from rat basophilic leukemia cells

International Nuclear Information System (INIS)

Hogaboom, G.K.; Cook, M.; Sarau, H.M.; Newton, J.F.; Crooke, S.T.

1986-01-01

Arachidonate 5-lipoxygenase (5-LO) from rat basophilic leukemia (RBL-1) cell high speed (105,000 x g for 60 min) supernatants was purified to electrophoretic homogeneity by gel filtration and anion-exchange protein-high pressure liquid chromatography (HPLC). The 5-LO rapidly converted [ 14 C]arachidonate at 20 0 C to [ 14 C]5-hydroperoxyeicosate-traenoic acid (HPETE) as determined by reversed phase-HPLC, scanning spectrophotometry and radiochemical detection. In addition, 5-LO converted both 5-HPETE and arachidonate to 5,12-dihydroxyeicosatetraenoic acids (diHETEs). The 5,12-diHETEs were identified as 6-trans-leukotriene (LT) B4 and 6-trans-12-epi-LTB4 as determined by reversed phase HPLC, scanning spectrophotometry and gas chromatography-mass spectrometry. These data indicate that the RBL-1 5-LO and LTA4 synthetase activities reside on the same protein and that it catalyzes the bioconversion of arachidonate to not only 5-HPETE but also to LTA4. The results suggest that a critical regulatory step in LT biosynthesis in mammalian systems involves the intricate coupling of the enzymes 5-LO and LTA4 synthetase and the interactions of their respective cofactors, substrates and reaction products

P17, an Original Host Defense Peptide from Ant Venom, Promotes Antifungal Activities of Macrophages through the Induction of C-Type Lectin Receptors Dependent on LTB4-Mediated PPARγ Activation

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Khaddouj Benmoussa

2017-11-01

Full Text Available Despite the growing knowledge with regard to the immunomodulatory properties of host defense peptides, their impact on macrophage differentiation and on its associated microbicidal functions is still poorly understood. Here, we demonstrated that the P17, a new cationic antimicrobial peptide from ant venom, induces an alternative phenotype of human monocyte-derived macrophages (h-MDMs. This phenotype is characterized by a C-type lectin receptors (CLRs signature composed of mannose receptor (MR and Dectin-1 expression. Concomitantly, this activation is associated to an inflammatory profile characterized by reactive oxygen species (ROS, interleukin (IL-1β, and TNF-α release. P17-activated h-MDMs exhibit an improved capacity to recognize and to engulf Candida albicans through the overexpression both of MR and Dectin-1. This upregulation requires arachidonic acid (AA mobilization and the activation of peroxisome proliferator-activated receptor gamma (PPARγ nuclear receptor through the leukotriene B4 (LTB4 production. AA/LTB4/PPARγ/Dectin-1-MR signaling pathway is crucial for P17-mediated anti-fungal activity of h-MDMs, as indicated by the fact that the activation of this axis by P17 triggered ROS production and inflammasome-dependent IL-1β release. Moreover, we showed that the increased anti-fungal immune response of h-MDMs by P17 was dependent on intracellular calcium mobilization triggered by the interaction of P17 with pertussis toxin-sensitive G-protein-coupled receptors on h-MDMs. Finally, we also demonstrated that P17-treated mice infected with C. albicans develop less severe gastrointestinal infection related to a higher efficiency of their macrophages to engulf Candida, to produce ROS and IL-1β and to kill the yeasts. Altogether, these results identify P17 as an original activator of the fungicidal response of macrophages that acts upstream PPARγ/CLRs axis and offer new immunomodulatory therapeutic perspectives in the field of

Identification of leukotriene D4 specific binding sites in the membrane preparation isolated from guinea pig lung

International Nuclear Information System (INIS)

Mong, S.; Wu, H.L.; Clark, M.A.; Stadel, J.M.; Gleason, J.G.; Crooke, S.T.

1984-01-01

A radioligand binding assay has been established to study leukotriene specific binding sites in the guinea pig and rabbit tissues. Using high specific activity [ 3 H]-leukotriene D4 [( 3 H]-LTD4), in the presence or absence of unlabeled LTD4, the diastereoisomer of LTD4 (5R,6S-LTD4), leukotriene E4 (LTE4) and the end-organ antagonist, FPL 55712, the authors have identified specific binding sites for [ 3 H]-LTD4 in the crude membrane fraction isolated from guinea pig lung. The time required for [ 3 H]-LTD4 binding to reach equilibrium was approximately 20 to 25 min at 37 degrees C in the presence of 10 mM Tris-HCl buffer (pH 7.5) containing 150 mM NaCl. The binding of [ 3 H]-LTD4 to the specific sites was saturable, reversible and stereospecific. The maximal number of binding sites (Bmax), derived from Scatchard analysis, was approximately 320 +/- 200 fmol per mg of crude membrane protein. The dissociation constants, derived from kinetic and saturation analyses, were 9.7 nM and 5 +/- 4 nM, respectively. The specific binding sites could not be detected in the crude membrane fraction prepared from guinea pig ileum, brain and liver, or rabbit lung, trachea, ileum and uterus. In radioligand competition experiments, LTD4, FPL 55712 and 5R,6S-LTD4 competed with [ 3 H]-LTD4. The metabolic inhibitors of arachidonic acid and SKF 88046, an antagonist of the indirectly-mediated actions of LTD4, did not significantly compete with [ 3 H]-LTD4 at the specific binding sites. These correlations indicated that these specific binding sites may be the putative leukotriene receptors in the guinea-pig lung

4-Hydroxynonenal enhances MMP-9 production in murine macrophages via 5-lipoxygenase-mediated activation of ERK and p38 MAPK

International Nuclear Information System (INIS)

Lee, Seung J.; Kim, Chae E.; Yun, Mi R.; Seo, Kyo W.; Park, Hye M.; Yun, Jung W.; Shin, Hwa K.; Bae, Sun S.; Kim, Chi D.

2010-01-01

Exaggerated levels of 4-hydroxynonenal (HNE) and 5-lipoxygenase (5-LO) co-exist in macrophages in atherosclerotic lesions, and activated macrophages produce MMP-9 that degrades atherosclerotic plaque constituents. This study investigated the effects of HNE on MMP-9 production, and the potential role for 5-LO derivatives in MMP-9 production in murine macrophages. Stimulation of J774A.1 cells with HNE led to activation of 5-LO, as measured by leukotriene B 4 (LTB 4 ) production. This was associated with an increased production of MMP-9, which was blunted by inhibition of 5-LO with MK886, a 5-LO inhibitor or with 5-LO siRNA. A cysteinyl-LT 1 (cysLT 1 ) receptor antagonist, REV-5901 as well as a BLT 1 receptor antagonist, U-75302, also attenuated MMP-9 production induced by HNE. Furthermore, LTB 4 and cysLT (LTC 4 and LTD 4 ) enhanced MMP-9 production in macrophages, suggesting a pivotal role for 5-LO in HNE-mediated production of MMP-9. Among the MAPK pathways, LTB 4 and cysLT enhanced phosphorylation of ERK and p38 MAPK, but not JNK. Linked to these results, a p38 MAPK inhibitor as well as an ERK inhibitor blunted MMP-9 production induced by LT. Collectively, these data suggest that 5-LO-derived LT mediates HNE-induced MMP-9 production via activation of ERK and p38 MAPK pathways, consequently leading to plaque instability in atherosclerosis.

Effects of balneotherapy on serum IL-1, PGE2 and LTB4 levels in fibromyalgia patients.

Science.gov (United States)

Ardiç, Füsum; Ozgen, Merih; Aybek, Hülya; Rota, Simin; Cubukçu, Duygu; Gökgöz, Ali

2007-03-01

The purpose of this study was to investigate the clinical effects of balneotherapy in the treatment of Fibromyalgia Syndrome (FMS) and to determine if balneotherapy influences serum levels of inflammation markers, IL-1, PGE2 and LTB4. 24 primary fibromyalgia female patients diagnosed according to American College of Rheumatology criteria were included to the study. Their ages ranged between 33 and 55 years. FMS patients were randomly assigned in two groups as, group 1 (n = 12) and group 2 (n = 12). Group 1 received 20-min bathing, once in a day for five days per week. Patients participated in the study for 3 weeks (total of 15 sessions) in Denizli. Group 2 did not receive balneotherapy. FMS patients were evaluated by tenderness measurements (tender point count and algometry), Visual Analogue Scale, Beck's Depression Index, Fibromyalgia Impact Questionnaire. Ten healthy women recruited group three as the controls. Serum PGE2, LTB4 and IL1-alpha levels were measured in all three groups. The biochemical measurements and clinical assessments were performed before and at the end of general period of therapy. Statistically significant alterations in algometric score, Visual Analogue score, Beck's Depression Index and PGE2 levels (P balneotherapy between group 1 and 2. Mean PGE2 level of FMS patients were higher compared to healthy control group (P balneotherapy IL-1 and LTB4 significantly decreased in group 1 (P balneotherapy is an effective choice of treatment in patients with FMS relieving the clinical symptoms, and possibly influencing the inflammatory mediators.

A convenient synthesis of deuterated leukotriene A sub 4 methyl ester

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Bestmann, H.J.; Roeder, T. (Erlangen-Nuernberg Univ., Erlangen (Germany, F.R.). Inst. fuer Organische Chemie); Meese, C.O. (Fischer-Bosch-Inst. fuer Klinische Pharmakologie, Stuttgart (Germany, F.R.))

1989-11-01

2,2,3,3-({sup 2}H{sub 4})-1-Iodopentane was prepared in four steps from propargyl alcohol and used in the C-alkylation of the THP-protected 3-butyne-1-ol. Subsequent protective group removal, semi-deuteration of the acetylenic alcohol and further transformation by known methods afforded the labelled key reagent 3,4,6,6,7,7-({sup 2}H{sub 6})-(Z)-(3-nonen-1-yl)triphenylphosphonium iodide. Wittig olefination of epoxy dienal with the ylide generated from the latter completed the convenient synthesis of hexadeuterated leukotriene A{sub 4} methyl ester. (author).

Anti-Inflammatory Benefits of Antibiotics: Tylvalosin Induces Apoptosis of Porcine Neutrophils and Macrophages, Promotes Efferocytosis, and Inhibits Pro-Inflammatory CXCL-8, IL1α, and LTB4 Production, While Inducing the Release of Pro-Resolving Lipoxin A4 and Resolvin D1.

Science.gov (United States)

Moges, Ruth; De Lamache, Dimitri Desmonts; Sajedy, Saman; Renaux, Bernard S; Hollenberg, Morley D; Muench, Gregory; Abbott, Elizabeth M; Buret, Andre G

2018-01-01

Excessive accumulation of neutrophils and their uncontrolled death by necrosis at the site of inflammation exacerbates inflammatory responses and leads to self-amplifying tissue injury and loss of organ function, as exemplified in a variety of respiratory diseases. In homeostasis, neutrophils are inactivated by apoptosis, and non phlogistically removed by neighboring macrophages in a process known as efferocytosis, which promotes the resolution of inflammation. The present study assessed the potential anti-inflammatory and pro-resolution benefits of tylvalosin, a recently developed broad-spectrum veterinary macrolide derived from tylosin. Recent findings indicate that tylvalosin may modulate inflammation by suppressing NF-κB activation. Neutrophils and monocyte-derived macrophages were isolated from fresh blood samples obtained from 12- to 22-week-old pigs. Leukocytes exposed to vehicle or to tylvalosin (0.1, 1.0, or 10 µg/mL; 0.096-9.6 µM) were assessed at various time points for apoptosis, necrosis, efferocytosis, and changes in the production of cytokines and lipid mediators. The findings indicate that tylvalosin increases porcine neutrophil and macrophage apoptosis in a concentration- and time-dependent manner, without altering levels of necrosis or reactive oxygen species production. Importantly, tylvalosin increased the release of pro-resolving Lipoxin A 4 (LXA 4 ) and Resolvin D1 (RvD 1 ) while inhibiting the production of pro-inflammatory Leukotriene B4 (LTB 4 ) in Ca 2+ ionophore-stimulated porcine neutrophils. Tylvalosin increased neutrophil phospholipase C activity, an enzyme involved in releasing arachidonic acid from membrane stores. Tylvalosin also inhibited pro-inflammatory chemokine (C-X-C motif) ligand 8 (CXCL-8, also known as Interleukin-8) and interleukin-1 alpha (IL-1α) protein secretion in bacterial lipopolysaccharide-stimulated macrophages. Together, these data illustrate that tylvalosin has potent immunomodulatory effects in porcine

Anti-Inflammatory Benefits of Antibiotics: Tylvalosin Induces Apoptosis of Porcine Neutrophils and Macrophages, Promotes Efferocytosis, and Inhibits Pro-Inflammatory CXCL-8, IL1α, and LTB4 Production, While Inducing the Release of Pro-Resolving Lipoxin A4 and Resolvin D1

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Ruth Moges

2018-04-01

Full Text Available Excessive accumulation of neutrophils and their uncontrolled death by necrosis at the site of inflammation exacerbates inflammatory responses and leads to self-amplifying tissue injury and loss of organ function, as exemplified in a variety of respiratory diseases. In homeostasis, neutrophils are inactivated by apoptosis, and non phlogistically removed by neighboring macrophages in a process known as efferocytosis, which promotes the resolution of inflammation. The present study assessed the potential anti-inflammatory and pro-resolution benefits of tylvalosin, a recently developed broad-spectrum veterinary macrolide derived from tylosin. Recent findings indicate that tylvalosin may modulate inflammation by suppressing NF-κB activation. Neutrophils and monocyte-derived macrophages were isolated from fresh blood samples obtained from 12- to 22-week-old pigs. Leukocytes exposed to vehicle or to tylvalosin (0.1, 1.0, or 10 µg/mL; 0.096–9.6 µM were assessed at various time points for apoptosis, necrosis, efferocytosis, and changes in the production of cytokines and lipid mediators. The findings indicate that tylvalosin increases porcine neutrophil and macrophage apoptosis in a concentration- and time-dependent manner, without altering levels of necrosis or reactive oxygen species production. Importantly, tylvalosin increased the release of pro-resolving Lipoxin A4 (LXA4 and Resolvin D1 (RvD1 while inhibiting the production of pro-inflammatory Leukotriene B4 (LTB4 in Ca2+ ionophore-stimulated porcine neutrophils. Tylvalosin increased neutrophil phospholipase C activity, an enzyme involved in releasing arachidonic acid from membrane stores. Tylvalosin also inhibited pro-inflammatory chemokine (C–X–C motif ligand 8 (CXCL-8, also known as Interleukin-8 and interleukin-1 alpha (IL-1α protein secretion in bacterial lipopolysaccharide-stimulated macrophages. Together, these data illustrate that tylvalosin has potent immunomodulatory effects

Impairment of Neutrophil Migration to Remote Inflammatory Site during Lung Histoplasmosis

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Alexandra I. Medeiros

2015-01-01

Full Text Available Histoplasma capsulatum (Hc induces a pulmonary disease in which leukotrienes promote activation and recruitment of effectors cells. It is also well-recognized that leukotriene B4 (LTB4 and platelet-activating factor (PAF induce leukocyte recruitment to inflammatory sites. We investigated the impact of pulmonary Hc infection on PMN migration to a remote inflammatory site. Our results show that pulmonary Hc infection impairs LTB4- or PAF-stimulated PMN recruitment to air pouch. Yet, remote inflammation did not modify PMN numbers in the bronchoalveolar lavage fluid (BALF of Hc-infected mice. Interestingly, the concomitant administration of PAF and LTB4 receptor antagonists inhibited PMN recruitment to both BALF and the remote site, demonstrating cooperation between both mediators. Along that line, our results show that PAF-elicited PMN chemotaxis was abrogated in 5-lipoxygenase-deficient animals. These results suggest caution in the indiscriminate use of anti-inflammatory drugs during infectious diseases.

Bronchial effects of leukotriene D4 inhalation in normal human lung

DEFF Research Database (Denmark)

Bisgaard, H; Groth, S

1987-01-01

airways in asthmatic patients out of attack. LTD4 caused a dose-dependent obstruction of the airways as measured by partial flow-volume curves and volume of trapped gas, yet only minor changes in forced expiratory volume in 1 s (FEV1) and peak expiratory flow rate. LTD4 was 1900-7000 times more potent......The aim of the study was to investigate whether inhaled leukotriene (LT) D4 could mimic the characteristics of asthmatic patients after allergen-induced attack, i.e. a prolonged subclinical bronchial obstruction, an increased reactivity of the airways and a late reaction. The effects of LTD4 were...... than histamine. LTD4 inhalations were almost symptomless as opposed to the irritative and dyspnoeic symptoms seen after inhalation of histamine. The time duration for the induced change in partial flow-volume curves was the same for the two drugs. Approximately 30 min elapsed until the bronchial...

Release of leukotriene C4 from human polymorphonuclear leucocytes as determined by radioimmunoassay

International Nuclear Information System (INIS)

Aehringhaus, U.; Woelbling, R.H.; Peskar, B.M.; Peskar, B.A.; Koenig, W.; Patrono, C.

1982-01-01

Rabbits were immunized with a conjugate of leukotriene (LT)C 4 and bovine serum albumin prepared by coupling the single free amino group of the hapten to the protein using gluteraldehyde. Binding of [ 3 H]LTC 4 to the antibodies obtained is inhibited by 50% with 1.5 ng LTC 4 . The relative cross-section of LTD 4 is 16% and of LTC 4 -methyl ester 3.6%. The validity of the radioimmunoassay was demonstrated by comparison with bioassay using the isolated guinea pig ileum. Using the radioimmunoassay it could be shown that endogenous LTC 4 is released in a dose-dependent manner by human polymorphonuclear leucocytes stimulated with the divalent cation ionophore A23187. (Auth.)

Elevated Plasma Level of Leukotrienes in Bronchial Asthma Patients: A Possible Clinical Relevance

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Mahmoud Mansour

1994-01-01

Full Text Available Plasma from bronchial asthma patients and healthy controls was investigated for the content of lipoxygenase products. After lipid extraction using SEP-PAK C18 Cartridges, the lipoxygenase products were measured by Enzyme-Immunoassay. Elevated chemotactic B4 was found in plasma from asthmatic patients with mean value (483±75 pmoUL, while the mean value in normal healthy donors was (140± 12.1 pmol/L (M±SE. The levels of spasmogenic cysteinyl containing leukotrienes were also very high in the bronchial asthma patients. Elevations of leukotriene B4 and cysteinyl containing leukotrienes were detected during attacks of bronchial asthma. These results suggest that leukotriene B4 may be important in the pathogenesis of bronchial asthma and confirmed that peptidoleukotrienes playa role as chemical mediators during the asthmatic attack.

A new practical method for the preparation of [3H6]-leukotrienes C4 and D4

International Nuclear Information System (INIS)

Belley, M.L.; Gareau, Y.; Zamboni, R.J.; Ahern, D.G.; Yang Hong

1995-01-01

A new method for the synthesis of highly deuterated or tritiated leukotrienes was developed. The higher reactivity of a terminal alkene compared to a 1,2-disubstituted one permitted the selective deuteration or tritiation of the diyne 14,15,19,19,20,20-hexadehydro LTC 4 troester 1. After hydrolysis, LTC 4 was obtained in 36% overall yield. An average of seven deuterium or tritium atoms was incorporated and the specific activity of the tritiated LTC 4 was greater than 180Ci/mmol. 1 was obtained from the addition of glutathione to 14,15,19,19,20,20-hexadehydro LTA 4 ethyl ester which was the product of a Wittig reaction between (3,8-nonanediyn-1-yl) triphenylphosphonium iodide and 5(S), 6(S), 7(E), 9(E) ethyl 5,6-epoxy-11-oxo-7,9-undecadienoate. (Author)

Leukotrienes are upregulated and associated with human T-lymphotropic virus type 1 (HTLV-1-associated neuroinflammatory disease.

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Bruno Caetano Trindade

Full Text Available Leukotrienes (LTs are lipid mediators involved in several inflammatory disorders. We investigated the LT pathway in human T-lymphotropic virus type 1 (HTLV-1 infection by evaluating LT levels in HTLV-1-infected patients classified according to the clinical status as asymptomatic carriers (HACs and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP patients. Bioactive LTB(4 and CysLTs were both increased in the plasma and in the supernatant of peripheral blood mononuclear cell cultures of HTLV-1-infected when compared to non-infected. Interestingly, CysLT concentrations were increased in HAM/TSP patients. Also, the concentration of plasma LTB(4 and LTC(4 positively correlated with the HTLV-1 proviral load in HTLV-1-infected individuals. The gene expression levels of LT receptors were differentially modulated in CD4(+ and CD8(+ T cells of HTLV-1-infected patients. Analysis of the overall plasma signature of immune mediators demonstrated that LT and chemokine amounts were elevated during HTLV-1 infection. Importantly, in addition to CysLTs, IP-10 was also identified as a biomarker for HAM/TSP activity. These data suggest that LTs are likely to be associated with HTLV-1 infection and HAM/TSP development, suggesting their putative use for clinical monitoring.

Promotor polymorphisms in leukotriene C4 synthase and risk of ischemic cerebrovascular disease

DEFF Research Database (Denmark)

Freiberg, J.J.; Tybjaerg-Hansen, A.; Sillesen, H.

2008-01-01

OBJECTIVE: Cysteinyl leukotrienes are involved in inflammation and possibly in early carotid atherosclerosis. We tested the hypothesis that the -444 A/C and -1072 G/A polymorphisms of the leukotriene C(4) synthase associate with risk of ischemic cerebrovascular disease. METHODS AND RESULTS: We...... genotyped 10 592 individuals from the Danish general population, the Copenhagen City Heart Study. During 24 years of follow-up, 557 individuals developed ischemic cerebrovascular disease. The allele frequency was 0.07 for -1072 A and 0.29 for -444 C. Cumulative incidence for ischemic cerebrovascular disease...... was higher for -1072 AA versus GG genotype (log-rank: P=0.002), and lower for -444 CC versus AA genotype (log-rank: P=0.008). Combined genotypes showed corresponding cumulative incidence differences (log-rank: P=0.003). Multifactorially adjusted hazard ratios for ischemic cerebrovascular disease were 2...

The inflammatory mediator leukotriene D4 induces subcellular β-catenin translocation and migration of colon cancer cells

International Nuclear Information System (INIS)

Salim, Tavga; Sand-Dejmek, Janna; Sjölander, Anita

2014-01-01

The abnormal activation of the Wnt/β-catenin pathway frequently occurs in colorectal cancer. The nuclear translocation of β-catenin activates the transcription of target genes that promote cell proliferation, survival, and invasion. The pro-inflammatory mediator leukotriene D 4 (LTD 4 ) exerts its effects through the CysLT 1 receptor. We previously reported an upregulation of CysLT 1 R in patients with colon cancer, suggesting the importance of leukotrienes in colon cancer. The aim of this study was to investigate the impact of LTD 4 on Wnt/β-catenin signaling and its effects on proliferation and migration of colon cancer cells. LTD 4 stimulation led to an increase in β-catenin expression, β-catenin nuclear translocation and the subsequent transcription of MYC and CCND1. Furthermore, LTD 4 significantly reduced the expression of E-cadherin and β-catenin at the plasma membrane and increased the migration and proliferation of HCT116 colon cancer cells. The effects of LTD 4 can be blocked by the inhibition of CysLT 1 R. Furthermore, LTD 4 induced the inhibition of glycogen synthase kinase 3 (GSK)-3β activity, indicating a crosstalk between the G-protein-coupled receptor CysLT 1 and the Wnt/β-catenin pathway. In conclusion, LTD 4 , which can be secreted from macrophages and leukocytes in the tumor microenvironment, induces β-catenin translocation and the activation of β-catenin target genes, resulting in the increased proliferation and migration of colon cancer cells. - Highlights: • Leukotriene D 4 (LTD 4 ) lowers membrane β-catenin but increases nuclear β-catenin levels in colon cancer cells. • In agreement, LTD 4 triggers inactivation of GSK-3β, activation of TCF/LEF and increased expression of Cyclin D1 and c-Myc. • LTD 4 also caused a significant reduction in the expression of E-cadherin and an increased migration of colon cancer cells

Upregulation of Leukotriene Receptors in Gastric Cancer

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Venerito, Marino [Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Leipziger Str. 44, Magdeburg 39120 (Germany); Kuester, Doerthe [Institute of Pathology, Otto-von-Guericke University, Leipziger Str. 44, Magdeburg 39120 (Germany); Harms, Caroline [Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Leipziger Str. 44, Magdeburg 39120 (Germany); Schubert, Daniel [Department of General, Visceral and Vascular Surgery, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, Magdeburg 39120 (Germany); Wex, Thomas, E-mail: thomas.wex@med.ovgu.de; Malfertheiner, Peter [Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Leipziger Str. 44, Magdeburg 39120 (Germany)

2011-08-08

Leukotrienes (LT) mediate allergic and inflammatory processes. Previously, we identified significant changes in the expression pattern of LT receptors in the gastric mucosa after eradication of Helicobacter pylori infection. The aim of the present study was to evaluate the expression of 5-lipoxygenase (5-LOX) and LT receptors in gastric cancer (GC). The expression of 5-LOX and receptors for LTB4 (BLT-1, BLT-2) and cysteinyl-LT (CysLT-1, CysLT-2) were analyzed by immunohistochemistry (IHC) in GC samples of 35 consecutive patients who underwent gastrectomy and in 29 tumor-free tissue specimens from gastric mucosa. Male-to-female ratio was 24:11. The median age was 70 years (range 34–91). Twenty-two patients had GC of intestinal, six of diffuse, six of mixed and one of undifferentiated type. The IHC analysis showed a nearly ubiquitous expression of studied proteins in GC (88–97%) and in tumor-free specimens as well (89–100%). An increase in the immunoreactive score of both BLT receptors and CysLT-1 was observed in GC compared to tumor-free gastric mucosa (p < 0.001 for BLT-1; p < 0.01 for BLT-2 and CysLT-1, Mann-Whitney U-test). No differences in the IHC expression of 5-LOX and CsyLT-2 were observed between GC and tumor-free mucosa. The expression of BLT-2, CysLT-1 and CysLT-2 was increased in GC of intestinal type when compared to the diffuse type (p < 0.05; Mann-Whitney U-test). LTB4 receptors and CysLT-1 are up-regulated in GC tissue implying a role in gastric carcinogenesis.

Sulfite induces release of lipid mediators by alveolar macrophages

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Beck-Speier, I.; Dayal, N.; Maier, L. [GSF - National Research Center for Environment and Health, Neuherberg (Germany). Inst. for Inhalation Biology; Denzlinger, C. [Tuebingen Univ. (Germany). Dept. II, Medical Clinic; Haberl, C. [Tuebingen Univ. (Germany). Dept. III, Medical Clinic

1998-03-01

Air pollutants are supposed to modulate physiological responses of alveolar macrophages (AM). This study was addressed to the question whether at neutral pH sulfur(IV) species in comparison to sulfur(VI) species cause AM to release proinflammatory mediators and which pathways are involved in their generation. Supernatants obtained from canine AM treated with sulfite (0.1 mM to 2 mM) enhanced the respiratory burst of canine neutrophils, measured by lucigenin-dependent chemiluminescence, whereas supernatants derived from AM treated with sulfate (1 mM) did not. The neutrophil-stimulating activity released by sulfite-treated AM consisted of platelet-activating factor (PAF) and leukotriene B{sub 4} (LTB{sub 4}) as shown by desensitization of the platelet-activating factor (PAF) and leukotriene B{sub 4} (LTB{sub 4}) as shown by desensitization of the corresponding receptors. Inhibitors of phospholipase A{sub 2} substantially suppressed release of neutrophil-stimulating activity by sulfite-treated AM. Inhibition of 5-lipoxygenase in sulfite-treated AM also reduced neutrophil-stimulating activity, while inhibition of cyclooxygenase had no effect. In conclusion, sulfite induces AM to release lipid mediators via phospholipase A{sub 2}- and 5-lipoxygenase-dependent pathways. These mediators activate neutrophils via the receptors for PAF and LTB{sub 4}. (orig.)

Lipoxin A4 and lipoxin B4 stimulate the release but not the oxygenation of arachidonic acid in human neutrophils: Dissociation between lipid remodeling and adhesion

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Nigam, S.; Fiore, S.; Luscinskas, F.W.; Serhan, C.N. (Brigham and Women' s Hospital, Boston, MA (USA))

1990-06-01

The profiles of actions of lipoxin A4 (LXA4) and lipoxin B4 (LXB4), two lipoxygenase-derived eicosanoids, were examined with human neutrophils. At nanomolar concentrations, LXA4 and LXB4 each stimulated the release of (1-14C)arachidonic acid from esterified sources in neutrophils. Lipoxin-induced release of (1-14C)arachidonic acid was both dose- and time-dependent and was comparable to that induced by the chemotactic peptide f-met-leu-phe. Time-course studies revealed that lipoxin A4 and lipoxin B4 each induced a biphasic release of (1-14C)arachidonic acid, which was evident within seconds (5-15 sec) in its initial phase and minutes (greater than 30 sec) in the second phase. In contrast, the all-trans isomers of LXA4 and LXB4 did not provoke (1-14C)AA release. Lipoxin-induced release of arachidonic acid was inhibited by prior treatment of the cells with pertussis toxin but not by its beta-oligomers, suggesting the involvement of guaninine nucleotide-binding regulatory proteins in this event. Dual radiolabeling of neutrophil phospholipid classes with (1-14C)arachidonic acid and (3H)palmitic acid showed that phosphatidylcholine was a major source of lipoxin-induced release of (1-14C)arachidonic acid. They also demonstrated that lipoxins rapidly stimulate both formation of phosphatidic acid as well as phospholipid remodeling. Although both LXA4 and LXB4 (10(-8)-10(-6) M) stimulated the release of (1-14C)arachidonic acid, neither compound evoked its oxygenation by either the 5- or 15-lipoxygenase pathways (including the formation of LTB4, 20-COOH-LTB4, 5-HETE, or 15-HETE). LXA4 and LXB4 (10(-7) M) each stimulated the elevation of cytosolic Ca2+ as monitored with Fura 2-loaded cells, albeit to a lesser extent than equimolar concentrations of FMLP. Neither lipoxin altered the binding of (3H)LTB4 to its receptor on neutrophils.

Cysteinyl leukotrienes in the urine of patients with liver diseases.

Science.gov (United States)

Uemura, M; Buchholz, U; Kojima, H; Keppler, A; Hafkemeyer, P; Fukui, H; Tsujii, T; Keppler, D

1994-10-01

The significance of cysteinyl leukotrienes was investigated in patients with liver diseases by measurements of leukotriene E4 and N-acetyl-leukotriene E4 in urine. A marked increase of renal cysteinyl leukotriene excretion was observed in patients with cirrhosis without and with ascites, intrahepatic cholestasis, and obstructive jaundice as compared with healthy subjects (leukotriene E4: means 82, 264, 221 and 142 versus 40 nmol/mol creatinine, respectively; N-acetyl-leukotriene E4: means 25, 64, 61 and 47 versus 13 nmol/mol creatinine, respectively). The urinary concentration of leukotriene E4 was positively correlated with the one of N-acetyl-leukotriene E4 (r = 0.81, p jaundice, the excretion of leukotriene E4 plus N-acetyl-leukotriene E4 was positively correlated with total serum bilirubin. In patients with cirrhosis and in those with obstructive jaundice, the cysteinyl leukotrienes in urine were negatively correlated with creatinine clearance. The elevated renal excretion of cysteinyl leukotrienes decreased after biliary drainage in patients with obstructive jaundice. These data support the concept that increased urinary excretion of cysteinyl leukotrienes in patients with cirrhosis is due to a reduced functional liver mass and that in patients with cholestasis it is mainly due to an impaired elimination into the biliary tract that results in a diversion to renal excretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Urinary leukotriene E4 at 12 months and influencing factors

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K Stencel-Gabriel

2016-01-01

• 3.        Department of Gynecology, Obstetrics and Oncological Gynecology, Bytom, Medical University of Silesia       Corresponding author: Krystyna Stencel-Gabriel ul. Batorego 15 41-902 Bytom   Keywords: leukotriene E4, infants, allergy, urine.   Summary Objective LTE4 is the end point of cysLTs pathway and its only stable product. Its role was discussed in asthma and AEDS. We aimed to investigate the impact of genetic and environmental factors ( sex, maternal positive family atopy history, breastfeeding, passive smoking and pet exposure . 60 newborns ( including 30 boys were enrolled in the study. Each child was examined at 12 months and urine samples for urinary LTE4 measurement were collected. All samples were processed using ACETM Enzyme Immunoassay Kit ( Cayman Chemical, Ann Arbor, MI, USA . The mean level of urinary LTE4 at 12 months was 186,99 pg/ml ( median: 159,0; CI 95%: 157,79- 221,59 . The Shapiro- Wilk test showed that the distribution of the levels of urinary LTE4 were abnormal. 12- month- old girls had higher urinary LTE4 levels than boys ( mean: 270,50 vs. 193,55 , but maternal positive atopy history, pet exposure, tobacco smoking or length of breastfeeding had no impact on urinary LTE4 excretion. Conclusions In conclusion, most of genetic or environmental factors do not change levels of urinary LTE4 in infants.

The inflammatory mediator leukotriene D{sub 4} induces subcellular β-catenin translocation and migration of colon cancer cells

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Salim, Tavga [Division of Cell and Experimental Pathology, Department of Laboratory Medicine, Lund University, Clinical Research Center, Skåne University Hospital, Malmö (Sweden); Sand-Dejmek, Janna [Division of Cell and Experimental Pathology, Department of Laboratory Medicine, Lund University, Clinical Research Center, Skåne University Hospital, Malmö (Sweden); Section of Surgery, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö (Sweden); Bayer HealthCare, Pharmaceuticals Medical Affairs, Solna (Sweden); Sjölander, Anita, E-mail: anita.sjolander@med.lu.se [Division of Cell and Experimental Pathology, Department of Laboratory Medicine, Lund University, Clinical Research Center, Skåne University Hospital, Malmö (Sweden)

2014-02-15

The abnormal activation of the Wnt/β-catenin pathway frequently occurs in colorectal cancer. The nuclear translocation of β-catenin activates the transcription of target genes that promote cell proliferation, survival, and invasion. The pro-inflammatory mediator leukotriene D{sub 4} (LTD{sub 4}) exerts its effects through the CysLT{sub 1} receptor. We previously reported an upregulation of CysLT{sub 1}R in patients with colon cancer, suggesting the importance of leukotrienes in colon cancer. The aim of this study was to investigate the impact of LTD{sub 4} on Wnt/β-catenin signaling and its effects on proliferation and migration of colon cancer cells. LTD{sub 4} stimulation led to an increase in β-catenin expression, β-catenin nuclear translocation and the subsequent transcription of MYC and CCND1. Furthermore, LTD{sub 4} significantly reduced the expression of E-cadherin and β-catenin at the plasma membrane and increased the migration and proliferation of HCT116 colon cancer cells. The effects of LTD{sub 4} can be blocked by the inhibition of CysLT{sub 1}R. Furthermore, LTD{sub 4} induced the inhibition of glycogen synthase kinase 3 (GSK)-3β activity, indicating a crosstalk between the G-protein-coupled receptor CysLT{sub 1} and the Wnt/β-catenin pathway. In conclusion, LTD{sub 4}, which can be secreted from macrophages and leukocytes in the tumor microenvironment, induces β-catenin translocation and the activation of β-catenin target genes, resulting in the increased proliferation and migration of colon cancer cells. - Highlights: • Leukotriene D{sub 4} (LTD{sub 4}) lowers membrane β-catenin but increases nuclear β-catenin levels in colon cancer cells. • In agreement, LTD{sub 4} triggers inactivation of GSK-3β, activation of TCF/LEF and increased expression of Cyclin D1 and c-Myc. • LTD{sub 4} also caused a significant reduction in the expression of E-cadherin and an increased migration of colon cancer cells.

PHARMACOGENOMICS OF PROSTAGLANDIN AND LEUKOTRIENE RECEPTORS

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José Antonio Cornejo-García

2016-09-01

Full Text Available Individual genetic background together with environmental effects are thought to be behind many human complex diseases. A number of genetic variants, mainly single nucleotide polymorphisms (SNPs, have been shown to be associated with various pathological and inflammatory conditions, representing potential therapeutic targets. Prostaglandins (PTGs and leukotrienes (LTs are eicosanoids derived from arachidonic acid and related polyunsaturated fatty acids that participate in both normal homeostasis and inflammatory conditions. These bioactive lipid mediators are synthesised through two major multistep enzymatic pathways: PTGs by cyclooxygenase and LTs by 5-lipoxygenase. The main physiological effects of PTGs include vasodilation and vascular leakage (PTGE2; mast cell maturation, eosinophil recruitment and allergic responses (PTGD2; vascular and respiratory smooth muscle contraction (PTGF2, and inhibition of platelet aggregation (PTGI2. LTB4 is mainly involved in neutrophil recruitment, vascular leakage, and epithelial barrier function, whereas cysteinyl LTs (CysLTs (LTC4, LTD4 and LTE4 induce bronchoconstriction and neutrophil extravasation, and also participate in vascular leakage. PTGs and LTs exert their biological functions by binding to cognate receptors, which belong to the seven transmembrane, G protein-coupled receptor superfamily. SNPs in genes encoding these receptors may influence their functionality and have a role in disease susceptibility and drug treatment response. In this review we summarize SNPs in PTGs and LTs receptors and their relevance in human diseases. We also provide information on gene expression. Finally, we speculate on future directions for this topic.

