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Sample records for proinflammatory cytokine-induced nitric

  1. Diclofenac enhances proinflammatory cytokine-induced phagocytosis of cultured microglia via nitric oxide production

    International Nuclear Information System (INIS)

    Kakita, Hiroki; Aoyama, Mineyoshi; Nagaya, Yoshiaki; Asai, Hayato; Hussein, Mohamed Hamed; Suzuki, Mieko; Kato, Shin; Saitoh, Shinji; Asai, Kiyofumi

    2013-01-01

    Influenza-associated encephalopathy (IAE) is a central nervous system complication with a high mortality rate, which is increased significantly by the non-steroidal anti-inflammatory drug diclofenac sodium (DCF). In the present study, we investigated the effects of DCF on brain immune cells (i.e. microglia) stimulated with three proinflammatory cytokines, namely tumor necrosis factor-α, interleukin-1β, and interferon-γ. Similar to previous findings in astrocytes, all three cytokines induced the expression of inducible NO synthase (iNOS), as well as NO production, in microglia. The addition of DCF to the culture system augmented iNOS expression and NO production. Immunocytochemical analysis and the phagocytosis assay revealed that cytokine treatment induced morphological changes to and phagocytosis by the microglia. The addition of DCF to the culture system enhanced microglial activation, as well as the phagocytic activity of cytokine-stimulated microglia. Inhibitors of nuclear factor (NF)-κB inhibited iNOS gene expression in cytokine-stimulated microglia with or without DCF, suggesting that the NF-κB pathway is one of the main signaling pathways involved. The iNOS inhibitor N G -monomethyl-L-arginine (L-NMMA) reduced both cytokine-induced phagocytosis and phagocytosis induced by the combination of cytokines plus DCF. Furthermore, the NO donor sodium nitroprusside induced phagocytosis, indicating that NO production is a key regulator of microglial phagocytosis. In conclusion, DCF acts synergistically with proinflammatory cytokines to increase the production of NO in microglia, leading to phagocytic activity of the activated microglia. These findings, together with previous observations regarding astrocytes, may explain the significant increase in mortality of IAE patients treated with DCF. - Highlights: ► Influenza-associated encephalopathy (IAE) is associated with a high mortality rate. ► Hyperimmunization in the brain is believed to be responsible for IAE

  2. Diclofenac enhances proinflammatory cytokine-induced phagocytosis of cultured microglia via nitric oxide production

    Energy Technology Data Exchange (ETDEWEB)

    Kakita, Hiroki [Department of Molecular Neurobiology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601 (Japan); Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601 (Japan); Aoyama, Mineyoshi, E-mail: ao.mine@med.nagoya-cu.ac.jp [Department of Molecular Neurobiology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601 (Japan); Nagaya, Yoshiaki; Asai, Hayato [Department of Molecular Neurobiology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601 (Japan); Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601 (Japan); Hussein, Mohamed Hamed [Neonatal Intensive Care Unit, Pediatric Hospital, Cairo University, Cairo 11559 (Egypt); Maternal and Child Health Department, VACSERA, 51 Wizaret El-Zeraa-Agouza, Giza 22311 (Egypt); Suzuki, Mieko [Department of Molecular Neurobiology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601 (Japan); Kato, Shin [Department of Molecular Neurobiology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601 (Japan); Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601 (Japan); Saitoh, Shinji [Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601 (Japan); Asai, Kiyofumi [Department of Molecular Neurobiology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601 (Japan)

    2013-04-15

    Influenza-associated encephalopathy (IAE) is a central nervous system complication with a high mortality rate, which is increased significantly by the non-steroidal anti-inflammatory drug diclofenac sodium (DCF). In the present study, we investigated the effects of DCF on brain immune cells (i.e. microglia) stimulated with three proinflammatory cytokines, namely tumor necrosis factor-α, interleukin-1β, and interferon-γ. Similar to previous findings in astrocytes, all three cytokines induced the expression of inducible NO synthase (iNOS), as well as NO production, in microglia. The addition of DCF to the culture system augmented iNOS expression and NO production. Immunocytochemical analysis and the phagocytosis assay revealed that cytokine treatment induced morphological changes to and phagocytosis by the microglia. The addition of DCF to the culture system enhanced microglial activation, as well as the phagocytic activity of cytokine-stimulated microglia. Inhibitors of nuclear factor (NF)-κB inhibited iNOS gene expression in cytokine-stimulated microglia with or without DCF, suggesting that the NF-κB pathway is one of the main signaling pathways involved. The iNOS inhibitor N{sup G}-monomethyl-L-arginine (L-NMMA) reduced both cytokine-induced phagocytosis and phagocytosis induced by the combination of cytokines plus DCF. Furthermore, the NO donor sodium nitroprusside induced phagocytosis, indicating that NO production is a key regulator of microglial phagocytosis. In conclusion, DCF acts synergistically with proinflammatory cytokines to increase the production of NO in microglia, leading to phagocytic activity of the activated microglia. These findings, together with previous observations regarding astrocytes, may explain the significant increase in mortality of IAE patients treated with DCF. - Highlights: ► Influenza-associated encephalopathy (IAE) is associated with a high mortality rate. ► Hyperimmunization in the brain is believed to be responsible for

  3. Diclofenac enhances proinflammatory cytokine-induced nitric oxide production through NF-κB signaling in cultured astrocytes

    International Nuclear Information System (INIS)

    Kakita, Hiroki; Aoyama, Mineyoshi; Hussein, Mohamed Hamed; Kato, Shin; Suzuki, Satoshi; Ito, Tetsuya; Togari, Hajime; Asai, Kiyofumi

    2009-01-01

    Recently, the number of reports of encephalitis/encephalopathy associated with influenza virus has increased. In addition, the use of a non-steroidal anti-inflammatory drug, diclofenac sodium (DCF), is associated with a significant increase in the mortality rate of influenza-associated encephalopathy. Activated astrocytes are a source of nitric oxide (NO), which is largely produced by inducible NO synthase (iNOS) in response to proinflammatory cytokines. Therefore, we investigated whether DCF enhances nitric oxide production in astrocytes stimulated with proinflammatory cytokines. We stimulated cultured rat astrocytes with three cytokines, interleukin-1β, tumor necrosis factor-α and interferon-γ, and then treated the astrocytes with DCF or acetaminophen (N-acetyl-p-aminophenol: APAP). iNOS and NO production in astrocyte cultures were induced by proinflammatory cytokines. The addition of DCF augmented NO production, but the addition of APAP did not. NF-κB inhibitors SN50 and MG132 inhibited iNOS gene expression in cytokine-stimulated astrocytes with or without DCF. Similarly, NF-κB p65 Stealth small interfering RNA suppressed iNOS gene expression in cytokine-stimulated astrocytes with or without DCF. LDH activity and DAPI staining showed that DCF induces cell damage in cytokine-stimulated astrocytes. An iNOS inhibitor, L-NMMA, inhibited the cytokine- and DCF-induced cell damage. In conclusion, this study demonstrates that iNOS and NO are induced in astrocyte cultures by proinflammatory cytokines. Addition of DCF further augments NO production. This effect is mediated via NF-κB signaling and leads to cell damage. The enhancement of DCF on NO production may explain the significant increase in the mortality rate of influenza-associated encephalopathy in patients treated with DCF.