Beta radiation induced luminescence of polycrystalline Cu-doped Li{sub 2}B{sub 4}O{sub 7}

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Cruz-Zaragoza, E., E-mail: ecruz@nucleares.unam.mx [Instituto de Ciencias Nucleares, Universidad Nacional Autónoma de México, A.P. 70543, México D.F. 04510, México (Mexico); Furetta, C. [Instituto de Ciencias Nucleares, Universidad Nacional Autónoma de México, A.P. 70543, México D.F. 04510, México (Mexico); Marcazzó, J.; Santiago, M. [Instituto de Física Arroyo Seco (UNCPBA) and CIFICEN (UNCPBA – CICPBA – CONICET), Pinto 399, 7000 Tandil (Argentina); Guarneros, C. [Centro de Investigación en Ciencia y Tecnología Avanzada- IPN, Carretera Puerto Industrial Altamira Km 14.5, 896000 Altamira, Tamaulipas, México (Mexico); Consejo Nacional de Ciencia y Tecnología, Av. Insurgentes Sur 1582, 03940 México D.F., México (Mexico); Pacio, M. [Centro de Investigación en Dispositivos Semiconductores, Instituto de Ciencias Universidad Autónoma de Puebla, Av. 14 Sur, 72570 Puebla, México (Mexico); Palomino, R. [Facultad de Ciencias Físico-Matemáticas, Benemérita Universidad Autónoma de Puebla, Av. San Claudio y 18 Sur, 72570 Puebla, México (Mexico)

2016-11-15

Thermoluminescence (TL) and radioluminescence (RL) properties of polycrystalline lithium tetraborate (Li{sub 2}B{sub 4}O{sub 7}) doped with different concentrations of copper (0.25, 0.5, 1 wt %) under beta irradiation have been investigated. The feasibility of using this borate in radiation dosimetry at low doses has been evaluated. Tissue equivalent Li{sub 2}B{sub 4}O{sub 7} was prepared by solid state reaction using mixing stoichiometric compositions of lithium carbonate (Li{sub 2}CO{sub 3}) and boric acid (H{sub 3}BO{sub 3}) and a solution of CuCl{sub 2} as dopant. The glow curve of the most efficient copper doped borate (Li{sub 2}B{sub 4}O{sub 7}:Cu 0.5 wt %) shows a main stable peak centered at 225 °C and a second low temperature peak centered at 80 °C. The low temperature peak fades completely after 24 h of storage in darkness and at room temperature or after an annealing at 120 °C for 10 s. The main peak of the Li{sub 2}B{sub 4}O{sub 7}:Cu remains constant. The TL response of Li{sub 2}B{sub 4}O{sub 7}:Cu shows good linearity in the analyzed dose range. The stability and repeatability of RL signals of the borate have been studied and the Li{sub 2}B{sub 4}O{sub 7}:Cu (0.5 wt %) shows the higher RL emission and a stable and repetitive response. Results show that polycrystalline Li{sub 2}B{sub 4}O{sub 7}:Cu has prospects to be used in beta radiation dosimetry. - Highlights: • Polycrystalline Cu-doped lithium tetraborate (LTB) was obtained by high temperature solid state reaction. • Beta-irradiated LTB:Cu (0.5 wt %) showed to have the highest TL and RL response. • A very good TL linearity in the dose range from 0.01 up to 100 Gy was obtained. • No fading is observed when an annealing at 120 °C for 10 s is carried out. • Results show that LTB:Cu has good prospects to be used in beta radiation dosimetry.

Urinary Leukotriene E4 Is Associated with Renal Function but Not with Endothelial Function in Type 2 Diabetes

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Arnar Rafnsson

2013-01-01

Full Text Available Leukotrienes are inflammatory and vasoactive mediators implicated in endothelium-dependent relaxations and atherosclerosis. Urinary leukotriene E4 (U-LTE4 is a validated disease marker of asthma and increases also in diabetes and acute coronary syndromes. The aim of the present study was to evaluate the association of U-LTE4 and CRP with endothelial function. Urine samples were obtained from 30 subjects (80% males; median age 65 with type 2 diabetes of at least two years duration and a median glomerular filtration rate (eGFR of 71 (14–129 mL/min. Reactive hyperemia index (RHI was used as a measure of microvascular endothelial function, whereas macrovascular endothelial function was determined be means of flow-mediated dilatation of the brachial artery (FMD. Decreased renal function was associated with lower concentrations of U-LTE4. In addition, U-LTE4 was correlated with serum creatinine (R=−0.572; P=0.001 and eGFR (R=0.517; P=0.0036. A stepwise multiple linear regression analysis identified eGFR as an independent predictor of U-LTE4 concentrations. In conclusion, the present results did not establish an association of U-LTE4 with endothelial dysfunction. However, eGFR was an independent predictor of U-LTE4, but not CRP, in this cohort, suggesting that GFR should be considered in biomarker studies of U-LTE4.

Endogenous leukotriene formation during anaphylactic shock

International Nuclear Information System (INIS)

Keppler, A.; Oerning, L.; Bernstroem, K.; Hammarstroem, S.

1987-01-01

Leukotriene (LT)C 4 is a biologically active substance, presumed to play major roles as a mediator of allergic and anaphylactic reactions. It is formed e.g. by basophilic and eosinophilic leukocytes, monocytes, macrophages, and mast cells. In cells having IgE receptors, bridging of these by divalent anti-IgE-receptor antibodies or by interaction between receptor-bound IgE and anti-IgE will induce LTC 4 formation. Leukotriene formation has also been demonstrated in other in vitro models of immediate hypersensivity. The biological actions of LTC 4 , comprise induction of airway obstruction, constriction of coronary arteries, hypotension, and plasma extravasation. Leukotriene formation in vivo may mediate anaphylactic shock symptoms and cause the death of an animal. In order to prove the presumed mediator role of this substance in anaphylactic reactions, it is necessary to demonstrate its endogenous formation during shock. Studies on the metabolism of LTC 4 have revealed rapid catabolism by various transformations of the peptide substituent. Recently, three metabolites were demonstrated to be excreted as end-products in man (LTE 4 ,) and the rat (N-acetyl LTE 4 and N-acetyl 11-trans LTE 4 ). By monitoring biliary N-acetyl LTE 4 levels, endogenous leukotriene formation in the rat was demonstrated in vivo after tissue trauma and endotoxin shock. We now wish to report evidence for endogenous leukotriene C 4 production during anaphylactic shock in guinea pigs. 37 refs. (author)

Effects of lactose as an inducer on expression of Helicobacter pylori rUreB and rHpaA,and Escherichia colirLTKA63 and rLTB

Institute of Scientific and Technical Information of China (English)

Jie Yan; Shou-Feng Zhao; Ya-Fei Mao; Yi-Hui Luo

2004-01-01

AIM: To demonstrate the effect of lactose as an inducer on expression of the recombinant proteins encoded by Helicobacter pylori ureB and hpaA, and Escherichia coli LTB and LTKA63 genes and to determine the optimal expression parameters.METHODS: By using SDS-PAGE and BIO-RAD gel image analysis system, the outputs of the target recombinant proteins expressed by pET32a-ureB-E. coliBL21, pET32ahpaA-E. coliBL21, pET32a-L TKA63-E. coliBL21 and pET32aLTB-E.coliBL21 were measured when using lactose as inducer at different dosages, original bacterial concentrations,various inducing temperatures and times. The results of the target protein expression induced by lactose were compared to those by isopropyl-β-D-thiogalactoside (IPTG).The proteins were expressed in E.coli.RESULTS: Lactose showed higher efficiency of inducing the expression of rHpaA, rUreB, rLTB and rLTKA63 than IPTG. The expression outputs of the target recombinant proteins induced at 37 ℃ were remarkably higher than those at 28 ℃. Other optimal expression parameters for the original bacterial concentrations, dosages of lactose and inducing time were 0.8, 50 g/L and 4 h for rHpaA; 0.8, 100 g/L and 4 h for rLTKA63; 1.2, 100 g/Land 5 h for both rUreB and rLTB, respectively.CONCLUSION: Lactose, a sugar with non-toxicity and low cost, is able to induce the recombinant genes to express the target proteins with higher efficiency than IPTG. The results in this study establish a beneficial foundation for industrial production of H pylori genetic engineering vaccine.

Contact Lens-Induced Discomfort and Inflammatory Mediator Changes in Tears.

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Masoudi, Simin; Zhao, Zhenjun; Stapleton, Fiona; Willcox, Mark

2017-01-01

Studies indicate that contact lens (CL) discontinuation mostly occurs because of dryness and discomfort symptoms. This study aimed to investigate relationships between changes in the concentration of tear inflammatory mediators with subjective comfort ratings with CL wear and no contact lens wear between morning and evening. Forty-five subjects collected tears twice daily in the morning and in the evening with or without lenses. Comfort was rated subjectively on a scale from 1 to 100 (where 100 was extremely comfortable) just before each tear collection. Tear samples were assayed for complement components (C3 and C3a), leukotriene B4 (LTB4), secretory phospholipase A2 (sPLA2), secretory immunoglobulin A (sIgA), and bradykinin using commercially available immuno-based assay kits. Comfort ratings showed a statistically significant decline from morning to evening both with CL (89.0±10.1 AM vs. 76.7±15.2 PM; P0.05). Leukotriene B4 levels were slightly higher in CL (CL 43.4±12.6 pg/ml vs. No CL 39.4±13.4 pg/mL; P=0.034), whereas the concentration of LTB4, C3, C3a, and sIgA dropped by the end of the day in the presence or absence of lens wear (Ptear levels were not correlated with comfort ratings in any of the conditions. Leukotriene B4 had a higher concentration in the evening, and when measured as a ratio to sIgA, there was a trend for increased concentration of this mediator during CL wear. Although specific mediators showed changes from morning to evening with and without lens wear, most of these were not correlated with subjective comfort ratings in lens wear. The only mediator that showed an increase in concentration during the day and during lens wear was LTB4, and further studies on this mediator are warranted.

Significance of production of peptide leukotrienes in murine traumatic shock

International Nuclear Information System (INIS)

Craft, D.V.; Lefer, D.J.; Hock, C.E.; Lefer, A.M.

1986-01-01

The authors studied the formation of a leukotriene metabolite in plasma and bile during traumatic shock. Anesthetized rats subjected to Noble-Collip drum trauma developed a lethal shock state characterized by a survival time of 1.9 +/- 0.3h, a 4.5-fold increase in plasma cathepsin D activity, and a reduction in mean arterial blood pressure to 45 +/- 2 mmHg compared with 108 +/- 5 mmHg in sham-shock controls. Plasma and bile samples were analyzed by reverse-phase high-pressure liquid chromatography (HPLC) for peptide leukotrienes, and their retention times were confirmed by co-elution with radioactive standards, radioimmunoassay (RIA), and UV spectrophotometry. No leukotrienes or metabolites were found in plasma. The major peptide leukotriene from bile was eluted between LTC 4 and LTD 4 and corresponds to a metabolite of LTE 4 , N-acetyl-LTE 4 , which is also produced during endotoxin shock. The metabolite increased nearly sevenfold in traumatic shock compared with sham trauma. The identity of the metabolite was confirmed by UV scan, which revealed a spectrum consistent with a peptide leukotriene and similar to that of previously reported spectra for N-acetyl-LTE 4 . In conclusion, peptide leukotrienes are rapidly cleared from the blood and appear in the bile as N-acetyl-LTE 4 , a metabolite of the peptide leukotrienes. These findings support a role of the peptide leukotrienes in the pathogenesis of traumatic shock

The anti-inflammatory effect of montelukast, a cysteinyl leukotriene receptor-1 antagonist, against estradiol-induced nonbacterial inflammation in the rat prostate.

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Said, Mahmoud M; Bosland, Maarten C

2017-02-01

There is no standard treatment of chronic nonbacterial prostatitis in humans. The current study was aimed to investigate the effect of montelukast, an antagonist of cysteinyl leukotriene receptor-1, against estrogen-induced, nonbacterial lateral lobe-specific prostate inflammation in rats. Male Wistar rats were randomized into five groups of six rats, including sham controls (group 1) and castrated rats (group 2), whereas nonbacterial prostatitis (NBP) was induced in groups 3-5 by castration followed by a daily subcutaneous injection of estradiol (0.25 mg/kg body weight) for 30 days. The rats were left otherwise untreated (group 3) or received a daily oral administration of montelukast (1 and 10 mg/kg body weight for groups 4 and 5, respectively) from the 17th day after castration for two consecutive weeks. Compared with sham controls, induction of NBP led to a significant increase in serum leukotriene B 4 (LTB4), tumor necrosis factor alpha (TNF-α), and interleukin 6 (IL-6) levels, along with a significant upregulation in the transcript level of proinflammatory molecules (nuclear factor kappa beta [NF-κβ] and inducible nitric oxide synthase [iNOS]), chemokines (monocyte chemoattractant protein-1 [MCP-1] and eotaxin), and E-selectin in the lateral prostate. Histological examination revealed intense inflammation in the prostate with leukocyte infiltration and acinar degeneration following estradiol treatment of castrated rats. Montelukast significantly suppressed the increase in serum and prostate proinflammatory mediators/chemokines expression and abolished the histologically inflammatory changes in the lateral prostate. These findings indicate that montelukast inhibits estradiol-induced NBP in a rat model through anti-inflammatory mechanisms, suggesting its future beneficial effect for the treatment of clinical chronic NBP.

Cysteinyl leukotrienes C4 and D4 downregulate human mast cell expression of toll-like receptors 1 through 7.

Science.gov (United States)

Karpov, V; Ilarraza, R; Catalli, A; Kulka, M

2018-01-01

Cysteinyl leukotrienes (CysLT) are potent inflammatory lipid molecules that mediate some of the pathophysiological responses associated with asthma such as bronchoconstriction, vasodilation and increased microvascular permeability. As a result, CysLT receptor antagonists (LRA), such as montelukast, have been used to effectively treat patients with asthma. We have recently shown that mast cells are necessary modulators of innate immune responses to bacterial infection and an important component of this innate immune response may involve the production of CysLT. However, the effect of LRA on innate immune receptors, particularly on allergic effector cells, is unknown. This study determined the effect of CysLT on toll-like receptor (TLR) expression by the human mast cell line LAD2. Real-time PCR analysis determined that LTC4, LTD4 and LTE4 downregulated mRNA expression of several TLR. Specifically in human CD34+-derived human mast cells (HuMC), LTC4 inhibited expression of TLR1, 2, 4, 5, 6 and 7 while LTD4 inhibited expression of TLR1-7. Montelukast blocked LTC4-mediated downregulation of all TLR, suggesting that these effects were mediated by activation of the CysLT1 receptor (CysLT1R). Flow cytometry analysis confirmed that LTC4 downregulated surface expression of TLR2 which was blocked by montelukast. These data show that CysLT can modulate human mast cell expression of TLR and that montelukast may be beneficial for innate immune responses mediated by mast cells.

Phase I Studies of Acebilustat: Pharmacokinetics, Pharmacodynamics, Food Effect, and CYP3A Induction.

Science.gov (United States)

Elborn, J S; Bhatt, L; Grosswald, R; Ahuja, S; Springman, E B

2017-01-01

Acebilustat is a new once-daily oral antiinflammatory drug in development for treatment of cystic fibrosis (CF) and other diseases. It is an inhibitor of leukotriene A4 hydrolase; therefore, production of leukotriene B4 (LTB4) in biological fluids provides a direct measure of the pharmacodynamic (PD) response to acebilustat treatment. Here we compare the pharmacokinetics (PK) and PD between CF patients and healthy volunteers, and investigate the food effect and CYP3A4 induction in healthy volunteers. No significant differences between study populations were observed for peak plasma level (C max ) or exposure (AUC). In healthy volunteers, a shift in time to C max (T max ) was observed after a high-fat meal, but there was no change in AUC. LTB4 production was reduced in the blood of both populations and in sputum from CF patients. Acebilustat did not induce CYP3A4. These results support continued clinical study of once-daily oral acebilustat in CF at doses of 50 and 100 mg. © 2016 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Studies on shallow traps in Li2B4O7:Eu,Mn

International Nuclear Information System (INIS)

Drozdowski, Winicjusz; Brylew, Kamil; Kaczmarek, Sławomir M.; Piwowarska, Danuta; Nakai, Yosuke; Tsuboi, Taiju; Huang, Wei

2014-01-01

Li 2 B 4 O 7 (LTB) single crystals doped with 0.5 mol% Mn and 0.005 mol% Eu have been grown by the Czochralski method. The presence of Eu 3+ has been confirmed by photoluminescence spectra of non-irradiated crystals, whereas the presence of Mn 2+ by absorption spectra of gamma-irradiated ones, as well as by EPR measurements. Unlike in most thermoluminescence studies on pure and doped LTB, performed usually above 300 K, glow curves have been recorded between 10 and 300 K in order to focus the attention on shallow traps. A broad, intense glow peak is observed around 80 K, with three weaker peaks at 205, 255, and 280 K. Based on supplementary T max  − T stop experiments, the trap parameters have been derived assuming that the glow curve is in fact formed by a superposition of a double Gaussian band related to a quasi-continuous distribution of trapping levels, and several glow peaks produced by discrete traps. The nature of the traps is also discussed. - Highlights: • Radioluminescence spectra of LTB:Eu,Mn have been measured at various temperatures. • Glow curves of LTB:Eu,Mn have been recorded between 10 and 300 K. • Thermoluminescence studies have been extended with the T max  − T stop method. • Trap parameters related to particular glow peaks have been derived. • Besides discrete traps a quasi-continuous distribution has been found

Non-invasive biomarkers and pulmonary function in smokers

OpenAIRE

Borrill, Zo? L; Roy, Kay; Vessey, Rupert S; Woodcock, Ashley A; Singh, Dave

2008-01-01

Zoë L Borrill1, Kay Roy1, Rupert S Vessey2, Ashley A Woodcock1, Dave Singh11Medicines Evaluation Unit, University of Manchester, Wythenshawe Hospital, Southmoor Rd, Manchester, UK; 2Glaxo Smith Kline, Philadelphia, USAAbstract: Limited information exists regarding measurement, reproducibility and interrelationships of non-invasive biomarkers in smokers. We compared exhaled breath condensate (EBC) leukotriene B4 (LTB4) and 8-isoprostane, exhaled nitric oxide, induced sputum, spirometr...

Pharmacological inhibition of eicosanoid synthesis and hyperalgesia in yeast-injected rat paws

International Nuclear Information System (INIS)

Opas, E.E.; Dallob, A.; Herold, E.; Luell, S.; Humes, J.L.

1986-01-01

Brewer's yeast caused an inflammation characterized by edema and hyperalgesia when injected into the hindpaw of a rat. These events were temporally distinct and each was associated with increases of specific arachidonic and oxygenation products. As determined by radioimmunoassay (RIA) on whole paw lipid extracts, the 5-lipoxygenase (5-LO) products, leukotrienes C 4 and D 4 and 5-hydroxyeicosatetraendic acid (5-HETE) were synthesized concurrently with the onset of edema (maximal at 15 minutes after yeast injection). The hyperalgesic phase of the inflammation (3-4 hr after yeast injection) was associated with increased tissue levels of the cyclooxygenase (CO) products, prostaglandin E 2 and thromboxane B 2 (TXB 2 ) as well as increases in levels of the 5-LO products, leukotriene B 4 (LTB 4 ) and 5-HETE. Pharmacological agents modulated the synthesis of eicosanoids and suppressed the hyperalgesic response

[Leukotriene antagonists: a new approach in the treatment of asthma].

Science.gov (United States)

Devillier, P; Bessard, G; Advenier, C

1997-06-01

Inflammation plays an essential role in the genesis of airflow obstruction and bronchial hyper-reactivity in the early stages of clinical asthma. The treatment of bronchial inflammation has become an essential element in the therapeutic strategy and principally rests on inhaled glucocorticoids. Amongst a number of inflammatory mediators leukotrienes occupy a privileged place by the power of their inflammatory and constrictor effects on bronchial smooth muscles. These properties have justified the clinical development of inhibitors of their synthesis and of specific antagonists to their receptors. Leukotriene antagonists are specific for a sub type of leukotriene receptors C4, D4 and E4 which is implicated in the majority of the bronchial constrictor and inflammatory effects of leukotrienes. The antagonists of Cys-LT1 receptor but also the inhibitors of the leukotriene synthesis exert an additive bronchodilator effect to those of B2 stimulants confirming an efficacious protection vis a vis bronchial provocation tests and above all they improve the clinical scores, lung function and also enable a decrease in the consumption of beta 2 agonists. The marketing of these products represents a major event because it corresponds to the advent of a new therapeutic class. The ease of administration by the oral route, their demonstrated efficacy and their good tolerance profile (in particular for ICI 204.219, and antagonists to Cys-LT1 receptors) are elements which foresee a success for this new asthmatic treatment. However numerous studies, notably comparative studies vis a vis reference treatments will be necessary to define their place in the strategic approach to the treatment of asthma.

Modulation of Polymorphonuclear Neutrophil Response to N-formyl-l-methionyl-l-leucyl-l-phenylalanine

Science.gov (United States)

1988-11-10

acid. This paradox remains · unresolved, but it is attractive to postulate that circumstances exist where PMNs release potent mediators such as LTB 4...Panel A represents 1· n.YI A2318i pretreatment.. panel B ’I ::· ,. r epre ~ent s 10 n\\1 A2318i pretreatment and panel C represents 100 n\\I : t... Paradox : Neutrophile Can, But Will Not, Respond to Ligand-Receptor Interactions by Forming Leukotriene B4 or it Metab olites. Biochem. J., 241:55

Effect of chitosan and coagulation factors on the wound repair phenotype of bioengineered blood clots.

Science.gov (United States)

Hoemann, Caroline D; Marchand, Catherine; Rivard, Georges-Etienne; El-Gabalawy, Hani; Poubelle, Patrice E

2017-11-01

Controlling the blood clot phenotype in a surgically prepared wound is an evolving concept in scaffold-guided tissue engineering. Here, we investigated the effect of added chitosan (80% or 95% Degree of Deacetylation, DDA) or coagulation factors (recombinant human Factor VIIa, Tissue Factor, thrombin) on inflammatory factors released by blood clots. We tested the hypothesis that 80% DDA chitosan specifically enhances leukotriene B 4 (LTB 4 ) production. Human or rabbit whole blood was combined with isotonic chitosan solutions, coagulation factors, or lipopolysaccharide, cultured in vitro at 37°C, and after 4hours the serum was assayed for LTB 4 or inflammatory factors. Only 80% DDA chitosan clots produced around 15-fold more LTB 4 over other clots including 95% DDA chitosan clots. All serum contained high levels of PDGF-BB and CXCL8. Normal clots produced very low type I cytokines compared to lipopolysaccharide clots, with even lower IL-6 and IL-12 and more CCL3/CCL4 produced by chitosan clots. Coagulation factors had no detectable effect on clot phenotype. Conclusion In blood clots from healthy individuals, 80% DDA chitosan has a unique influence of inducing more LTB 4 , a potent neutrophil chemoattractant, with similar production of PDGF-BB and CXCL8, and lower type I cytokines, compared to whole blood clots. Copyright © 2017 Elsevier B.V. All rights reserved.

ENVIRONMENTAL TECHNOLOGY VERIFICATION REPORT LASER TOUCH AND TECHNOLOGIES, LLC LASER TOUCH MODEL LT-B512

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The Environmental Technology Verification report discusses the technology and performance of Laser Touch model LT-B512 targeting device manufactured by Laser Touch and Technologies, LLC, for manual spray painting operations. The relative transfer efficiency (TE) improved an avera...

Verification of the production of peptide leukotrienes (LT) in traumatic shock

International Nuclear Information System (INIS)

Hock, C.E.; Craft, D.V.; Lefer, D.J.; Lefer, A.M.

1986-01-01

Both lipoxygenase inhibition and leukotriene receptor antagonism have been demonstrated to provide significant protection in traumatic shock. Despite these findings, leukotrienes have not been found in circulating blood in Noble-Collip drum induced traumatic shock using radioimmunoassay techniques. Anesthetized rats subjected to Noble-Collip drum trauma developed a shock state characterized by a significant reduction in mean arterial blood pressure, a 4.5 fold increase in plasma cathepsin D activity, a 3-fold increase in myocardial depressant factor activity and a mean survival time of 1.9 +/- 0.3 hours. Plasma and bile samples were analyzed by reverse phase high pressure liquid chromatography to determine LT production in this shock model. No detectable peptide leukotrienes or their metabolites were found in plasma. The major peptide leukotriene from bile eluted between LTC 4 and LTD 4 and corresponds to a metabolite of LTE 4 , N-acetyl-LTE 4 . This metabolite increased from 6 +/- 3 to 41 +/- 4 units in traumatic shock when compared to sham trauma (p 4 , LTD 4 and LTE 4 (10 μg/kg/h) also resulted in the metabolism of > 90% of the parent LT to this metabolite in bile. Therefore, plasma LTs accumulate in the bile following trauma in rats. Moreover, LTC 4 , LTD 4 and LTE 4 apparently are rapidly metabolized to N-acetyl LTE 4 . These findings further support a role for leukotrienes in the pathogenesis of traumatic shock in rats

BLT1-mediated O-GlcNAcylation is required for NOX2-dependent migration, exocytotic degranulation and IL-8 release of human mast cell induced by Trichomonas vaginalis-secreted LTB4.

Science.gov (United States)

Min, Arim; Lee, Young Ah; Kim, Kyeong Ah; Shin, Myeong Heon

2018-05-31

Trichomonas vaginalis is a sexually-transmitted protozoan parasite that causes vaginitis and cervicitis. Although mast cell activation is important for provoking tissue inflammation during infection with parasites, information regarding the signaling mechanisms in mast cell activation and T. vaginalis infection is limited. O-linked N-acetylglucosamine (O-GlcNAc) is a post-translational modification of serine and threonine residues that functions as a critical regulator of intracellular signaling, regulated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). We investigated if O-GlcNAcylation was associated with mast cell activation induced by T. vaginalis-derived secretory products (TvSP). Modified TvSP collected from live trichomonads treated with the 5-lipooxygenase inhibitor AA861 inhibited migration of mast cells. This result suggested that mast cell migration was caused by stimulation of T. vaginalis-secreted leukotrienes. Using the BLT1 antagonist U75302 or BLT1 siRNA, we found that migration of mast cells was evoked via LTB 4 receptor (BLT1). Furthermore, TvSP induced protein O-GlcNAcylation and OGT expression in HMC-1 cells, which was prevented by transfection with BLT1 siRNA. TvSP-induced migration, ROS generation, CD63 expression and IL-8 release were significantly suppressed by pretreatmemnt with OGT inhibitor ST045849 or OGT siRNA. These results suggested that BLT1-mediated OGlcNAcylation was important for mast cell activation during trichomoniasis. Copyright © 2018. Published by Elsevier Masson SAS.

Simultaneous initiation of degranulation and inhibition of leukotriene release by soman in human basophils

Energy Technology Data Exchange (ETDEWEB)

Meier, H.L.; Warner, J.; MacGlashan, D.W.

1995-12-31

Previous studies noted that the serine esterase inhibitor, soman, could induce histamine release from human basophils. To investigate the mechanisms by which soman causes histamine release (a preformed mediator), we also examined its ability to induce leukotriene release (a newly synthesized mediator) from basophils. We found that no leukotriene release followed activation with soman, while histamine release was usually greater than 70%. In addition, soman and diisopropyl-fluorophosphate were found actively to suppress low level spontaneous leukotriene release as well as ongoing leukotriene release induced by anti-IgE antibody. Soman (0.3 mM) was able to stop leukotriene release as rapidly as the calcium chelator, EDTA. In a series of control experiments, it was noted that soman did not influence the metabolism of LTC4 to LTD4 or LTE4 (for which little metabolism occurred), eliminating the possibility that reduced LTC4 release could have resulted from its enhanced metabolism. Therefore, using one compound (soman), basophils could be simultaneously activated to degranulate while having the pathway leading to leukotriene release actively suppressed. These results provide further evidence that histamine and leukotriene release are independent pathways resulting from the activation of basophils.

Determination of thromboxanes, leukotrienes and lipoxins using high-temperature capillary liquid chromatography-tandem mass spectrometry and on-line sample preparation

DEFF Research Database (Denmark)

Dahl, Sandra Rinne; Kleiveland, Charlotte Ramstad; Kassem, Moustapha

2009-01-01

An on-line strong cation-exchange (SCX)-reversed-phase (RP) capillary liquid chromatographic (cLC) method with ion-trap tandem mass spectrometric (IT-MS/MS) detection for the simultaneous determination of thromboxane (TX) B(2), TXB(3), leukotriene (LT) B(4), LTD(4) and lipoxin (LX) A(4) in cell...

Immune responses of a chimaeric protein vaccine containing Mycoplasma hyopneumoniae antigens and LTB against experimental M. hyopneumoniae infection in pigs.

Science.gov (United States)

Marchioro, Silvana B; Sácristan, Rubén Del Pozo; Michiels, Annelies; Haesebrouck, Freddy; Conceição, Fabricio R; Dellagostin, Odir A; Maes, Dominiek

2014-08-06

A recombinant chimaeric protein containing three Mycoplasma hyopneumoniae antigens (C-terminal portion of P97, heat shock protein P42, and NrdF) fused to an adjuvant, the B subunit of heat-labile enterotoxin of Escherichia coli (LTB), was used to immunize pigs against enzootic pneumonia. The systemic and local immune responses, as well as the efficacy of the chimaeric protein in inducing protection against experimental M. hyopneumoniae infection were evaluated. In total, 60 male piglets, purchased from a M. hyopneumoniae-free herd, at 4 weeks of age were randomly allocated to six different experimental groups of 10 animals each: recombinant chimaeric protein by intramuscular (IM) (1) or intranasal (IN) (2) administration, commercial bacterin by IM administration (3), and the adjuvant LTB by IM (4, control group A) or IN (5, control group B) administration. All groups were immunized at 24 and 38 days of age and challenged at 52 days of age. The sixth group that was not challenged was used as the negative control (IN [n=5] or IM [n=5] administration of the LTB adjuvant). Compared with the non-challenged group, administration of the chimaeric protein induced significant (Phyopneumoniae infection in pigs. This lack of effectiveness points towards the need for further studies to improve the efficacy of this subunit-based vaccine approach. Copyright © 2014 Elsevier Ltd. All rights reserved.

Effects of carnitine and its congeners on eicosanoid discharge from rat cells: implications for release of TNFα

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Ingrid M. Garrelds

1993-01-01

Full Text Available THE acyl carrier coenzyme A (CoA is involved in fatty acid metabolism. The carnitine/CoA ratio is of particular importance in regulating the transport of long-chain fatty acids into mitochondria for oxidation. Also CoA has a role in the formation and breakdown of products from both the cyclooxygenase and lipoxygenase pathways of the precursor arachidonic acid. In the present study the effect of 4 days feeding of 300 mg/kg/day of L-carnitine, acetyl Lcarnitine and propionyl L-carnitine on the basal and calcium ionophore (A23187 stimulated release of arachidonic acid metabolites from rat carrageenin elicited peritoneal cells was investigated. There were two series of experiments carried out. In the first, the harvested peritoneal cell population consisted of less than 90% macrophages and additional polymorphonuclear (PMN leucocytes. The basal release of prostaglandin E2 (PGE2, 6-ketoprostaglandin F1α (6-keto-PGF1α and leukotriene B4 (LTB4 was stimulated by all treatments. The A23187 stimulated release of 6-keto-PGF1α and LTB4 was increased by all three compounds. The 6-keto-PGF1α:TxB2 and 6-keto-PGF1α:LTB4 ratios were increased by carnitine treatment. These results suggested that carnitine could modify the macrophage component of an inflammatory site in vivo. In the second series of experiments the harvested cell population was highly purified (>95% macrophages and none of the compounds fed to the rats caused a change of either eicosanoid or TNFα formation. Moreover the 6-keto-PGF1α:TxB2 and 6-keto-PGF1α:LTB4 ratios were not enhanced by any of the compounds tested. It is conceivable that in the first series the increased ratios 6-keto-PGF1α:TxB2 and 6-keto-PGF1α:LTB4 reflected the effect of carnitine or its congeners on PMN leucocytes rather than on macrophages.

The chemotactic activity of sputum from patients with bronchiectasis.

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Mikami, M; Llewellyn-Jones, C G; Bayley, D; Hill, S L; Stockley, R A

1998-03-01

Persistent polymorphonuclear neutrophil (PMN) recruitment to airway is thought to be an important component of continuing inflammation and progression of chronic destructive lung diseases. Although chemoattractants are required for the PMN to migrate, the nature of the chemoattractants in the airways has not yet been clarified. We therefore investigated the contribution of interleukin-8 (IL-8) and leukotriene-B4 (LTB4) to the chemotactic activity of lung secretions by inhibiting their activity using a monoclonal antibody to IL-8 and an LTB4 receptor antagonist (LY293111 sodium). Fifty-nine sputum samples obtained from 19 patients with bronchiectasis were studied. In preliminary studies the chemotactic responses to IL-8 and LTB4 were found to be additive, and we were able to remove their contribution independently with the appropriate antibody and antagonist. The chemotactic activity of the secretions was related to the macroscopic appearance (mucoid, mucopurulent, and purulent), and this appeared to be related to an increase in IL-8 contribution. Chemotactic activity was reduced by antibiotic therapy and again that seemed to relate to a reduction in the IL-8 contribution. The contributions of LTB4 were similar among the three types of sputum in varying clinical states. These data suggest that LTB4 and IL-8 are important chemotactic factors in lung secretions from such patients, although IL-8 appears to play a more important role during acute exacerbations. These results may be useful in determining therapeutic strategies for chronic destructive lung diseases in the future.

Cathodoluminescence and Thermoluminescence of Undoped LTB and LTB:A (A = Cu, Ag, Mn)

Science.gov (United States)

2013-03-01

and Mn Ions for Nonlinear Applications.” Acta Physica Polonica A 107, no. 3 (2005): 507-518. [22] Kimball Physics, Inc.. Operator’s Manual: EMG...CATHODOLUMINESCENCE AND THERMOLUMINESCENCE OF UNDOPED LTB AND LTB:A ( A = Cu, Ag, Mn) THESIS Zachary L. Hadfield, USA AFIT-ENP-13-M-13...STATEMENT A . APPROVED FOR PUBLIC RELEASE; DISTRIBUTION UNLIMITED The views expressed in this thesis are those of the author and

Influence of leukotriene gene polymorphisms on chronic rhinosinusitis

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Duval Melanie

2008-03-01

Full Text Available Abstract Background Chronic rhinosinusitis (CRS is increasingly viewed as an inflammatory condition of the sinonasal mucosa interacting with bacteria and/or fungi. However, factors conferring susceptibility to disease remain unknown. Advances in genomics offer powerful tools to explore this disorder. The goal of this study was to evaluate the effect of single nucleotide polymorphisms (SNP on CRS in a panel of genes related to cysteinyl leukotriene metabolism. Methods Severe cases of CRS and postal code match controls were recruited prospectively. A total of 206 cases and 200 controls were available for the present study. Using a candidate gene approach, five genes related to cysteinyl leukotriene metabolism were assessed. For each gene, we selected the maximally informative set of common SNPs (tagSNPs using the European-derived (CEU HapMap dataset. These SNPs are in arachidonate 5-lipoxygenase (ALOX5, arachidonate 5-lipoxygenase-activating protein (ALOX5AP, leukotriene C4 synthase (LTC4S, cysteinyl leukotriene receptor 1 (CYSLTR1 and cysteinyl leukotriene receptor 2 (CYSLTR2 genes. Results A total of 59 SNPs were genotyped to capture the common genetic variations within these genes. Three SNPs located within the ALOX5, CYSLTR1 and ALOX5AP genes reached the nominal p-value threshold (p Conclusion While these initial results do not support that polymorphsims in genes assessed involved in the leukotriene pathways are contributing to the pathogenesis of CRS, this initial study was not powered to detect polymorphisms with relative risk of 2.0 or less, where we could expect many gene effects for complex diseases to occur. Thus, despite this lack of significant association noted in this study, we believe that validation with external populations and the use of better-powered studies in the future may allow more conclusive findings.

Cysteinyl leukotriene E4 activates human group 2 innate lymphoid cells and enhances the effect of prostaglandin D2 and epithelial cytokines.

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Salimi, Maryam; Stöger, Linda; Liu, Wei; Go, Simei; Pavord, Ian; Klenerman, Paul; Ogg, Graham; Xue, Luzheng

2017-10-01

Group 2 innate lymphoid cells (ILC2s) are a potential innate source of type 2 cytokines in the pathogenesis of allergic conditions. Epithelial cytokines (IL-33, IL-25, and thymic stromal lymphopoietin [TSLP]) and mast cell mediators (prostaglandin D 2 [PGD 2 ]) are critical activators of ILC2s. Cysteinyl leukotrienes (cysLTs), including leukotriene (LT) C 4 , LTD 4 , and LTE 4 , are metabolites of arachidonic acid and mediate inflammatory responses. Their role in human ILC2s is still poorly understood. We sought to determine the role of cysLTs and their relationship with other ILC2 stimulators in the activation of human ILC2s. For ex vivo studies, fresh blood from patients with atopic dermatitis and healthy control subjects was analyzed with flow cytometry. For in vitro studies, ILC2s were isolated and cultured. The effects of cysLTs, PGD 2 , IL-33, IL-25, TSLP, and IL-2 alone or in combination on ILC2s were defined by using chemotaxis, apoptosis, ELISA, Luminex, quantitative RT-PCR, and flow cytometric assays. The effect of endogenous cysLTs was assessed by using human mast cell supernatants. Human ILC2s expressed the LT receptor CysLT 1 , levels of which were increased in atopic subjects. CysLTs, particularly LTE 4 , induced migration, reduced apoptosis, and promoted cytokine production in human ILC2s in vitro. LTE 4 enhanced the effect of PGD 2 , IL-25, IL-33, and TSLP, resulting in increased production of type 2 and other proinflammatory cytokines. The effect of LTE 4 was inhibited by montelukast, a CysLT 1 antagonist. Interestingly, addition of IL-2 to LTE 4 and epithelial cytokines significantly amplified ILC2 activation and upregulated expression of the receptors for IL-33 and IL-25. CysLTs, particularly LTE 4 , are important contributors to the triggering of human ILC2s in inflammatory responses, particularly when combined with other ILC2 activators. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

LTB-R1: an alternative to swine mycoplasmal pneumoniae control LTB-R1: uma alternativa para o controle da pneumonia micoplásmica suína

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Fabrício Rochedo Conceição

2003-11-01

Full Text Available Mycoplasmal pneumoniae is the main respiratory disease in swine. The most efficient way to control it is through the use of vaccines (bacterins, whose production cost is high. The objective of this work was to develop a new alternative for controlling Swine Mycoplasmal Pneumoniae, based on a recombinant subunit vaccine containing the R1 region of P97 adhesin of Mycoplasma hyopneumoniae fused to the B subunit of the heat-labile enterotoxin of Escherichia coli (rLTB-R1. In this work we report the amplification of the genes, genetic fusion between LTB and R1 coding sequences, cloning, construction of the expression vector, as well as expression and purification of rLTB-R1 in E. coli.A Pneumonia Micoplásmica é a doença respiratória mais importante dos suínos. A forma mais eficaz de controlá-la é mediante a utilização de vacinas (bacterinas, cujo custo de produção é elevado. Uma nova alternativa para o controle desta doença, baseada em uma vacina de subunidade recombinante contendo a região R1 da adesina P97 de Mycoplasma hyopneumoniae fusionada a subunidade B da enterotoxina termolábel de Escherichia coli (rLTB-R1, foi o alvo deste trabalho. Nele abordou-se a amplificação dos genes, a fusão genética entre as seqüências codificadoras para LTB e R1, a clonagem, a construção do vetor de expressão, assim como a expressão em E. coli e purificação da rLTBR1.

Acrolein increases 5-lipoxygenase expression in murine macrophages through activation of ERK pathway.

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Kim, Chae E; Lee, Seung J; Seo, Kyo W; Park, Hye M; Yun, Jung W; Bae, Jin U; Bae, Sun S; Kim, Chi D

2010-05-15

Episodic exposure to acrolein-rich pollutants has been linked to acute myocardial infarction, and 5-lipoxygenase (5-LO) is involved in the production of matrix metalloproteinase-9 (MMP-9), which destabilizes atherosclerotic plaques. Thus, the present study determined the effect of acrolein on 5-LO/leukotriene B(4) (LTB(4)) production in murine macrophages. Stimulation of J774A.1 cells with acrolein led to increased LTB(4) production in association with increased 5-LO expression. Acrolein-evoked 5-LO expression was blocked by pharmacological inhibition of the ERK pathway, but not by inhibitors for JNK and p38 MAPK pathways. In line with these results, acrolein exclusively increased the phosphorylation of ERK among these MAPK, suggesting a role for the ERK pathway in acrolein-induced 5-LO expression with subsequent production of LTB(4). Among the receptor tyrosine kinases including epidermal growth factor receptor (EGFR) and platelet derived growth factor receptor (PDGFR), acrolein-evoked ERK phosphorylation was attenuated by AG1478, an EGFR inhibitor, but not by AG1295, a PDGFR inhibitor. In addition, acrolein-evoked 5-LO expression was also inhibited by inhibition of EGFR pathway, but not by inhibition of PDGFR pathway. These observations suggest that acrolein has a profound effect on the 5-LO pathway via an EGFR-mediated activation of ERK pathway, leading to acute ischemic syndromes through the generation of LTB(4), subsequent MMP-9 production and plaque rupture.

Acrolein increases 5-lipoxygenase expression in murine macrophages through activation of ERK pathway

International Nuclear Information System (INIS)

Kim, Chae E.; Lee, Seung J.; Seo, Kyo W.; Park, Hye M.; Yun, Jung W.; Bae, Jin U.; Bae, Sun S.; Kim, Chi D.

2010-01-01

Episodic exposure to acrolein-rich pollutants has been linked to acute myocardial infarction, and 5-lipoxygenase (5-LO) is involved in the production of matrix metalloproteinase-9 (MMP-9), which destabilizes atherosclerotic plaques. Thus, the present study determined the effect of acrolein on 5-LO/leukotriene B 4 (LTB 4 ) production in murine macrophages. Stimulation of J774A.1 cells with acrolein led to increased LTB 4 production in association with increased 5-LO expression. Acrolein-evoked 5-LO expression was blocked by pharmacological inhibition of the ERK pathway, but not by inhibitors for JNK and p38 MAPK pathways. In line with these results, acrolein exclusively increased the phosphorylation of ERK among these MAPK, suggesting a role for the ERK pathway in acrolein-induced 5-LO expression with subsequent production of LTB 4 . Among the receptor tyrosine kinases including epidermal growth factor receptor (EGFR) and platelet derived growth factor receptor (PDGFR), acrolein-evoked ERK phosphorylation was attenuated by AG1478, an EGFR inhibitor, but not by AG1295, a PDGFR inhibitor. In addition, acrolein-evoked 5-LO expression was also inhibited by inhibition of EGFR pathway, but not by inhibition of PDGFR pathway. These observations suggest that acrolein has a profound effect on the 5-LO pathway via an EGFR-mediated activation of ERK pathway, leading to acute ischemic syndromes through the generation of LTB 4 , subsequent MMP-9 production and plaque rupture.

Ligand-induced tyrosine phosphorylation of cysteinyl leukotriene receptor 1 triggers internalization and signaling in intestinal epithelial cells

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Parhamifar, Ladan; Sime, Wondossen; Yudina, Yuliana

2010-01-01

Leukotriene D(4) (LTD(4)) belongs to the bioactive lipid group known as eicosanoids and has implications in pathological processes such as inflammation and cancer. Leukotriene D(4) exerts its effects mainly through two different G-protein-coupled receptors, CysLT(1) and CysLT(2). The high affinit...

Frondanol, a Nutraceutical Extract from Cucumaria frondosa, Attenuates Colonic Inflammation in a DSS-Induced Colitis Model in Mice

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Sandeep B. Subramanya

2018-04-01

Full Text Available Frondanol is a nutraceutical lipid extract of the intestine of the edible Atlantic sea cucumber, Cucumaria frondosa, with potent anti-inflammatory effects. In the current study, we investigated Frondanol as a putative anti-inflammatory compound in an experimental model of colonic inflammation. C57BL/6J male black mice (C57BL/6J were given 3% dextran sodium sulfate (DSS in drinking water for 7 days to induce colitis. The colitis group received oral Frondanol (100 mg/kg body weight/per day by gavage and were compared with a control group and the DSS group. Disease activity index (DAI and colon histology were scored for macroscopic and microscopic changes. Colonic tissue length, myeloperoxidase (MPO concentration, neutrophil and macrophage marker mRNA, pro-inflammatory cytokine proteins, and their respective mRNAs were measured using ELISA and real-time RT-PCR. The tissue content of leukotriene B4 (LTB4 was also measured using ELISA. Frondanol significantly decreased the DAI and reduced the inflammation-associated changes in colon length as well as macroscopic and microscopic architecture of the colon. Changes in tissue MPO concentrations, neutrophil and macrophage mRNA expression (F4/80 and MIP-2, and pro-inflammatory cytokine content (IL-1β, IL-6 and TNF-α both at the protein and mRNA level were significantly reduced by Frondanol. The increase in content of the pro-inflammatory mediator leukotriene B4 (LTB4 induced by DSS was also significantly inhibited by Frondanol. It was thus found that Frondanol supplementation attenuates colon inflammation through its potent anti-inflammatory activity.

Is there a role for leukotrienes as mediators of ethanol-induced gastric mucosal damage?

International Nuclear Information System (INIS)

Wallace, J.L.; Beck, P.L.; Morris, G.P.

1988-01-01

The role of leukotriene (LT) C 4 as a mediator of ethanol-induced gastric mucosal damage was investigated. Rats were pretreated with a number of compounds, including inhibitors of leukotriene biosynthesis and agents that have previously been shown to reduce ethanol-induced damage prior to oral administration of absolute ethanol. Ethanol administration resulted in a fourfold increase in LTC 4 synthesis. LTC 4 synthesis could be reduced significantly by pretreatment with L651,392 or dexamethosone without altering the susceptibility of the gastric mucosa to ethanol-induced damage. Furthermore, changes in LBT 4 synthesis paralleled the changes in LTC 4 synthesis observed after ethanol administration. The effects of ethanol on gastric eicosanoid synthesis were further examined using an ex vivo gastric chamber preparation that allowed for application of ethanol to only one side of the stomach. These studies confirm that ethanol can stimulate gastric leukotriene synthesis independent of the production of hemorrhagic damage. Inhibition of LTC 4 synthesis does not confer protection to the mucosa, suggesting that LTC 4 does not play an important role in the etiology of ethanol-induced gastric damage

Non-genomic action of beclomethasone dipropionate on bronchoconstriction caused by leukotriene C4 in precision cut lung slices in the horse

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Fugazzola Maria

2012-09-01

Full Text Available Abstract Background Glucocorticoids have been proven to be effective in the therapy of recurrent airway obstruction (RAO in horses via systemic as well as local (inhalative administration. Elective analysis of the effects of this drug on bronchoconstriction in viable lung tissue offers an insight into the mechanism of action of the inflammatory cascade occurring during RAO which is still unclear. The mechanism of action of steroids in treatment of RAO is thought to be induced through classical genomic pathways. We aimed at electively studying the effects of the glucocorticoid beclomethasone dipropionate on equine precision-cut lung slices (PCLS. PCLS were used to analyze ex-vivo effects of beclomethasone on inhibiting bronchoconstriction in the horse. The inhibiting effect was measured through instillation of a known mediator of inflammation and bronchoconstriction, leukotriene C4. For this, the accessory lobes of 13 horses subjected to euthanasia for reasons unrelated to the respiratory apparatus were used to obtain viable lung slices. Results After 30 minutes of PCLS incubation, beclomethasone showed to significantly inhibit the contraction of the bronchioles after instillation with leukotriene C4. The EC50 values of the two contraction curves (LTC4 with and without BDP differed significantly from each other (p = 0.002. The possibility of a non-genomic rapid mechanism of action seems likely since transcriptional activities require a longer lag period. Conclusions In human neuroendocrinology, high levels of glucocorticoids have been proven to function via a non-genomic mechanism of membrane receptors. The concentration of beclomethasone used on the lung slices in our study can be considered as high. This allows speculation about similar rapid non-genomic mechanisms of high-dosage inhaled glucocorticoids in the lower airways of horses. However, further assessment on a molecular basis is needed to confirm this.

Protolichesterinic acid, isolated from the lichen Cetraria islandica, reduces LRRC8A expression and volume-sensitive release of organic osmolytes in human lung epithelial cancer cells

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Thorsteinsdottir, Unnur Arna; Thorsteinsdottir, Margret; Lambert, Ian Henry

2016-01-01

/mL, 24 h) has no effect on VSOAC. Hence, length of PA's fatty acid chain adds to γ-lactone's inhibitory action. 5-Lipoxygenase (5-LO) activity is essential for swelling-induced activation of VSOAC. PA has no effect on cellular concentration of leukotrienes (5-HETE/LTB4) under hypotonic conditions...

A Pilot Study: Effects of Dietary Supplementation with α-Linolenic Acid-Enriched Perilla Seed Oil on Bronchial Asthma

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Kozo Ashida

1997-01-01

Full Text Available N-3 fatty acids, such as fish oil, have been reported to have some beneficial effects in patients with bronchial asthma. The effects of dietary supplementation with perilla seed oil rich in a-linolenic acid (α-LNA, parent n-3 fatty acid, were studied in five patients with asthma. The symptoms of asthma and mean peak flow rates (PFR both early in the morning and in the evening were improved 2 weeks after dietary supplementation and the increases in PFR were significant (P<0.05. The generation of leukotriene B4 (LTB4 by peripheral leukocytes stimulated with the Ca2+ ionophore A23187 was significantly suppressed from 77.6 to 41.6 ng/5Xl06 cells by dietary supplementation (P<0.05. The generation of leukotriene C4 (LTC4 by leukocytes was also significantly suppressed from 64.0 to 38.8 ng/5x106 cells after supplementation with perilla seed oil (P<0.05. These results suggest that dietary supplementation with perilla seed oil is beneficial for the treatment of asthma.

Comparison of the effect of timegadine, levamisole, and D-penicillamine on human neutrophil metabolism of endogenous arachidonic acid and chemotaxis

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Nielsen, O.H.; Ahnfelt-Roenne, I. Department of Pharmacology, Leo Pharmaceutical Products, Ballerup; Elmgreen, J.

1988-01-01

The effect of timegadine, a novel experimental antirheumatic drug, on human neutrophil (PMN) 5-lipoxygenase activity and leukotriene B/sub 4/ (LTB/sub 4/) chemotaxis was compared with that of two second-line antiinflammatory drugs, D-penicillamine and levamisole. 1-/sup 14/C-Arachidonic acid (AA) was incorporated into the purified cells until steady state conditions were obtained. After preincubation with serial dilutions of the three drugs, AA release and metabolism was stimulated with calcium ionophore A23187. The radioactive eicosanoids released were extracted and separated by thinlayer chromatography, followed by autoradiography and quantitative laser densitometry. Chemotaxi of PMNs towards LTB/sub 4/ was measured in a modified Boyden chamber. Timegardine showed dose-dependent inhibition of both the 5-lipoxygenase pathway (IC50 3.4 x 10/sup -5/ M), and of chemotaxis (IC50 3 x 10/sup -4/ M). Inhibition of the release of AA from phospholipids, however, occurred only at therapeutically irrelevant doses (millimolar concentrations). Levamisole and D-penicillamine did not inhibit any of the cell functions investigated. Inhibition of both neutrophil motility and cellular synthesis of pro-inflammatory eicosanoids, may thus contribute to the clinical effects of timegadine in rheumatoid arthritis.

SRS-A leukotrienes decrease the activity of human respiratory cilia

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Bisgaard, H; Pedersen, M

1987-01-01

We have studied the effects of the slow reacting substance of anaphylaxis (SRS-A) constituents leukotrienes (LT) C4 and D4 on the ciliary activity of human respiratory cells. The ciliary beat frequency on human nasal cells harvested by cell scraping from the inferior turbinate was measured...

The effect of the leukotriene antagonist pranlukast on pediatric acute otitis media.

Science.gov (United States)

Nakamura, Yoshihisa; Hamajima, Yuki; Suzuki, Motohiko; Esaki, Shinichi; Yokota, Makoto; Oshika, Masanori; Takagi, Ippei; Yasui, Keiko; Miyamoto, Naoya; Sugiyama, Kazuko; Nakayama, Meiho; Murakami, Shingo

2016-08-01

Conventional treatment for acute otitis media mainly targets bacteria with antibiotics, neglecting to control for mediators of inflammation. Mediators of inflammation, such as leukotrienes, have been identified in patients with acute otitis media (AOM) or subsequent secretory otitis media (SOM). They can cause functional eustachian tube dysfunction or increase mucous in the middle ear, causing persistent SOM following AOM. The objective of the present study was to evaluate whether or not administration of pranlukast, a widely used leukotriene C4, D4, and E4 antagonist, together with antibiotics could inhibit the progression to SOM. Children with AOM, who were from two to 12 years old, were randomly divided into two groups as follows: a control group in which 50 patients received antibiotic-based conventional treatment according to guidelines for treating AOM proposed by the Japan Otological Society (version 2006); and a pranlukast group, in which 52 patients were administered pranlukast for up to 28 days as well as given conventional treatment. Cases were regarded as persistent SOM when a tympanogram was type B or C2 four weeks after treatment was initiated. Two patients in the pranlukast group and 3 patients in the control group were excluded because they relapsed AOM within 28 days after initial treatment. Therefore, the analysis included 50 and 47 subjects in the pranlukast and control groups, respectively. The percentage of patients diagnosed with persistent SOM (22.0%) was significantly smaller in the pranlukast group compared with the control group (44.7%) (p = 0.018, chi-squared test). The results indicate that combined treatment of AOM with antibiotics and a leukotriene antagonist to control inflammation is useful for preventing progression to persistent SOM. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Selective blockade of leukotriene production by a single dose of the FPL 64170XX 0.5% enema in active ulcerative colitis

DEFF Research Database (Denmark)

Kjeldsen, J; Laursen, L S; Hillingsø, Jens

1995-01-01

5-Lipoxygenase products of arachidonic acid metabolism are thought to play a central role in the secondary amplification of the inflammatory response of several inflammatory diseases, including ulcerative colitis. FPL 64170XX is a selective inhibitor of the enzyme 5-lipoxygenase. Concentrations...... containing 0.5% of FPL 64170XX. Repeated measures analysis of leukotriene B4, after adjusting for baseline, showed a significant treatment effect (P = 0.0014). The concentration of leukotriene B4 from rectal dialysates in patients receiving the active drug dropped to 15% (95% confidence interval 5......-40%) of the placebo level in the second dialysis following administration of FPL 64170XX 0.5%. By contrast, prostaglanding E2 concentrations doubled (P = 0.0068) in patients receiving FPL 64170XX 0.5% with no change in the placebo group. These findings demonstrate that a single dose of FPL 64170XX 0.5% enema...

Thermoelastic properties of ScB2, TiB2, YB4 and HoB4

DEFF Research Database (Denmark)

Waskowska, A.; Gerward, L.; Staun Olsen, J.

2011-01-01

(4)GPa). No pressure-induced phase transformations are observed in any of the above borides up to about 20GPa. A continuous temperature-driven orthorhombic distortion is observed for HoB4 below 285K. Values of the thermal expansion coefficient are reported for ScB2 and HoB4 at 293, 200 and 100K...

Effects of Xingbi gel on leukotriene E4 and immunoglobulin E production and nasal eosinophilia in a guinea pig model for allergic rhinitis.

Science.gov (United States)

Ai, Si; Zheng, Jian; Chu, Ke-Dan; Zhang, Hong-Sheng

2015-06-01

Allergic rhinitis (AR) is a chronic inflammatory disease of the nasal airways.Many therapies do not have immediate effects,even which have side-effects.However,the effects of Xingbi gel for the treatment of AR was investigated. We investigated the effects of Xingbi gel on serum levels of leukotriene E4 (LTE4) and immunoglobulin E (IgE), as well as eosinophil counts in the nasal mucosa using a guinea pig model of allergic rhinitis (AR). In addition to a healthy control group without AR, guinea pigs with AR were randomly divided into untreated AR control group, low-dose Xingbi gel (0.2483 g/mL) group, high-dose Xingbi gel (0.4966 g/mL) group, and budesonide group. Compared to the healthy controls, untreated AR guinea pigs had significantly higher ethology scores, serum LTE4 and IgE levels, and nasal mucosa eosinophil counts (p guinea pigs (p production and reducing eosinophilia in the nasal mucosa.

75 FR 27956 - Airworthiness Directives; Airbus Model A300 B4-600, B4-600R, and F4-600R Series Airplanes, and...

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2010-05-19

... B4-600, B4-600R, and F4-600R Series Airplanes, and Model C4-605R Variant F Airplanes (Collectively...-203, and B4-203 airplanes; Model A300 B4-601, B4- 603, B4-620, B4-622, B4-605R, B4-622R, F4-605R, F4...

75 FR 60611 - Airworthiness Directives; Airbus Model A300 B4-600, B4-600R, and F4-600R Series Airplanes, and...

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2010-10-01

... Airworthiness Directives; Airbus Model A300 B4-600, B4-600R, and F4-600R Series Airplanes, and Model A300 C4...; Model A300 B4-601, B4- 603, B4-620, B4-622, B4-605R, B4-622R, F4-605R, F4-622R, and C4-605R Variant F...-- Dated-- A300 series airplanes......... A300-32A0447..... April 22, 2004. A300 B4-600, B4-600R, and F4...

76 FR 59008 - Airworthiness Directives; Airbus Model A300 B4-600, B4-600R, and F4-600R Series Airplanes, and...

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2011-09-23

... Airworthiness Directives; Airbus Model A300 B4-600, B4-600R, and F4-600R Series Airplanes, and Model C4-605R... to Airbus Model A300 B4-601, B4-603, B4-620, B4-622, B4-605R, B4-622R, F4-605R, F4-622R, and C4-605R...

76 FR 27242 - Airworthiness Directives; Airbus Model A300 B4-600, B4-600R, and F4-600R Series Airplanes, and...

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2011-05-11

... Airworthiness Directives; Airbus Model A300 B4-600, B4-600R, and F4-600R Series Airplanes, and Model C4-605R... applies to all Airbus Model A300 B4-601, B4-603, B4- 620, B4-622, B4-605R, B4-622R, F4-605R, F4-622R, and...

Leukotriene D4 induces chemotaxis in human eosinophilc cell line, EoL-1 cells via CysLT1 receptor activation.

Science.gov (United States)

Shirasaki, Hideaki; Kanaizumi, Etsuko; Himi, Tetsuo

2017-11-01

Numerous reports have shown that cysteinyl leukotrienes (CysLTs) contribute to tissue accumulation of eosinophils in allergic airway inflammation. To date, only a few studies have reported that CysLTs promote chemotactic activity of human eosinophils in vitro. The purpose of this study was to investigate whether CysLTs promote chemotaxis in the human eosinophilic cell line, EoL-1. EoL-1 cells were induced to differentiate into mature eosinophil-like cells via incubation with butyric acid and cytokines (IL-3, IL-5 and GM-CSF). The chemotactic activity of the differentiated EoL-1 cells was assessed using the commercial cell migration assay kit. LTD 4 elicited dose-related chemotactic activity in the differntiated EoL-1 cells in the range of 1-100 nM. A typical bell-shaped dose-response curve was observed with optimal activity at 10 nM. The chemotactic activity elicited by LTD 4 (10 nM) was significantly inhibited by montelukast (control, 345 ± 19.2 × 10 3 RFU; LTD 4 10 nM alone, 511 ± 39.2 × 10 3 RFU; LTD 4 10 nM plus montelukast 100 nM, 387 ± 28.2 × 10 3 RFU). LTD 4 induces migration in eosinophilic cells via activation of CysLT1 receptor. The present in vitro model may be useful for elucidation of the mechanism underlying CysLT-induced tissue eosinophilia.

Acute respiratory effects and biomarkers of inflammation due to welding-derived nanoparticle aggregates.

Science.gov (United States)

Dierschke, Katrin; Isaxon, Christina; Andersson, Ulla B K; Assarsson, Eva; Axmon, Anna; Stockfelt, Leo; Gudmundsson, Anders; Jönsson, Bo A G; Kåredal, Monica; Löndahl, Jakob; Pagels, Joakim; Wierzbicka, Aneta; Bohgard, Mats; Nielsen, Jörn

2017-07-01

Welders are exposed to airborne particles from the welding environment and often develop symptoms work-related from the airways. A large fraction of the particles from welding are in the nano-size range. In this study we investigate if the welders' airways are affected by exposure to particles derived from gas metal arc welding in mild steel in levels corresponding to a normal welding day. In an exposure chamber, 11 welders with and 10 welders without work-related symptoms from the lower airways and 11 non-welders without symptoms, were exposed to welding fumes (1 mg/m 3 ) and to filtered air, respectively, in a double-blind manner. Symptoms from eyes and upper and lower airways and lung function were registered. Blood and nasal lavage (NL) were sampled before, immediately after and the morning after exposure for analysis of markers of oxidative stress. Exhaled breath condensate (EBC) for analysis of leukotriene B4 (LT-B4) was sampled before, during and immediately after exposure. No adverse effects of welding exposure were found regarding symptoms and lung function. However, EBC LT-B4 decreased significantly in all participants after welding exposure compared to filtered air. NL IL-6 increased immediately after exposure in the two non-symptomatic groups and blood neutrophils tended to increase in the symptomatic welder group. The morning after, neutrophils and serum IL-8 had decreased in all three groups after welding exposure. Remarkably, the symptomatic welder group had a tenfold higher level of EBC LT-B4 compared to the two groups without symptoms. Despite no clinical adverse effects at welding, changes in inflammatory markers may indicate subclinical effects even at exposure below the present Swedish threshold limit (8 h TWA respirable dust).

76 FR 38069 - Airworthiness Directives; Airbus Model A300 B4-600, B4-600R, and F4-600R Series Airplanes, and...

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2011-06-29

... B4-600, B4-600R, and F4-600R Series Airplanes, and Model C4-605R Variant F Airplanes (Collectively...-603, B4-620, B4-622, B4-605R, B4-622R, F4-605R, F4-622R, and C4-605R Variant F airplanes; and Model...

Complete genomic sequences for hepatitis C virus subtypes 4b, 4c, 4d, 4g, 4k, 4l, 4m, 4n, 4o, 4p, 4q, 4r and 4t.

Science.gov (United States)

Li, Chunhua; Lu, Ling; Wu, Xianghong; Wang, Chuanxi; Bennett, Phil; Lu, Teng; Murphy, Donald

2009-08-01

In this study, we characterized the full-length genomic sequences of 13 distinct hepatitis C virus (HCV) genotype 4 isolates/subtypes: QC264/4b, QC381/4c, QC382/4d, QC193/4g, QC383/4k, QC274/4l, QC249/4m, QC97/4n, QC93/4o, QC139/4p, QC262/4q, QC384/4r and QC155/4t. These were amplified, using RT-PCR, from the sera of patients now residing in Canada, 11 of which were African immigrants. The resulting genomes varied between 9421 and 9475 nt in length and each contains a single ORF of 9018-9069 nt. The sequences showed nucleotide similarities of 77.3-84.3 % in comparison with subtypes 4a (GenBank accession no. Y11604) and 4f (EF589160) and 70.6-72.8 % in comparison with genotype 1 (M62321/1a, M58335/1b, D14853/1c, and 1?/AJ851228) reference sequences. These similarities were often higher than those currently defined by HCV classification criteria for subtype (75.0-80.0 %) and genotype (67.0-70.0 %) division, respectively. Further analyses of the complete and partial E1 and partial NS5B sequences confirmed these 13 'provisionally assigned subtypes'.

Scale-up operations of CuSOB4B-NaB2BSOB4B electrolytic ...

African Journals Online (AJOL)

Scale-up techniques were established for an Inclined Cathode Electrochemical Cell (ICEC) for the removal of copper ions from a CuSOB4B-NaB2BSOB4B solution at reduced operation power consumption. The scale-up relationshi-ps were derived and applied in conjunction with scale-up factors. With a scale-up factor of 2, ...

Anti-inflammatory effects of chronic aspirin on brain arachidonic acid metabolites

Science.gov (United States)

Basselin, Mireille; Ramadan, Epolia; Chen, Mei; Rapoport, Stanley I.

2010-01-01

Pro-inflammatory and anti-inflammatory mediators derived from arachidonic acid (AA) modulate peripheral inflammation and its resolution. Aspirin (ASA) is a unique non-steroidal anti-inflammatory drug, which switches AA metabolism from prostaglandin E2 (PGE2) and thromboxane B2 (TXB2) to lipoxin A4 (LXA4) and 15-epi-LXA4. However it is unknown whether chronic therapeutic doses of ASA are anti-inflammatory in the brain. We hypothesized that ASA would dampen increases in brain concentrations of AA metabolites in a rat model of neuroinflammation, produced by a 6-day intracerebroventricular infusion of bacterial lipopolysaccharide (LPS). In rats infused with LPS (0.5 ng/h) and given ASA-free water to drink, concentrations in high-energy microwaved brain of PGE2, TXB2 and leukotriene B4 (LTB4) were elevated. In rats infused with artificial cerebrospinal fluid, 6 weeks of treatment with a low (10 mg/kg/day) or high (100 mg/kg/day) ASA dose in drinking water decreased brain PGE2, but increased LTB4, LXA4 and 15-epi-LXA4 concentrations. Both doses attenuated the LPS effects on PGE2, and TXB2. The increments in LXA4 and 15-epi-LXA4 caused by high-dose ASA were significantly greater in LPS-infused rats. The ability of ASA to increase anti-inflammatory LXA4 and 15-epi-LXA4 and reduce pro-inflammatory PGE2 and TXB2 suggests considering aspirin further for treating clinical neuroinflammation. PMID:20981485

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2011-01-05

... Airworthiness Directives; Airbus Model A300 B4-600, B4-600R, and F4-600R Series Airplanes, and Model C4-605R...-622, B4-605R, B4-622R, F4-605R, F4-622R, and C4-605R Variant F airplanes, certificated in any category...

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2011-05-19

... B4-600, B4-600R, and F4-600R Series Airplanes, and Model C4-605R Variant F Airplanes (Collectively... B4-605R and B4-622R airplanes; A300 F4-605R and F4-622R airplanes; A300 C4-605R Variant F airplanes...

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2010-12-10

... Airworthiness Directives; Airbus Model A300 B4-600, B4-600R, and F4-600R Series Airplanes, and Model C4-605R... airplanes; Model A300 B4-605R and B4-622R airplanes; Model A300 F4-605R and F4-622R airplanes; Model A300 C4...

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2011-07-18

... Airworthiness Directives; Airbus Model A300 B4-600, B4-600R, and F4-600R Series Airplanes, and Model A300 C4... A300 B4-605R and B4-622R airplanes, Model A300 F4-605R and F4-622R airplanes, and Model A300 C4- [[Page...

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2011-07-06

... Airworthiness Directives; Airbus Model A300 B4-600, B4-600R, and F4-600R Series Airplanes, and Model C4-605R... B4-605R and B4-622R airplanes; Model A300 F4-605R and F4-622R airplanes; Model A300 C4-605R Variant F...

Systems Li2B4O7 (Na2B4O7, K2B4O7)-N2H3H4OH-H2O at 25 deg C

International Nuclear Information System (INIS)

Skvortsov, V.G.; Sadetdinov, Sh.V.; Akimov, V.M.; Mitrasov, Yu.N.; Petrova, O.V.; Klopov, Yu.N.

1994-01-01

Phase equilibriums in the Li 2 B 4 O 7 (Na 2 B 4 O 7 , K 2 B 4 O 7 )-N 2 H 3 H 4 OH-H 2 O systems were investigated by methods of isothermal solubility, refractometry and PH-metry at 25 deg C for the first time. Lithium and sodium tetraborates was established to form phases of changed composition mM 2 B 4 O 7 ·nN 2 H 3 C 2 H 4 OH·XH 2 O, where M=Li, Na with hydrazine ethanol. K 2 B 4 O 7 ·4H 2 O precipitates in solid phase in the case of potassium salt. Formation of isomorphous mixtures was supported by X-ray diffraction and IR spectroscopy methods

Generalized Second Law of Thermodynamics in Parabolic LTB Inhomogeneous Cosmology

International Nuclear Information System (INIS)

Sheykhi, A.; Moradpour, H.; Sarab, K. Rezazadeh; Wang, B.

2015-01-01

We study thermodynamics of the parabolic Lemaitre–Tolman–Bondi (LTB) cosmology supported by a perfect fluid source. This model is the natural generalization of the flat Friedmann–Robertson–Walker (FRW) universe, and describes an inhomogeneous universe with spherical symmetry. After reviewing some basic equations in the parabolic LTB cosmology, we obtain a relation for the deceleration parameter in this model. We also obtain a condition for which the universe undergoes an accelerating phase at the present time. We use the first law of thermodynamics on the apparent horizon together with the Einstein field equations to get a relation for the apparent horizon entropy in LTB cosmology. We find out that in LTB model of cosmology, the apparent horizon's entropy could be feeded by a term, which incorporates the effects of the inhomogeneity. We consider this result and get a relation for the total entropy evolution, which is used to examine the generalized second law of thermodynamics for an accelerating universe. We also verify the validity of the second law and the generalized second law of thermodynamics for a universe filled with some kinds of matters bounded by the event horizon in the framework of the parabolic LTB model. (paper)

75 FR 28480 - Airworthiness Directives; Airbus Model A300 Series Airplanes; Model A300 B4-600, B4-600R, F4-600R...

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2010-05-21

... Airworthiness Directives; Airbus Model A300 Series Airplanes; Model A300 B4-600, B4-600R, F4-600R Series..., B4-622, B4- 605R, B4-622R, F4-605R, F4-622R, and C4-605R Variant F airplanes; and Model A310-203...

76 FR 18960 - Airworthiness Directives; Airbus Model A300 B4-600, B4-600R, and F4-600R Series Airplanes, and...

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2011-04-06

... B4-600, B4-600R, and F4-600R Series Airplanes, and Model C4-605R Variant F Airplanes (Collectively... July 20, 2005; have been performed in service. (2) Airbus Model A300 B4-605R, B4-622R, F4-605R, and F4... C4-600R, and A300 F4-600R series airplanes (fitted with a trim tank), all serial numbers, except...

Synthesis of leukotrienes labelled with deuterium: [11,12,14,15-2H4]-LTA4, -LTC4, -LTD4 and -LTE4

International Nuclear Information System (INIS)

Lellouche, J.P.; Aubert, F.; Noel, J.P.; Boullais, C.; Beaucourt, J.P.

1989-01-01

Semi-hydrogenation by D 2 gas on Lindlar catalyst of an acetylenic precursor led to [11,12,14,15- 2 H 4 ]-LTA 4 methyl ester. Nucleophilic opening of the epoxide ring by amino thioacids accorded, after saponification, the corresponding deuterated peptidoleukotrienes LTC 4 , LTD 4 and LTE 4 . (author)

Thermophysical properties of the ionic liquids [EMIM][B(CN)4] and [HMIM][B(CN)4].

Science.gov (United States)

Koller, Thomas M; Rausch, Michael H; Ramos, Javier; Schulz, Peter S; Wasserscheid, Peter; Economou, Ioannis G; Fröba, Andreas P

2013-07-18

In the present study, the thermophysical properties of the tetracyanoborate-based ionic liquids (ILs) 1-ethyl-3-methylimidazolium tetracyanoborate ([EMIM][B(CN)4]) and 1-hexyl-3-methylimidazolium tetracyanoborate ([HMIM][B(CN)4]) obtained by both experimental methods and molecular dynamics (MD) simulations are presented. Conventional experimental techniques were applied for the determination of refractive index, density, interfacial tension, and self-diffusion coefficients for [HMIM][B(CN)4] at atmospheric pressure in the temperature range from 283.15 to 363.15 K. In addition, surface light scattering (SLS) experiments provided accurate viscosity and interfacial tension data. As no complete molecular parametrization was available for the MD simulations of [HMIM][B(CN)4], our recently developed united-atom force field for [EMIM][B(CN)4] was partially transferred to the homologous IL [HMIM][B(CN)4]. Deviations between our simulated and experimental data for the equilibrium properties are less than ±0.3% in the case of density and less than ±8% in the case of interfacial tension for both ILs. Furthermore, the calculated and measured data for the transport properties viscosity and self-diffusion coefficient are in good agreement, with deviations of less than ±30% over the whole temperature range. In addition to a comparison with the literature, the influence of varying cation chain length on thermophysical properties of [EMIM][B(CN)4] and [HMIM][B(CN)4] is discussed.

Leukotriene signaling in the extinct human subspecies Homo denisovan and Homo neanderthalensis. Structural and functional comparison with Homo sapiens.

Science.gov (United States)

Adel, Susan; Kakularam, Kumar Reddy; Horn, Thomas; Reddanna, Pallu; Kuhn, Hartmut; Heydeck, Dagmar

2015-01-01

Mammalian lipoxygenases (LOXs) have been implicated in cell differentiation and in the biosynthesis of pro- and anti-inflammatory lipid mediators. The initial draft sequence of the Homo neanderthalensis genome (coverage of 1.3-fold) suggested defective leukotriene signaling in this archaic human subspecies since expression of essential proteins appeared to be corrupted. Meanwhile high quality genomic sequence data became available for two extinct human subspecies (H. neanderthalensis, Homo denisovan) and completion of the human 1000 genome project provided a comprehensive database characterizing the genetic variability of the human genome. For this study we extracted the nucleotide sequences of selected eicosanoid relevant genes (ALOX5, ALOX15, ALOX12, ALOX15B, ALOX12B, ALOXE3, COX1, COX2, LTA4H, LTC4S, ALOX5AP, CYSLTR1, CYSLTR2, BLTR1, BLTR2) from the corresponding databases. Comparison of the deduced amino acid sequences in connection with site-directed mutagenesis studies and structural modeling suggested that the major enzymes and receptors of leukotriene signaling as well as the two cyclooxygenase isoforms were fully functional in these two extinct human subspecies. Copyright © 2014 Elsevier Inc. All rights reserved.

76 FR 6581 - Airworthiness Directives; Airbus Model A300 B4-600, B4-600R, and F4-600R Series Airplanes, and...

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2011-02-07

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Directional crystallization of B4C-NbB2 and B4C-MoB2 eutectic compositions

International Nuclear Information System (INIS)

Paderno, Varvara; Paderno, Y.B.; Filippov, Vladimir; Liashchenko, Alfred

2004-01-01

We studied the directional crystallization of different compositions in B 4 C-NbB 2 and B 4 C-MoB 2 systems. The eutectic compositions for both systems are evaluated. It is shown that in the first system the rod-like eutectic structure is formed, in second, the 'Chinese hieroglyphics'. In both cases high hardness and high microplasticity are observed, which are much more than for individual component phases. These compositions may be considered as a new kind of self-strengthening composite materials

The shunt from the cyclooxygenase to lipoxygenase pathway in human osteoarthritic subchondral osteoblasts is linked with a variable expression of the 5-lipoxygenase-activating protein.