  4. Apolipoprotein CIII Reduces Proinflammatory Cytokine-Induced Apoptosis in Rat Pancreatic Islets via the Akt Prosurvival Pathway

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    Størling, Joachim; Juntti-Berggren, Lisa; Olivecrona, Gunilla

    2011-01-01

    Apolipoprotein CIII (ApoCIII) is mainly synthesized in the liver and is important for triglyceride metabolism. The plasma concentration of ApoCIII is elevated in patients with type 1 diabetes (T1D), and in vitro ApoCIII causes apoptosis in pancreatic ß-cells in the absence of inflammatory stress...... of the survival serine-threonine kinase Akt. Inhibition of the Akt signaling pathway by the phosphatidylinositol 3 kinase inhibitor LY294002 counteracted the antiapoptotic effect of ApoCIII on cytokine-induced apoptosis. We conclude that ApoCIII in the presence of T1D-relevant proinflammatory cytokines reduces...

  5. Indoline-3-propionate and 3-aminopropyl carbamates reduce lung injury and pro-inflammatory cytokines induced in mice by LPS.

    Science.gov (United States)

    Finkin-Groner, E; Moradov, D; Shifrin, H; Bejar, C; Nudelman, A; Weinstock, M

    2015-02-01

    In the search for safer and effective anti-inflammatory agents, we investigated the effect of methyl indoline-3-propionate and indoline-3-(3-aminopropyl) carbamates on LPS-induced lung injury and pro-inflammatory cytokines in mice. Their mechanism of action was determined in murine peritoneal macrophages. Lung injury was induced by intratracheal infusion of LPS and assessed by the change in lung weight and structure by light microscopy after staining by haematoxylin and eosin. In LPS-activated macrophages, MAPK proteins and IκBα were measured by Western blotting and the transcription factors, AP-1 and NF-κB by electromobility shift assay. Cytokines in the plasma and spleen of mice injected with LPS were measured by elisa-based assay. AN917 and AN680 (1-10 pM) decreased TNF-α protein in macrophages by inhibiting phosphorylation of p38 MAPK, IκBα degradation and activation of AP-1 and NF-κB without affecting cell viability. In vivo, these compounds (10 μmol · kg(-1)) markedly decreased lung injury induced by LPS and the elevation of TNF-α and IL-6 in lung, plasma and spleen. Activation of α-7nACh receptors contributed to the reduction of TNF-α by AN917, which inhibited AChE in the spleen by 35%. Indoline carbamates are potent inhibitors of pro-inflammatory mediators in murine macrophages and in mice injected with LPS, acting via the p38 MAPK, AP-1 and NF-κB cascades. Indirect α-7nACh receptor activation by AN917, through inhibition of AChE, contributes to its anti-inflammatory effect. Indoline carbamates may have therapeutic potential for lung injury and other diseases associated with chronic inflammation without causing immunosuppression. © 2014 The British Pharmacological Society.

  6. Astrocyte-derived proinflammatory cytokines induce hypomyelination in the periventricular white matter in the hypoxic neonatal brain.

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    Yiyu Deng

    Full Text Available Hypoxic exposure in the perinatal period causes periventricular white matter damage (PWMD, a condition associated with myelination abnormalities. Under hypoxic conditions, glial cells were activated and released a large number of inflammatory mediators in the PWM in neonatal brain, which may result in oligodendrocyte (OL loss and axonal injury. This study aims to determine if astrocytes are activated and generate proinflammatory cytokines that may be coupled with the oligodendroglial loss and hypomyelination observed in hypoxic PWMD. Twenty-four 1-day-old Wistar rats were exposed to hypoxia for 2 h. The rats were then allowed to recover under normoxic conditions for 7 or 28 days before being killed. Another group of 24 rats kept outside the chamber was used as age-matched controls. Upregulated expression of TNF-α and IL-1β was observed in astrocytes in the PWM of P7 hypoxic rats by double immunofluorescence, western blotting and real time RT-PCR. This was linked to apoptosis and enhanced expression of TNF-R1 and IL-1R1 in APC(+ OLs. PLP expression was decreased significantly in the PWM of P28d hypoxic rats. The proportion of myelinated axons was markedly reduced by electron microscopy (EM and the average g-ratios were higher in P28d hypoxic rats. Upregulated expression of TNF-α and IL-1β in primary cultured astrocytes as well as their corresponding receptors in primary culture APC(+ oligodendrocytes were detected under hypoxic conditions. Our results suggest that following a hypoxic insult, astrocytes in the PWM of neonatal rats produce inflammatory cytokines such as TNF-α and IL-1β, which induce apoptosis of OLs via their corresponding receptors associated with them. This results in hypomyelination in the PWM of hypoxic rats.