Science.gov (United States)

Maxis, Kelitha; Delalandre, Aline; Martel-Pelletier, Johanne; Pelletier, Jean-Pierre; Duval, Nicolas; Lajeunesse, Daniel

2006-01-01

Osteoarthritis (OA) is characterized by articular cartilage degradation and hypertrophic bone changes with osteophyte formation and abnormal bone remodeling. Two groups of OA patients were identified via the production of variable and opposite levels of prostaglandin E2 (PGE2) or leukotriene B4 (LTB4) by subchondral osteoblasts, PGE2 levels discriminating between low and high subgroups. We studied whether the expression of 5-lipoxygenase (5-LO) or 5-LO-activating protein (FLAP) is responsible for the shunt from prostaglandins to leukotrienes. FLAP mRNA levels varied in low and high OA groups compared with normal, whereas mRNA levels of 5-LO were similar in all osteoblasts. Selective inhibition of cyclooxygenase-2 (COX-2) with NS-398-stimulated FLAP expression in the high OA osteoblasts subgroup, whereas it was without effect in the low OA osteoblasts subgroup. The addition of PGE2 to the low OA osteoblasts subgroup decreased FLAP expression but failed to affect it in the high OA osteoblasts subgroup. LTB4 levels in OA osteoblasts were stimulated about twofold by 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) plus transforming growth factor-beta (TGF-beta), a situation corresponding to their effect on FLAP mRNA levels. Treatments with 1,25(OH)2D3 and TGF-beta also modulated PGE2 production. TGF-beta stimulated PGE2 production in both OA osteoblast groups, whereas 1,25(OH)2D3 alone had a limited effect but decreased the effect of TGF-beta in the low OA osteoblasts subgroup. This modulation of PGE2 production was mirrored by the synthesis of COX-2. IL-18 levels were only slightly increased in a subgroup of OA osteoblasts compared with normal; however, no relationship was observed overall between IL-18 and PGE2 levels in normal and OA osteoblasts. These results suggest that the shunt from the production of PGE2 to LTB4 is through regulation of the expression of FLAP, not 5-LO, in OA osteoblasts. The expression of FLAP in OA osteoblasts is also modulated differently by 1,25(OH

Protective effects of a standard extract of Mangifera indica L. (VIMANG) against mouse ear edemas and its inhibition of eicosanoid production in J774 murine macrophages.

Science.gov (United States)

Garrido, G; González, D; Lemus, Y; Delporte, C; Delgado, R

2006-06-01

A standard aqueous extract of Mangifera indica L., used in Cuba as antioxidant under the brand name VIMANG, was tested in vivo for its anti-inflammatory activity, using commonly accepted assays. The standard extract of M. indica, administered orally (50-200mg/kg body wt.), reduced ear edema induced by arachidonic acid (AA) and phorbol myristate acetate (PMA) in mice. In the PMA model, M. indica extract also reduced myeloperoxidase (MPO) activity. In vitro studies were performed using macrophage cell line J774 stimulated with pro-inflammatory stimuli lipopolysaccharide-interferon gamma (LPS-IFNgamma) or calcium ionophore A23187 to determine prostaglandin PGE(2) or leukotriene LTB(4) release, respectively. The extract inhibited the induction of PGE(2) and LTB(4) with IC(50) values of 21.7 and 26.0microg/ml, respectively. Mangiferin (a glucosylxanthone isolated from the extract) also inhibited these AA metabolites (PGE(2), IC(50) value=17.2microg/ml and LTB(4), IC(50) value=2.1microg/ml). These results represent an important contribution to the elucidation of the mechanism involved in the anti-inflammatory and anti-nociceptive effects reported for the standard extract of M. indica VIMANG.

Role of leukotrienes in asthma pathophysiology

DEFF Research Database (Denmark)

Bisgaard, H

2000-01-01

Inflammation is an essential component of asthma pathophysiology. While beta(2)-agonists are often used for short-term relief of acute bronchospasm, anti-inflammatory agents are required for the long-term management of chronic inflammation in this disease. Corticosteroids have emerged as the first......-line anti-inflammatory therapy for asthma management. However, in some patients, especially children, the high doses of corticosteroids that may be required to control features of hyperresponsiveness, including exercise-induced asthma, raise safety concerns. Thus, there is a need for complementary anti......-inflammatory, steroid-sparing agents in asthma therapy. Several inflammatory mediators have been targeted in an attempt to thwart this inflammatory process, but so far with little success. The cysteinyl leukotrienes (CysLT), LTC(4), LTD(4), and LTE(4), have been shown to be essential mediators in asthma, making them...

Photoelectron spectroscopy of B4O4 (-): Dual 3c-4e π hyperbonds and rhombic 4c-4e o-bond in boron oxide clusters.

Science.gov (United States)

Tian, Wen-Juan; Zhao, Li-Juan; Chen, Qiang; Ou, Ting; Xu, Hong-Guang; Zheng, Wei-Jun; Zhai, Hua-Jin; Li, Si-Dian

2015-04-07

Gas-phase anion photoelectron spectroscopy (PES) is combined with global structural searches and electronic structure calculations at the hybrid Becke 3-parameter exchange functional and Lee-Yang-Parr correlation functional (B3LYP) and single-point coupled-cluster with single, double, and perturbative triple excitations (CCSD(T)) levels to probe the structural and electronic properties and chemical bonding of the B4O4 (0/-) clusters. The measured PES spectra of B4O4 (-) exhibit a major band with the adiabatic and vertical detachment energies (ADE and VDE) of 2.64 ± 0.10 and 2.81 ± 0.10 eV, respectively, as well as a weak peak with the ADE and VDE of 1.42 ± 0.08 and 1.48 ± 0.08 eV. The former band proves to correspond to the Y-shaped global minimum of Cs B4O4 (-) ((2)A″), with the calculated ADE/VDE of 2.57/2.84 eV at the CCSD(T) level, whereas the weak band is associated with the second lowest-energy, rhombic isomer of D2h B4O4 (-) ((2)B2g) with the predicted ADE/VDE of 1.43/1.49 eV. Both anion structures are planar, featuring a B atom or a B2O2 core bonded with terminal BO and/or BO2 groups. The same Y-shaped and rhombic structures are also located for the B4O4 neutral cluster, albeit with a reversed energy order. Bonding analyses reveal dual three-center four-electron (3c-4e) π hyperbonds in the Y-shaped B4O4 (0/-) clusters and a four-center four-electron (4c-4e) π bond, that is, the so-called o-bond in the rhombic B4O4 (0/-) clusters. This work is the first experimental study on a molecular system with an o-bond.

76 FR 19724 - Airworthiness Directives; Airbus Model A300 B4-600, B4-600R, and F4-600R Series Airplanes, and...

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2011-04-08

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In-silico design, expression, and purification of novel chimeric Escherichia coli O157:H7 OmpA fused to LTB protein in Escherichia coli.

Directory of Open Access Journals (Sweden)

Aytak Novinrooz

Full Text Available E. coli O157:H7, one of the major EHEC serotypes, is capable of developing bloody diarrhea, hemorrhagic colitis (HC, and fatal hemolytic uremic syndrome (HUS and is accompanied by high annual economic loss worldwide. Due to the increased risk of HC and HUS development following antibiotic therapy, the prevention of infections caused by this pathogen is considered to be one of the most effective ways of avoiding the consequences of this infection. The main aim of the present study was to design, express, and purify a novel chimeric protein to develope human vaccine candidate against E. coli O157:H7 containing loop 2-4 of E. coli O157:H7, outer membrane protein A (OmpA, and B subunit of E. coli heat labile enterotoxin (LTB which are connected by a flexible peptide linker. Several online databases and bioinformatics software were utilized to choose the peptide linker among 537 analyzed linkers, design the chimeric protein, and optimize the codon of the relative gene encoding this protein. Subsequently, the recombinant gene encoding OmpA-LTB was synthesized and cloned into pET-24a (+ expression vector and transferred to E. coli BL21(DE3 cells. The expression of OmpA-LTB chimeric protein was then carried out by induction of cultured E. coli Bl21 (DE3 cells with 1mM isopropyl-β-D-thiogalactopyranoside (IPTG. The purification of OmpA-LTB was then performed by nickel affinity chromatography. Expression and purification were analyzed by sodium dodecyl sulphate poly acrylamide gel electrophoresis. Moreover, the identity of the expressed protein was analyzed by western blotting. SDS-PAGE and western immunoblotting confirmed the successful expression of a 27 KDa recombinant protein after 24 hours at 37°C post-IPTG induction. OmpA-LTB was then successfully purified, using nickel affinity chromatography under denaturing conditions. The yield of purification was 12 mg per liter of culture media. Ultimately, we constructed the successful design and efficient

Photoelectron spectroscopy of B4O4-: Dual 3c-4e π hyperbonds and rhombic 4c-4e o-bond in boron oxide clusters

Science.gov (United States)

Tian, Wen-Juan; Zhao, Li-Juan; Chen, Qiang; Ou, Ting; Xu, Hong-Guang; Zheng, Wei-Jun; Zhai, Hua-Jin; Li, Si-Dian

2015-04-01

Gas-phase anion photoelectron spectroscopy (PES) is combined with global structural searches and electronic structure calculations at the hybrid Becke 3-parameter exchange functional and Lee-Yang-Parr correlation functional (B3LYP) and single-point coupled-cluster with single, double, and perturbative triple excitations (CCSD(T)) levels to probe the structural and electronic properties and chemical bonding of the B4O40/- clusters. The measured PES spectra of B4O4- exhibit a major band with the adiabatic and vertical detachment energies (ADE and VDE) of 2.64 ± 0.10 and 2.81 ± 0.10 eV, respectively, as well as a weak peak with the ADE and VDE of 1.42 ± 0.08 and 1.48 ± 0.08 eV. The former band proves to correspond to the Y-shaped global minimum of Cs B4O4- (2A″), with the calculated ADE/VDE of 2.57/2.84 eV at the CCSD(T) level, whereas the weak band is associated with the second lowest-energy, rhombic isomer of D2h B4O4- (2B2g) with the predicted ADE/VDE of 1.43/1.49 eV. Both anion structures are planar, featuring a B atom or a B2O2 core bonded with terminal BO and/or BO2 groups. The same Y-shaped and rhombic structures are also located for the B4O4 neutral cluster, albeit with a reversed energy order. Bonding analyses reveal dual three-center four-electron (3c-4e) π hyperbonds in the Y-shaped B4O40/- clusters and a four-center four-electron (4c-4e) π bond, that is, the so-called o-bond in the rhombic B4O40/- clusters. This work is the first experimental study on a molecular system with an o-bond.

Photoelectron spectroscopy of B4O4−: Dual 3c-4e π hyperbonds and rhombic 4c-4e o-bond in boron oxide clusters

International Nuclear Information System (INIS)

Tian, Wen-Juan; Chen, Qiang; Ou, Ting; Li, Si-Dian; Zhao, Li-Juan; Xu, Hong-Guang; Zheng, Wei-Jun; Zhai, Hua-Jin

2015-01-01

Gas-phase anion photoelectron spectroscopy (PES) is combined with global structural searches and electronic structure calculations at the hybrid Becke 3-parameter exchange functional and Lee-Yang-Parr correlation functional (B3LYP) and single-point coupled-cluster with single, double, and perturbative triple excitations (CCSD(T)) levels to probe the structural and electronic properties and chemical bonding of the B 4 O 4 0/− clusters. The measured PES spectra of B 4 O 4 − exhibit a major band with the adiabatic and vertical detachment energies (ADE and VDE) of 2.64 ± 0.10 and 2.81 ± 0.10 eV, respectively, as well as a weak peak with the ADE and VDE of 1.42 ± 0.08 and 1.48 ± 0.08 eV. The former band proves to correspond to the Y-shaped global minimum of C s B 4 O 4 − ( 2 A″), with the calculated ADE/VDE of 2.57/2.84 eV at the CCSD(T) level, whereas the weak band is associated with the second lowest-energy, rhombic isomer of D 2h B 4 O 4 − ( 2 B 2g ) with the predicted ADE/VDE of 1.43/1.49 eV. Both anion structures are planar, featuring a B atom or a B 2 O 2 core bonded with terminal BO and/or BO 2 groups. The same Y-shaped and rhombic structures are also located for the B 4 O 4 neutral cluster, albeit with a reversed energy order. Bonding analyses reveal dual three-center four-electron (3c-4e) π hyperbonds in the Y-shaped B 4 O 4 0/− clusters and a four-center four-electron (4c-4e) π bond, that is, the so-called o-bond in the rhombic B 4 O 4 0/− clusters. This work is the first experimental study on a molecular system with an o-bond

Pressure effect on structural, elastic, and thermodynamic properties of tetragonal B4C4

Directory of Open Access Journals (Sweden)

Baobing Zheng

2015-03-01

Full Text Available The compressibility, elastic anisotropy, and thermodynamic properties of the recently proposed tetragonal B4C4 (t-B4C4 are investigated under high temperature and high pressure by using of first-principles calculations method. The elastic constants, bulk modulus, shear modulus, Young’s modulus, Vickers hardness, Pugh’s modulus ratio, and Poisson’s ratio for t-B4C4 under various pressures are systematically explored, the obtained results indicate that t-B4C4 is a stiffer material. The elastic anisotropies of t-B4C4 are discussed in detail under pressure from 0 GPa to 100 GPa. The thermodynamic properties of t-B4C4, such as Debye temperature, heat capacity, and thermal expansion coefficient are investigated by the quasi-harmonic Debye model.

Protectin DX, a double lipoxygenase product of DHA, inhibits both ROS production in human neutrophils and cyclooxygenase activities

Science.gov (United States)

Liu, Miao; Boussetta, Tarek; Makni-Maalej, Karama; Fay, Michèle; Driss, Fathi; El-Benna, Jamel; Lagarde, Michel; Guichardant, Michel

2014-01-01

Neutrophils play a major role in inflammation by releasing large amounts of reactive oxygen species (ROS) produced by NADPH oxidase (NOX) and myeloperoxidase (MPO). This ROS overproduction is mediated by phosphorylation of the NOX subunits with an uncontrolled manner. Therefore, targeting neutrophil subunits would represent a promising strategy to moderate NOX activity, lower ROS, and other inflammatory agents, such as cytokines and leukotrienes, produced by neutrophils. For this purpose, we investigated the effects of protectin DX (PDX) - a docosahexaenoic acid (DHA) di-hydroxylated product which inhibits blood platelet aggregation - on neutrophil activation in vitro. We found that PDX decreases ROS production, inhibits NOX activation and MPO release from neutrophils. We also confirm, that PDX is an anti-aggregatory and anti-inflammatory agent by inhibiting both cyclooxygenase-1 and -2 (COX-1 and COX-2, E.C. 1.14.99.1) as well as COX-2 in lipopolysaccharides (LPS)-treated human neutrophils. However, PDX has no effect on the 5-lipoxygenase pathway that produces the chemotactic agent leukotriene B4 (LTB4). Taken together, our results suggest that PDX could be a protective agent against neutrophil invasion in chronic inflammatory diseases. PMID:24254970

76 FR 47430 - Airworthiness Directives; Airbus Model A300 B4-600, A300 B4-600R, and A300 F4-600R Series...

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2011-08-05

... Airworthiness Directives; Airbus Model A300 B4-600, A300 B4-600R, and A300 F4-600R Series Airplanes, and Model..., B4-622R, F4-605R, F4-622R, and C4-605R Variant F airplanes; and Model A310-203, -204, -221, -222...

76 FR 25259 - Airworthiness Directives; Airbus Model A300 B4-600, A300 B4-600R, and A300 F4-600R Series...

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2011-05-04

... Airworthiness Directives; Airbus Model A300 B4-600, A300 B4-600R, and A300 F4-600R Series Airplanes, and Model...-605R, B4-622R, F4-605R, F4-622R, and C4-605R Variant F airplanes; and Model A310-203, -204, -221, -222...

Pathophysiology of the cysteinyl leukotrienes and effects of leukotriene receptor antagonists in asthma

DEFF Research Database (Denmark)

Bisgaard, H

2001-01-01

, exudation of macromolecules and edema. The cysteinyl leukotrienes also have potent chemoattractant properties for eosinophils, causing an influx of eosinophils into the airway mucosa, which further fuels the inflammatory process. In addition, the cysteinyl leukotrienes are potent secretagogues and reduce...... and pranlukast inhibit bronchoconstriction in asthmatic patients undergoing allergen, exercise, cold air or aspirin challenge. They attenuate the hallmarks of asthmatic inflammation, including eosinophilia in the airway mucosa and peripheral blood. Moreover, exhaled nitric oxide concentrations, another correlate...

Analysis of Exhaled Leukotrienes in Nonasthmatic Adult Patients with Seasonal Allergic Rhinitis

Czech Academy of Sciences Publication Activity Database

Čáp, P.; Pehal, F.; Malý, Marek; Chládek, J.

2005-01-01

Roč. 60, č. 2 (2005), s. 171-176 ISSN 0105-4538 Source of funding: V - iné verejné zdroje Keywords : allergic rhinitis * asthma * breath condensate * gas-chromatography/mass spectrometry analysis * leukotrienes Subject RIV: BB - Applied Statistics, Operational Research Impact factor: 4.120, year: 2005

Immunogenicity of nuclear-encoded LTB:ST fusion protein from Escherichia coli expressed in tobacco plants.

Science.gov (United States)

Rosales-Mendoza, Sergio; Soria-Guerra, Ruth E; Moreno-Fierros, Leticia; Govea-Alonso, Dania O; Herrera-Díaz, Areli; Korban, Schuyler S; Alpuche-Solís, Ángel G

2011-06-01

Enterotoxigenic Escherichia coli (ETEC) is one of the main causative agents of diarrhea in infants and for travelers. Inclusion of a heat-stable (ST) toxin into vaccine formulations is mandatory as most ETEC strains can produce both heat-labile (LT) and ST enterotoxins. In this study, a genetic fusion gene encoding for an LTB:ST protein has been constructed and transferred into tobacco via Agrobacterium tumefaciens-mediated transformation. Transgenic tobacco plants carrying the LTB:ST gene are then subjected to GM1-ELISA revealing that the LTB:ST has assembled into pentamers and displays antigenic determinants from both LTB and ST. Protein accumulation of up to 0.05% total soluble protein is detected. Subsequently, mucosal and systemic humoral responses are elicited in mice orally dosed with transgenic tobacco leaves. This has suggested that the plant-derived LTB:ST is immunogenic via the oral route. These findings are critical for the development of a plant-based vaccine capable of eliciting broader protection against ETEC and targeting both LTB and ST. Features of this platform in comparison to transplastomic approaches are discussed.

Combination of Dll4/Notch and Ephrin-B2/EphB4 targeted therapy is highly effective in disrupting tumor angiogenesis

International Nuclear Information System (INIS)

Djokovic, Dusan; Gill, Parkash S; Duarte, Antonio; Trindade, Alexandre; Gigante, Joana; Badenes, Marina; Silva, Lilliana; Liu, Ren; Li, Xiuqing; Gong, Ming; Krasnoperov, Valery

2010-01-01

Dll4/Notch and Ephrin-B2/EphB4 pathways play critical roles in tumor vessel development and maturation. This study evaluates the efficacy of the inhibition of both signaling pathways, alone and in combination, in reducing the growth of an autochthonous mouse tumor and assesses potential adverse effects. We used the transgenic RIP1-Tag2 tumor model to study the effects of 1) inhibition of Dll4/Notch by either Dll4 allelic deletion or use of a soluble extracellular Dll4 (sDll4), 2) inhibition of Ephrin-B2/EphB4 signaling by a soluble extracellular EphB4 fused to albumin (sEphB4-Alb), and 3) inhibition of both pathways by sEphB4-Alb combined with either Dll4 allelic deletion or sDll4. To investigate adverse effects, we used inducible endothelial-specific Dll4 knock-out mice, treated with sEphB4-Alb, and carried out histopathological analysis. Dll4 allele deletion or soluble Dll4 treatment resulted in increased tumor vessel density, reduced mural cell recruitment and vessel perfusion which resulted in reduced tumor size. The soluble EphB4 instead reduced vessel density and vessel perfusion, leading to reduction of tumor size. Greater efficacy was observed when sEphB4-Alb was combined with either Dll4 allele deletion or sDll4 in regards to tumor size, vessel perfusion and mural cell recruitment. Induced endothelial specific Dll4 loss-of-function caused hepatic vascular alterations, which were prevented by concomitant sEphB4-Alb treatment. Combination targeting of Dll4/Notch and Ephrin-B2/EphB4 has potential for clinical investigation, providing cumulative efficacy and increased safety over Dll4/Notch inhibition alone

Leukotriene-mediated neuroinflammation, toxic brain damage, and neurodegeneration in acute methanol poisoning

Czech Academy of Sciences Publication Activity Database

Zakharov, S.; Kotíková, K.; Nurieva, O.; Hlušička, J.; Kačer, P.; Urban, P.; Vaněčková, M.; Seidl, Z.; Diblík, P.; Kuthan, P.; Navrátil, Tomáš; Pelclová, D.

2017-01-01

Roč. 55, č. 4 (2017), s. 249-259 ISSN 1556-3650 Institutional support: RVO:61388955 Keywords : brain damage * leukotrienes * methanol poisoning * Neuroinflammation * nontraumatic brain injury * sequelae of poisoning Subject RIV: CG - Electrochemistry OBOR OECD: Electrochemistry (dry cells, batteries, fuel cells, corrosion metals, electrolysis) Impact factor: 3.677, year: 2016

Development of an ErbB4 monoclonal antibody that blocks neuregulin-1-induced ErbB4 activation in cancer cells

Energy Technology Data Exchange (ETDEWEB)

Okazaki, Shogo [Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582 (Japan); Nakatani, Fumi [Cell Biology Laboratory, Department of Pharmaceutical Sciences, Faculty of Pharmacy, Kinki University, Higashiosaka, Osaka 577-8502 Japan (Japan); Masuko, Kazue; Tsuchihashi, Kenji [Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582 (Japan); Ueda, Shiho; Masuko, Takashi [Cell Biology Laboratory, Department of Pharmaceutical Sciences, Faculty of Pharmacy, Kinki University, Higashiosaka, Osaka 577-8502 Japan (Japan); Saya, Hideyuki [Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582 (Japan); Nagano, Osamu, E-mail: osmna@sb3.so-net.ne.jp [Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582 (Japan)

2016-01-29

The use of monoclonal antibodies (mAbs) for cancer therapy is one of the most important strategies for current cancer treatment. The epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases, which regulates cancer cell proliferation, survival, and migration, is a major molecular target for antibody-based therapy. ErbB4/HER4, which contains a ligand-binding extracellular region, is activated by several ligands, including neuregulins (NRGs), heparin-binding EGF-like growth factor, betacellulin and epiregulin. Although there are clinically approved antibodies for ErbB1 and ErbB2, there are no available therapeutic mAbs for ErbB4, and it is not known whether ErbB4 is a useful target for antibody-based cancer therapy. In this study, we developed an anti-ErbB4 mAb (clone P6-1) that suppresses NRG-dependent activation of ErbB4 and examined its effect on breast cancer cell proliferation in the extracellular matrix. - Highlights: • We newly generated four clones of human ErbB4 specific mAb. • ErbB4 mAb clone P6-1 blocks ErbB4 phosphorylation induced by NRG-1. • ErbB4 mAb clone P6-1 suppresses NRG-1-promoted breast cancer cells proliferation on three dimensional culture condition.

Development of an ErbB4 monoclonal antibody that blocks neuregulin-1-induced ErbB4 activation in cancer cells

International Nuclear Information System (INIS)

Okazaki, Shogo; Nakatani, Fumi; Masuko, Kazue; Tsuchihashi, Kenji; Ueda, Shiho; Masuko, Takashi; Saya, Hideyuki; Nagano, Osamu

2016-01-01

The use of monoclonal antibodies (mAbs) for cancer therapy is one of the most important strategies for current cancer treatment. The epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases, which regulates cancer cell proliferation, survival, and migration, is a major molecular target for antibody-based therapy. ErbB4/HER4, which contains a ligand-binding extracellular region, is activated by several ligands, including neuregulins (NRGs), heparin-binding EGF-like growth factor, betacellulin and epiregulin. Although there are clinically approved antibodies for ErbB1 and ErbB2, there are no available therapeutic mAbs for ErbB4, and it is not known whether ErbB4 is a useful target for antibody-based cancer therapy. In this study, we developed an anti-ErbB4 mAb (clone P6-1) that suppresses NRG-dependent activation of ErbB4 and examined its effect on breast cancer cell proliferation in the extracellular matrix. - Highlights: • We newly generated four clones of human ErbB4 specific mAb. • ErbB4 mAb clone P6-1 blocks ErbB4 phosphorylation induced by NRG-1. • ErbB4 mAb clone P6-1 suppresses NRG-1-promoted breast cancer cells proliferation on three dimensional culture condition.

Combustion of Na2B4O7 + Mg + C to synthesis B4C powders

International Nuclear Information System (INIS)

Jiang Guojian; Xu Jiayue; Zhuang Hanrui; Li Wenlan

2009-01-01

Boron carbide powder was fabricated by combustion synthesis (CS) method directly from mixed powders of borax (Na 2 B 4 O 7 ), magnesium (Mg) and carbon. The adiabatic temperature of the combustion reaction of Na 2 B 4 O 7 + 6 Mg + C was calculated. The control of the reactions was achieved by selecting reactant composition, relative density of powder compact and gas pressure in CS reactor. The effects of these different influential factors on the composition and morphologies of combustion products were investigated. The results show that, it is advantageous for more Mg/Na 2 B 4 O 7 than stoichiometric ratio in Na 2 B 4 O 7 + Mg + C system and high atmosphere pressure in the CS reactor to increase the conversion degree of reactants to end product. The final product with the minimal impurities' content could be fabricated at appropriate relative density of powder compact. At last, boron carbide without impurities could be obtained after the acid enrichment and distilled water washing.

Qatar Exoplanet Survey : Qatar-3b, Qatar-4b, and Qatar-5b

Science.gov (United States)

Alsubai, Khalid; Mislis, Dimitris; Tsvetanov, Zlatan I.; Latham, David W.; Bieryla, Allyson; Buchhave, Lars A.; Esquerdo, Gilbert A.; Bramich, D. M.; Pyrzas, Stylianos; Vilchez, Nicolas P. E.; Mancini, Luigi; Southworth, John; Evans, Daniel F.; Henning, Thomas; Ciceri, Simona

2017-04-01

We report the discovery of Qatar-3b, Qatar-4b, and Qatar-5b, three new transiting planets identified by the Qatar Exoplanet Survey. The three planets belong to the hot Jupiter family, with orbital periods of {P}{{Q}3{{b}}} = 2.50792 days, {P}{{Q}4{{b}}} = 1.80539 days, and {P}{{Q}5{{b}}} = 2.87923 days. Follow-up spectroscopic observations reveal the masses of the planets to be {M}{{Q}3{{b}}} = 4.31 ± 0.47 {M}{{J}}, {M}{{Q}4{{b}}} = 6.10 ± 0.54 {M}{{J}}, and {M}{{Q}5{{b}}} = 4.32 ± 0.18 {M}{{J}}, while model fits to the transit light curves yield radii of {R}{{Q}3{{b}}} = 1.096 ± 0.14 {R}{{J}}, {R}{{Q}4{{b}}} = 1.135 ± 0.11 {R}{{J}}, and {R}{{Q}5{{b}}} = 1.107 ± 0.064 {R}{{J}}. The host stars are low-mass main sequence stars with masses and radii M Q3 = 1.145 ± 0.064 M ⊙, M Q4 = 0.896 ± 0.048 M ⊙, M Q5 = 1.128 ± 0.056 M ⊙ and R Q3 = 1.272 ± 0.14 R ⊙, R Q4 = 0.849 ± 0.063 R ⊙, and R Q5 = 1.076 ± 0.051 R ⊙ for Qatar-3, 4, and 5 respectively. The V magnitudes of the three host stars are V Q3 = 12.88, V Q4 = 13.60, and V Q5 = 12.82. All three new planets can be classified as heavy hot Jupiters (M > 4 M J).

Zileuton, 5-lipoxygenase inhibitor, acts as a chemopreventive agent in intestinal polyposis, by modulating polyp and systemic inflammation.

Directory of Open Access Journals (Sweden)

Elias Gounaris

Full Text Available Leukotrienes and prostaglandins, products of arachidonic acid metabolism, sustain both systemic and lesion-localized inflammation. Tumor-associated Inflammation can also contribute to the pathogenesis of colon cancer. Patients with inflammatory bowel disease (IBD have increased risk of developing colon cancer. The levels of 5-lipoxygenase (5-LO, the key enzyme for leukotrienes production, are increased in colon cancer specimens and colonic dysplastic lesions. Here we report that Zileuton, a specific 5-LO inhibitor, can prevent polyp formation by efficiently reducing the tumor-associated and systemic inflammation in APCΔ468 mice.In the current study, we inhibited 5-LO by dietary administration of Zileuton in the APCΔ468 mouse model of polyposis and analyzed the effect of in vivo 5-LO inhibition on tumor-associated and systemic inflammation.Zileuton-fed mice developed fewer polyps and displayed marked reduction in systemic and polyp-associated inflammation. Pro-inflammatory cytokines and pro-inflammatory innate and adaptive immunity cells were reduced both in the lesions and systemically. As part of tumor-associated inflammation Leukotriene B4 (LTB4, product of 5-LO activity, is increased focally in human dysplastic lesions. The 5-LO enzymatic activity was reduced in the serum of Zileuton treated polyposis mice.This study demonstrates that dietary administration of 5-LO specific inhibitor in the polyposis mouse model decreases polyp burden, and suggests that Zileuton may be a potential chemo-preventive agent in patients that are high-risk of developing colon cancer.

7 CFR 15b.4 - Discrimination prohibited.

Science.gov (United States)

2010-01-01

... 7 Agriculture 1 2010-01-01 2010-01-01 false Discrimination prohibited. 15b.4 Section 15b.4... ACTIVITIES RECEIVING FEDERAL FINANCIAL ASSISTANCE General Provisions § 15b.4 Discrimination prohibited. (a... in, be denied the benefits of, or otherwise be subjected to discrimination under any program or...

15 CFR 8b.4 - Discrimination prohibited.

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2010-01-01

... 15 Commerce and Foreign Trade 1 2010-01-01 2010-01-01 false Discrimination prohibited. 8b.4 Section 8b.4 Commerce and Foreign Trade Office of the Secretary of Commerce PROHIBITION OF DISCRIMINATION... Provisions § 8b.4 Discrimination prohibited. (a) General. No qualified handicapped individual shall, on the...

Prostaglandin (PG) E3 synthesis elicted by adrenergic stimuli in guinea-pig trachea (GPT) is mediated primarily by B2 adrenergic receptors

International Nuclear Information System (INIS)

Nadel, G.L.; Malik, K.U.; Lew, D.B.

1990-01-01

The purpose of this study was to examine arachidonic acid (AA) metabolism and to characterize the type of adrenergic receptor (AR) involved in the production of the major metabolite of this fatty acid. [ 14 C]AA was incubated with GPT-rings and the radiolabelled products were extracted and separated by TLC method. The medium was also assayed for radiolabelled immunoreactive PG's (iPG's) and leukotrienes (LT) B4 and C4 by RIA or Enzyme immunoassay (EIA) after exposure to various AR agonists. [ 14 C]AA was incorporated into GPT-rings and metabolized mainly into iPGE2 and smaller amounts into PGF2α. Trace amounts of PGD2 and 6-keto-PGF1α but not LTB4 or LTC4 were detected by RIA and/or EIA. Incubation of GPT rings for 15 minutes with isoproterenol and salbutamol resulted in a significant increase of PGE2 synthesis (optimum conc: 10 -7 , 10 -7 M respectively). In contrast, dobutamine, norepinephrine, phenylnephrine and xylazine (up to 10 -6 M) did not significantly increase PGE2 production. Isoproterenol-induced iPGE2 production was inhibited by a selective β2 antagonist, butoxamine (70%: 10 -7 M, 91%: 10 -6 M) and somewhat reduced by β1 antagonists practolol and metoprolol (30-64%:10 -6 M). These data suggest that isoproterenol induced iPGE2 synthesis is primarily mediated via activation of β2 adrenergic receptor

Role of LTA4H Polymorphism in Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome Occurrence and Clinical Severity in Patients Infected with HIV.

Science.gov (United States)

Narendran, Gopalan; Kavitha, Dhanasekaran; Karunaianantham, Ramesh; Gil-Santana, Leonardo; Almeida-Junior, Jilson L; Reddy, Sirasanambatti Devarajulu; Kumar, Marimuthu Makesh; Hemalatha, Haribabu; Jayanthi, Nagesh Nalini; Ravichandran, Narayanan; Krishnaraja, Raja; Prabhakar, Angamuthu; Manoharan, Tamizhselvan; Nithyananthan, Lokeswaran; Arjunan, Gunasundari; Natrajan, Mohan; Swaminathan, Soumya; Andrade, Bruno B

2016-01-01

Paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is an inflammatory phenomenon complicating HIV management in coincidental tuberculosis (TB) infection, upon immune reconstitution driven by antiretroviral therapy (ART). Leukotriene A4 hydroxylase (LTA4H), an enzyme which converts LTA4 to LTB4, regulates the balance between the anti-inflammatory lipoxins and pro-inflammatory LTB4, with direct implications in TB-driven inflammation. In humans, a single nucleotide polymorphism (SNP) in the LTA4H promoter which regulates its transcriptional activity (rs17525495) has been identified and described to impact clinical severity of TB presentation and response to corticosteroid therapy. Notably, the role of LTA4H on TB-IRIS has not been previously evaluated. Here, we performed an exploratory investigation testing the association of LTA4H polymorphism with respect to frequency of TB-IRIS occurrence and severity of TB-IRIS presentation in HIV-TB co-infected individuals. Genotypic evaluation of the LTA4H enzyme from available samples was retrospectively correlated with clinical data captured in case sheets including IRIS details. The cohort included patients recruited from a prospective cohort study nested within a randomized clinical trial (NCT0933790) of ART-naïve HIV+ patients with newly diagnosed rifampicin sensitive pulmonary TB in South India. Frequency of the wild type genotype (CC), as well as of the mutant genotypes (CT or TT) in the IRIS and non-IRIS patients was estimated. Comparative analyses were performed between wild genotype (CC) and the mutant genotypes (CT or TT) and tested for association between the LTA4H polymorphisms and IRIS incidence and clinical severity. A total of 142 eligible ART-naïve patients were included in the analyses. Eighty-six individuals exhibited the wild genotype (CC) while 56 had mutant genotypes (43-CT and only 13-TT). Variant allele frequency was 0.23 and 0.26 in non-IRIS group and in IRIS

Ordering effects in benzo[1,2-b:4,5-b']difuran-thieno[3,4-c]pyrrole-4,6- dione polymers with >7% solar cell efficiency

KAUST Repository

Warnan, Julien; Cabanetos, Clement; El Labban, Abdulrahman; Hansen, Michael Ryan; Tassone, Christopher J.; Toney, Michael F.; Beaujuge, Pierre

2014-01-01

Benzo[1,2-b:4,5-b']difuran-thieno[3,4-c]pyrrole-4,6-dione (PBDFTPD) polymers prepared by microwave-assisted synthesis can achieve power conversion efficiencies (PCEs) >7% in bulk-heterojunction solar cells with phenyl-C61/71-butyric acid methyl

Magnetic anomaly in superconducting TmRh4B4

International Nuclear Information System (INIS)

Smith, J.L.; Huang, C.Y.; Tsou, J.J.; Ho, J.C.

1978-01-01

The magnetic and superconducting properties of TmRh 4 B 4 (which becomes superconducting at 9.6 K) by means of ac and dc magnetic susceptibility and specific heat measurements are investigated. At 10.7 K, an ac susceptibility peak similar to those found in spin glasses has been observed. In addition, a pronounced specific heat peak has been observed at 11.4 K. The susceptibility peak is essentially unaffected by substitution of 1% Lu or Er for the Tm, but it diminishes when much larger amounts of Er are substituted. The physical origin of this anomalous peak will be discussed

5-Methyl-4-oxo-4,6-dihydro-3H-pyridazino[4,5-b]carbazole-1-carbonitrile

Directory of Open Access Journals (Sweden)

Norbert Haider

2010-02-01

Full Text Available The title compound was prepared in excellent yield from 5-methyl-4-oxo-4,6-dihydro-3H-pyridazino[4,5-b]carbazole-1-carbaldehyde by treatment with hydroxylamine hydrochloride in formic acid without isolation of the intermediate oxime.

26 CFR 1.50B-4 - Partnerships.

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2010-04-01

... § 1.50A-3, or if the partnership fails to pay comparable wages and such failure is subject to the... 26 Internal Revenue 1 2010-04-01 2010-04-01 true Partnerships. 1.50B-4 Section 1.50B-4 Internal... Credit for Expenses of Work Incentive Programs § 1.50B-4 Partnerships. (a) General rule—(1) In general...

26 CFR 1.167(b)-4 - Other methods.

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2010-04-01

... 26 Internal Revenue 2 2010-04-01 2010-04-01 false Other methods. 1.167(b)-4 Section 1.167(b)-4...) INCOME TAXES (CONTINUED) Itemized Deductions for Individuals and Corporations § 1.167(b)-4 Other methods. (a) Under section 167(b)(4) a taxpayer may use any consistent method of computing depreciation, such...