  7. Nitric oxide-releasing agents enhance cytokine-induced tumor necrosis factor synthesis in human mononuclear cells

    NARCIS (Netherlands)

    Eigler, A; Sinha, B; Endres, S

    1993-01-01

    In septic shock tumor necrosis factor (TNF) leads to increased nitric oxide (NO) production by induction of NO synthase. An inverse regulatory effect, the influence of NO on cytokine synthesis, has rarely been investigated. The present study assessed the influence of NO-releasing agents on TNF

  8. Nitric oxide-releasing flurbiprofen reduces formation of proinflammatory hydrogen sulfide in lipopolysaccharide-treated rat

    Science.gov (United States)

    Anuar, Farhana; Whiteman, Matthew; Siau, Jia Ling; Kwong, Shing Erl; Bhatia, Madhav; Moore, Philip K

    2006-01-01

    The biosynthesis of both nitric oxide (NO) and hydrogen sulfide (H2S) is increased in lipopolysaccharide (LPS)-injected mice and rats but their interaction in these models is not known. In this study we examined the effect of the NO donor, nitroflurbiprofen (and the parent molecule flurbiprofen) on NO and H2S metabolism in tissues from LPS-pretreated rats. Administration of LPS (10 mg kg−1, i.p.; 6 h) resulted in an increase (PFlurbiprofen (21 mg kg−1, i.p.) was without effect. These results show for the first time that nitroflurbiprofen downregulates the biosynthesis of proinflammatory H2S and suggest that such an effect may contribute to the augmented anti-inflammatory activity of this compound. These data also highlight the existence of ‘crosstalk' between NO and H2S in this model of endotoxic shock. PMID:16491094

  9. Melanocortin peptides inhibit production of proinflammatory cytokines and nitric oxide by activated microglia.

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    Delgado, R; Carlin, A; Airaghi, L; Demitri, M T; Meda, L; Galimberti, D; Baron, P; Lipton, J M; Catania, A

    1998-06-01

    Inflammatory processes contribute to neurodegenerative disease, stroke, encephalitis, and other central nervous system (CNS) disorders. Activated microglia are a source of cytokines and other inflammatory agents within the CNS and it is therefore important to control glial function in order to preserve neural cells. Melanocortin peptides are pro-opiomelanocortin-derived amino acid sequences that include alpha-melanocyte-stimulating hormone (alpha-MSH) and adrenocorticotropic hormone (ACTH). These peptides have potent and broad anti-inflammatory effects. We tested effects of alpha-MSH (1-13), alpha-MSH (11-13), and ACTH (1-24) on production of tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and nitric oxide (NO) in a cultured murine microglial cell line (N9) stimulated with lipopolysaccharide (LPS) plus interferon gamma (IFN-gamma). Melanocortin peptides inhibited production of these cytokines and NO in a concentration-related fashion, probably by increasing intracellular cAMP. When stimulated with LPS + IFN-gamma, microglia increased release of alpha-MSH. Production of TNF-alpha, IL-6, and NO was greater in activated microglia after innmunoneutralization of endogenous alpha-MSH. The results suggest that alpha-MSH is an autocrine factor in microglia. Because melanocortin peptides inhibit production of pro-inflammatory mediators by activated microglia they might be useful in treatment of inflammatory/degenerative brain disorders.

  10. Transduction of PEP-1-heme oxygenase-1 into insulin-producing INS-1 cells protects them against cytokine-induced cell death

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    Lee, Su Jin; Kang, Hyung Kyung [Department of Physiology, College of Medicine, Hallym University, Chunchon 200-702 (Korea, Republic of); Song, Dong Keun [Department of Pharmacology, College of Medicine, Hallym University, Chunchon 200-702 (Korea, Republic of); Eum, Won Sik; Park, Jinseu [Department of Biomedical Science and Research Institute of Bioscience and Biotechnology, Hallym University, Chunchon 200-702 (Korea, Republic of); Choi, Soo Young, E-mail: sychoi@hallym.ac.kr [Department of Biomedical Science and Research Institute of Bioscience and Biotechnology, Hallym University, Chunchon 200-702 (Korea, Republic of); Kwon, Hyeok Yil, E-mail: hykwon@hallym.ac.kr [Department of Physiology, College of Medicine, Hallym University, Chunchon 200-702 (Korea, Republic of)

    2015-06-05

    Pro-inflammatory cytokines play a crucial role in the destruction of pancreatic β-cells, thereby triggering the development of autoimmune diabetes mellitus. We recently developed a cell-permeable fusion protein, PEP-1-heme oxygenase-1 (PEP-1-HO-1) and investigated the anti-inflammatory effects in macrophage cells. In this study, we transduced PEP-1-HO-1 into INS-1 insulinoma cells and examined its protective effect against cytokine-induced cell death. PEP-1-HO-1 was successfully delivered into INS-1 cells in time- and dose-dependent manner and was maintained within the cells for at least 48 h. Pre-treatment with PEP-1-HO-1 increased the survival of INS-1 cells exposed to cytokine mixture (IL-1β, IFN-γ, and TNF-α) in a dose-dependent manner. PEP-1-HO-1 markedly decreased cytokine-induced production of reactive oxygen species (ROS), nitric oxide (NO), and malondialdehyde (MDA). These protective effects of PEP-1-HO-1 against cytokines were correlated with the changes in the levels of signaling mediators of inflammation (iNOS and COX-2) and cell apoptosis/survival (Bcl-2, Bax, caspase-3, PARP, JNK, and Akt). These results showed that the transduced PEP-1-HO-1 efficiently prevented cytokine-induced cell death of INS-1 cells by alleviating oxidative/nitrosative stresses and inflammation. Further, these results suggested that PEP-1-mediated HO-1 transduction may be a potential therapeutic strategy to prevent β-cell destruction in patients with autoimmune diabetes mellitus. - Highlights: • We showed that PEP-1-HO-1 was efficiently delivered into INS-1 cells. • Transduced PEP-1-HO-1 exerted a protective effect against cytokine-induced cell death. • Transduced PEP-1-HO-1 inhibited cytokine-induced ROS and NO accumulation. • PEP-1-HO-1 suppressed cytokine-induced expression of iNOS, COX-2, and Bax. • PEP-1-HO-1 transduction may be an efficient tool to prevent β-cell destruction.

  11. Transduction of PEP-1-heme oxygenase-1 into insulin-producing INS-1 cells protects them against cytokine-induced cell death

    International Nuclear Information System (INIS)

    Lee, Su Jin; Kang, Hyung Kyung; Song, Dong Keun; Eum, Won Sik; Park, Jinseu; Choi, Soo Young; Kwon, Hyeok Yil

    2015-01-01

    Pro-inflammatory cytokines play a crucial role in the destruction of pancreatic β-cells, thereby triggering the development of autoimmune diabetes mellitus. We recently developed a cell-permeable fusion protein, PEP-1-heme oxygenase-1 (PEP-1-HO-1) and investigated the anti-inflammatory effects in macrophage cells. In this study, we transduced PEP-1-HO-1 into INS-1 insulinoma cells and examined its protective effect against cytokine-induced cell death. PEP-1-HO-1 was successfully delivered into INS-1 cells in time- and dose-dependent manner and was maintained within the cells for at least 48 h. Pre-treatment with PEP-1-HO-1 increased the survival of INS-1 cells exposed to cytokine mixture (IL-1β, IFN-γ, and TNF-α) in a dose-dependent manner. PEP-1-HO-1 markedly decreased cytokine-induced production of reactive oxygen species (ROS), nitric oxide (NO), and malondialdehyde (MDA). These protective effects of PEP-1-HO-1 against cytokines were correlated with the changes in the levels of signaling mediators of inflammation (iNOS and COX-2) and cell apoptosis/survival (Bcl-2, Bax, caspase-3, PARP, JNK, and Akt). These results showed that the transduced PEP-1-HO-1 efficiently prevented cytokine-induced cell death of INS-1 cells by alleviating oxidative/nitrosative stresses and inflammation. Further, these results suggested that PEP-1-mediated HO-1 transduction may be a potential therapeutic strategy to prevent β-cell destruction in patients with autoimmune diabetes mellitus. - Highlights: • We showed that PEP-1-HO-1 was efficiently delivered into INS-1 cells. • Transduced PEP-1-HO-1 exerted a protective effect against cytokine-induced cell death. • Transduced PEP-1-HO-1 inhibited cytokine-induced ROS and NO accumulation. • PEP-1-HO-1 suppressed cytokine-induced expression of iNOS, COX-2, and Bax. • PEP-1-HO-1 transduction may be an efficient tool to prevent β-cell destruction

  12. Simvastatin Attenuates Contrast-Induced Nephropathy through Modulation of Oxidative Stress, Proinflammatory Myeloperoxidase, and Nitric Oxide

    Directory of Open Access Journals (Sweden)

    Ketab E. Al-Otaibi

    2012-01-01

    Full Text Available Contrast media- (CM- induced nephropathy is a serious complication of radiodiagnostic procedures. Available data suggests that the development of prophylaxis strategies is limited by poor understanding of pathophysiology of CM-induced nephropathy. Present study was designed to determine the role of oxidative stress, myeloperoxidase, and nitric oxide in the pathogenesis of iohexol model of nephropathy and its modification with simvastatin (SSTN. Adult Sprague Dawley rats were divided into seven groups. After 24 h of water deprivation, all the rats except in control and SSTN-only groups were injected (10 ml/kg with 25% glycerol. After 30 min, SSTN (15, 30, and 60 mg/kg was administered orally, daily for 4 days. Twenty-four hours after the glycerol injection, iohexol was infused (8 ml/kg through femoral vein over a period of 2 min. All the animals were sacrificed on day 5 and blood and kidneys were collected for biochemical and histological studies. The results showed that SSTN dose dependently attenuated CM-induced rise of creatinine, urea, and structural abnormalities suggesting its nephroprotective effect. A significant increase in oxidative stress (increased lipid hydroperoxides and reduced glutathione levels and myeloperoxidase (MPO and decreased nitric oxide in CM group were reversed by SSTN. These findings support the use of SSTN to combat CM-induced nephrotoxicity.

  13. Bojesodok-eum, a Herbal Prescription, Ameliorates Acute Inflammation in Association with the Inhibition of NF-κB-Mediated Nitric Oxide and ProInflammatory Cytokine Production

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    Kook Ho Sohn

    2012-01-01

    Full Text Available Bojesodok-eum (BSE is a herbal prescription consisting of Coptidis Rhizoma and Scutellariae Radix as main components. This paper investigated the effects of BSE on the induction of nitric oxide (NO, prostaglandin E2 (PGE2, and proinflammatory cytokines that are caused by lipopolysaccharide (LPS in murine macrophage cell line and on the paw edema formation in animals. Administration of BSE (0.3 g/kg and 1 g/kg in rats significantly inhibited carrageenan-induced paw edema formation, as did dexamethasone, an anti-inflammatory positive control drug. In cell model, treatment of BSE decreased the production of NO and PGE2 in RAW264.7 cells stimulated by LPS. BSE also inhibited the expression of iNOS and COX-2 protein as well as COX activity in a concentration-dependent manner. Consistently, BSE suppressed the ability of LPS to produce TNF-α, interleukin-1β, and interleukin-6. LPS treatment induced nuclear NF-κB level and I-κBα phosphorylation, which were inhibited subsequent treatment of BSE, suggesting its repression of LPS-inducible NF-κB activation. BSE abrogated the induction of NO, PGE2, and proinflammatory cytokines, as well as iNOS and COX-2 protein expression in RAW264.7 cells stimulated by LPS as mediated with NF-κB inhibition.

  14. Beneficial effects of cytokine induced hyperlipidemia.

    Science.gov (United States)

    Feingold, K R; Hardardóttir, I; Grunfeld, C

    1998-01-01

    lipoproteins binding toxic agents and neutralizing their harmful effects. Thus, cytokines induce marked changes in lipid metabolism that lead to hyperlipidemia which represents part of the innate immune response and may be beneficial to the host.

  15. Effect of nitric oxide-releasing derivative of indomethacin on Prevotella intermedia lipopolysaccharide-induced production of proinflammatory mediators in murine macrophages.

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    Choe, So-Hui; Choi, Eun-Young; Hyeon, Jin-Yi; Choi, In Soon; Kim, Sung-Jo

    2017-10-14

    The purpose of this study was to investigate the influences of NCX 2121, a nitric oxide (NO)-releasing derivative of indomethacin, upon the generation of proinflammatory mediators using murine macrophages activated by lipopolysaccharide (LPS) isolated from Prevotella intermedia, which is one of the pathogens implicated in periodontal diseases. Inducible NO synthase (iNOS)-derived NO, IL-1β and IL-6 as well as their relevant mRNA were significantly attenuated by NCX 2121 in RAW264.7 cells activated by P. intermedia LPS. NCX 2121 was much more effective than the parental compound indomethacin in reducing these proinflammatory mediators. NCX 2121 triggered induction of heme oxygenase-1 (HO-1) in cells exposed to P. intermedia LPS, and its inhibitory influence upon P. intermedia LPS-elicited NO generation was notably blocked by SnPP treatment. NCX 2121 attenuated NF-κB-dependent SEAP release induced by P. intermedia LPS. NCX 2121 did not display inhibitory action towards IκB-α degradation triggered by LPS. Instead, it significantly diminished nuclear translocation as well as DNA-binding action of NF-κB p50 subunit elicited by P. intermedia LPS. Further, NCX 2121 significantly up-regulated SOCS1 mRNA expression in cells challenged with P. intermedia LPS. In summary, NCX 2121 down-regulates P. intermedia LPS-elicited generation of NO, IL-1β and IL-6 in murine macrophages in a mechanism that involves anti-inflammatory HO-1 induction as well as decrement of NF-κB activation, which may be associated with SOCS1 expression. NCX 2121 may have potential benefits as a host immunomodulatory agent for the therapy of periodontal disease. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Alteration in cellular viability, pro-inflammatory cytokines and nitric oxide production in nephrotoxicity generation by Amphotericin B: involvement of PKA pathway signaling.