Leukotrienes and 8-isoprostane in exhaled breath condensate in bronchoprovocation tests with occupational allergens

Czech Academy of Sciences Publication Activity Database

Klusáčková, P.; Lebedová, J.; Kačer, P.; Kuzma, Marek; Brabec, Marek; Pelclová, D.; Fenclová, Z.; Navrátil, Tomáš

2008-01-01

Roč. 78, 4-5 (2008), s. 281-292 ISSN 0952-3278 Institutional research plan: CEZ:AV0Z50200510; CEZ:AV0Z10300504; CEZ:AV0Z40400503 Keywords : occupational allergens * leukotrienes * 8-isoprostane Subject RIV: CC - Organic Chemistry Impact factor: 1.366, year: 2008

45 CFR 73b.4 - Proceedings.

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2010-10-01

... 45 Public Welfare 1 2010-10-01 2010-10-01 false Proceedings. 73b.4 Section 73b.4 Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ADMINISTRATION DEBARMENT OR SUSPENSION OF FORMER EMPLOYEES... reasonable cause to believe that a former officer or employee, including a former special Government employee...

B7-2 expressed on EL4 lymphoma suppresses antitumor immunity by an interleukin 4-dependent mechanism.

Science.gov (United States)

Stremmel, C; Greenfield, E A; Howard, E; Freeman, G J; Kuchroo, V K

1999-03-15

For T cells to become functionally activated they require at least two signals. The B7 costimulatory molecules B7-1 and B7-2 provide the "second signal" pivotal for T cell activation. In this report, we studied the relative roles of B7-1 and B7-2 molecules in the induction of antitumor immunity to the T cell thymoma, EL4. We generated EL4 tumor cells that expressed B7-1, B7-2, and B7-1+B7-2 by transfecting murine cDNAs. Our results demonstrate that EL4-B7-1 cells are completely rejected in syngeneic mice. Unlike EL4-B7-1 cells, we find that EL4-B7-2 cells are not rejected but progressively grow in the mice. A B7-1- and B7-2-EL4 double transfectant was generated by introducing B7-2 cDNA into the EL4-B7-1 tumor line that regressed in vivo. The EL4-B7-1+B7-2 double transfectant was not rejected when implanted into syngeneic mice but progressively grew to produce tumors. The double transfectant EL4 cells could costimulate T cell proliferation that could be blocked by anti-B7-1 antibodies, anti-B7-2 antibodies, or hCTLA4 immunoglobulin, showing that the B7-1 and B7-2 molecules expressed on the EL4 cells were functional. In vivo, treatment of mice implanted with double-transfected EL4 cells with anti-B7-2 monoclonal antibody resulted in tumor rejection. Furthermore, the EL4-B7-2 and EL4-B7-1+B7-2 cells, but not the wild-type EL4 cells, were rejected in interleukin 4 (IL-4) knockout mice. Our data suggests that B7-2 expressed on some T cell tumors inhibits development of antitumor immunity, and IL-4 appears to play a critical role in abrogation of the antitumor immune response.

CAREN-4, ENDF/B Utility, Discontinuity Check at Resonance Region Boundary. CHECK-4, ENDF/B Utility, Structure Consistency Check and Format Check. CRECT, ENDF/B Utility, Data Correlation and Data Update. DICT-4, ENDF/B Utility, Section Table of Contents Generator. LISTF-4, ENDF/B Utility, Data Listing. RIGEL-4, ENDF/B Utility, Data Retrieval, BCD to BIN Conversion. SUMUP-4, ENDF/B Utility, Partial Cross-Sections Sum Check Against Tot Cross-Sections

Energy Technology Data Exchange (ETDEWEB)

NONE

1975-08-01

Description of problem or function: These programs are updated versions of ENDF/B checking, retrieval, and display codes capable of processing the Version-IV data files. RIGEL4 retrieves ENDF/B data and changes mode (BCD-BIN) or arrangement. Updated version processes decay data (mf=1, mt=457) and error files. CHECK4 checks the structure, consistency, and formats of ENDF data files. Updated version recognizes newly defined mt and mf numbers, checks mt=457 and the formats of the error files, contains RSIC photon file changes. SUMUP4 checks whether partial cross sections add up to the total. Updated version flags grid points present in the partial cross section, absent in the total. LISTF4 produces interpreted listings of ENDF/B data. Updated version lists mt=457, skips over error files, contains minor corrections. PLOTF4 produces plots of ENDF/B data. Updated version plots mt=457, skips over error files, contains minor corrections. RESEND processes ENDF materials with resonance parameters into a pointwise form. Capability of processing Adler-Adler parameters added. CRECT corrects ENDF/B data files. DICT4 generates a section table of contents (dictionary) for ENDF/B materials. CAREN4 tests for discontinuities across the limits of resonance ranges of an ENDF/B material. Updated version contains minor corrections.

Real-time PCR quantification of human complement C4A and C4B genes

Directory of Open Access Journals (Sweden)

Fust George

2006-01-01

Full Text Available Abstract Background The fourth component of human complement (C4, an essential factor of the innate immunity, is represented as two isoforms (C4A and C4B in the genome. Although these genes differ only in 5 nucleotides, the encoded C4A and C4B proteins are functionally different. Based on phenotypic determination, unbalanced production of C4A and C4B is associated with several diseases, such as systemic lupus erythematosus, type 1 diabetes, several autoimmune diseases, moreover with higher morbidity and mortality of myocardial infarction and increased susceptibility for bacterial infections. Despite of this major clinical relevance, only low throughput, time and labor intensive methods have been used so far for the quantification of C4A and C4B genes. Results A novel quantitative real-time PCR (qPCR technique was developed for rapid and accurate quantification of the C4A and C4B genes applying a duplex, TaqMan based methodology. The reliable, single-step analysis provides the determination of the copy number of the C4A and C4B genes applying a wide range of DNA template concentration (0.3–300 ng genomic DNA. The developed qPCR was applied to determine C4A and C4B gene dosages in a healthy Hungarian population (N = 118. The obtained data were compared to the results of an earlier study of the same population. Moreover a set of 33 samples were analyzed by two independent methods. No significant difference was observed between the gene dosages determined by the employed techniques demonstrating the reliability of the novel qPCR methodology. A Microsoft Excel worksheet and a DOS executable are also provided for simple and automated evaluation of the measured data. Conclusion This report describes a novel real-time PCR method for single-step quantification of C4A and C4B genes. The developed technique could facilitate studies investigating disease association of different C4 isotypes.

Differential effects of BDNF and neurotrophin 4 (NT4) on endocytic sorting of TrkB receptors.

Science.gov (United States)

Proenca, Catia C; Song, Minseok; Lee, Francis S

2016-08-01

Neurotrophins are a family of growth factors playing key roles in the survival, development, and function of neurons. The neurotrophins brain-derived neurotrophic factor (BDNF) and NT4 both bind to and activate TrkB receptors, however, they mediate distinct neuronal functions. The molecular mechanism of how TrkB activation by BDNF and NT4 leads to diverse outcomes is unknown. Here, we report that BDNF and NT4 lead to differential endocytic sorting of TrkB receptors resulting in diverse biological functions in cultured cortical neurons. Fluorescent microscopy and surface biotinylation experiments showed that both neurotrophins stimulate internalization of TrkB with similar kinetics. Exposure to BDNF for 2-3 h reduced the surface pool of TrkB receptors to half, whereas a longer treatment (4-5 h) with NT4 was necessary to achieve a similar level of down-regulation. Although BDNF and NT4 induced TrkB phosphorylation with similar intensities, BDNF induced more rapid ubiquitination and degradation of TrkB than NT4. Interestingly, TrkB receptor ubiquitination by these ligands have substantially different pH sensitivities, resulting in varying degrees of receptor ubiquitination at lower pH levels. Consequently, NT4 was capable of maintaining longer sustained downstream signaling activation that correlated with reduced TrkB ubiquitination at endosomal pH. Thus, by leading to altered endocytic trafficking itineraries for TrkB receptors, BDNF and NT4 elicit differential TrkB signaling in terms of duration, intensity, and specificity, which may contribute to their functional differences in vivo. The neurotrophins, brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT4), both bind to and activate TrkB receptors, however, they mediate distinct neuronal functions. Here, we propose that BDNF and NT4 lead to differential endocytic sorting of TrkB receptors resulting in diverse biological functions. BDNF induces more rapid ubiquitination and degradation of TrkB than NT4

11B study of spin dynamics in Y/sub 1-x/RE/sub x/Rh4B4

International Nuclear Information System (INIS)

Kumagai, K.; Fradin, F.Y.

1982-06-01

There has been intense interest in re-entrance and coexistence in ternary rare earth magnetic superconductors of the form RE Rh 4 B 4 . Of particular interest in this investigation is the effect of the superconducting state on the RKKY (Yosida, 1957) coupling between RE ions. Since one expects the conduction electron spin susceptibility chi/sup e/(q) to be cut off for q - 1 for the RE moments in the superconducting state. This paper reports on the spin dynamics of the RE ions using the 11 B nuclear magnetic relaxation rate T 1- 1 in dilute Y/sub 1-x/RE/sub x/Rh 4 B 4 (RE = Gd and Er)

EphB4 as a therapeutic target in mesothelioma

International Nuclear Information System (INIS)

Liu, Ren; Ferguson, Benjamin D; Zhou, Yue; Naga, Kranthi; Salgia, Ravi; Gill, Parkash S; Krasnoperov, Valery

2013-01-01

Malignant pleural mesothelioma (MPM) often develops decades following exposure to asbestos. Current best therapy produces a response in only half of patients, and the median survival with this therapy remains under a year. A search for novel targets and therapeutics is underway, and recently identified targets include VEGF, Notch, and EphB4-Ephrin-B2. Each of these targets has dual activity, promoting tumor cell growth as well as tumor angiogenesis. We investigated EphB4 expression in 39 human mesothelioma tissues by immunohistochemistry. Xenograft tumors established with human mesothelioma cells were treated with an EphB4 inhibitor (monomeric soluble EphB4 fused to human serum albumin, or sEphB4-HSA). The combinatorial effect of sEphB4-HSA and biologic agent was also studied. EphB4 was overexpressed in 72% of mesothelioma tissues evaluated, with 85% of epithelioid and 38% of sarcomatoid subtypes demonstrating overexpression. The EphB4 inhibitor sEphB4-HSA was highly active as a single agent to inhibit tumor growth, accompanied by tumor cell apoptosis and inhibition of PI3K and Src signaling. Combination of sEphB4-HSA and the anti-VEGF antibody (Bevacizumab) was superior to each agent alone and led to complete tumor regression. EphB4 is a potential therapeutic target in mesothelioma. Clinical investigation of sEphB4-HSA as a single agent and in combination with VEGF inhibitors is warranted

Staphylococcus aureus and influenza A virus stimulate human bronchoalveolar cells to release histamine and leukotrienes

DEFF Research Database (Denmark)

Clementsen, P; Bisgaard, H; Pedersen, M

1989-01-01

persons were stimulated with Staph. aureus no release of leukotriene C4 was found. The mediator release caused by bacteria and virus might be of importance for the exacerbation of bronchial asthma in upper respiratory tract infections, since histamine is assumed to increase the epithelial permeability...

Systems Li[sub 2]B[sub 4]O[sub 7] (Na[sub 2]B[sub 4]O[sub 7], K[sub 2]B[sub 4]O[sub 7])-N[sub 2]H[sub 3]H[sub 4]OH-H[sub 2]O at 25 deg C. Sistemy Li[sub 2]B[sub 4]O[sub 7] (Na[sub 2]B[sub 4]O[sub 7], K[sub 2]B[sub 4]O[sub 7])-N[sub 2]H[sub 3]H[sub 4]OH-H[sub 2]O pri 25 grad S

Energy Technology Data Exchange (ETDEWEB)

Skvortsov, V G; Sadetdinov, Sh V; Akimov, V M; Mitrasov, Yu N; Petrova, O V; Klopov, Yu N [Chuvashskij Gosudarstvennyj Pedagogicheskij Inst., Cheboksary (Russian Federation) Universitet Druzhby Narodov, Moscow (Russian Federation)

1994-02-01

Phase equilibriums in the Li[sub 2]B[sub 4]O[sub 7] (Na[sub 2]B[sub 4]O[sub 7], K[sub 2]B[sub 4]O[sub 7])-N[sub 2]H[sub 3]H[sub 4]OH-H[sub 2]O systems were investigated by methods of isothermal solubility, refractometry and PH-metry at 25 deg C for the first time. Lithium and sodium tetraborates was established to form phases of changed composition mM[sub 2]B[sub 4]O[sub 7][center dot]nN[sub 2]H[sub 3]C[sub 2]H[sub 4]OH[center dot]XH[sub 2]O, where M=Li, Na with hydrazine ethanol. K[sub 2]B[sub 4]O[sub 7][center dot]4H[sub 2]O precipitates in solid phase in the case of potassium salt. Formation of isomorphous mixtures was supported by X-ray diffraction and IR spectroscopy methods.

[Escherichia coli heat-labile enterotoxin B subunit enhances the immune response against canine parvovirus VP2 in mice immunized by VP2 DNA vaccine].

Science.gov (United States)

Han, Dongmei; Zhong, Fei; Li, Xiujin; Wang, Wei; Wang, Xingxing; Pan, Sumin

2011-01-01

To investigate the effect of Escherichia coli heat-labile enterotoxin (LT) B subunit (LTB) gene on canine parvovirus (CPV) VP2 gene vaccine. The LTB gene was amplified by PCR from genomic DNA of E. coli 44815 strain. The VP2-70 fragment (210 bp) encoding major epitope of VP2 (70 amino acids) was amplified by PCR from a plasmid encoding VP2 gene. VP2-70 and LTB genes were inserted into the eukaryotic vector to construct VP2-70 gene,LTB gene and VP2-70-LTB fused gene vectors. The mice were immunized with VP2-70 vector, VP2-70-LTB fused vector, or VP2-70 vector plus LTB vector, respectively. The antibody titers at the different time were measured by using ELISA method. The spleen lymphocyte proliferation activity was analyzed by 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. The sequence of VP2-70 and LTB genes was identified. The recombinant VP2-70 and LTB proteins could be expressed in HEK293T cells in a secretory manner. The mice immunized with VP2-70 vector, VP2-70-LTB vector or VP2-70 vector plus LTB vector could generate the specific antibody against VP2 protein. The antibody titer immunized with VP2-70-LTB vector reached 1:5120 at 35 d post immunization, significantly higher than that of other two groups (P vaccine in mice.

B7-2 Expressed on EL4 Lymphoma Suppresses Antitumor Immunity by an Interleukin 4–dependent Mechanism

Science.gov (United States)

Stremmel, C.; Greenfield, E.A.; Howard, E.; Freeman, G.J.; Kuchroo, V.K.

1999-01-01

For T cells to become functionally activated they require at least two signals. The B7 costimulatory molecules B7-1 and B7-2 provide the “second signal” pivotal for T cell activation. In this report, we studied the relative roles of B7-1 and B7-2 molecules in the induction of antitumor immunity to the T cell thymoma, EL4. We generated EL4 tumor cells that expressed B7-1, B7-2, and B7-1+B7-2 by transfecting murine cDNAs. Our results demonstrate that EL4–B7-1 cells are completely rejected in syngeneic mice. Unlike EL4–B7-1 cells, we find that EL4–B7-2 cells are not rejected but progressively grow in the mice. A B7-1– and B7-2–EL4 double transfectant was generated by introducing B7-2 cDNA into the EL4–B7-1 tumor line that regressed in vivo. The EL4–B7-1+B7-2 double transfectant was not rejected when implanted into syngeneic mice but progressively grew to produce tumors. The double transfectant EL4 cells could costimulate T cell proliferation that could be blocked by anti–B7-1 antibodies, anti–B7-2 antibodies, or hCTLA4 immunoglobulin, showing that the B7-1 and B7-2 molecules expressed on the EL4 cells were functional. In vivo, treatment of mice implanted with double-transfected EL4 cells with anti–B7-2 monoclonal antibody resulted in tumor rejection. Furthermore, the EL4–B7-2 and EL4–B7-1+B7-2 cells, but not the wild-type EL4 cells, were rejected in interleukin 4 (IL-4) knockout mice. Our data suggests that B7-2 expressed on some T cell tumors inhibits development of antitumor immunity, and IL-4 appears to play a critical role in abrogation of the antitumor immune response. PMID:10075975

CASMO5 JENDL-4.0 and ENDF/B-VII.1beta4 libraries

International Nuclear Information System (INIS)

Rhodes, J.; Gheorghiu, N.; Ferrer, R.

2012-01-01

This paper details the generation of neutron data libraries for the CASMO5 lattice physics code based on the recently released JENDL-4.0 and ENDF/B-VII.1beta4 nuclear data evaluations. This data represents state-of-the-art nuclear data for late-2011. The key features of the new evaluations are briefly described along with the procedure for processing of this data into CASMO5, 586-energy group neutron data libraries. Finally some CASMO5 results for standard UO 2 and MOX critical experiments for the two new libraries and the current ENDF/B-VII.0 CASMO5 library are presented including the B and W 1810 series, DIMPLE S06A, S06B, TCA reflector criticals with iron plates and the PNL-30-35 MOX criticals. The results show that CASMO5 with the new libraries is performing well for these criticals with a very slight edge in results to the JENDL-4.0 nuclear data evaluation over the ENDF/B-VII.1beta4 evaluation. Work is currently underway to generate a CASMO5 library based on the final ENDF/B-VII.R1 evaluation released Dec. 22, 2011. (authors)

Short syntheses of enantiopure calystegine B-2, B-3, and B-4

DEFF Research Database (Denmark)

Skaanderup, Philip Robert; Madsen, Robert

2001-01-01

Calystegine B-2 B-3, and B-4 have been prepared in 5 steps from the benzyl protected methyl 6-iodoglycopyranosides of glucose, galactose and mannose, respectively, by using a zinc-mediated domino reaction followed by ring-closing olefin metathesis as the key steps.......Calystegine B-2 B-3, and B-4 have been prepared in 5 steps from the benzyl protected methyl 6-iodoglycopyranosides of glucose, galactose and mannose, respectively, by using a zinc-mediated domino reaction followed by ring-closing olefin metathesis as the key steps....

40 CFR 721.9662 - Thieno[3,4-b]-1,4-dioxin, 2,3-dihydro- (9CI).

Science.gov (United States)

2010-07-01

... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Thieno[3,4-b]-1,4-dioxin, 2,3-dihydro... Specific Chemical Substances § 721.9662 Thieno[3,4-b]-1,4-dioxin, 2,3-dihydro- (9CI). (a) Chemical...-b]-1,4-dioxin, 2,3-dihydro- (9CI) (PMN P-95-1825; CAS No. 126213-50-1) is subject to reporting under...

Prostaglandin (PG) E3 synthesis elicted by adrenergic stimuli in guinea-pig trachea (GPT) is mediated primarily by B2 adrenergic receptors

Energy Technology Data Exchange (ETDEWEB)

Nadel, G.L.; Malik, K.U.; Lew, D.B. (Univ. of Tennessee, Memphis (United States))

1990-02-26

The purpose of this study was to examine arachidonic acid (AA) metabolism and to characterize the type of adrenergic receptor (AR) involved in the production of the major metabolite of this fatty acid. ({sup 14}C)AA was incubated with GPT-rings and the radiolabelled products were extracted and separated by TLC method. The medium was also assayed for radiolabelled immunoreactive PG's (iPG's) and leukotrienes (LT) B4 and C4 by RIA or Enzyme immunoassay (EIA) after exposure to various AR agonists. ({sup 14}C)AA was incorporated into GPT-rings and metabolized mainly into iPGE2 and smaller amounts into PGF2{alpha}. Trace amounts of PGD2 and 6-keto-PGF1{alpha} but not LTB4 or LTC4 were detected by RIA and/or EIA. Incubation of GPT rings for 15 minutes with isoproterenol and salbutamol resulted in a significant increase of PGE2 synthesis (optimum conc: 10{sup {minus}7}, 10{sup {minus}7}M respectively). In contrast, dobutamine, norepinephrine, phenylnephrine and xylazine (up to 10{sup {minus}6}M) did not significantly increase PGE2 production. Isoproterenol-induced iPGE2 production was inhibited by a selective {beta}2 antagonist, butoxamine (70%: 10{sup {minus}7}M, 91%: 10{sup {minus}6}M) and somewhat reduced by {beta}1 antagonists practolol and metoprolol (30-64%:10{sup {minus}6}M). These data suggest that isoproterenol induced iPGE2 synthesis is primarily mediated via activation of {beta}2 adrenergic receptor.

Urinary leukotriene E4 and 11-dehydro-thromboxane B2 excretion in children with bronchial asthma

Directory of Open Access Journals (Sweden)

Kaori Yoshikawa

2004-01-01

Conclusions: The present findings suggest that high levels of CysLTs and TXA2 are associated with the pathogenesis of bronchial asthma. The measurement of urinary LTE4 and 11DTXB2 would be useful in understanding the individual pathogenesis of asthmatic children.

Cutting Edge: 2B4-Mediated Coinhibition of CD4+ T Cells Underlies Mortality in Experimental Sepsis.

Science.gov (United States)

Chen, Ching-Wen; Mittal, Rohit; Klingensmith, Nathan J; Burd, Eileen M; Terhorst, Cox; Martin, Greg S; Coopersmith, Craig M; Ford, Mandy L

2017-09-15

Sepsis is a leading cause of death in the United States, but the mechanisms underlying sepsis-induced immune dysregulation remain poorly understood. 2B4 (CD244, SLAM4) is a cosignaling molecule expressed predominantly on NK cells and memory CD8 + T cells that has been shown to regulate T cell function in models of viral infection and autoimmunity. In this article, we show that 2B4 signaling mediates sepsis lymphocyte dysfunction and mortality. 2B4 expression is increased on CD4 + T cells in septic animals and human patients at early time points. Importantly, genetic loss or pharmacologic inhibition of 2B4 significantly increased survival in a murine cecal ligation and puncture model. Further, CD4-specific conditional knockouts showed that 2B4 functions on CD4 + T cell populations in a cell-intrinsic manner and modulates adaptive and innate immune responses during sepsis. Our results illuminate a novel role for 2B4 coinhibitory signaling on CD4 + T cells in mediating immune dysregulation. Copyright © 2017 by The American Association of Immunologists, Inc.

Effect of selective phosphodiesterase inhibitors on the rat eosinophil chemotactic response in vitro

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Alves Alessandra C

1997-01-01

Full Text Available In the present study, we have performed a comparative analysis of the effect of selective inhibitors of phosphodiesterase (PDE type III, IV and V on eosinophil chemotaxis triggered by platelet activating factor (PAF and leukotriene B4 (LTB4 in vitro. The effect of the analogues N6-2'-O-dibutyryladenosine 3':5' cyclic monophosphate (Bt2 cyclic AMP and N2-2'-O- dibutyrylguanosine 3':5' cyclic monophosphate (Bt2 cyclic GMP has also been determined. The eosinophils were obtained from the peritoneal cavity of naive Wistar rats and purified in discontinuous Percoll gradients to 85-95% purity. We observed that pre-incubation of eosinophils with the PDE type IV inhibitor rolipram suppressed the chemotactic response triggered by PAF and LTB4, in association with an increase in the intracellular levels of cyclic AMP. In contrast, neither zaprinast (type V inhibitor nor type III inhibitors milrinone and SK&F 94836 affected the eosinophil migration. Only at the highest concentration tested did the analogue Bt2 cyclic AMP suppress the eosinophil chemotaxis, under conditions where Bt2 cyclic GMP was ineffective. We have concluded that inhibition of PDE IV, but not PDE III or V, was able to block the eosinophil chemotaxis in vitro, suggesting that the suppressive activity of selective PDE IV inhibitors on tissue eosinophil accumulation may, at least, be partially dependent on their ability to directly inhibit the eosinophil migration.

Comparative Analysis of Tear Film Levels of Inflammatory Mediators in Contact Lens Users.

Science.gov (United States)

Yüksel Elgin, Cansu; İskeleli, Güzin; Talaz, Serap; Akyol, Sibel

2016-04-01

To compare tear films levels of various inflammatory cytokines in asymptomatic contact lens (CL) users. CL users of rigid gas-permeable CLs (RGPCL) (group 1) or silicone hydrogel CLs (SiHCL) (group 2) were compared with non-CL-using healthy subjects (group 3). Tear samples were collected from subjects in each group after ensuring that there were no complications secondary to CL wear in the CL-wearing participants. Tear-film levels of interleukins (ILs)-1β, -6, and -8; granulocyte-macrophage colony-stimulating factor (GM-CSF) (using the Luminex method); and leukotriene B4 (LTB4) (using the ELISA method) were determined. Cytokine levels were compared among the three groups using analysis-of-variance (ANOVA) and Kruskall-Wallis tests. There were significant differences in concentrations of IL-1β, GM-CSF and LTB4 among the three groups (p = 0.002, p = 0.021 and p = 0.009, respectively), as shown by the Kruskall-Wallis test comparing all three groups for the three cytokines. There were no significant differences for IL-6 and IL-8 (p = 0.079 and 0.094, respectively) when all three groups were compared. There were substantial statistically significant differences between RGPCL users, SiHCL users and control subjects in levels of tear film cytokines. Although CL users were asymptomatic, changes in tear-film levels of several important inflammatory mediators revealed that a chronic inflammatory process occurs during CL wear.

Dissociation of 5' proximal helical regions in messenger RNAs by eukaryotic initiation factors 4F, 4A, and 4B

International Nuclear Information System (INIS)

Thach, R.E.; Lawson, T.G.; Lee, K.A.; Abramson, R.D.; Merrick, W.C.

1987-01-01

Ray, et al. demonstrated that the susceptibility of mRNAs to cleavage by ribonucleases is greatly increased by eIF-4A and eIF-4F in an ATP-dependent reaction, and that this reaction is enhanced by the presence of eIF-4B. They now report direct evidence for the dissociation of helical regions at the 5' ends of mRNAs by these factors. Helices were generated at the 5' ends of reovirus and rabbit globin mRNAs by hybridizing to them 32 P-labeled cDNA pentadecamers. The dissociation of the cDNAs from the mRNAs was monitored by Sephadex gel filtration. Addition of eIF-4F to hybrids caused the dissociation of small amounts of cDNAs, and this dissociation required ATP. Addition of eIF-4B stimulated this activity. Neither eIF-4B nor eIF-4A alone caused significant ATP-dependent dissociation, but they did so in combination. Interestingly, cDNAs that were hybridized to 5' distal regions were dissociated with efficiencies and rates similar to those of 5' proximal cDNAs. The presence of unlabelled cDNAs hybridized 5' proximally did not affect distal cDNA dissociation. These results confirm the earlier suggestion that eIF-4A, eIF-4B and eIF-4F play important roles in the disruption of mRNA secondary structure during initiation

Formalin-inactivated EV71 vaccine candidate induced cross-neutralizing antibody against subgenotypes B1, B4, B5 and C4A in adult volunteers.

Directory of Open Access Journals (Sweden)

Ai-Hsiang Chou

Full Text Available Enterovirus 71 (EV71 has caused several epidemics of hand, foot and mouth diseases (HFMD in Asia. No effective EV71 vaccine is available. A randomized and open-label phase I clinical study registered with ClinicalTrials.gov #NCT01268787, aims to evaluate the safety, reactogenicity and immunogenicity of a formalin-inactivated EV71 vaccine candidate (EV71vac at 5- and 10-µg doses. In this study we report the cross-neutralizing antibody responses from each volunteer against different subgenotypes of EV71 and CVA16.Sixty eligible healthy adults were recruited and vaccinated. Blood samples were obtained on day 0, 21 and 42 and tested against B1, B4, B5, C2, C4A, C4B and CVA16 for cross-neutralizing antibody responses.The immunogenicity of both 5- and 10- µg doses were found to be very similar. Approximately 45% of the participants had 4-fold increase in Nt, but there was no further increase in Nt after the second dose. EV71vac induced very strong cross-neutralizing antibody responses in >85% of volunteers without pre-existing Nt against subgenotype B1, B5 and C4A. EV71vac elicited weak cross-neutralizing antibody responses (∼20% of participants against a C4B and Coxsackie virus A16. Over 90% of vaccinated volunteers did not develop cross-neutralizing antibody responses (Nt<8 against a C2 strain. EV71vac can boost and significantly enhance the neutralizing antibody responses in volunteers who already had pre-vaccination antibodies against EV71 and/or CVA16.EV71vac is efficient in eliciting cross-neutralizing antibody responses against EV71 subgenotypes B1, B4, B5, and C4A, and provides the rationale for its evaluation in phase II clinical trials.ClinicalTrials.gov NCT01268787.

The superfamily of C3b/C4b-binding proteins

DEFF Research Database (Denmark)

Kristensen, Torsten; D'Eustachio, P; Ogata, R T

1987-01-01

The determination of primary structures by amino acid and nucleotide sequencing for the C3b-and/or C4b-binding proteins H, C4BP, CR1, B, and C2 has revealed the presence of a common structural element. This element is approximately 60 amino acids long and is repeated in a tandem fashion, commencing...... at the amino-terminal end of each molecule. Two other complement components, C1r and C1s, have two of these repeating units in the carboxy-terminal region of their noncatalytic A chains. Three noncomplement proteins, beta 2-glycoprotein I (beta 2I), the interleukin 2 receptor (IL 2 receptor), and the b chain...... of factor XIII, have 4, 2 and 10 of these repeating units, respectively. These proteins obviously belong to the above family, although there is no evidence that they interact with C3b and/or C4b. Human haptoglobin and rat leukocyte common antigen also contain two and three repeating units, respectively...

Urinary leukotriene E(4), eosinophil protein X, and nasal eosinophil cationic protein are not associated with respiratory symptoms in 1-year-old children.

Science.gov (United States)

Wojnarowski, C; Halmerbauer, G; Mayatepek, E; Gartner, C; Frischer, T; Forster, J; Kuehr, J

2001-09-01

Eosinophilic airways inflammation forms the pathophysiologic basis for a proportion of children at risk of developing recurrent wheezing. Early preventive measures and/or anti-inflammatory treatment may be guided by the identification of such children. We aimed to study the relationship between respiratory symptoms and indirect markers of airway inflammation. We measured eosinophil protein X (EPX) and leukotriene E(4) (LTE(4)) in urine, as well as eosinophil cationic protein (ECP) in nasal lavages, in a random sample of 1-year-old children with a family history of atopy who participated in an international multicenter study on the prevention of allergy in Europe. For urine analyses, 10 children with upper respiratory illness and 19 healthy children without a family history of atopy were also enrolled. Endogenous urinary LTE(4) was separated by HPLC and determined by enzyme immunoassay with a specific antibody. The concentrations of nasal ECP and urinary EPX were determined by RIA analysis. One hundred and ten children (mean age: 1.05+/-0.1 years) were enrolled. Prolonged coughing during the first year of life was reported in 29 children, wheezy breathing in 17 children, and dry skin in 33 children. A doctor's diagnosis of wheezy bronchitis was given to 17 children. Sensitization to dust mites (specific IgE > or =1.43 ML/units) was detected in two children. Children with a doctor's diagnosis of atopic dermatitis within the first 12 months of life (n=6) had significantly higher urinary EPX than children without this (66.7 vs 30.1 microg/mmol creatinine, P=0.01). Urinary excretion of EPX and LTE4 showed a weak correlation (r=0.22, P=0.02). There were no significant differences in urinary excretion of EPX and LTE(4) or nasal ECP between children with and without respiratory symptoms (P>0.1). At the age of 1 year, urinary EPX is increased in children with atopic dermatitis. With regard to respiratory symptoms, urinary and nasal inflammatory parameters are not helpful in

6-(4-Bromophenyl-2-(4-fluorobenzylimidazo[2,1-b][1,3,4]thiadiazole

Directory of Open Access Journals (Sweden)

Afshan Banu

2011-04-01

Full Text Available In the title compound, C17H11BrFN3S, the imidazothiadiazole and bromophenyl rings are individually almost planar, with maximum deviations of 0.0215 (4 and 0.0044 (4 Å, respectively, and are inclined at an angle of 27.34 (3° with respect to each other. The dihedral angle between the mean planes of the fluorobenzyl and imidazothiadiazole rings is 79.54 (3°. The crystal structure is stabilized by intermolecular C—H...N interactions resulting in chains of molecules along the b axis.

Ordering effects in benzo[1,2-b:4,5-b']difuran-thieno[3,4-c]pyrrole-4,6- dione polymers with >7% solar cell efficiency

KAUST Repository

Warnan, Julien

2014-05-15

Benzo[1,2-b:4,5-b\\']difuran-thieno[3,4-c]pyrrole-4,6-dione (PBDFTPD) polymers prepared by microwave-assisted synthesis can achieve power conversion efficiencies (PCEs) >7% in bulk-heterojunction solar cells with phenyl-C61/71-butyric acid methyl ester (PCBM). In "as-cast" PBDFTPD-based devices solution-processed without a small-molecule additive, high PCEs can be obtained in spite of the weak propensity of the polymers to self-assemble and form π-aggregates in thin films. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Interface interaction in the B4C/(Fe-B-C) system

International Nuclear Information System (INIS)

Aizenshtein, M.; Mizrahi, I.; Froumin, N.; Hayun, S.; Dariel, M.P.; Frage, N.

2008-01-01

The wetting behavior in the B 4 C/(Fe-C-B) system was investigated in order to clarify the role of Fe additions on the sinterability of B 4 C. Iron and its alloys with C and B react with the boron carbide substrate and form a reaction zone consisting of a fine mixture of FeB and graphite. The apparent contact angles are relatively low for the alloys with a moderate concentration of the boron and carbon and allow liquid phase sintering to occur in the B 4 C-Fe mixtures. A dilatometric study of the sintering kinetics confirms that liquid phase sintering actually takes place and leads to improved mass transfer. A thermodynamic analysis of the ternary Fe-B-C system allows accounting for the experimental observations

Evidence for the involvement of 5-lipoxygenase products in ethanol-induced intestinal plasma protein loss

International Nuclear Information System (INIS)

Beck, I.T.; Boyd, A.J.; Dinda, P.K.

1988-01-01

In this study the authors investigated whether the products of 5-lipoxygenase (5-LO) were involved in the jejunal microvascular injury induced by intraluminal ethanol (ETH). A group of rabbits was given orally a selective inhibitor of 5-LO in two 10-mg doses, 24, and 2 h before the experiments. A jejunal segment was perfused with a control solution (control segment) and an adjacent segment with an ETH-containing solution (ETH-perfused segment). In a series of experiments, they measured 5-LO activity of the jejunal segments of both groups using the generation of leukotriene B 4 (LTB 4 ) as an index. In a second series of experiments, they determined the ETH-induced intraluminal protein loss, which was taken as a measure of mucosal microvascular damage. The ETH-induced increase in protein loss was significantly lower in the treated than in the untreated group. These findings suggest that products of 5-LO are involved in the ETH-induced jejunal microvascular injury

Anti-Inflammatory Activity and Mechanism of a Lipid Extract from Hard-Shelled Mussel (Mytilus Coruscus on Chronic Arthritis in Rats

Directory of Open Access Journals (Sweden)

Guipu Li

2014-01-01

Full Text Available The present study was designed to investigate the anti-inflammatory activity and mechanism of a lipid extract from hard-shelled mussel (Mytilus coruscus on adjuvant-induced (AIA and collagen-induced arthritis (CIA in rats. AIA and CIA rats that received hard-shelled mussel lipid extract (HMLE group at a dose of 100 mg/kg demonstrated significantly lower paw swelling and arthritic index, but higher body weight gain than those which received olive oil (control group. Similar results were found in arthritic rats that received New Zealand green-lipped mussel lipid extract (GMLE at the same dosage. The levels of leukotriene B4 (LTB4, prostaglandin E2 (PGE2, thromboxane B2 (TXB2 in the serum, and interleukin-1β (IL-1β, IL-6, interferon-γ (INF-γ, tumor necrosis factor-α (TNF-α in the ankle joint synovial fluids of HMLE group rats were significantly lower than those of control group. However, the levels of IL-4 and IL-10 in HMLE group rats were significantly higher than those in the control group. Decreased mRNA expressions of matrix metalloproteinase 1 (MMP1 and MMP13, but increased tissue inhibitor of metalloproteinase 1 (TIMP1 were observed in the knee joint synovium tissues of HMLE group rats when compared with the control group. No hepatotoxicity was observed in both HMLE and GMLE group rats. The present results indicated that HMLE had a similarly strong anti-inflammatory activity as GMLE. Such a strong efficacy could result from the suppression of inflammatory mediators (LTB4, PGE2, TXB2, pro-inflammatory cytokines (IL-1β, IL-6, INF-γ, TNF-α and MMPs (MMP1, MMP13, and the promotion of anti-inflammatory cytokines (IL-4, IL-10 and TIMPs (TIMP1 productions.

Magnetic fluctuations in UNi4B

DEFF Research Database (Denmark)

Mentink, S.A.M.; Mason, T.E.; Buyers, W.J.L.

1997-01-01

We investigate the magnetic fluctuation spectrum of the geometrically frustrated antiferromagnetic compound UNi4B, which partially orders below T-N = 20 K. An overdamped spin excitation is observed at the AF wave vector around 2.4 meV. Low-frequency, weakly Q-dependent inelastic scattering...