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    França, F D; Ferreira, A F; Lara, R C; Rossoni, J V; Costa, D C; Moraes, K C M; Tagliati, C A; Chaves, M M

    2014-12-01

    Amphotericin B is one of the most effective antifungal agents; however, its use is often limited owing to adverse effects, especially nephrotoxicity. The purpose of this study was to evaluate the effect of inhibiting the PKA signaling pathway in nephrotoxicity using Amphotericin B from the assessment of cell viability, pro-inflammatory cytokines and nitric oxide (NO) production in LLC-PK1 and MDCK cell lines. Amphotericin B proved to be cytotoxic for both cell lines, as assessed by the mitochondrial enzyme activity (MTT) assay; caused DNA fragmentation, determined by flow cytometry using the propidium iodide (PI) dye; and activated the PKA pathway (western blot assay). In MDCK cells, the inhibition of the PKA signaling pathway (using the H89 inhibitor) caused a significant reduction in DNA fragmentation. In both cells lines the production of interleukin-6 (IL)-6 proved to be a dependent PKA pathway, whereas tumor necrosis factor-alpha (TNF-α) was not influenced by the inhibition of the PKA pathway. The NO production was increased when cells were pre-incubated with H89 followed by Amphotericin B, and this production produced a dependent PKA pathway in LLC-PK1 and MDCK cells lines. Therefore, considering the present study's results as a whole, it can be concluded that the inhibition of the PKA signaling pathway can aid in reducing the degree of nephrotoxicity caused by Amphotericin B. Copyright © 2013 John Wiley & Sons, Ltd.

  17. Twenty Years of Research on Cytokine-Induced Sickness Behavior*

    Science.gov (United States)

    Dantzer, Robert; Kelley, Keith W.

    2007-01-01

    Cytokine-induced sickness behavior was recognized within a few years of the cloning and expression of interferon-α, IL-1 and IL-2, which occurred around the time that the first issue of Brain, Behavior, and Immunity was published in 1987. Phase I clinical trials established that injection of recombinant cytokines into cancer patients led to a variety of psychological disturbances. It was subsequently shown that physiological concentrations of proinflammatory cytokines that occur after infection act in the brain to induce common symptoms of sickness, such as loss of appetite, sleepiness, withdrawal from normal social activities, fever, aching joints and fatigue. This syndrome was defined as sickness behavior and is now recognized to be part of a motivational system that reorganizes the organism's priorities to facilitate recovery from the infection. Cytokines convey to the brain that an infection has occurred in the periphery, and this action of cytokines can occur via the traditional endocrine route via the blood or by direct neural transmission via the afferent vagus nerve. The finding that sickness behavior occurs in all mammals and birds indicates that communication between the immune system and brain has been evolutionarily conserved and forms an important physiological adaptive response that favors survival of the organism during infections. The fact that cytokines act in the brain to induce physiological adaptations that promote survival has led to the hypothesis that inappropriate, prolonged activation of the innate immune system may be involved in a number of pathological disturbances in the brain, ranging from Alzheimers' disease to stroke. Conversely, the newly-defined role of cytokines in a wide variety of systemic co-morbid conditions, ranging from chronic heart failure to obesity, may begin to explain changes in the mental state of these subjects. Indeed, the newest findings of cytokine actions in the brain offer some of the first clues about the

  18. NCX 4040, a nitric oxide-donating aspirin derivative, inhibits Prevotella intermedia lipopolysaccharide-induced production of proinflammatory mediators in murine macrophages.

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    Choi, Eun-Young; Choe, So-Hui; Hyeon, Jin-Yi; Park, Hae Ryoun; Choi, Jeom-Il; Choi, In Soon; Kim, Sung-Jo

    2015-12-05

    In this study, the effects and underlying mechanisms of NCX 4040, a nitric oxide (NO)-donating aspirin derivative, on the production of proinflammatory mediators were examined using murine macrophages exposed to lipopolysaccharide (LPS) from Prevotella intermedia, a pathogen implicated in the etiology of periodontal disease. NCX 4040 significantly reduced P. intermedia LPS-induced production of inducible NO synthase (iNOS)-derived NO, IL-1β and IL-6 as well as their mRNA expression in RAW264.7 cells. Notably, NCX 4040 was much more effective than the parental compound aspirin in reducing LPS-induced production of inflammatory mediators. NCX 4040 induced the expression of heme oxygenase-1 (HO-1) in cells treated with P. intermedia LPS, and the suppressive effect of NCX 4040 on LPS-induced NO production was significantly reversed by SnPP, a competitive HO-1 inhibitor. NCX 4040 did not influence LPS-induced phosphorylation of JNK and p38. IκB-α degradation as well as nuclear translocation and DNA-binding activities of NF-κB p65 and p50 subunits induced by P. intermedia LPS were significantly reduced by NCX 4040. Besides, LPS-induced phosphorylation of STAT1 and STAT3 was significantly down-regulated by NCX 4040. Further, NCX 4040 elevated the SOCS1 mRNA in cells stimulated with LPS. This study indicates that NCX 4040 inhibits P. intermedia LPS-induced production of NO, IL-1β and IL-6 in murine macrophages through anti-inflammatory HO-1 induction and suppression of NF-κB, STAT1 and STAT3 activation, which is associated with the activation of SOCS1 signaling. NCX 4040 could potentially be a promising tool in the treatment of periodontal disease, although further studies are required to verify this. Copyright © 2015 Elsevier B.V. All rights reserved.

  19. Spontaneous and cytokine induced basophil adhesion evaluated by microtiter assay

    DEFF Research Database (Denmark)

    Quan, Sha; Poulsen, Lars K; Reimert, Claus Michael

    2002-01-01

    We have developed a microtiter assay for evaluating basophil spontaneous adhesion to extracellular matrix (ECM) proteins exemplified by fibronectin and cytokine induced basophil adhesion to bovine serum albumin (BSA). The percentage of basophils adhering to either ECM or BSA was quantified...

  20. Co-culture of neural crest stem cells (NCSC and insulin producing beta-TC6 cells results in cadherin junctions and protection against cytokine-induced beta-cell death.

    Directory of Open Access Journals (Sweden)

    Anongnad Ngamjariyawat

    Full Text Available PURPOSE: Transplantation of pancreatic islets to Type 1 diabetes patients is hampered by inflammatory reactions at the transplantation site leading to dysfunction and death of insulin producing beta-cells. Recently we have shown that co-transplantation of neural crest stem cells (NCSCs together with the islet cells improves transplantation outcome. The aim of the present investigation was to describe in vitro interactions between NCSCs and insulin producing beta-TC6 cells that may mediate protection against cytokine-induced beta-cell death. PROCEDURES: Beta-TC6 and NCSC cells were cultured either alone or together, and either with or without cell culture inserts. The cultures were then exposed to the pro-inflammatory cytokines IL-1β and IFN-γ for 48 hours followed by analysis of cell death rates (flow cytometry, nitrite production (Griess reagent, protein localization (immunofluorescence and protein phosphorylation (flow cytometry. RESULTS: We observed that beta-TC6 cells co-cultured with NCSCs were protected against cytokine-induced cell death, but not when separated by cell culture inserts. This occurred in parallel with (i augmented production of nitrite from beta-TC6 cells, indicating that increased cell survival allows a sustained production of nitric oxide; (ii NCSC-derived laminin production; (iii decreased phospho-FAK staining in beta-TC6 cell focal adhesions, and (iv decreased beta-TC6 cell phosphorylation of ERK(T202/Y204, FAK(Y397 and FAK(Y576. Furthermore, co-culture also resulted in cadherin and beta-catenin accumulations at the NCSC/beta-TC6 cell junctions. Finally, the gap junction inhibitor carbenoxolone did not affect cytokine-induced beta-cell death during co-culture with NCSCs. CONCLUSION: In summary, direct contacts, but not soluble factors, promote improved beta-TC6 viability when co-cultured with NCSCs. We hypothesize that cadherin junctions between NCSC and beta-TC6 cells promote powerful signals that maintain beta

  1. Abrupt reflow enhances cytokine-induced proinflammatory activation of endothelial cells during simulated shock and resuscitation

    NARCIS (Netherlands)

    Li, Ranran; Zijlstra, Jan G.; Kamps, Jan A. A. M.; van Meurs, Matijs; Molema, Grietje

    2014-01-01

    Circulatory shock and resuscitation are associated with systemic hemodynamic changes, which may contribute to the development of MODS (multiple organ dysfunction syndrome). In this study, we used an in vitro flow system to simulate the consecutive changes in blood flow as occurring during

  2. Pannexin-2-deficiency sensitizes pancreatic beta-cells to cytokine-induced apoptosis in vitro and impairs glucose tolerance in vivo

    DEFF Research Database (Denmark)

    Berchtold, Lukas A.; Miani, Michela; Diep, Thi A.

    2017-01-01

    -cells, and β-cell lines. The expression of Panx2, but not Panx1, was downregulated by interleukin-1β (IL-1β) plus interferon-γ (IFNγ), two pro-inflammatory cytokines suggested to contribute to β-cell demise in type 1 diabetes (T1D). siRNA-mediated knockdown (KD) of Panx2 aggravated cytokine-induced apoptosis...... in rat INS-1E cells and primary rat β-cells, suggesting anti-apoptotic properties of Panx2. An anti-apoptotic function of Panx2 was confirmed in isolated islets from Panx2-/- mice and in human EndoC-βH1 cells. Panx2 KD was associated with increased cytokine-induced activation of STAT3 and higher...

  3. Unique proliferation response in odontoblastic cells derived from human skeletal muscle stem cells by cytokine-induced matrix metalloproteinase-3

    International Nuclear Information System (INIS)

    Ozeki, Nobuaki; Hase, Naoko; Kawai, Rie; Yamaguchi, Hideyuki; Hiyama, Taiki; Kondo, Ayami; Nakata, Kazuhiko; Mogi, Makio

    2015-01-01

    A pro-inflammatory cytokine mixture (CM: interleukin (IL)-1β, tumor necrosis factor-α and interferon-γ) and IL-1β-induced matrix metalloproteinase (MMP)-3 activity have been shown to increase the proliferation of rat dental pulp cells and murine stem cell-derived odontoblast-like cells. This suggests that MMP-3 may regulate wound healing and regeneration in the odontoblast-rich dental pulp. Here, we determined whether these results can be extrapolated to human dental pulp by investigating the effects of CM-induced MMP-3 up-regulation on the proliferation and apoptosis of purified odontoblast-like cells derived from human skeletal muscle stem cells. We used siRNA to specifically reduce MMP-3 expression. We found that CM treatment increased MMP-3 mRNA and protein levels as well as MMP-3 activity. Cell proliferation was also markedly increased, with no changes in apoptosis, upon treatment with CM and following the application of exogenous MMP-3. Endogenous tissue inhibitors of metalloproteinases were constitutively expressed during all experiments and unaffected by MMP-3. Although treatment with MMP-3 siRNA suppressed cell proliferation, it also unexpectedly increased apoptosis. This siRNA-mediated increase in apoptosis could be reversed by exogenous MMP-3. These results demonstrate that cytokine-induced MMP-3 activity regulates cell proliferation and suppresses apoptosis in human odontoblast-like cells. - Highlights: • Pro-inflammatory cytokines induce MMP-3 activity in human odontoblast-like cells. • Increased MMP-3 activity can promote cell proliferation in odontoblasts. • Specific loss of MMP-3 increases apoptosis in odontoblasts. • MMP-3 has potential as a promising new target for pupal repair and regeneration

  4. Unique proliferation response in odontoblastic cells derived from human skeletal muscle stem cells by cytokine-induced matrix metalloproteinase-3

    Energy Technology Data Exchange (ETDEWEB)

    Ozeki, Nobuaki; Hase, Naoko; Kawai, Rie; Yamaguchi, Hideyuki; Hiyama, Taiki [Department of Endodontics, School of Dentistry, Aichi Gakuin University, 2-11 Suemori-dori, Chikusa-ku, Nagoya 464-8651, Aichi (Japan); Kondo, Ayami [Department of Medicinal Biochemistry, School of Pharmacy, Aichi Gakuin University, 1-100 Kusumoto, Chikusa-ku, Nagoya 464-8650 (Japan); Nakata, Kazuhiko [Department of Endodontics, School of Dentistry, Aichi Gakuin University, 2-11 Suemori-dori, Chikusa-ku, Nagoya 464-8651, Aichi (Japan); Mogi, Makio, E-mail: makio@dpc.agu.ac.jp [Department of Medicinal Biochemistry, School of Pharmacy, Aichi Gakuin University, 1-100 Kusumoto, Chikusa-ku, Nagoya 464-8650 (Japan)