Granzyme B mediated function of Parvovirus B19-specific CD4+ T cells

Science.gov (United States)

Kumar, Arun; Perdomo, Maria F; Kantele, Anu; Hedman, Lea; Hedman, Klaus; Franssila, Rauli

2015-01-01

A novel conception of CD4+ T cells with cytolytic potential (CD4+ CTL) is emerging. These cells appear to have a part in controlling malignancies and chronic infections. Human parvovirus B19 can cause a persistent infection, yet no data exist on the presence of B19-specific CD4+ CTLs. Such cells could have a role in the pathogenesis of some autoimmune disorders reported to be associated with B19. We explored the cytolytic potential of human parvovirus B19-specific T cells by stimulating peripheral blood mononuclear cell (PBMC) with recombinant B19-VP2 virus-like particles. The cytolytic potential was determined by enzyme immunoassay-based quantitation of granzyme B (GrB) and perforin from the tissue culture supernatants, by intracellular cytokine staining (ICS) and by detecting direct cytotoxicity. GrB and perforin responses with the B19 antigen were readily detectable in B19-seropositive individuals. T-cell depletion, HLA blocking and ICS experiments showed GrB and perforin to be secreted by CD4+ T cells. CD4+ T cells with strong GrB responses were found to exhibit direct cytotoxicity. As anticipated, ICS of B19-specific CD4+ T cells showed expected co-expression of GrB, perforin and interferon gamma (IFN-γ). Unexpectedly, also a strong co-expression of GrB and interleukin 17 (IL-17) was detected. These cells expressed natural killer (NK) cell surface marker CD56, together with the CD4 surface marker. To our knowledge, this is the first report on virus-specific CD4+ CTLs co-expressing CD56 antigen. Our results suggest a role for CD4+ CTL in B19 immunity. Such cells could function within both immune regulation and triggering of autoimmune phenomena such as systemic lupus erythematosus (SLE) or rheumatoid arthritis. PMID:26246896

Impact of botanical oils on polyunsaturated fatty acid metabolism and leukotriene generation in mild asthmatics

Science.gov (United States)

2013-01-01

Background Dietary supplementation with botanical oils that contain n-6 and n-3 eighteen carbon chain (18C)-PUFA such as γ linolenic acid (GLA, 18:3n-6), stearidonic acid (SDA, 18:4n-3) and α linolenic acid (ALA, 18:3n-3) have been shown to impact PUFA metabolism, alter inflammatory processes including arachidonic acid (AA) metabolism and improve inflammatory disorders. Methods The diet of mild asthmatics patients was supplemented for three weeks with varying doses of two botanical seed oils (borage oil [Borago officinalis, BO] and echium seed oil [Echium plantagineum; EO]) that contain SDA, ALA and GLA. A three week wash out period followed. The impact of these dietary manipulations was evaluated for several biochemical endpoints, including in vivo PUFA metabolism and ex vivo leukotriene generation from stimulated leukocytes. Results Supplementation with several EO/BO combinations increased circulating 20–22 carbon (20–22C) PUFAs, including eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and dihommo-gammalinolenic acid (DGLA), which have been shown to inhibit AA metabolism and inflammation without impacting circulating AA levels. BO/EO combinations also inhibited ex vivo leukotriene generation with some combinations attenuating cysteinyl leukotriene generation in stimulated basophils by >50% and in stimulated neutrophils by >35%. Conclusions This study shows that dietary supplementation with BO/EO alters 20–22C PUFA levels and attenuates leukotriene production in a manner consistent with a reduction in inflammation. PMID:24088297

Impaired neonatal macrophage phagocytosis is not explained by overproduction of prostaglandin E2

Directory of Open Access Journals (Sweden)

Ballinger Megan N

2011-12-01

Full Text Available Abstract Background Neonates and young infants manifest increased susceptibility to bacterial, viral and fungal lung infections. Previous work has identified a role for eicosanoids in mediating host defense functions of macrophages. This study examines the relationship between alveolar macrophage (AM host defense and production of lipid mediators during the neonatal period compared to adult AMs. Methods AMs were harvested from young (day 7 and day 14 and adult (~10 week rats. The functionality of these cells was assessed by examining their ability to phagocytose opsonized targets, produce cytokines, eicosanoids and intracellular cAMP measured by enzyme immunoassays, and gene expression of proteins, enzymes and receptors essential for eicosanoid generation and phagocytosis measured by real time RT-PCR. Results AMs from young animals (day 7 and 14 were defective in their ability to phagocytose opsonized targets and produce tumor necrosis factor (TNF- α. In addition, young AMs produce more prostaglandin (PG E2, a suppressor of host defense, and less leukotriene (LT B4, a promoter of host defense. Young AMs express higher levels of enzymes responsible for the production of PGE2 and LTB4; however, there was no change in the expression of E prostanoid (EP receptors or LT receptors. Despite the similar EP profiles, young AMs are more responsive to PGE2 as evidenced by their increased production of the important second messenger, cyclic AMP. In addition, young AMs express higher levels of PDE3B and lower levels of PDE4C compared to adult AMs. However, even though the young AMs produced a skewed eicosanoid profile, neither the inhibition of PGE2 by aspirin nor the addition of exogenous LTB4 rescued the defective opsonized phagocytosis. Examination of a receptor responsible for mediating opsonized phagocytosis showed a significant decrease in the gene expression levels of the Fcgamma receptor in young (day 7 AMs compared to adult AMs. Conclusion These

EphB4 promotes or suppresses Ras/MEK/ERK pathway in a context-dependent manner: Implications for EphB4 as a cancer target.

Science.gov (United States)

Xiao, Zhan; Carrasco, Rosa; Kinneer, Krista; Sabol, Darrin; Jallal, Bahija; Coats, Steve; Tice, David A

2012-06-01

EphB4 is a member of the Eph receptor tyrosine kinase family shown to act in neuronal guidance and mediate venal/arterial separation. In contrast to these more established roles, EphB4's function in cancer is much less clear. Here we illustrate both tumor promoting as well as suppressing roles of EphB4, by showing that its activation resulted in inhibition of the Ras/ERK pathway in endothelial cells but activation of the same pathway in MCF-7 breast cancer cells. This was true if EphB4 was stimulated with EphrinB2, its natural ligand, or an agonistic monoclonal antibody for EphB4. Correspondingly, EphB4 activation stimulated MCF7 growth while inhibiting HUVEC cell proliferation. The reason for these dramatic differences is due to functional coupling of EphB4 to different downstream effectors. Reduction of p120 RasGAP in HUVEC cells attenuated the inhibitory effect of EphB4 activation on the ERK pathway, whereas knockdown of PP2A in MCF7 cells attenuated EphB4 activation of the ERK pathway. This represents the first time a functional coupling between Eph receptor and PP2A has been demonstrated leading to activation of an oncogenic pathway. Our study illustrates the caveats and potential challenges of targeting EphB4 for cancer therapy due to the conflicting effects on cancer cell and endothelial cell compartments.

Aspirin-triggered lipoxin A4 and lipoxin A4 up-regulate transcriptional corepressor NAB1 in human neutrophils.

Science.gov (United States)

Qiu, F H; Devchand, P R; Wada, K; Serhan, C N

2001-12-01

Aspirin-triggered 15-epi-lipoxin A4 (ATL) is an endogenous lipid mediator that mimics the actions of native lipoxin A4, a putative "stop signal" involved in regulating resolution of inflammation. A metabolically more stable analog of ATL, 15-epi-16-(para-fluoro)-phenoxy-lipoxin A4 analog (ATLa), inhibits neutrophil recruitment in vitro and in vivo and displays potent anti-inflammatory actions. ATLa binds with high affinity to the lipoxin A4 receptor, a G protein-coupled receptor on the surface of leukocytes. In this study, we used freshly isolated human neutrophils to examine ATLa's potential for initiating rapid nuclear responses. Using differential display reverse transcription polymerase chain reaction, we identified a subset of genes that was selectively up-regulated upon short exposure of polymorphonuclear leukocytes to ATLa but not to the chemoattractant leukotriene B4 or vehicle alone. We further investigated ATLa regulation of one of the genes, NAB1, a transcriptional corepressor identified previously as a glucocorticoid-responsive gene in hamster smooth muscle cells. Treatment of human neutrophils with pertussis toxin blocked ATLa up-regulation of NAB1. In addition, ATLa stimulated NAB1 gene expression in murine lung vascular smooth muscle in vivo. These findings provide evidence for rapid transcriptional induction of a cassette of genes via an ATLa-stimulated G protein-coupled receptor pathway that is potentially protective and overlaps with the anti-inflammatory glucocorticoid regulatory circuit.

Structure determination of two structural analogs, named 3-[1-(2-fluoro-4-biphenyl)ethyl]-6-(4-fluorophenyl)-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole (C23H16F2N4S) and 3-[1-(2-fluoro-4-biphenyl)ethyl]-6-(4-chlorophenyl)-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole (C23H16ClFN4S) by synchrotron X-ray powder diffraction

Energy Technology Data Exchange (ETDEWEB)

Gündoğdu, Gülsüm; Aytaç, Sevim Peri; Müller, Melanie; Tozkoparan, Birsen; Kaynak, Filiz Betül

2017-12-01

Two novel compounds, 3-[1-(2-fluoro-4-biphenyl)ethyl]-6-(4-fluorophenyl)-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole (C₂₃H₁₆F₂N₄S) (1) and 3-[1-(2-fluoro-4-biphenyl)ethyl]-6-(4-chlorophenyl)-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole (C₂₃H₁₆ClFN₄S) (2), have been designed and synthesized as cytotoxic agents. The compounds were characterized by infrared, proton nuclear magnetic resonance, mass spectral data, elemental analysis and X-ray powder diffraction. The present study comprises spectral data and crystal structures of these novel compounds determined from synchrotron X-ray powder diffraction data. The structure solutions were obtained by simulated annealing. The final structures were achieved by Rietveld refinement using soft restraints for all bond lengths, bond angles, and planar groups. Both compounds crystallize in space group$P\\bar 1$,Z= 2, with the unit-cell parametersa= 6.37433(9),b= 11.3641(2),c= 14.09115(19) Å,α= 80.1740(8)°,β= 85.1164(8)°,γ= 80.9831(10)°,V= 991.55(3) ųof compound (1) anda= 6.53736(6),b= 11.55725(15),c= 14.01373(13) Å,α= 80.3323(7)°,β= 84.8939(6)°,γ= 79.3954(8)°,V= 1024.08(2) ųof compound (2). Structural analyses reveal that the title compounds are isostructural.

Effect of the Ti/B4C mole ratio on the reaction products and reaction mechanism in an Al–Ti–B4C powder mixture

International Nuclear Information System (INIS)

Zhang, Jingjing; Lee, Jung-Moo; Cho, Young-Hee; Kim, Su-Hyeon; Yu, Huashun

2014-01-01

The effect of the Ti/B 4 C mole ratio on the fabrication behavior of Al composites is investigated using Al–Ti–B 4 C powder mixtures as reactants. The quick spontaneous infiltration (QSI) process combined with the combustion reaction and DTA analysis were used. According to the thermodynamic predictions, which are verified in the experimental results, TiB 2 is formed in all the samples whereas TiC is only formed in reactants with a Ti/B 4 C mole ratio of more than two. The C atoms from the reacted B 4 C do not move into TiC but instead they move into Al 3 BC or Al 4 C 3 when the Ti/B 4 C mole ratio is less than two. In addition, the reaction mechanism with a Ti/B 4 C mole ratio of 0.75 is investigated extensively. - Highlights: • The critical role of the Ti/B 4 C mole ratio on the reaction products of Al–Ti–B 4 C was studied using experiments. • The experimental results are also supported by thermodynamic calculations presented in this paper. • The reaction mechanism with a Ti/B 4 C mole ratio of 0.75 is investigated extensively

26 CFR 48.4161(b)-4 - Tax-free sales.

Science.gov (United States)

2010-04-01

... 26 Internal Revenue 16 2010-04-01 2010-04-01 true Tax-free sales. 48.4161(b)-4 Section 48.4161(b)-4 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) MISCELLANEOUS EXCISE TAXES MANUFACTURERS AND RETAILERS EXCISE TAXES Sporting Goods § 48.4161(b)-4 Tax-free sales. For...

Nosocomial outbreak of neonatal gastroenteritis caused by a new serotype 4, subtype 4B human rotavirus.

Science.gov (United States)

Gerna, G; Forster, J; Parea, M; Sarasini, A; Di Matteo, A; Baldanti, F; Langosch, B; Schmidt, S; Battaglia, M

1990-07-01

A nosocomial outbreak of rotavirus gastroenteritis involving 52 newborns occurred between June and September 1988 at the University Children's Hospital of Freiburg, Federal Republic of Germany. Stools from 27 representative patients were examined for rotavirus serotypes, using a monoclonal antibody-based enzyme-linked immunosorbent assay. The electropherotype was also examined by polyacrylamide gel electrophoresis of genomic RNA. As many as 18 patients were found to be infected by serotype 4, subtype 4B strain, and in all of them the same electropherotype was detected. Although rotavirus from the remaining nine patients could not be typed, the electropherotype in four was identical to that of the serotype 4, subtype 4B strain. Thus, most of the patients in the outbreak were infected by the same rotavirus strain. Retrospective epidemiological studies showed that the 4B strain began to circulate at the hospital in January 1988, whereas only rotavirus serotypes 1, 3, and 4A were detected in 1985-1987. The primary case of the outbreak was presumably a newborn with acute gastroenteritis, admitted to the hospital from a small maternity unit in the same urban area. During the outbreak, 12 of 44 healthy newborns in the nurseries of the Children's Hospital and other maternity hospitals were found to be asymptomatic rotavirus carriers, and in three of the newborns the same 4B strain was detected. This is the first reported outbreak caused by a serotype 4, subtype 4B strain.

Fra SK 4b til MH 17

DEFF Research Database (Denmark)

Stræde, Therkel

2015-01-01

Om den nazistiske besættelsespolitik i Sydøstukraine og Sonderkommando 4b's udryddelse af jøder på den egn, hvor Malaysian Airlines MH 17 styrtede ned den 17. juli 2014......Om den nazistiske besættelsespolitik i Sydøstukraine og Sonderkommando 4b's udryddelse af jøder på den egn, hvor Malaysian Airlines MH 17 styrtede ned den 17. juli 2014...

Improved Photovoltaic Performance of a Semicrystalline Narrow Bandgap Copolymer Based on 4H-Cyclopenta[2,1-b : 3,4-b ']dithiophene Donor and Thiazolo[5,4-d]thiazole Acceptor Units

NARCIS (Netherlands)

Van Mierloo, Sarah; Hadipour, Afshin; Spijkman, Mark-Jan; Van den Brande, Niko; Ruttens, Bart; Kesters, Jurgen; D'Haen, Jan; Van Assche, Guy; de Leeuw, Dago M.; Aernouts, Tom; Manca, Jean; Lutsen, Laurence; Vanderzande, Dirk J.; Maes, Wouter; Haen, Jan D’

2012-01-01

A solution processable narrow bandgap polymer composed of alternating 2,5-dithienylthiazolo[5,4-d]thiazole and asymmetrically alkyl-substituted 4H-cyclopenta[2,1-b:3,4-b']dithiophene units (PCPDT-DTTzTz) was synthesized by Suzuki polycondensation and the donor acceptor copolymer was thoroughly

Photoluminescence in Pb{sup 2+} activated SrB{sub 4}O{sub 7} and SrB{sub 2}O{sub 4} phosphors

Energy Technology Data Exchange (ETDEWEB)

Gawande, A.B., E-mail: gawandeab@gmail.com [Department of Physics, SGB Amravati University, Amravati-444602, Maharashtra (India); Ingle, J.T. [J. D. Institute of Engineering and Technology, Yavatmal, Maharashtra (India); Sonekar, R.P., E-mail: sonekar_rp@yahoo.com [Department of Physics, G.S. College, Khamgaon District, Buldhana, Maharashtra (India); Omanwar, S.K. [Department of Physics, SGB Amravati University, Amravati-444602, Maharashtra (India)

2014-05-01

The powder samples of SrB{sub 4}O{sub 7}:Pb{sup 2+} and SrB{sub 2}O{sub 4}:Pb{sup 2+} were prepared by solution combustion synthesis method. The synthesis is based on the exothermic reaction between the fuel (Urea) and Oxidizer (Ammonium nitrate). The synthesized materials were characterized using TG–DTA, powder XRD, SEM and the photoluminescence properties were studied using a Hitachi F-7000 spectrophotometer at room temperature. Both the samples SrB{sub 4}O{sub 7}:Pb{sup 2+} and SrB{sub 2}O{sub 4}:Pb{sup 2+} show broad emission of Pb{sup 2+} respectively at 307 nm and 360 nm (corresponds to {sup 3}P{sub 1} to {sup 1}S{sub 0} transition). The optimum concentrations of Pb{sup 2+} in both the phosphors SrB{sub 4}O{sub 7}:Pb{sup 2+} and SrB{sub 2}O{sub 4}:Pb{sup 2+} were found to be 3 mol% (relative to Sr) and for this concentration the critical transfer distance R{sub 0} were calculated to be 10.21 Å and 12.22 Å respectively. The Stokes shifts were calculated to be respectively 4464 cm{sup −1} and 8454 cm{sup −1}. The emission bands of both the phosphors are in the UV region and the phosphors can be potential candidates for application in UV lamps. - Highlights: • SrB{sub 4}O{sub 7}:Pb{sup 2+} and SrB{sub 2}O{sub 4}:Pb{sup 2+} have been synthesized by Novel solution combustion synthesis technique. • The synthesized materials were characterized using TG–DTA, powder XRD and SEM. • Photoluminescence spectra of synthesized materials showed the characteristic transition in Pb{sup 2+}. • Stokes shift, optimum concentration and critical transfer distance R{sub 0} were determined.

Effect of increased HoxB4 on human megakaryocytic development

International Nuclear Information System (INIS)

Zhong, Yiming; Sullenbarger, Brent; Lasky, Larry C.

2010-01-01

Research highlights: → HoxB4 overexpression in human TF1 cells increased the expression of CD61 and CD41a. → HoxB4 fusion protein enhanced megakaryocytic development of CD34 + cord blood cells. → Ectopic HoxB4 increased Tpo receptor expression and decreased c-Myb expression. → HoxB4 RNA silencing increased c-Myb expression and decreased Fli-1 expression. -- Abstract: In order to produce clinically useful quantities of platelets ex vivo we may need to firstly enhance early self-renewal of hematopoietic stem cells (HSCs) and/or megakaryocyte (Mk) progenitors. The homeodomain transcription factor HoxB4 has been shown to be an important regulator of stem cell renewal and hematopoiesis; however, its effect on megakaryopoiesis is unclear. In this study, we investigated the effect of HoxB4 overexpression or RNA silencing on megakaryocytic development in the human TF1 progenitor cell line; we then used recombinant tPTD-HoxB4 fusion protein to study the effect of exogenous HoxB4 on megakaryocytic development of human CD34 positively-selected cord blood cells. We found that ectopic HoxB4 in TF1 cells increased the antigen expression of CD61and CD41a, increased the gene expression of thrombopoietin receptor (TpoR), Scl-1, Cyclin D1, Fog-1 and Fli-1 while it decreased c-Myb expression. HoxB4 RNA silencing in TF1 cells decreased the expression of CD61 and CD41a and decreased Fli-1 expression while it increased the expression of c-Myb. Recombinant tPTD-HoxB4 fusion protein increased the percentages and absolute numbers of CD41a and CD61 positive cells during megakaryocytic differentiation of CD34 positively-selected cord blood cells and increased the numbers of colony-forming unit-megakaryocyte (CFU-Mk). Adding tPTD-HoxB4 fusion protein increased the gene expression of TpoR, Cyclin D1, Fog-1 and Fli-1 while it inhibited c-Myb expression. Our data suggest that increased HoxB4 enhanced early megakaryocytic development in human TF1 cells and CD34 positively-selected cord

Effect of increased HoxB4 on human megakaryocytic development

Energy Technology Data Exchange (ETDEWEB)

Zhong, Yiming [Department of Pathology, The Ohio State University, Columbus, OH (United States); Program in Molecular, Cellular, and Developmental Biology, The Ohio State University, Columbus, OH (United States); Sullenbarger, Brent [Department of Pathology, The Ohio State University, Columbus, OH (United States); Lasky, Larry C., E-mail: Lasky.4@osu.edu [Department of Pathology, The Ohio State University, Columbus, OH (United States); Program in Molecular, Cellular, and Developmental Biology, The Ohio State University, Columbus, OH (United States)

2010-07-30

Research highlights: {yields} HoxB4 overexpression in human TF1 cells increased the expression of CD61 and CD41a. {yields} HoxB4 fusion protein enhanced megakaryocytic development of CD34{sup +} cord blood cells. {yields} Ectopic HoxB4 increased Tpo receptor expression and decreased c-Myb expression. {yields} HoxB4 RNA silencing increased c-Myb expression and decreased Fli-1 expression. -- Abstract: In order to produce clinically useful quantities of platelets ex vivo we may need to firstly enhance early self-renewal of hematopoietic stem cells (HSCs) and/or megakaryocyte (Mk) progenitors. The homeodomain transcription factor HoxB4 has been shown to be an important regulator of stem cell renewal and hematopoiesis; however, its effect on megakaryopoiesis is unclear. In this study, we investigated the effect of HoxB4 overexpression or RNA silencing on megakaryocytic development in the human TF1 progenitor cell line; we then used recombinant tPTD-HoxB4 fusion protein to study the effect of exogenous HoxB4 on megakaryocytic development of human CD34 positively-selected cord blood cells. We found that ectopic HoxB4 in TF1 cells increased the antigen expression of CD61and CD41a, increased the gene expression of thrombopoietin receptor (TpoR), Scl-1, Cyclin D1, Fog-1 and Fli-1 while it decreased c-Myb expression. HoxB4 RNA silencing in TF1 cells decreased the expression of CD61 and CD41a and decreased Fli-1 expression while it increased the expression of c-Myb. Recombinant tPTD-HoxB4 fusion protein increased the percentages and absolute numbers of CD41a and CD61 positive cells during megakaryocytic differentiation of CD34 positively-selected cord blood cells and increased the numbers of colony-forming unit-megakaryocyte (CFU-Mk). Adding tPTD-HoxB4 fusion protein increased the gene expression of TpoR, Cyclin D1, Fog-1 and Fli-1 while it inhibited c-Myb expression. Our data suggest that increased HoxB4 enhanced early megakaryocytic development in human TF1 cells and CD34

[A study on the construction, expression and immunosterility of Lagurus laguru zona pellucida 3 DNA vaccine pVAX1-sig-LTB-lZP3-C3d3].

Science.gov (United States)

Li, Chen-Chen; Yu, Ji-Yun; Jiang, Min; Tu, Yi-Xian; Ma, Xiao-Lin; Zhang, Fu-Chun

2011-09-01

To enhance the immunocontraceptive effect of Lagurus lagurus zona pellucida 3 DNA vaccine, and to achieve the prospect of application through the pVAX1-sig-LTB-lZP3-C3d3 different immunity pathway. Two adjuvant molecules were constructed into the recombinant plasmid pVAX1-sig-LTB-lZP3-C3d3 as DNA vaccine which contains Escherichia coli heat-labile enterotoxin B subunit and the molecular adjuvant 3 copies of C3d. The results of RT-PCR and western blot showed that the DNA vaccine was expressed in mRNA and protein level. The female C57BL/6 mice were immunized by three ways: intramuscular injection, intranasal or oral route.Antibody levels and types were detected by ELISA. ELISA results showed that recombinant plasmid pVAX1-sig-LTB-lZP3-C3d3 immunization induced specific IgG, IgA levels were significantly different comparing with control (Psig-LTB-lZP3-C3d3 can induce the specific immune response efficiently and enhance the immunocontraceptive effects.

12 CFR Appendix B to Subpart B of... - Article 4A, Funds Transfers

Science.gov (United States)

2010-01-01

... 12 Banks and Banking 2 2010-01-01 2010-01-01 false Article 4A, Funds Transfers B Appendix B to...—Article 4A, Funds Transfers Part 1—Subject Matter and Definitions Section 4A-101. Short Title This Article... otherwise provided in section 4A-108, this Article applies to funds transfers defined in section 4A-104...

Interface interaction in the B{sub 4}C/(Fe-B-C) system

Energy Technology Data Exchange (ETDEWEB)

Aizenshtein, M. [Department of Material Engineering, Ben-Gurion University, P.O. Box 653, Beer-Sheva 84105 (Israel); NRC-Negev, P.O. Box 9001, Beer-Sheva 84190 (Israel); Mizrahi, I.; Froumin, N.; Hayun, S.; Dariel, M.P. [Department of Material Engineering, Ben-Gurion University, P.O. Box 653, Beer-Sheva 84105 (Israel); Frage, N. [Department of Material Engineering, Ben-Gurion University, P.O. Box 653, Beer-Sheva 84105 (Israel)], E-mail: nfrage@bgu.ac.il

2008-11-15

The wetting behavior in the B{sub 4}C/(Fe-C-B) system was investigated in order to clarify the role of Fe additions on the sinterability of B{sub 4}C. Iron and its alloys with C and B react with the boron carbide substrate and form a reaction zone consisting of a fine mixture of FeB and graphite. The apparent contact angles are relatively low for the alloys with a moderate concentration of the boron and carbon and allow liquid phase sintering to occur in the B{sub 4}C-Fe mixtures. A dilatometric study of the sintering kinetics confirms that liquid phase sintering actually takes place and leads to improved mass transfer. A thermodynamic analysis of the ternary Fe-B-C system allows accounting for the experimental observations.

(4bS,8aS-1-Isopropyl-4b,8,8-trimethyl-4b,5,6,7,8,8a,9,10-octahydrophenanthren-2-yl acetate

Directory of Open Access Journals (Sweden)

Radouane Oubabi

2014-03-01

Full Text Available The hemisynthesis of the title compound, C22H32O2, was carried out through direct acetylation reaction of the naturally occurring diterpene totarol [systematic name: (4bS,8aS-4b,8,8-trimethyl-1-propan-2-yl-5,6,7,8a,9,10-hexahydrophenanthren-2-ol]. The molecule is built up from three fused six membered rings, one saturated and two unsaturated. The central unsaturated ring has a half-chair conformation, whereas the other unsaturated ring displays a chair conformation. The absolute configuration is deduced from the chemical pathway. The value of the Hooft parameter [−0.10 (6] allowed this absolute configuration to be confirmed.

Characterization and modulation of canine mast cell derived eicosanoids

Science.gov (United States)

Lin, Tzu-Yin; London, Cheryl A.

2013-01-01

Mast cells play an important role in both innate and acquired immunity as well as several pathological conditions including allergy, arthritis and neoplasia. They influence these processes by producing a variety of mediators including cytokines, chemokines and eicosanoids. Very little is currently known about the spectrum of inflammatory mediators, particularly eicosanoids (prostaglandins and leukotrienes), produced by canine mast cells. This is important since modulating mast cell derived eicosanoids may help in the treatment of autoimmune and inflammatory disorders. The purpose of this study was to investigate the spectrum of eicosanoids produced by normal canine mast cells and to evaluate the effects of cytokines and non-steroidal anti-inflammatory mediators (NSAIDS) on eicosanoid production and release. Canine bone marrow derived cultured mast cells (cBMCMCs) expressed COX-1, COX-2, and 5-LOX and synthesized and released PGD2, PGE2, LTB4, and LTC4 following activation by a variety of stimuli. The selective COX-2 NSAIDs carprofen (Rimadyl®) and deracoxib (Deramaxx®) inhibited PGD2 and PGE2 production but only slightly inhibited LTB4 and LTC4. The mixed COX-1/COX-2 inhibitor piroxicam blocked PGD2 and PGE2 production, but upregulated LTC4 following treatment while tepoxilan (Zubrin®), a pan COX/LOX inhibitor, markedly reduced the production of all eicosanoids. The LOX inhibitor nordihydroguaiaretic acid (NDGA) prevented LTB4/LTC4 release and BMBMC degranulation. Pre-incubation of cBMCMCs with IL-4 and SCF sensitized these cells to degranulation in response to substance P. In conclusion, canine BMCMCs produce an array of eicosanoids similar to those produced by mast cells from other species. Tepoxilan appeared to be the most effective NSAID for blocking eicosanoid production and thus may be useful for modulating mast cell mediated responses in dogs. PMID:20036014

Synthesis and antimicrobial activity of some novel fused heterocyclic 1,2,4-triazolo [3,4-b][1,3,4] thiadiazine derivatives

Science.gov (United States)

Sahu, Jagdish K.; Ganguly, Swastika; Kaushik, Atul

2014-01-01

In the present investigation, the synthesis and antimicrobial evaluation of 1,2,4-triazolo [3,4-b][1,3,4] thiadiazine including different pharmacophores are aimed at. In this study, a series of 6-aryl-3- (3,4 -dialkoxyphenyl)-7H -[1,2,4]triazolo [3,4-b][1,3,4] thiadiazine (7a-7k) was synthesized by condensing 4-amino-5-(3,4-dialkoxyphenyl)-4H-[1,2,4]- triazole-3-thiol (6) with various aromatic carboxylic acids in the presence of phenacyl bromides through one-pot reaction. Eleven fused heterocyclic derivatives were successfully synthesized. The structures of these newly synthesized compounds were characterized by IR, 1H NMR and mass spectroscopic studies. All the synthesized compounds were screened for their antimicrobial evaluation. Some of the compounds exhibited promising antimicrobial activity. From the present study it may be concluded that synthesized compounds are fruitful in terms of their structural novelty and marked biological activities. These compounds could be further modified to develop potential and safer antifungal agents. PMID:24959418

Mutagenicity, stable DNA adducts, and abasic sites induced in Salmonella by phenanthro[3,4-b]- and phenanthro[4,3-b]thiophenes, sulfur analogs of benzo[c]phenanthrene

Energy Technology Data Exchange (ETDEWEB)

Swartz, Carol D. [Department of Environmental Science and Engineering, University of North Carolina, Chapel Hill, NC 27599 (United States); King, Leon C.; Nesnow, Stephen [Environmental Carcinogenesis Division, US Environmental Protection Agency, Research Triangle Park, NC, 27711 (United States); Umbach, David M. [Biostatistics Branch, National Institute of Environmental Health Sciences, National Institutes of Health, DHHS, Research Triangle Park, NC 27709 (United States); Kumar, Subodh [Environmental Toxicology and Chemistry Laboratory, Great Lakes Center, State University of New York College at Buffalo, Buffalo, NY 14222 (United States); DeMarini, David M. [Environmental Carcinogenesis Division, US Environmental Protection Agency, Research Triangle Park, NC, 27711 (United States)], E-mail: demarini.david@epa.gov

2009-02-10

Sulfur-containing polycyclic aromatic hydrocarbons (thia-PAHs or thiaarenes) are common constituents of air pollution and cigarette smoke, but only a few have been studied for health effects. We evaluated the mutagenicity in Salmonella TA98, TA100, and TA104 of two sulfur-containing derivatives of benzo[c]phenanthrene, phenanthro[3,4-b]thiophene (P[3,4-b]T), and phenanthro[4,3-b]thiophene (P[4,3-b]T) as well as their dihydrodiol and sulfone derivatives. In addition, we assessed levels of stable DNA adducts (by {sup 32}P-postlabeling) as well as abasic sites (by an aldehydic-site assay) produced by six of these compounds in TA100. P[3,4-b]T and its 6,7- and 8,9-diols, P[3,4-b]T sulfone, P[4,3-b]T, and its 8,9-diol were mutagenic in TA100. P[3,4-b]T sulfone, the most potent mutagen, was approximately twice as potent as benzo[a]pyrene in both TA98 and TA100. Benzo-ring dihydrodiols were much more potent than K-region dihydrodiols, which had little or no mutagenic activity in any strain. P[3,4-b]T sulfone produced abasic sites and not stable DNA adducts; the other five compounds examined, B[c]P, B[c]P 3,4-diol, P[3,4-b]T, P[3,4-b]T 8,9-diol, and P[4,3-b]T 8,9-diol, produced only stable DNA adducts. P[3,4-b]T sulfone was the only compound that produced significant levels of frameshift mutagenicity and induced mutations primarily at GC sites. In contrast, B[c]P, its 3,4-diol, and the 8,9 diols of the phenanthrothiophenes induced mutations primarily at AT sites. P[3,4-b]T was not mutagenic in TA104, whereas P[3,4-b]T sulfone was. The two isomeric forms (P[3,4-b]T and P[4,3-b]T) are apparently activated differently, with the latter, but not the former, involving a diol pathway. This study is the first illustrating the potential importance of abasic sites in the mutagenicity of thia-PAHs.

Quantum oscillation measurements of β-LuAlB{sub 4}

Energy Technology Data Exchange (ETDEWEB)

Reiss, Pascal; Baglo, Jordan; Chen, Xiaoye; Tan, HongEn; Sutherland, Michael; Grosche, F. Malte [Cavendish Laboratory, University of Cambridge, Cambridge (United Kingdom); Friedemann, Sven [HH Wills Laboratory, University of Bristol, Bristol (United Kingdom); Goh, Swee K. [Chinese University of Hong Kong, Shatin, N.T. (China); Kuga, Kentaro; Nakatsuji, Satoru [Institute for Solid State Physics, University of Tokyo, Kashiwa (Japan); Harima, Hisatomo [Department of Physics, Graduate School of Science, Kobe University, Kobe (Japan)

2016-07-01

The Yb-based heavy fermion superconductor β-YbAlB{sub 4} displays a quantum critical point without tuning by applied pressure, magnetic field, or doping, which has been attributed to an unusual renormalised band structure. Quantum oscillation measurements of the Fermi surface in β-YbAlB{sub 4} have so far proved inconclusive, motivating us to undertake a detailed study of the isostructural reference compound β-LuAlB{sub 4}, which in contrast to the Yb compound is characterised by a filled 4f shell. We present comprehensive results from rotation and mass studies in β-LuAlB{sub 4}, which broadly agree with band structure calculations and display moderate mass enhancements contrasting with the much larger enhancements seen in β-YbAlB{sub 4} - further emphasising the important contribution of f electrons to the itinerant electron physics of β-YbAlB{sub 4}.

32 CFR 806b.4 - Privacy Act complaints.

Science.gov (United States)

2010-07-01

... be identified, the local Privacy Act officer will assume these duties. Issues that cannot be resolved... 32 National Defense 6 2010-07-01 2010-07-01 false Privacy Act complaints. 806b.4 Section 806b.4 National Defense Department of Defense (Continued) DEPARTMENT OF THE AIR FORCE ADMINISTRATION PRIVACY ACT...

Production of thermoluminescent dosemeters based on MgB4O7: Dy and MgB4O7: Tm

International Nuclear Information System (INIS)

Souza, Luiza Freire de; Souza, Divanizia N.

2013-01-01

The thermoluminescent dosimetry (TL) is a well-established technique for the detection of ionizing radiation in hospitals, clinics, and industrial establishments where there is the need to quantify the radiation. For this practice is require the use phosphors which are sensitive to radiation. Some phosphors are already commonly used in this practice, for example, TLD-100 (LiF: Mg, Ti), CaSO 4 :Tm and CaSO 4 :Dy. A compound that was most recently introduced in dosimetry and has many advantageous features to detect neutrons, electrons and gamma is the magnesium tetraborate (MgB 4 O 7 ), but the undoped material is not good for dosimetry, since signal does not show satisfactory thermoluminescence. The present work presents the analysis of the compound MgB 4 O 7 when doped with rare earth elements, thulium (Tm) and dysprosium (Dy). The production of MgB 4 O 7 : Dy and MgB 4 O 7 : Tm occurred under acidic conditions. Following the process of crystal growth, several tests were made on phosphors produced to verify the quality of materials as TL dosimeter. Initially, was made the identification of the crystalline phases found in the material, using the technique of X-ray diffractometry, and then were evaluated and compared the TL emission curves of the crystals with two different types of dopants, to this, the samples were irradiated with different radiation sources: 137 Cs (0,66 MeV), 60 Co (1.25 MeV) and X-rays (0.41 MeV) and based on the results was evaluated the energy dependence of phosphors. Another characteristic analyzed, was the decay of TL signal for the material (fading). The results show that the material can be an excellent TL dosimeter when doped with rare earth elements Dy and Tm. (author)

Suicidal gene therapy with rabbit cytochrome P450 4B1/4-ipomeanol, 2-aminoanthracene system in glioma cell

International Nuclear Information System (INIS)

Jang, Su Jin; Kang, Joo Hyun; Kim, Kwang Il; Lee, Tae Sup; Lee, Yong Jin; Woo, Kwang Sun; Chung, Wee Sup; Cheon, Gi Jeong; Choi, Chang Woon; Lim, Sang Moo

2010-01-01

Suicidal gene therapy is based on the transduction of tumor cells with 'suicide' genes encoding for prodrugactivating enzymes that render target cells susceptible to prodrug treatment. Suicidal gene therapy results in the death of tumor with the expression of gene encoding enzyme that converts non-toxic prodrug into cytotoxic product. Cytochrome P450 4B1 (CYP4B1) activates 4- ipomeanol (4-ipo) and 2-aminoanthracene (2-AA) to cytotoxic furane epoxide and unsaturated dialdehyde intermediate. In this study, therapeutic effects of suicidal gene therapy with rabbit CYP4B1/4-ipo or CYP4B1/2-AA system

Macrophage migration inhibitory factor counter-regulates dexamethasone-induced annexin 1 expression and influences the release of eicosanoids in murine macrophages.