    2015-02-01

    A pro-inflammatory cytokine mixture (CM: interleukin (IL)-1β, tumor necrosis factor-α and interferon-γ) and IL-1β-induced matrix metalloproteinase (MMP)-3 activity have been shown to increase the proliferation of rat dental pulp cells and murine stem cell-derived odontoblast-like cells. This suggests that MMP-3 may regulate wound healing and regeneration in the odontoblast-rich dental pulp. Here, we determined whether these results can be extrapolated to human dental pulp by investigating the effects of CM-induced MMP-3 up-regulation on the proliferation and apoptosis of purified odontoblast-like cells derived from human skeletal muscle stem cells. We used siRNA to specifically reduce MMP-3 expression. We found that CM treatment increased MMP-3 mRNA and protein levels as well as MMP-3 activity. Cell proliferation was also markedly increased, with no changes in apoptosis, upon treatment with CM and following the application of exogenous MMP-3. Endogenous tissue inhibitors of metalloproteinases were constitutively expressed during all experiments and unaffected by MMP-3. Although treatment with MMP-3 siRNA suppressed cell proliferation, it also unexpectedly increased apoptosis. This siRNA-mediated increase in apoptosis could be reversed by exogenous MMP-3. These results demonstrate that cytokine-induced MMP-3 activity regulates cell proliferation and suppresses apoptosis in human odontoblast-like cells. - Highlights: • Pro-inflammatory cytokines induce MMP-3 activity in human odontoblast-like cells. • Increased MMP-3 activity can promote cell proliferation in odontoblasts. • Specific loss of MMP-3 increases apoptosis in odontoblasts. • MMP-3 has potential as a promising new target for pupal repair and regeneration.

  5. Oenothera laciniata inhibits lipopolysaccharide induced production of nitric oxide, prostaglandin E2, and proinflammatory cytokines in RAW264.7 macrophages.

    Science.gov (United States)

    Yoon, Weon-Jong; Ham, Young Min; Yoo, Byoung-Sam; Moon, Ji-Young; Koh, Jaesook; Hyun, Chang-Gu

    2009-04-01

    We elucidated the pharmacological and biological effects of Oenothera laciniata extracts on the production of inflammatory mediators in macrophages. The CH(2)Cl(2) fraction of O. laciniata extract effectively inhibited LPS-induced NO, PGE(2), and proinflammatory cytokine production in RAW264.7 cells. These inhibitory effects of the CH(2)Cl(2) fraction of O. laciniata were accompanied by decreases in the expression of iNOS and COX-2 proteins and iNOS, COX-2, TNF-alpha, IL-1beta, and IL-6 mRNA. Asiatic acid and quercetin were present in the HPLC fingerprint of the O. laciniata extract. We tested the potential application of O. laciniata extract as a cosmetic material by performing primary skin irritation tests. In New Zealand white rabbits, primary irritation tests revealed that application of O. laciniata extracts (1%) did not induce erythema or edema formation. Human skin primary irritation tests were performed on the normal skin (upper back) of 30 volunteers to determine if any material in O. laciniata extracts had irritation or sensitization potential. In these assays, O. laciniata extracts did not induce any adverse reactions. Based on these results, we suggest that O. laciniata extracts be considered possible anti-inflammatory candidates for topical application.

  6. Improved Activation toward Primary Colorectal Cancer Cells by Antigen-Specific Targeting Autologous Cytokine-Induced Killer Cells

    Directory of Open Access Journals (Sweden)

    Claudia Schlimper

    2012-01-01

    Full Text Available Adoptive therapy of malignant diseases with cytokine-induced killer (CIK cells showed promise in a number of trials; the activation of CIK cells from cancer patients towards their autologous cancer cells still needs to be improved. Here, we generated CIK cells ex vivo from blood lymphocytes of colorectal cancer patients and engineered those cells with a chimeric antigen receptor (CAR with an antibody-defined specificity for carcinoembryonic antigen (CEA. CIK cells thereby gained a new specificity as defined by the CAR and showed increase in activation towards CEA+ colon carcinoma cells, but less in presence of CEA− cells, indicated by increased secretion of proinflammatory cytokines. Redirected CIK activation was superior by CAR-mediated CD28-CD3ζ than CD3ζ signaling only. CAR-engineered CIK cells from colon carcinoma patients showed improved activation against their autologous, primary carcinoma cells from biopsies resulting in more efficient tumour cell lysis. We assume that adoptive therapy with CAR-modified CIK cells shows improved selectivity in targeting autologous tumour lesions.

  7. Alpha-Melanocyte Stimulating Hormone Protects against Cytokine-Induced Barrier Damage in Caco-2 Intestinal Epithelial Monolayers.

    Directory of Open Access Journals (Sweden)

    Judit Váradi

    Full Text Available Alpha-melanocyte-stimulating hormone (α-MSH is a potent anti-inflammatory peptide with cytoprotective effect in various tissues. The present investigation demonstrates the ability of α-MSH to interact with intestinal epithelial cell monolayers and mitigate inflammatory processes of the epithelial barrier. The protective effect of α-MSH was studied on Caco-2 human intestinal epithelial monolayers, which were disrupted by exposure to tumor necrosis factor-α and interleukin-1β. The barrier integrity was assessed by measuring transepithelial electric resistance (TEER and permeability for marker molecules. Caco-2 monolayers were evaluated by immunohistochemistry for expression of melanocortin-1 receptor and tight junction proteins ZO-1 and claudin-4. The activation of nuclear factor kappa beta (NF-κB was detected by fluorescence microscopy and inflammatory cytokine expression was assessed by flow cytometric bead array cytokine assay. Exposure of Caco-2 monolayers to proinflammatory cytokines lowered TEER and increased permeability for fluorescein and albumin, which was accompanied by changes in ZO-1 and claudin-4 immunostaining. α-MSH was able to prevent inflammation-associated decrease of TEER in a dose-dependent manner and reduce the increased permeability for paracellular marker fluorescein. Further immunohistochemistry analysis revealed proinflammatory cytokine induced translocation of the NF-κB p65 subunit into Caco-2 cell nuclei, which was inhibited by α-MSH. As a result the IL-6 and IL-8 production of Caco-2 monolayers were also decreased with different patterns by the addition of α-MSH to the culture medium. In conclusion, Caco-2 cells showed a positive immunostaining for melanocortin-1 receptor and α-MSH protected Caco-2 cells against inflammatory barrier dysfunction and inflammatory activation induced by tumor necrosis factor-α and interleukin-1β cytokines.