Science.gov (United States)

Sun, Yu; Wang, Yu; Li, Jia-Hui; Zhu, Shi-Hui; Tang, Hong-Tai; Xia, Zhao-Fan

2013-10-01

Macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine and glucocorticoid (GC) counter-regulator, has emerged as an important modulator of inflammatory responses. However, the molecular mechanisms of MIF counter-regulation of GC still remain incomplete. In the present study, we investigated whether MIF mediated the counter-regulation of the anti-inflammatory effect of GC by affecting annexin 1 in RAW 264.7 macrophages. We found that stimulation of RAW 264.7 macrophages with lipopolysaccharide (LPS) resulted in down-regulation of annexin 1, while GC dexamethasone (Dex) or Dex plus LPS led to significant up-regulation of annexin 1 expression. RNA interference-mediated knockdown of intracellular MIF increased annexin 1 expression with or without incubation of Dex, whereas Dex-induced annexin 1 expression was counter-regulated by the exogenous application of recombinant MIF. Moreover, recombinant MIF counter-regulated, in a dose-dependent manner, inhibition of cytosolic phospholipase A2α (cPLA2α) activation and prostaglandin E2 (PGE2 ) and leukotriene B4 (LTB4 ) release by Dex in RAW 264.7 macrophages stimulated with LPS. Endogenous depletion of MIF enhanced the effects of Dex, reflected by further decease of cPLA2α expression and lower PGE2 and LTB4 release in RAW 264.7 macrophages. Based on these data, we suggest that MIF counter-regulates Dex-induced annexin 1 expression, further influencing the activation of cPLA2α and the release of eicosanoids. These findings will add new insights into the mechanisms of MIF counter-regulation of GC. © 2013 John Wiley & Sons Ltd.

EphB4 localises to the nucleus of prostate cancer cells

International Nuclear Information System (INIS)

Mertens-Walker, Inga; Lisle, Jessica E.; Nyberg, William A.; Stephens, Carson R.; Burke, Leslie; Rutkowski, Raphael; Herington, Adrian C.; Stephenson, Sally-Anne

2015-01-01

The EphB4 receptor tyrosine kinase is over-expressed in a variety of different epithelial cancers including prostate where it has been shown to be involved in survival, migration and angiogenesis. We report here that EphB4 also resides in the nucleus of prostate cancer cell lines. We used in silico methods to identify a bipartite nuclear localisation signal (NLS) in the extracellular domain and a monopartite NLS sequence in the intracellular kinase domain of EphB4. To determine whether both putative NLS sequences were functional, fragments of the EphB4 sequence containing each NLS were cloned to create EphB4NLS-GFP fusion proteins. Localisation of both NLS-GFP proteins to the nuclei of transfected cells was observed, demonstrating that EphB4 contains two functional NLS sequences. Mutation of the key amino residues in both NLS sequences resulted in diminished nuclear accumulation. As nuclear translocation is often dependent on importins we confirmed that EphB4 and importin-α can interact. To assess if nuclear EphB4 could be implicated in gene regulatory functions potential EphB4-binding genomic loci were identified using chromatin immunoprecipitation and Lef1 was confirmed as a potential target of EphB4-mediated gene regulation. These novel findings add further complexity to the biology of this important cancer-associated receptor. - Highlights: • The EphB4 protein can be found in the nucleus of prostate cancer cell lines. • EphB4 contains two functional nuclear localisation signals. • Chromatin immunoprecipitation has identified potential genome sequences to which EphB4 binds. • Lef1 is a confirmed target for EphB4-mediated gene regulation

EphB4 localises to the nucleus of prostate cancer cells

Energy Technology Data Exchange (ETDEWEB)

Mertens-Walker, Inga, E-mail: inga.mertenswalker@qut.edu.au [Institute of Health and Biomedical Innovation, Queensland University of Technology, Woolloongabba, QLD (Australia); Australian Prostate Cancer Research Centre—Queensland, Translational Research Institute, 37 Kent Street, Woolloongabba 4102, QLD (Australia); Lisle, Jessica E. [Institute of Health and Biomedical Innovation, Queensland University of Technology, Woolloongabba, QLD (Australia); Australian Prostate Cancer Research Centre—Queensland, Translational Research Institute, 37 Kent Street, Woolloongabba 4102, QLD (Australia); Nyberg, William A. [Institute of Health and Biomedical Innovation, Queensland University of Technology, Woolloongabba, QLD (Australia); Stephens, Carson R. [Institute of Health and Biomedical Innovation, Queensland University of Technology, Woolloongabba, QLD (Australia); Australian Prostate Cancer Research Centre—Queensland, Translational Research Institute, 37 Kent Street, Woolloongabba 4102, QLD (Australia); Burke, Leslie [Institute of Health and Biomedical Innovation, Queensland University of Technology, Woolloongabba, QLD (Australia); Rutkowski, Raphael; Herington, Adrian C.; Stephenson, Sally-Anne [Institute of Health and Biomedical Innovation, Queensland University of Technology, Woolloongabba, QLD (Australia); Australian Prostate Cancer Research Centre—Queensland, Translational Research Institute, 37 Kent Street, Woolloongabba 4102, QLD (Australia)

2015-04-10

The EphB4 receptor tyrosine kinase is over-expressed in a variety of different epithelial cancers including prostate where it has been shown to be involved in survival, migration and angiogenesis. We report here that EphB4 also resides in the nucleus of prostate cancer cell lines. We used in silico methods to identify a bipartite nuclear localisation signal (NLS) in the extracellular domain and a monopartite NLS sequence in the intracellular kinase domain of EphB4. To determine whether both putative NLS sequences were functional, fragments of the EphB4 sequence containing each NLS were cloned to create EphB4NLS-GFP fusion proteins. Localisation of both NLS-GFP proteins to the nuclei of transfected cells was observed, demonstrating that EphB4 contains two functional NLS sequences. Mutation of the key amino residues in both NLS sequences resulted in diminished nuclear accumulation. As nuclear translocation is often dependent on importins we confirmed that EphB4 and importin-α can interact. To assess if nuclear EphB4 could be implicated in gene regulatory functions potential EphB4-binding genomic loci were identified using chromatin immunoprecipitation and Lef1 was confirmed as a potential target of EphB4-mediated gene regulation. These novel findings add further complexity to the biology of this important cancer-associated receptor. - Highlights: • The EphB4 protein can be found in the nucleus of prostate cancer cell lines. • EphB4 contains two functional nuclear localisation signals. • Chromatin immunoprecipitation has identified potential genome sequences to which EphB4 binds. • Lef1 is a confirmed target for EphB4-mediated gene regulation.

Topological sigma B model in 4-dimensions

International Nuclear Information System (INIS)

Jun, Hyun-Keun; Park, Jae-Suk

2008-01-01

We propose a 4-dimensional version of topological sigma B-model, governing maps from a smooth compact 4-manifold M to a Calabi-Yau target manifold X. The theory depends on complex structure of X, while is independent of Kaehler metric of X. The theory is also a 4-dimensional topological field theory in the sense that the theory is independent of variation of Riemannian metric of the source 4-manifold M, potentially leading to new smooth invariant of 4-manifolds. We argue that the theory also comes with a topological family parametrized by the extended moduli space of complex structures.

Bronchial effects of leukotriene D4 inhalation in normal human lung

DEFF Research Database (Denmark)

Bisgaard, H; Groth, S

1987-01-01

obstruction had decreased by 50% of the maximum effect, and no delayed reaction was observed within 10 h. The reactivity of the airways did not change during 10 h after inhalation of LTD4 as tested by repeated exercise challenges. Pretreatment with ipratropium bromide prevented the effect of LTD4 on FEV1, yet...

Solid-State Synthesis and Structure of the Enigmatic Ammonium Octaborate: (NH4)2[B7O9(OH)5]·3/4B(OH)3·5/4H2O.

Science.gov (United States)

Neiner, Doinita; Sevryugina, Yulia V; Schubert, David M

2016-09-06

The compound known since the 19th century as ammonium octaborate was structurally characterized revealing the ammonium salt of the ribbon isomer of the heptaborate anion, [B7O9(OH)5](2-), with boric acid and water molecules. Of composition (NH4)2B7.75O12.63·4.88H2O, it approximates the classical ammonium octaborate composition (NH4)2B8O13·6H2O and has the structural formula {(NH4)2[B7O9(OH)5]}4·3B(OH)3·5H2O. It spontaneously forms at room temperature in solid-state mixtures of ammonium tetraborate and ammonium pentaborate. It crystallizes in the monoclinic space group P21/c with a = 11.4137(2) Å, b = 11.8877(2) Å, c = 23.4459(3) Å, β = 90.092(1)°, V = 3181.19(8) Å(3), and Z = 2 and contains well-ordered ammonium cations and [B7O9(OH)5](2-) anions and disordered B(OH)3 and H2O molecules linked by extensive H bonding. Expeditious solid-state formation of the heptaborate anion under ambient conditions has important implications for development of practical syntheses of industrially useful borates.

The cysteinyl leukotriene 2 receptor contributes to all-trans retinoic acid-induced differentiation of colon cancer cells

International Nuclear Information System (INIS)

Bengtsson, Astrid M; Jönsson, Gunilla; Magnusson, Cecilia; Salim, Tavga; Axelsson, Cecilia; Sjölander, Anita

2013-01-01

Cysteinyl leukotrienes (CysLTs) are potent pro-inflammatory mediators that are increased in samples from patients with inflammatory bowel diseases (IBDs). Individuals with IBDs have enhanced susceptibility to colon carcinogenesis. In colorectal cancer, the balance between the pro-mitogenic cysteinyl leukotriene 1 receptor (CysLT 1 R) and the differentiation-promoting cysteinyl leukotriene 2 receptor (CysLT 2 R) is lost. Further, our previous data indicate that patients with high CysLT 1 R and low CysLT 2 R expression have a poor prognosis. In this study, we examined whether the balance between CysLT 1 R and CysLT 2 R could be restored by treatment with the cancer chemopreventive agent all-trans retinoic acid (ATRA). To determine the effect of ATRA on CysLT 2 R promoter activation, mRNA level, and protein level, we performed luciferase gene reporter assays, real-time polymerase chain reactions, and Western blots in colon cancer cell lines under various conditions. ATRA treatment induces CysLT 2 R mRNA and protein expression without affecting CysLT 1 R levels. Experiments using siRNA and mutant cell lines indicate that the up-regulation is retinoic acid receptor (RAR) dependent. Interestingly, ATRA also up-regulates mRNA expression of leukotriene C 4 synthase, the enzyme responsible for the production of the ligand for CysLT 2 R. Importantly, ATRA-induced differentiation of colorectal cancer cells as shown by increased expression of MUC-2 and production of alkaline phosphatase, both of which could be reduced by a CysLT 2 R-specific inhibitor. This study identifies a novel mechanism of action for ATRA in colorectal cancer cell differentiation and demonstrates that retinoids can have anti-tumorigenic effects through their action on the cysteinyl leukotriene pathway

Synthesis, characterization and anti cancer activity of some fluorinated 3,6-diaryl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles

Directory of Open Access Journals (Sweden)

Deepak Chowrasia

2017-05-01

Full Text Available A series of fluorinated 3,6-diaryl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles (2a–2i was synthesized by condensation of various substituted 4-amino-5-phenyl-4H-1,2,4-triazole-3-thiols (1a–1i with penta fluoro benzoic acid in good yields (60–80%. The synthesized compounds were screened for anticancer activity against three cancerous cell lines MCF7 (human breast cancer, SaOS-2 (human osteosarcoma and K562 (human myeloid leukemia. The compounds showed moderate to good antiproliferative potency against the studied cell lines. Among these, compound 2b showed higher antiproliferative activity (IC50 22.1, 19 and 15 μM against MCF7, SaOS-2 and K562, respectively while 2a exhibited least antiproliferative activity (IC50 30.2, 39 and 29.4 μM against MCF7, SaOS-2 and K562 cells, respectively. Therefore, the present study demonstrates that fluorine substituted 3,6-diaryl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles would be a better prospective in the development of anticancer drugs.

17 CFR 260.11b-4 - Definition of “cash transaction” in section 311(b)(4).

Science.gov (United States)

2010-04-01

... transaction”, as used in section 311(b)(4), means any transaction in which full payment for goods or securities sold is made within 7 days after delivery of the goods or securities in currency or in checks or...

Suicidal gene therapy with rabbit cytochrome P450 4B1/4-ipomeanol, 2-aminoanthracene system in glioma cell

Energy Technology Data Exchange (ETDEWEB)

Jang, Su Jin; Kang, Joo Hyun; Kim, Kwang Il; Lee, Tae Sup; Lee, Yong Jin; Woo, Kwang Sun; Chung, Wee Sup; Cheon, Gi Jeong; Choi, Chang Woon; Lim, Sang Moo [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)

2010-10-15

Suicidal gene therapy is based on the transduction of tumor cells with 'suicide' genes encoding for prodrugactivating enzymes that render target cells susceptible to prodrug treatment. Suicidal gene therapy results in the death of tumor with the expression of gene encoding enzyme that converts non-toxic prodrug into cytotoxic product. Cytochrome P450 4B1 (CYP4B1) activates 4- ipomeanol (4-ipo) and 2-aminoanthracene (2-AA) to cytotoxic furane epoxide and unsaturated dialdehyde intermediate. In this study, therapeutic effects of suicidal gene therapy with rabbit CYP4B1/4-ipo or CYP4B1/2-AA system

Structural annotation of Beta-1,4-N-acetyl galactosaminyltransferase 1 (B4GALNT1) causing Hereditary Spastic Paraplegia 26.

Science.gov (United States)

Dad, Rubina; Malik, Uzma; Javed, Aneela; Minassian, Berge A; Hassan, Muhammad Jawad

2017-08-30

Beta-1,4-N-acetyl galactosaminyltransferase 1, B4GALNT1, is a GM2/GD2 synthase, involved in the expression of glycosphingolipids (GSLs) containing sialic acid. Mutations in the gene B4GALNT1 cause Hereditary Spastic Paraplegia 26 (HSP26). In present study we have made attempt to predict the potential structural of the human B4GALNT1 protein. The results illustrated that the amino acid sequences of B4GALNT1 are not 100% conserved among selected twenty species. One signal peptide and one transmembrane domain predicted in human wild type B4GALNT1 protein with aliphatic index of 92.76 and theoretical (iso-electric point) pI of 8.93. It was a kind of unstable protein with Grand average of hydropathicity (GRAVY) of -0.127. Various post-translational modifications were also predicted to exist in B4GALNT1 and predicted to interact with different proteins including ST8SIA5, SLC33A1, GLB1 and others. In the final round, reported missense mutations have shown the further decrease in stability of the protein. This in-silico analysis of B4GALNT1 protein will provide the basis for the further studies on structural variations and biological pathways involving B4GALNT1 in the HSP26. Copyright © 2017. Published by Elsevier B.V.

MS4a4B, a CD20 homologue in T cells, inhibits T cell propagation by modulation of cell cycle.

Directory of Open Access Journals (Sweden)

Hui Xu

2010-11-01

Full Text Available MS4a4B, a CD20 homologue in T cells, is a novel member of the MS4A gene family in mice. The MS4A family includes CD20, FcεRIβ, HTm4 and at least 26 novel members that are characterized by their structural features: with four membrane-spanning domains, two extracellular domains and two cytoplasmic regions. CD20, FcεRIβ and HTm4 have been found to function in B cells, mast cells and hematopoietic cells respectively. However, little is known about the function of MS4a4B in T cell regulation. We demonstrate here that MS4a4B negatively regulates mouse T cell proliferation. MS4a4B is highly expressed in primary T cells, natural killer cells (NK and some T cell lines. But its expression in all malignant T cells, including thymoma and T hybridoma tested, was silenced. Interestingly, its expression was regulated during T cell activation. Viral vector-driven overexpression of MS4a4B in primary T cells and EL4 thymoma cells reduced cell proliferation. In contrast, knockdown of MS4a4B accelerated T cell proliferation. Cell cycle analysis showed that MS4a4B regulated T cell proliferation by inhibiting entry of the cells into S-G2/M phase. MS4a4B-mediated inhibition of cell cycle was correlated with upregulation of Cdk inhibitory proteins and decreased levels of Cdk2 activity, subsequently leading to inhibition of cell cycle progression. Our data indicate that MS4a4B negatively regulates T cell proliferation. MS4a4B, therefore, may serve as a modulator in the negative-feedback regulatory loop of activated T cells.

MS4a4B, a CD20 homologue in T cells, inhibits T cell propagation by modulation of cell cycle.

Science.gov (United States)

Xu, Hui; Yan, Yaping; Williams, Mark S; Carey, Gregory B; Yang, Jingxian; Li, Hongmei; Zhang, Guang-Xian; Rostami, Abdolmohamad

2010-11-01

MS4a4B, a CD20 homologue in T cells, is a novel member of the MS4A gene family in mice. The MS4A family includes CD20, FcεRIβ, HTm4 and at least 26 novel members that are characterized by their structural features: with four membrane-spanning domains, two extracellular domains and two cytoplasmic regions. CD20, FcεRIβ and HTm4 have been found to function in B cells, mast cells and hematopoietic cells respectively. However, little is known about the function of MS4a4B in T cell regulation. We demonstrate here that MS4a4B negatively regulates mouse T cell proliferation. MS4a4B is highly expressed in primary T cells, natural killer cells (NK) and some T cell lines. But its expression in all malignant T cells, including thymoma and T hybridoma tested, was silenced. Interestingly, its expression was regulated during T cell activation. Viral vector-driven overexpression of MS4a4B in primary T cells and EL4 thymoma cells reduced cell proliferation. In contrast, knockdown of MS4a4B accelerated T cell proliferation. Cell cycle analysis showed that MS4a4B regulated T cell proliferation by inhibiting entry of the cells into S-G2/M phase. MS4a4B-mediated inhibition of cell cycle was correlated with upregulation of Cdk inhibitory proteins and decreased levels of Cdk2 activity, subsequently leading to inhibition of cell cycle progression. Our data indicate that MS4a4B negatively regulates T cell proliferation. MS4a4B, therefore, may serve as a modulator in the negative-feedback regulatory loop of activated T cells.

B7-2 Expressed on EL4 Lymphoma Suppresses Antitumor Immunity by an Interleukin 4–dependent Mechanism

OpenAIRE

Stremmel, C.; Greenfield, E.A.; Howard, E.; Freeman, G.J.; Kuchroo, V.K.

1999-01-01

For T cells to become functionally activated they require at least two signals. The B7 costimulatory molecules B7-1 and B7-2 provide the “second signal” pivotal for T cell activation. In this report, we studied the relative roles of B7-1 and B7-2 molecules in the induction of antitumor immunity to the T cell thymoma, EL4. We generated EL4 tumor cells that expressed B7-1, B7-2, and B7-1+B7-2 by transfecting murine cDNAs. Our results demonstrate that EL4–B7-1 cells are completely rejected in sy...

Ligand stimulation of ErbB4 and a constitutively-active ErbB4 mutant result in different biological responses in human pancreatic tumor cell lines

International Nuclear Information System (INIS)

Mill, Christopher P.; Gettinger, Kathleen L.; Riese, David J.

2011-01-01

Pancreatic cancer is the fourth leading cause of cancer death in the United States. Indeed, it has been estimated that 37,000 Americans will die from this disease in 2010. Late diagnosis, chemoresistance, and radioresistance of these tumors are major reasons for poor patient outcome, spurring the search for pancreatic cancer early diagnostic and therapeutic targets. ErbB4 (HER4) is a member of the ErbB family of receptor tyrosine kinases (RTKs), a family that also includes the Epidermal Growth Factor Receptor (EGFR/ErbB1/HER1), Neu/ErbB2/HER2, and ErbB3/HER3. These RTKs play central roles in many human malignancies by regulating cell proliferation, survival, differentiation, invasiveness, motility, and apoptosis. In this report we demonstrate that human pancreatic tumor cell lines exhibit minimal ErbB4 expression; in contrast, these cell lines exhibit varied and in some cases abundant expression and basal tyrosine phosphorylation of EGFR, ErbB2, and ErbB3. Expression of a constitutively-dimerized and -active ErbB4 mutant inhibits clonogenic proliferation of CaPan-1, HPAC, MIA PaCa-2, and PANC-1 pancreatic tumor cell lines. In contrast, expression of wild-type ErbB4 in pancreatic tumor cell lines potentiates stimulation of anchorage-independent colony formation by the ErbB4 ligand Neuregulin 1β. These results illustrate the multiple roles that ErbB4 may be playing in pancreatic tumorigenesis and tumor progression.

Photochemistry of U(BH4)4 and U(BD4)4

International Nuclear Information System (INIS)

Paine, R.T.; Schonberg, P.R.; Light, R.W.; Danen, W.C.; Freund, S.M.

1979-01-01

U(BH 4 ) 4 and U(BD 4 ) 4 are observed to undergo complex degradation reactions promoted by broadband UV radiation. The primary products of these reactions appear to be U(BH 4 ) 3 , B 2 H 6 , H 2 , U(BD 4 ) 3 , B 2 D 6 and D 2 . Further, U(BD 4 ) 4 undergoes a related decomposition reaction under the influence of CO 2 laser irradiation at 924.97 cm -1 . (author)

Chemical interaction of B4C, B, and C with Mo/Si layered structures

International Nuclear Information System (INIS)

Rooij-Lohmann, V. I. T. A. de; Veldhuizen, L. W.; Zoethout, E.; Yakshin, A. E.; Kruijs, R. W. E. van de; Thijsse, B. J.; Gorgoi, M.; Schaefers, F.; Bijkerk, F.

2010-01-01

To enhance the thermal stability, B 4 C diffusion barrier layers are often added to Mo/Si multilayer structures for extreme ultraviolet optics. Knowledge about the chemical interaction between B 4 C and Mo or Si, however is largely lacking. Therefore, the chemical processes during annealing up to 600 deg. C of a Mo/B 4 C/Si layered structure have been investigated in situ with hard x-ray photoelectron spectroscopy and ex situ with depth profiling x-ray photoelectron spectroscopy. Mo/B/Si and Mo/C/Si structures have also been analyzed as reference systems. The chemical processes in these systems have been identified, with two stages being distinguished. In the first stage, B and C diffuse and react predominantly with Mo. MoSi x forms in the second stage. If the diffusion barrier consists of C or B 4 C, a compound forms that is stable up to the maximum probed temperature and annealing time. We suggest that the diffusion barrier function of B 4 C interlayers as reported in literature can be caused by the stability of the formed compound, rather than by the stability of B 4 C itself.

Ethyl (E-2-(2,7-dimethyl-5-oxo-4H,5H-pyrano[4,3-b]pyran-4-ylideneacetate

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Oulemda Bassou

2017-02-01

Full Text Available In the title compound, C14H14O5, the two heterocyclic rings are coplanar (r.m.s. deviation = 0.008 Å, with the largest deviation from the mean plane being 0.012 (1 Å. The mean plane through the acetate group is inclined slightly with respect to the oxopyrano[4,3-b]pyran-4-yl system, as indicated by the dihedral angle of 1.70 (7° between them. Two intramolecular hydrogen bonds, completing S(6 ring motifs, are observed in the molecule. In the crystal, molecules are linked by weak C—H...O hydrogen bonds involving the same acceptor atom, forming chains propagating along the c-axis direction and enclosing R21(6 ring motifs. The chains are linked via offset π–π interactions [intercentroid distance = 3.622 (1 Å], involving inversion-related oxopyrano[4,3-b]pyran-4-yl ring systems, forming slabs parallel to the bc plane.

Flavonoids such as luteolin, fisetin and apigenin are inhibitors of interleukin-4 and interleukin-13 production by activated human basophils.

Science.gov (United States)

Hirano, Toru; Higa, Shinji; Arimitsu, Junsuke; Naka, Tetsuji; Shima, Yoshihito; Ohshima, Shiro; Fujimoto, Minoru; Yamadori, Tomoki; Kawase, Ichiro; Tanaka, Toshio

2004-06-01

We have previously shown that fisetin, a flavonol, inhibits IL-4 and IL-13 synthesis by allergen- or anti-IgE-antibody-stimulated basophils. This time, we investigated the inhibition of IL-4 and IL-13 production by basophils by other flavonoids and attempted to determine the fundamental structure of flavonoids related to inhibition. We additionally investigated whether flavonoids suppress leukotriene C4 synthesis by basophils and IL-4 synthesis by T cells in response to anti-CD3 antibody. Highly purified peripheral basophils were stimulated for 12 h with anti-IgE antibody alone or anti-IgE antibody plus IL-3 in the presence of various concentrations of 18 different kinds of flavones and flavonols. IL-4 and IL-13 concentrations in the supernatants were then measured. Leukotriene C4 synthesis was also measured after basophils were stimulated for 1 h in the presence of flavonoids. Regarding the inhibitory activity of flavonoids on IL-4 synthesis by T cells, peripheral blood mononuclear cells were cultured with flavonoids in anti-CD3-antibody-bound plates for 2 days. Luteolin, fisetin and apigenin were found to be the strongest inhibitors of both IL-4 and IL-13 production by basophils but did not affect leukotriene C4 synthesis. At higher concentrations, these flavonoids suppressed IL-4 production by T cells. Based on a hierarchy of inhibitory activity, the basic structure for IL-4 inhibition by basophils was determined. Due to the inhibitory activity of flavonoids on IL-4 and IL-13 synthesis, it can be expected that the intake of flavonoids, depending on the quantity and quality, may ameliorate allergic symptoms or prevent the onset of allergic diseases. Copyright 2004 S. Karger AG, Basel

Duplex unwinding and ATPase activities of the DEAD-box helicase eIF4A are coupled by eIF4G and eIF4B

Science.gov (United States)

Özeş, Ali R.; Feoktistova, Kateryna; Avanzino, Brian C.; Fraser, Christopher S.

2011-01-01

Eukaryotic initiation factor 4A (eIF4A) is a DEAD-box helicase that stimulates translation initiation by unwinding mRNA secondary structure. The accessory proteins, eIF4G, eIF4B, and eIF4H enhance the duplex unwinding activity of eIF4A, but the extent to which they modulate eIF4A activity is poorly understood. Here, we use real time fluorescence assays to determine the kinetic parameters of duplex unwinding and ATP hydrolysis by these initiation factors. To ensure efficient duplex unwinding, eIF4B and eIF4G cooperatively activate the duplex unwinding activity of eIF4A. Our data reveal that eIF4H is much less efficient at stimulating eIF4A unwinding activity than eIF4B, implying that eIF4H is not able to completely substitute for eIF4B in duplex unwinding. By monitoring unwinding and ATPase assays using identical conditions, we demonstrate that eIF4B couples the ATP hydrolysis cycle of eIF4A with strand separation, thereby minimizing non-productive unwinding events. Using duplex substrates with altered GC contents, but with similar predicted thermal stabilities, we further show that the rate of formation of productive unwinding complexes is strongly influenced by the local stability per base pair in addition to the stability of the entire duplex. This finding explains how a change in the GC content of a hairpin while maintaining overall predicted thermal stability is able to influence translation initiation. PMID:21840318

Effect of the Ti/B{sub 4}C mole ratio on the reaction products and reaction mechanism in an Al–Ti–B{sub 4}C powder mixture

Energy Technology Data Exchange (ETDEWEB)

Zhang, Jingjing [Key Laboratory of Liquid Structure and Heredity of Materials, Ministry of Education, Shandong University, Jinan 250100 (China); Light Metal Division, Korea Institute of Materials Science, Changwon 642-831 (Korea, Republic of); Lee, Jung-Moo, E-mail: jmoolee@kims.re.kr [Light Metal Division, Korea Institute of Materials Science, Changwon 642-831 (Korea, Republic of); Cho, Young-Hee; Kim, Su-Hyeon [Light Metal Division, Korea Institute of Materials Science, Changwon 642-831 (Korea, Republic of); Yu, Huashun [Key Laboratory of Liquid Structure and Heredity of Materials, Ministry of Education, Shandong University, Jinan 250100 (China)

2014-10-15

The effect of the Ti/B{sub 4}C mole ratio on the fabrication behavior of Al composites is investigated using Al–Ti–B{sub 4}C powder mixtures as reactants. The quick spontaneous infiltration (QSI) process combined with the combustion reaction and DTA analysis were used. According to the thermodynamic predictions, which are verified in the experimental results, TiB{sub 2} is formed in all the samples whereas TiC is only formed in reactants with a Ti/B{sub 4}C mole ratio of more than two. The C atoms from the reacted B{sub 4}C do not move into TiC but instead they move into Al{sub 3}BC or Al{sub 4}C{sub 3} when the Ti/B{sub 4}C mole ratio is less than two. In addition, the reaction mechanism with a Ti/B{sub 4}C mole ratio of 0.75 is investigated extensively. - Highlights: • The critical role of the Ti/B{sub 4}C mole ratio on the reaction products of Al–Ti–B{sub 4}C was studied using experiments. • The experimental results are also supported by thermodynamic calculations presented in this paper. • The reaction mechanism with a Ti/B{sub 4}C mole ratio of 0.75 is investigated extensively.

Molecular characterization of the recombinant protein RmLTI-BmCG-LTB: Protective immunity against Rhipicephalus (Boophilus microplus.

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Bárbara Guimarães Csordas

Full Text Available The bovine tick Rhipicephalus (Boophilus microplus is found in several tropical and subtropical regions of the world. This parasite transmits pathogens that cause disease, such as babesiosis (Babesia bovis and B. bigemina and anaplasmosis (Anaplasma marginale. Tick infestations cause enormous livestock losses, and controlling tick infestations and the transmission of tick-borne diseases remains a challenge for the livestock industry. Because the currently available commercial vaccines offer only partial protection against R. (B. microplus, there is a need for more efficient vaccines. Several recombinant antigens have been evaluated using different immunization strategies, and they show great promise. This work describes the construction and immunological characterization of a multi-antigen chimera composed of two R. (B. microplus antigens (RmLTI and BmCG and one Escherichia coli antigen (B subunit, LTB. The immunogenic regions of each antigen were selected and combined to encode a single polypeptide. The gene was cloned and expressed in E. coli. For all of the experiments, two groups (treated and control of four Angus heifers (3-6 months old were used. The inoculation was performed via intramuscular injection with 200 μg of purified recombinant chimeric protein and adjuvated. The chimeric protein was recognized by specific antibodies against each subunit and by sera from cattle inoculated with the chimera. Immunization of RmLTI-BmCG-LTB cattle reduced the number of adult female ticks by 6.29% and vaccination of cattle with the chimeric antigen provided 55.6% efficacy against R. (B. microplus infestation. The results of this study indicate that the novel chimeric protein is a potential candidate for the future development of a more effective vaccine against R. (B. microplus.

Cellular uptake of exogenous calcineurin B is dependent on TLR4/MD2/CD14 complexes, and CnB is an endogenous ligand of TLR4.

Science.gov (United States)

Yang, Jinju; Qin, Nannan; Zhang, Hongwei; Yang, Rui; Xiang, Benqiong; Wei, Qun

2016-04-19

Our previous research showed that recombinant calcineurin B (rhCnB) stimulates cytokine secretion by immune cells, probably through TLR4. Exogenous CnB can be incorporated into many different tumour cells in vitro, but the mode of uptake and receptors required remain unknown. Here, we report that exogenous CnB is taken up by cells in a time- and concentration-dependent manner via clathrin-dependent receptor-mediated internalization. Our findings further confirm that uptake is mediated by the TLR4/MD2 complex together with the co-receptor CD14. The MST results revealed a high affinity between CnB and the TLR4 receptor complex. No binding was detected between CnB and LPS. CnB inhibited the uptake of LPS, and LPS also inhibited the uptake of CnB. These results indicate that the uptake of exogenous CnB did not occur through LPS and that CnB was not a chaperone of LPS. Thus, we conclude that TLR4 receptor complexes were required for the recognition and internalization of exogenous CnB. CnB could be a potential endogenous ligand of TLR4 and function as an agonist of TLR4. These properties of CnB support its potential for development as an anti-cancer drug.

KONSUMSI MIKRONUTRIEN DAN EKSPRESI GEN eNOS3 ALEL INTRO 4a4b PADA PENDERITA HIPERTENSI ETNIK MINANGKABAU

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Delmi Sulastri

2011-05-01

Full Text Available AbstrakGen eNOS3 varian intron 4a4b merupakan salah satu gen yang berhubungan dengan kejadian hipertensi esensial. Kemampuan Gen eNOS3 varian ini untuk mensintesis enzim nitric oxide synthase (NOS berkurang sehingga sintesis Nitric oxide (NO menurun. Senyawa NO adalah suatu senyawa vasoaktif yang menyebabkan vasodilatasi pembuluh darah.Penelitian pada subjek hipertensi dan normotensi berusia 30-65 tahun bertujuan untuk melihat pengaruh mikronutrien terhadap ekspresi gen eNOS3 alel intron 4a4b. 130 subjek, diwawancara pola makannya lalu dilakukan analisis asupan mikronutrien, gen eNOS3, serta kadar NO plasma. Data yang diperoleh dianalisis menggunakan uji T dan chi-square.Kadar NO plasma penderita hipertensi adalah 26.91 + 15.40 μM/L dan normotensi 25.79 + 15.04 μM/L. 55.5% subjek hipertensi memiliki gen eNOS3 varian intron 4b dan 69% subjek normotensi mempunyai varian intron 4a4b. Kadar NO plasma rendah, (66.7% ditemukan pada subjek hipertensi dengan varian intron 4b. Tidak terdapat hubungan bermakna asupan mikronutrien dengan kadar NO plasma pada subjek hipertensi.Hasil ini tidak mendukung pengaruh konsumsi mikronutrien terhadap kadar NO plasma pada penderita hipertensi dengan gen eNOS3 varian intron 4a4b.Kata Kunci : hipertensi esensial, gen eNOS3, kadar NO plasmaAbstracteNOS 3 gene intron 4a4b allel is one of the important genes which is related to hypertesion essensial. This gene expresses the nitric oxide synthase (NOS enzyme which regulates the synthesis of Nitric oxide (NO in human body. NO causes vasodilatation, which decreases peripheral resistant and blood pressure.A research has been done based on cross sectional study on hypertension patients and those with normal blood pressure in the range of 30-65 years old. The main of this research is to evaluate the influence of micronutrient consumption on eNOS3 gene intron 4a4b allel expression in hypertension subjects in Minangkabau ethnicity. 130 subjects interviewed about micronutrient

The crystal structure of 6-(4-chlorophenyl-2-(4-methylbenzylimidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde

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A. Sowmya

2016-10-01

Full Text Available In the title imidazo[2,1-b][1,3,4]thiadiazole derivative, C19H14ClN3OS, the 4-methylbenzyl and chlorophenyl rings are inclined to the planar imidazo[2,1-b][1,3,4]thiadiazole moiety (r.m.s. deviation = 0.012 Å by 64.5 (1 and 3.7 (1°, respectively. The molecular structure is primarily stabilized by a strong intramolecular C—H...O hydrogen bond, leading to the formation of a pseudo-seven-membered S(7 ring motif, and a short intramolecular C—H...N contact forming an S(5 ring motif. In the crystal, molecules are linked by pairs of C—H...S hydrogen bonds, forming inversion dimers. The dimers are linked by C—H...O and C—H...π interactions, forming chains propagating along [110].

Heat release from B4C oxidation in steam and air

International Nuclear Information System (INIS)

Belovsky, L.

1996-01-01

BWR and some PWR cores contain boron carbide (B 4 C) as neutron absorber. During a severe accident, the B 4 C can potentially react with steam under release of heat and hydrogen. Although models for B 4 C oxidation already exist in MELCOR and SCDAP/RELAP5, a development of a new model for another computer code seems to be difficult due to a missing comprehensive description of the current modelling methodology and scarce experimental data. The aim of this paper is to highlight the key points of the B 4 C oxidation using the existing available experimental data and to perform a simple heat balance analysis of the B 4 C/steam and B 4 C/air chemical reactions. The analysis of literature data shows that the B 4 C oxidation phenomenon is qualitatively well described below 1000 deg. C. However, no reliable data exist for the reaction kinetics especially above this temperature. It was found that the experimental results strongly depend on the experimental arrangement. The reaction heats, calculated in this study, indicate that the B 4 C oxidation is an exothermic reaction, releasing more heat in air than in steam. The formation of boric acids from the boron oxide increases the heat release from B 4 C by ∼ 10%, in the worst case. Although the total heat, released in a PWR core from the B 4 C oxidation, is probably much smaller than the heat released from the Zr/steam reaction, it is not excluded that the B 4 C oxidation can locally contribute to the damage of the control elements due to local overheating. Modelling of these phenomena is, however, very difficult due to the complex geometry of the liquefied control elements and due to absence of suitable data on the reaction kinetics. (author). 25 refs, 2 figs, 3 tabs

Pseudomonas aeruginosa ExoU augments neutrophil transepithelial migration.

Science.gov (United States)

Pazos, Michael A; Lanter, Bernard B; Yonker, Lael M; Eaton, Alex D; Pirzai, Waheed; Gronert, Karsten; Bonventre, Joseph V; Hurley, Bryan P

2017-08-01

Excessive neutrophil infiltration of the lungs is a common contributor to immune-related pathology in many pulmonary disease states. In response to pathogenic infection, airway epithelial cells produce hepoxilin A3 (HXA3), initiating neutrophil transepithelial migration. Migrated neutrophils amplify this recruitment by producing a secondary gradient of leukotriene B4 (LTB4). We sought to determine whether this two-step eicosanoid chemoattractant mechanism could be exploited by the pathogen Pseudomonas aeruginosa. ExoU, a P. aeruginosa cytotoxin, exhibits phospholipase A2 (PLA2) activity in eukaryotic hosts, an enzyme critical for generation of certain eicosanoids. Using in vitro and in vivo models of neutrophil transepithelial migration, we evaluated the impact of ExoU expression on eicosanoid generation and function. We conclude that ExoU, by virtue of its PLA2 activity, augments and compensates for endogenous host neutrophil cPLA2α function, leading to enhanced transepithelial migration. This suggests that ExoU expression in P. aeruginosa can circumvent immune regulation at key signaling checkpoints in the neutrophil, resulting in exacerbated neutrophil recruitment.

Pseudomonas aeruginosa ExoU augments neutrophil transepithelial migration.

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Michael A Pazos

2017-08-01

Full Text Available Excessive neutrophil infiltration of the lungs is a common contributor to immune-related pathology in many pulmonary disease states. In response to pathogenic infection, airway epithelial cells produce hepoxilin A3 (HXA3, initiating neutrophil transepithelial migration. Migrated neutrophils amplify this recruitment by producing a secondary gradient of leukotriene B4 (LTB4. We sought to determine whether this two-step eicosanoid chemoattractant mechanism could be exploited by the pathogen Pseudomonas aeruginosa. ExoU, a P. aeruginosa cytotoxin, exhibits phospholipase A2 (PLA2 activity in eukaryotic hosts, an enzyme critical for generation of certain eicosanoids. Using in vitro and in vivo models of neutrophil transepithelial migration, we evaluated the impact of ExoU expression on eicosanoid generation and function. We conclude that ExoU, by virtue of its PLA2 activity, augments and compensates for endogenous host neutrophil cPLA2α function, leading to enhanced transepithelial migration. This suggests that ExoU expression in P. aeruginosa can circumvent immune regulation at key signaling checkpoints in the neutrophil, resulting in exacerbated neutrophil recruitment.

Eicosanoid and cytokine levels in plasma of patients during mesenteric infarction

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N. Nathan

1997-01-01

Full Text Available Multible organ failure (MOF induced by mesenteric infarction is associated with a high mortality rate. This study reports eicosanoid and cytokine levels in the blood of three atherosclerotic patients who ultimately died from MOF induced by mesenteric infarction. High plasma levels of 6- keto-prostaglandin (PG F1α (the stable metabolite of PGI2, interleukin (IL-6 and IL-8 are observed whereas plasma tumour necrosis factor alpha (TNFα, TxB2 (the stable metabolite of TxA2, PGE2, leukotrienes (LTB4 and LTC4, and whole blood platelet-activating factor levels are not different from values obtained in similarly severe atherosclerotic patients. This short report questioned the clinical involvement of TNFα during such a pathology where a persistent translocation of endotoxin has been observed through the gut endothelial barrier. Activation of phospholipase A2 is suggested by the increase in the stable metabolite of PGI2 and might be by itself or through lipidic metabolites, a major systemic stimulus of IL-6 and IL-8 production.

Repeated allergen exposure reduce early phase airway response and leukotriene release despite upregulation of 5-lipoxygenase pathways

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Cui Zhi-Hua

2012-03-01

Full Text Available Abstract Background Allergen induced early phase airway response and airway plasma exudation are predominantly mediated by inflammatory mast cell mediators including histamine, cysteinyl leukotrienes (cysLTs and thromboxane A2 (TXA2. The aim of the present study was to evaluate whether repeated allergen exposure affects early phase airway response to allergen challenge. Methods A trimellitic anhydride (TMA sensitized guinea pig model was used to investigate the effects of low dose repeated allergen exposure on cholinergic airway responsiveness, early phase airway response and plasma exudation, as well as local airway production of mast cell derived cysteinyl leukotrienes and thromboxane B2 (TXB2 after allergen challenge. Results Repeated low dose allergen exposure increased cholinergic airway responsiveness. In contrast, early phase airway response and plasma exudation in response to a high-dose allergen challenge were strongly attenuated after repeated low dose allergen exposure. Inhibition of the airway response was unspecific to exposed allergen and independent of histamine receptor blocking. Furthermore, a significant reduction of cysteinyl leukotrienes and TXB2 was found in the airways of animals repeatedly exposed to a low dose allergen. However, in vitro stimulation of airway tissue from animals repeatedly exposed to a low dose allergen with arachidonic acid and calcium ionophore (A23187 induced production of cysteinyl leukotrienes and TXB2, suggesting enhanced activity of 5-lipoxygenase and cyclooxygenase pathways. Conclusions The inhibition of the early phase airway response, cysteinyl leukotriene and TXB2 production after repeated allergen exposure may result from unresponsive effector cells.

Depleted Reactor Analysis With MCNP-4B

International Nuclear Information System (INIS)

Caner, M.; Silverman, L.; Bettan, M.

2004-01-01

Monte Carlo neutronics calculations are mostly done for fresh reactor cores. There is today an ongoing activity in the development of Monte Carlo plus burnup code systems made possible by the fast gains in computer processor speeds. In this work we investigate the use of MCNP-4B for the calculation of a depleted core of the Soreq reactor (IRR-1). The number densities as function of burnup were taken from the WIMS-D/4 cell code calculations. This particular code coupling has been implemented before. The Monte Carlo code MCNP-4B calculates the coupled transport of neutrons and photons for complicated geometries. We have done neutronics calculations of the IRR-1 core with the WIMS and CITATION codes in the past Also, we have developed an MCNP model of the IRR-1 standard fuel for a criticality safety calculation of a spent fuel storage pool

Rab5 Enhances Classical Swine Fever Virus Proliferation and Interacts with Viral NS4B Protein to Facilitate Formation of NS4B Related Complex

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Jihui Lin

2017-08-01

Full Text Available Classical swine fever virus (CSFV is a fatal pig pestivirus and causes serious financial losses to the pig industry. CSFV NS4B protein is one of the most important viral replicase proteins. Rab5, a member of the small Rab GTPase family, is involved in infection and replication of numerous viruses including hepatitis C virus and dengue virus. Until now, the effects of Rab5 on the proliferation of CSFV are poorly defined. In the present study, we showed that Rab5 could enhance CSFV proliferation by utilizing lentivirus-mediated constitutive overexpression and eukaryotic plasmid transient overexpression approaches. On the other hand, lentivirus-mediated short hairpin RNA knockdown of Rab5 dramatically inhibited virus production. Co-immunoprecipitation, glutathione S-transferase pulldown and laser confocal microscopy assays further confirmed the interaction between Rab5 and CSFV NS4B protein. In addition, intracellular distribution of NS4B-Red presented many granular fluorescent signals (GFS in CSFV infected PK-15 cells. Inhibition of basal Rab5 function with Rab5 dominant negative mutant Rab5S34N resulted in disruption of the GFS. These results indicate that Rab5 plays a critical role in facilitating the formation of the NS4B related complexes. Furthermore, it was observed that NS4B co-localized with viral NS3 and NS5A proteins in the cytoplasm, suggesting that NS3 and NS5A might be components of the NS4B related complex. Taken together, these results demonstrate that Rab5 positively modulates CSFV propagation and interacts with NS4B protein to facilitate the NS4B related complexes formation.

2-Isobutyl-6-(4-methoxyphenylimidazo[2,1-b][1,3,4]thiadiazole

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Hoong-Kun Fun

2011-02-01

Full Text Available In the title compound, C15H17N3OS, the dihedral angle between the statistically planar imidazo[2,1-b][1,3,4]thiadiazole fused-ring system (r.m.s. deviation = 0.002 Å and the methyoxbenzene ring is 4.52 (6°. In the crystal, molecules are arranged into columns and stacked down the a axis. The crystal structure is stabilized by weak C—H...π and π–π interactions [centroid–centroid separations = 3.6053 (8 and 3.7088 (7 Å].

Effects of B4C control rod degradation under severe accident

Energy Technology Data Exchange (ETDEWEB)

Seo, Si-Won; Park, Sang-Gil; Han, Sang-Ku [Atomic Creative Technology Co., Daejeon (Korea, Republic of)

2016-10-15

Boron carbide (B4C) is widely used as absorber material in western boiling water reactor (BWR), some PWR, EPR and Russian RBMK and VVERs. B4C oxidation is one of the important phenomena of in-vessel. In the present paper, the main results and knowledge gained regarding the B4C control rod degradation from above mentioned experiments are reviewed and arranged to inform its significance on the severe accident consequences. In this paper, the role of B4C control rod oxidation and the subsequent degradation on the severe accident consequences is reviewed with available literature and report of previous experimental program regarding the B4C oxidation. From this review, it seems that the contribution of this B4C oxidation on the accident progression to the further severe accident situation is not negligible. For the future work, the extensive experimental data interpretation will be performed to assess quantitatively the effect of B4C oxidation and degradation on the various postulated severe accident conditions.

Discovery of Dengue Virus NS4B Inhibitors

Science.gov (United States)

Wang, Qing-Yin; Dong, Hongping; Zou, Bin; Karuna, Ratna; Wan, Kah Fei; Zou, Jing; Susila, Agatha; Yip, Andy; Shan, Chao; Yeo, Kim Long; Xu, Haoying; Ding, Mei; Chan, Wai Ling; Gu, Feng; Seah, Peck Gee; Liu, Wei; Lakshminarayana, Suresh B.; Kang, CongBao; Lescar, Julien; Blasco, Francesca; Smith, Paul W.

2015-01-01

ABSTRACT The four serotypes of dengue virus (DENV-1 to -4) represent the most prevalent mosquito-borne viral pathogens in humans. No clinically approved vaccine or antiviral is currently available for DENV. Here we report a spiropyrazolopyridone compound that potently inhibits DENV both in vitro and in vivo. The inhibitor was identified through screening of a 1.8-million-compound library by using a DENV-2 replicon assay. The compound selectively inhibits DENV-2 and -3 (50% effective concentration [EC50], 10 to 80 nM) but not DENV-1 and -4 (EC50, >20 μM). Resistance analysis showed that a mutation at amino acid 63 of DENV-2 NS4B (a nonenzymatic transmembrane protein and a component of the viral replication complex) could confer resistance to compound inhibition. Genetic studies demonstrate that variations at amino acid 63 of viral NS4B are responsible for the selective inhibition of DENV-2 and -3. Medicinal chemistry improved the physicochemical properties of the initial “hit” (compound 1), leading to compound 14a, which has good in vivo pharmacokinetics. Treatment of DENV-2-infected AG129 mice with compound 14a suppressed viremia, even when the treatment started after viral infection. The results have proven the concept that inhibitors of NS4B could potentially be developed for clinical treatment of DENV infection. Compound 14a represents a potential preclinical candidate for treatment of DENV-2- and -3-infected patients. IMPORTANCE Dengue virus (DENV) threatens up to 2.5 billion people and is now spreading in many regions in the world where it was not previously endemic. While there are several promising vaccine candidates in clinical trials, approved vaccines or antivirals are not yet available. Here we describe the identification and characterization of a spiropyrazolopyridone as a novel inhibitor of DENV by targeting the viral NS4B protein. The compound potently inhibits two of the four serotypes of DENV (DENV-2 and -3) both in vitro and in vivo. Our

Production of thermoluminescent dosemeters based on MgB{sub 4}O{sub 7}: Dy and MgB{sub 4}O{sub 7}: Tm; Producao de dosimetros termoluminescentes a base de MgB{sub 4}O{sub 7}: Dy e MgB{sub 4}O{sub 7}: Tm

Energy Technology Data Exchange (ETDEWEB)

Souza, Luiza Freire de; Souza, Divanizia N., E-mail: luizaf25@hotmail.com, E-mail: divanizi@ufs.br [Universidade Federal de Sergipe (UFS), Sao Cristovao, SE (Brazil). Programa de Pos-Graduacao em Fisica

2013-07-01

The thermoluminescent dosimetry (TL) is a well-established technique for the detection of ionizing radiation in hospitals, clinics, and industrial establishments where there is the need to quantify the radiation. For this practice is require the use phosphors which are sensitive to radiation. Some phosphors are already commonly used in this practice, for example, TLD-100 (LiF: Mg, Ti), CaSO{sub 4}:Tm and CaSO{sub 4}:Dy. A compound that was most recently introduced in dosimetry and has many advantageous features to detect neutrons, electrons and gamma is the magnesium tetraborate (MgB{sub 4}O{sub 7}), but the undoped material is not good for dosimetry, since signal does not show satisfactory thermoluminescence. The present work presents the analysis of the compound MgB{sub 4}O{sub 7} when doped with rare earth elements, thulium (Tm) and dysprosium (Dy). The production of MgB{sub 4}O{sub 7}: Dy and MgB{sub 4}O{sub 7}: Tm occurred under acidic conditions. Following the process of crystal growth, several tests were made on phosphors produced to verify the quality of materials as TL dosimeter. Initially, was made the identification of the crystalline phases found in the material, using the technique of X-ray diffractometry, and then were evaluated and compared the TL emission curves of the crystals with two different types of dopants, to this, the samples were irradiated with different radiation sources: {sup 137}Cs (0,66 MeV), {sup 60}Co (1.25 MeV) and X-rays (0.41 MeV) and based on the results was evaluated the energy dependence of phosphors. Another characteristic analyzed, was the decay of TL signal for the material (fading). The results show that the material can be an excellent TL dosimeter when doped with rare earth elements Dy and Tm. (author)

Back-reaction and effective acceleration in generic LTB dust models

International Nuclear Information System (INIS)

Sussman, Roberto A

2011-01-01

We provide a thorough examination of the conditions for the existence of back-reaction and an 'effective' acceleration (in the context of Buchert's averaging formalism) in regular generic spherically symmetric Lemaitre-Tolman-Bondi (LTB) dust models. By considering arbitrary spherical comoving domains,we verify rigorously the fulfillment of these conditions expressed in terms of suitable scalar variables that are evaluated at the boundary of every domain. Effective deceleration necessarily occurs in all domains in (a) the asymptotic radial range of models converging to a FLRW background (b) the asymptotic time range of non-vacuum hyperbolic models (c) LTB self-similar solutions and (d) near a simultaneous big bang. Accelerating domains are proven to exist in the following scenarios: (i) central vacuum regions(ii) central (non-vacuum) density voids (iii) the intermediate radial range of models converging to a FLRW background (iv) the asymptotic radial range of models converging to a Minkowski vacuum and (v) domains near and or intersecting a non-simultaneous big bang. All these scenarios occur in hyperbolic models with negative averaged and local spatial curvature though scenarios (iv) and (v) are also possible in low density regions of a class of elliptic models in which the local spatial curvature is negative but its average is positive. Rough numerical estimates between -0.003 and -0.5 were found for the effective deceleration parameter. While the existence of accelerating domains cannot be ruled out in models converging to an Einstein-de Sitter background and in domains undergoing gravitational collapse the conditions for this are very restrictive. The results obtained may provide important theoretical clues on the effects of back-reaction and averaging in more general non-spherical models. Communicated by L Andersson (paper)

Prodrug-activating Gene Therapy with Rabbit Cytochrome P450 4B1/4-Ipomeanol or 2-Aminoanthracene System in Glioma Cells

Energy Technology Data Exchange (ETDEWEB)

Jang, Su Jin; Kang, Joo Hyun; Lee, Tae Sup; Kim, Sung Joo; Kim, Kwang Il; Lee, Yong Jin; Cheon, Gi Jeong; Choi, Chang Woon; Lim, Sang Moo [Korea Institute of Radiological and Medical Sciences (KIRAMS), Seoul (Korea, Republic of)

2010-09-15

We determined the cytotoxic properties of cytochrome P450 4B1 (CYP4B1) activated 4-ipomeanol (4-ipo) and 2-aminoanthracene (2-AA) in rat glioma to verify the CYP4B1/4-ipo or 2-AA system for prodrug-activating gene therapy. The cyp4B1 cDNA was cloned into pcDNA3.1/ Hygro from rabbit lung total RNA (pcDAN-cyp4B1). Lentiviral vector encoding firefly luciferase (fLuc) was infected into C6 (rat glioma), and the fLuc-expressing cell was selected (C6-L). After transfection with pcDNA-cyp4B1 vector into C6-L, the single clone expressing cyp4B1 gene was selected (C6-CL). Prodrug for various concentrations of 4-ipo or 2-AA was treated for 72 h and 96 h. The cell survival rate of C6-CL was determined using MTT assay and trypan-blue dye exclusion methods. By RT-PCR analysis, fLuc and CYP4B1 expression was detected in C6-CL, but not in C6. MTT assay and trypan-blue dye exclusion showed that IC'5'0 of C6-CL was 0.3 mM and <0.01 mM after 4-ipo or 2-AA treatment at 96 h or 72 h exposure, respectively. Cell survivals of C6-CL were more rapidly reduced after treatment with 4-ipo or 2-AA than those of C6-L cells. The cell survival rate with MTT and trypan-blue dye exclusion assay was well correlated with fLuc activity in C6-CL cells. Conclusions CYP4B1-based prodrug-activating gene therapy may have the potential to treat glioma and the cytotoxic effects of CYP4B1 enzyme activated 4-ipo or 2-AA in C6, and could be clearly determined by bioluminescent activity in C6-CL.

Commissioning (Phases 4, 4A, 4B)

National Research Council Canada - National Science Library

Schofield, Andrew

1997-01-01

Phase 4 marked the completion of ANS&A's commitments under the BAA, as the new large centrifuge at the Waterways Experiment Station was commissioned and a series of research experiments were undertaken to demonstrate the breadth of new...

Li2Sr4B12O23: A new alkali and alkaline-earth metal mixed borate with [B10O18]6− network and isolated [B2O5]4− unit

International Nuclear Information System (INIS)

Zhang Min; Pan Shilie; Han Jian; Yang Zhihua; Su Xin; Zhao Wenwu

2012-01-01

A novel ternary lithium strontium borate Li 2 Sr 4 B 12 O 23 crystal with size up to 20 mm×10 mm×4 mm has been grown via the top-seeded solution growth method below 730 °C. Single-crystal XRD analyses showed that Li 2 Sr 4 B 12 O 23 crystallizes in the monoclinic space group P2 1 /c with a=6.4664(4) Å, b=8.4878(4) Å, c=15.3337(8) Å, β=102.02(3)°, Z=2. The crystal structure is composed of [B 10 O 18 ] 6− network and isolated [B 2 O 5 ] 4− unit. The IR spectrum further confirmed the presence of both BO 3 and BO 4 groups. TG-DSC and Transmission spectrum were reported. Band structures and density of states were calculated. - Graphical abstract: A new phase, Li 2 Sr 4 B 12 O 23 , has been discovered in the ternary M 2 O–M′O–B 2 O 3 (M=alkali-metal, M′=alkalineearth metal) system. The crystal structure consists of [B 10 O 18 ] 6− network and isolated [B 2 O 5 ] 4− unit. Highlights: ► Li 2 Sr 4 B 12 O 23 is a a novel borate discovered in the M 2 O–M′O–B 2 O 3 (M=alkali-metal, M′=alkaline-earth metal) system. ► Li 2 Sr 4 B 12 O 23 crystal structure has a three-dimensional crystal structure with [B 10 O 18 ] 6− network and isolated [B 2 O 5 ] 4− unit. ► Sr 1 and Sr 2 are located in two different channels constructed by 3 ∞ [B 10 O 18 ] network.

Performance of scientific computing platforms with MCNP4B

International Nuclear Information System (INIS)

McLaughlin, H.E.; Hendricks, J.S.

1998-01-01

Several computing platforms were evaluated with the MCNP4B Monte Carlo radiation transport code. The DEC AlphaStation 500/500 was the fastest to run MCNP4B. Compared to the HP 9000-735, the fastest platform 4 yr ago, the AlphaStation is 335% faster, the HP C180 is 133% faster, the SGI Origin 2000 is 82% faster, the Cray T94/4128 is 1% faster, the IBM RS/6000-590 is 93% as fast, the DEC 3000/600 is 81% as fast, the Sun Sparc20 is 57% as fast, the Cray YMP 8/8128 is 57% as fast, the sun Sparc5 is 33% as fast, and the Sun Sparc2 is 13% as fast. All results presented are reproducible and allow for comparison to computer platforms not included in this study. Timing studies are seen to be very problem dependent. The performance gains resulting from advances in software were also investigated. Various compilers and operating systems were seen to have a modest impact on performance, whereas hardware improvements have resulted in a factor of 4 improvement. MCNP4B also ran approximately as fast as MCNP4A

Peculiar features of thermal emission of GdB4 and GdB6 single crystals

International Nuclear Information System (INIS)

Ostrovskij, E.K.; Taran, A.A.; Kovalev, A.V.; Tkachenko, V.F.; Dudnik, E.M.; Matvienko, A.A.

1990-01-01

Thermoemission parameters of single crystals (410) GdB 4 and (110) GdB 6 are studied. Work function is calculated by total current. It is stated that work function of GdB 6 within temperature range of 1500-1880 K after 80 h of annealing varies from 2.95 to 3.10 eV practically with the same temperature coefficient as GdB 4 , i.e. 4.1x10 -4 eV/K. It is shown that single crystal gadolinium hexaboride during the high-temperature annealing in the surface region (∼70 mm) is transformed into gadolinium tetraboride. Influence of free air has been first studied on the GdB 4 emissivity which is determined to increase to p=1.3x10 -2 Pa within the range of T=1640-1840 K

B{sub 4}C thin films for neutron detection

Energy Technology Data Exchange (ETDEWEB)

Hoeglund, Carina [European Spallation Source ESS AB, P.O. Box 176, SE-221 00 Lund (Sweden); Department of Physics, Chemistry and Biology (IFM), Thin Film Physics Division, Linkoeping University, SE-581 83 Linkoeping (Sweden); Birch, Jens; Jensen, Jens; Hultman, Lars [Department of Physics, Chemistry and Biology (IFM), Thin Film Physics Division, Linkoeping University, SE-581 83 Linkoeping (Sweden); Andersen, Ken; Hall-Wilton, Richard [European Spallation Source ESS AB, P.O. Box 176, SE-221 00 Lund (Sweden); Bigault, Thierry; Buffet, Jean-Claude; Correa, Jonathan; Esch, Patrick van; Guerard, Bruno; Piscitelli, Francesco [Institute Laue Langevin, Rue Jules Horowitz, FR-380 00 Grenoble (France); Khaplanov, Anton [European Spallation Source ESS AB, P.O. Box 176, SE-221 00 Lund (Sweden); Institute Laue Langevin, Rue Jules Horowitz, FR-380 00 Grenoble (France); Vettier, Christian [European Spallation Source ESS AB, P.O. Box 176, SE-221 00 Lund (Sweden); European Synchrotron Radiation Facility, BP 220, FR-380 43 Grenoble Cedex 9 (France); Vollenberg, Wilhelmus [Vacuum, Surfaces and Coatings Group (TE/VSC), CERN, CH-1211 Geneva 23 (Switzerland)

2012-05-15

Due to the very limited availability of {sup 3}He, new kinds of neutron detectors, not based on {sup 3}He, are urgently needed. Here, we present a method to produce thin films of {sup 10}B{sub 4}C, with maximized detection efficiency, intended to be part of a new generation of large area neutron detectors. B{sub 4}C thin films have been deposited onto Al-blade and Si wafer substrates by dc magnetron sputtering from {sup nat}B{sub 4}C and {sup 10}B{sub 4}C targets in an Ar discharge, using an industrial deposition system. The films were characterized with scanning electron microscopy, elastic recoil detection analysis, x-ray reflectivity, and neutron radiography. We show that the film-substrate adhesion and film purity are improved by increased substrate temperature and deposition rate. A deposition rate of 3.8 A/s and substrate temperature of 400 deg. C result in films with a density close to bulk values and good adhesion to film thickness above 3 {mu}m. Boron-10 contents of almost 80 at. % are obtained in 6.3 m{sup 2} of 1 {mu}m thick {sup 10}B{sub 4}C thin films coated on Al-blades. Initial neutron absorption measurements agree with Monte Carlo simulations and show that the layer thickness, number of layers, neutron wavelength, and amount of impurities are determining factors. The study also shows the importance of having uniform layer thicknesses over large areas, which for a full-scale detector could be in total {approx}1000 m{sup 2} of two-side coated Al-blades with {approx}1 {mu}m thick {sup 10}B{sub 4}C films.

B7-H4 as a Target for Breast Cancer Immunotherapy

Science.gov (United States)

2013-06-01

papain proteinase K pronase trypsin B7-H4R B """""" B7-H4R-APC CD25-FITC...Figure 5. B7-H4 receptor is protease resistant. Karpas 299 cells were treated with 0.3 mg/mL papain , 0.025 mg/mL proteinase K, 0.15 mg/mL pronase

A novel homozygous AP4B1 mutation in two brothers with AP-4 deficiency syndrome and ocular anomalies.

Science.gov (United States)

Accogli, Andrea; Hamdan, Fadi F; Poulin, Chantal; Nassif, Christina; Rouleau, Guy A; Michaud, Jacques L; Srour, Myriam

2018-04-01

Adaptor protein complex-4 (AP-4) is a heterotetrameric protein complex which plays a key role in vesicle trafficking in neurons. Mutations in genes affecting different subunits of AP-4, including AP4B1, AP4E1, AP4S1, and AP4M1, have been recently associated with an autosomal recessive phenotype, consisting of spastic tetraplegia, and intellectual disability (ID). The overlapping clinical picture among individuals carrying mutations in any of these genes has prompted the terms "AP-4 deficiency syndrome" for this clinically recognizable phenotype. Using whole-exome sequencing, we identified a novel homozygous mutation (c.991C>T, p.Q331*, NM_006594.4) in AP4B1 in two siblings from a consanguineous Pakistani couple, who presented with severe ID, progressive spastic tetraplegia, epilepsy, and microcephaly. Sanger sequencing confirmed the mutation was homozygous in the siblings and heterozygous in the parents. Similar to previously reported individuals with AP4B1 mutations, brain MRI revealed ventriculomegaly and white matter loss. Interestingly, in addition to the typical facial gestalt reported in other AP-4 deficiency cases, the older brother presented with congenital left Horner syndrome, bilateral optic nerve atrophy and cataract, which have not been previously reported in this condition. In summary, we report a novel AP4B1 homozygous mutation in two siblings and review the phenotype of AP-4 deficiency, speculating on a possible role of AP-4 complex in eye development. © 2018 Wiley Periodicals, Inc.

Crystal structure of PrRh4.8B2

International Nuclear Information System (INIS)

Higashi, Iwami; Shishido, Toetsu; Takei, Humihiko; Kobayashi, Takaaki

1988-01-01

The crystal structure of a new rare earth ternary boride PrRh 4.8 B 2 was investigated, by single-crystal X-ray diffractometry. PrRh 4.8 B 2 crystallizes in the orthorhombic space group Immm with a = 9.697(4), b = 5.577(2), c = 25.64(3) A, Z=12. The intensity data were collected on a four-circle diffractometer with graphite-monochromatized Mo Kα radiation. The structure was solved by the Patterson method and refined with a full-matrix least-squares program to an R value (equal to Σvertical strokeΔFvertical stroke/Σvertical strokeF 0 vertical stroke) of 0.055 for 1176 reflections. (orig.)

Gravitational entropies in LTB dust models

International Nuclear Information System (INIS)

Sussman, Roberto A; Larena, Julien

2014-01-01

We consider generic Lemaître–Tolman–Bondi (LTB) dust models to probe the gravitational entropy proposals of Clifton, Ellis and Tavakol (CET) and of Hosoya and Buchert (HB). We also consider a variant of the HB proposal based on a suitable quasi-local scalar weighted average. We show that the conditions for entropy growth for all proposals are directly related to a negative correlation of similar fluctuations of the energy density and Hubble scalar. While this correlation is evaluated locally for the CET proposal, it must be evaluated in a non-local domain dependent manner for the two HB proposals. By looking at the fulfilment of these conditions at the relevant asymptotic limits we are able to provide a well grounded qualitative description of the full time evolution and radial asymptotic scaling of the three entropies in generic models. The following rigorous analytic results are obtained for the three proposals: (i) entropy grows when the density growing mode is dominant, (ii) all ever-expanding hyperbolic models reach a stable terminal equilibrium characterized by an inhomogeneous entropy maximum in their late time evolution; (iii) regions with decaying modes and collapsing elliptic models exhibit unstable equilibria associated with an entropy minimum (iv) near singularities the CET entropy diverges while the HB entropies converge; (v) the CET entropy converges for all models in the radial asymptotic range, whereas the HB entropies only converge for models asymptotic to a Friedmann–Lemaître–Robertson–Walker background. The fact that different independent proposals yield fairly similar conditions for entropy production, time evolution and radial scaling in generic LTB models seems to suggest that their common notion of a ‘gravitational entropy’ may be a theoretically robust concept applicable to more general spacetimes. (paper)

Mixing thermodynamic properties of 1-butyl-4-methylpyridinium tetrafluoroborate [b4mpy][BF{sub 4}] with water and with an alkan-1ol (methanol to pentanol)

Energy Technology Data Exchange (ETDEWEB)

Ortega, J. [Laboratorio de Termodinamica y Fisicoquimica de Fluidos, Parque Cientifico-Tecnologico, Campus Universitario de Tafira, Universidad de Las Palmas de Gran Canaria, 35071-Las Palmas de Gran Canaria, Canary Islands (Spain)], E-mail: jortega@dip.ulpgc.es; Vreekamp, R.; Penco, E.; Marrero, E. [Laboratorio de Termodinamica y Fisicoquimica de Fluidos, Parque Cientifico-Tecnologico, Campus Universitario de Tafira, Universidad de Las Palmas de Gran Canaria, 35071-Las Palmas de Gran Canaria, Canary Islands (Spain)

2008-07-15

This article presents a study of the behaviour in solution of 1-butyl-4-methylpyridinium tetrafluoroborate [b4mpy][BF{sub 4}] in water and in the first five alkanols of the series methanol to pentan-1-ol. The excess enthalpies, H{sub m}{sup E} and volumes, V{sub m}{sup E} were determined at the temperatures (298.15 and 318.15) K. At these temperatures, the [b4mpy][BF{sub 4}] was completely miscible in water, methanol, and ethanol, but only partially miscible in the other alkanols. A solubility study was carried out and the (liquid + liquid) equilibria of the ([b4mpy][BF{sub 4}] + alkanol) systems were experimentally determined, evaluating zones of complete miscibility and determining the UCST in each case. The mixtures with water gave positive values of H{sub m}{sup E} and V{sub m}{sup E}, being also positive the changes of these quantities with temperature. The mixtures with alkanols gave values of H{sub m}{sup E}>0 and V{sub m}{sup E}<0, and for these binary mixtures (dH{sub m}{sup E}/dT){sub p}>0 and (dV{sub m}{sup E}/dT){sub p}<0. For all cases, results were interpreted and compared with data obtained in mixtures with another isomer [b3mpy][BF{sub 4}]. Excess properties were correlated with a suitable equation and the area and volume parameters were calculated for [b4mpy][BF{sub 4}].

Benzo[1,2-b:4,5-b’]dithiophene-Pyrido[3,4-b]pyrazine Small-Molecule Donors for Bulk Heterojunction Solar Cells

KAUST Repository

Wolf, Jannic Sebastian; Babics, Maxime; Wang, Kai; Saleem, Qasim; Liang, Ru-Ze; Hansen, Michael Ryan; Beaujuge, Pierre

2016-01-01

We report on the synthesis, material properties and BHJ solar cell characteristics of a set of π-conjugated small-molecule (SM) donors composed of benzo[1,2-b:4,5-b′]dithiophene (BDT) and pyrido[3,4-b]pyrazine (PP) units – examining the perspectives of alkyl-substituted PP acceptor motifs in SM designs. In these systems (SM1-4), both the type of side chains derived from the PP motifs and the presence of ring-substituents on BDT critically impact (i) molecular packing, and (ii) thin-film morphologies and charge transport in BHJ solar cells. With the appropriate side-chain pattern, the ring-substituted analogue SM4 stands out: achieving efficiencies of ca. 6.5% with PC71BM, and fine-scale morphologies comparable to those obtained with some of the best-performing polymer donors in BHJ solar cells. 1H-1H DQ-SQ NMR analyses are used to examine the distinct self-assembly pattern of SM4, expected to factor into the development of the BHJ morphology.

Benzo[1,2-b:4,5-b’]dithiophene-Pyrido[3,4-b]pyrazine Small-Molecule Donors for Bulk Heterojunction Solar Cells

KAUST Repository

Wolf, Jannic Sebastian

2016-01-22

We report on the synthesis, material properties and BHJ solar cell characteristics of a set of π-conjugated small-molecule (SM) donors composed of benzo[1,2-b:4,5-b′]dithiophene (BDT) and pyrido[3,4-b]pyrazine (PP) units – examining the perspectives of alkyl-substituted PP acceptor motifs in SM designs. In these systems (SM1-4), both the type of side chains derived from the PP motifs and the presence of ring-substituents on BDT critically impact (i) molecular packing, and (ii) thin-film morphologies and charge transport in BHJ solar cells. With the appropriate side-chain pattern, the ring-substituted analogue SM4 stands out: achieving efficiencies of ca. 6.5% with PC71BM, and fine-scale morphologies comparable to those obtained with some of the best-performing polymer donors in BHJ solar cells. 1H-1H DQ-SQ NMR analyses are used to examine the distinct self-assembly pattern of SM4, expected to factor into the development of the BHJ morphology.

Murid herpesvirus-4 exploits dendritic cells to infect B cells.

Directory of Open Access Journals (Sweden)

Miguel Gaspar

2011-11-01

Full Text Available Dendritic cells (DCs play a central role in initiating immune responses. Some persistent viruses infect DCs and can disrupt their functions in vitro. However, these viruses remain strongly immunogenic in vivo. Thus what role DC infection plays in the pathogenesis of persistent infections is unclear. Here we show that a persistent, B cell-tropic gamma-herpesvirus, Murid Herpesvirus-4 (MuHV-4, infects DCs early after host entry, before it establishes a substantial infection of B cells. DC-specific virus marking by cre-lox recombination revealed that a significant fraction of the virus latent in B cells had passed through a DC, and a virus attenuated for replication in DCs was impaired in B cell colonization. In vitro MuHV-4 dramatically altered the DC cytoskeleton, suggesting that it manipulates DC migration and shape in order to spread. MuHV-4 therefore uses DCs to colonize B cells.

Transcellular lipoxygenase metabolism between monocytes and platelets

Energy Technology Data Exchange (ETDEWEB)

Bigby, T.D.; Meslier, N. (Univ. of California, San Francisco (USA))

1989-09-15

We have examined the effects of co-culture and in vitro co-stimulation on lipoxygenase metabolism in monocytes and platelets. Monocytes were obtained from the peripheral blood of normal volunteers by discontinuous gradient centrifugation and adherence to tissue culture plastic. Platelets were obtained from the platelet-rich plasma of the same donor. When 10(9) platelets and 2.5 x 10(6) monocytes were co-stimulated with 1 microM A23187, these preparations released greater quantities of 12(S)-hydroxy-10-trans-5,8,14-cis-eicosatetraenoic acid, 5(S),12-(S)dihydroxy-6,10-trans-8,14-cis-eicosatetraenoic acid, and leukotriene C4, 5(S)-hydroxy-6(R)-S-glutathionyl-7,9-trans-11,14-cis-eicosatetraenoic (LTC4) when compared with monocytes alone. Release of arachidonic acid, 5-HETE, delta 6-trans-LTB4, and delta 6-trans-12-epi-LTB4 from monocytes was decreased in the presence of platelets. A dose-response curve was constructed and revealed that the above changes became evident when the platelet number exceeded 10(7). Dual radiolabeling experiments with 3H- and 14C-arachidonic acid revealed that monocytes provided arachidonic acid, 5-HETE, and LTA4 for further metabolism by the platelet. Monocytes did not metabolize platelet intermediates detectably. In addition, as much as 1.2 microM 12(S)-hydroxy-10-trans-5,8,14-cis-eicosatetraenoic acid and 12(S)-hydroperoxy-10-trans-5,8,14-cis-eicosatetraenoic acid had no effect on monocyte lipoxygenase metabolism. Platelets were capable of converting LTA4 to LTC4, but conversion of LTA4 to LTB4 was not detected. We conclude that the monocyte and platelet lipoxygenase pathways undergo a transcellular lipoxygenase interaction that differs from the interaction of the neutrophil and platelet lipoxygenase pathways. In this interaction monocytes provide intermediate substrates for further metabolic conversion by platelets in an unidirectional manner.

Synthesis, DNA binding and cytotoxic activity of pyrimido[4',5':4,5]thieno(2,3-b)quinoline with 9-hydroxy-4-(3-diethylaminopropylamino) and 8-methoxy-4-(3-diethylaminopropylamino) substitutions.

Science.gov (United States)

KiranKumar, Hulihalli N; RohitKumar, Heggodu G; Advirao, Gopal M

2018-01-01

Two new derivatives of pyrimido[4',5';4,5]thieno(2,3-b)quinoline (PTQ), 9-hydroxy-4-(3-diethylaminopropylamino)pyrimido[4',5';4,5]thieno(2,3-b)quinoline (Hydroxy-DPTQ) and 8-methoxy-4-(3-diethylaminopropylamino)pyrimido[4',5';4,5]thieno(2,3-b)quinoline (Methoxy-DPTQ) were synthesized and their DNA binding ability was analyzed using spectroscopy (UV-visible, fluorescence and circular dichroism), ethidium bromide dye displacement assay, melting temperature (T m ) analysis and computational docking studies. The hypochromism in UV-visible spectrum and increased fluorescence emission of Hydroxy-DPTQ and Methoxy-DPTQ in the presence of DNA suggested the molecule-DNA interaction. The association constants calculated from UV-visible and spectral titrations were of the order 10 4 to 10 6 M -1 . Circular dichroism studies corroborated the induced conformational changes in DNA upon addition of molecules. The change in the ellipticity was observed both in negative and positive peak of DNA, thus, suggesting the intercalation of molecules. The observed displacement of ethidium bromide from the DNA and increased T m , upon addition of DNA confirmed the intercalative mode of binding. This was further validated by computational docking, which showed clear intercalation of molecules into the d(GpC)-d(CpG) site of the receptor DNA. Anticancer activities of these molecules are evaluated by using MTT assay. Both molecules showed antiproliferative activity against all the three cancer cells studied, with Hydroxy-DPTQ being more potential molecule among the two. IC 50 value of Hydroxy-DPTQ and Methoxy-DPTQ were in the range of 3-5μM and 130-250μM, respectively. Copyright © 2017 Elsevier B.V. All rights reserved.

Pilot clinical study of the effects of ginger root extract on eicosanoids in colonic mucosa of subjects at increased risk for colorectal cancer.

Science.gov (United States)