  8. Cytokine-induced activation of glial cells in the mouse brain is enhanced at an advanced age.

    Science.gov (United States)

    Deng, X-H; Bertini, G; Xu, Y-Z; Yan, Z; Bentivoglio, M

    2006-08-25

    Numerous neurological diseases which include neuroinflammatory components exhibit an age-related prevalence. The aging process is characterized by an increase of inflammatory mediators both systemically and in the brain, which may prime glial cells. However, little information is available on age-related changes in the glial response of the healthy aging brain to an inflammatory challenge. This problem was here examined using a mixture of the proinflammatory cytokines interferon-gamma and tumor necrosis factor-alpha, which was injected intracerebroventricularly in young (2-3.5 months), middle-aged (10-11 months) and aged (18-21 months) mice. Vehicle (phosphate-buffered saline) was used as control. After a survival of 1 or 2 days (all age groups) or 4 days (young and middle-aged animals), immunohistochemically labeled astrocytes and microglia were investigated both qualitatively and quantitatively. In all age groups, astrocytes were markedly activated in periventricular as well as in deeper brain regions 2 days following cytokine treatment, whereas microglia activation was already evident at 24 h. Interestingly, cytokine-induced activation of both astrocytes and microglia was significantly more marked in the brain of aged animals, in which it included numerous ameboid microglia, than of younger age groups. Moderate astrocytic activation was also seen in the hippocampal CA1 field of vehicle-treated aged mice. FluoroJade B histochemistry and the terminal deoxynucleotidyl transferase-mediated UTP nick-end labeling technique, performed at 2 days after cytokine administration, did not reveal ongoing cell death phenomena in young or aged animals. This indicated that glial cell changes were not secondary to neuronal death. Altogether, the findings demonstrate for the first time enhanced activation of glial cells in the old brain, compared with young and middle-aged subjects, in response to cytokine exposure. Interestingly, the results also suggest that such enhancement

  9. Cytokine-induced killer cells are type II natural killer T cells

    Directory of Open Access Journals (Sweden)

    Schmidt-Wolf, Ingo G.H.

    2007-09-01

    Full Text Available Background: Until now, cytokine-induced killer (CIK cells were assumed to be part of the type I natural killer T (NKT cell population, but it was not yet investigated if this is correct. Methods: For analysis, CIK cells were generated by various culture conditions. Human type I NKT cells express a T cell receptor (TCR composed of an invariant Vα24-JαQ chain combined with one of several Vβ chains. The Vα24 is a reliable marker for the presence of these TCRs. Results: While comparing cultures stimulated with different substances, we observed the lack of any Vα24 on the surface of CIK culture cells. Conclusion: We conclude that CIK cells do not belong to the type I NKT cells.

  10. Autologous cytokine-induced killer cell immunotherapy may improve overall survival in advanced malignant melanoma patients.

    Science.gov (United States)

    Zhang, Yong; Zhu, Yu'nan; Zhao, Erjiang; He, Xiaolei; Zhao, Lingdi; Wang, Zibing; Fu, Xiaomin; Qi, Yalong; Ma, Baozhen; Song, Yongping; Gao, Quanli

    2017-11-01

    Our study was conducted to explore the efficacy of autologous cytokine-induced killer (CIK) cells in patients with advanced malignant melanoma. Materials & Methods: Here we reviewed 113 stage IV malignant melanoma patients among which 68 patients received CIK cell immunotherapy alone, while 45 patients accepted CIK cell therapy combined with chemotherapy. Results: We found that the median survival time in CIK cell group was longer than the combined therapy group (21 vs 15 months, p = 0.07). In addition, serum hemoglobin level as well as monocyte proportion and lymphocyte count were associated with patients' survival time. These indicated that CIK cell immunotherapy might extend survival time in advanced malignant melanoma patients. Furthermore, serum hemoglobin level, monocyte proportion and lymphocyte count could be prognostic indicators for melanoma.

  11. Immunotherapy using dendritic cells and cytokine-induced killer for kidney cancer

    International Nuclear Information System (INIS)

    Chen Lijun; Xu Yuanbin; Zhao Li; Qu Nan; Sun Zhenpeng; Li Xuechao; Zhao Jiyu; Wang Bin; Wang Huixian

    2008-01-01

    Objective: To investigate the clinical efficacy of immunotherapy using dendritic cells (DC) and cytokine-induced killer (CIK)in treatment of patients with kidney cancer. Methods: Sixty patients with kidney cancer were divided into 2 groups randomly: the control group and immunotherapy group. Peripheral blood mononuclear cells (PBMC) were seperated from the patients who received immunotherapy first, then DC and CIK were induced and cultured with GM-CSF and IL4 in vitro. The immunotherapy group received DC four times and CIK twice at an interval of 14 days after routine treatment. The control group received only chemotherapy. T lymphocyte subtypes and NK cells in peripheral blood, the white cells and the values of liver and kidney biochemistry of two group of patients were analyzed and clinical efficacy were ob- served, so were side effects. Results: Clinical efficacy showed significant statistical difference between the two groups (P + , CD4 + , CD4 + /CD8 + and NK cell in the immunotherapy group increased after treatment, which showed significant statistical difference compared with those before treatment(P value was 0.010, 0.026, 0.021, 0.016, respectively). Changes in cell immune indexes (CD3 + , CD4 + , CD4 + /CD8 + ) in immunotherapy group and Control group showed significant statistical difference (P value was 0.001,0.023,0.012, respectively). Conclusion: Immunotherapy using dendritic cells and cytokine-induced killer combined with routine treatment can improve T lymphocyte subtypes and NK cell ratio in peripheral blood of the patients with kidney cancer, and may play an important role in the treatment of kidney cancer. It can enhance clinical efficacy in patients with kidney cancer and can improve prognosis. (authors)

  12. Artichoke, Cynarin and Cyanidin Downregulate the Expression of Inducible Nitric Oxide Synthase in Human Coronary Smooth Muscle Cells

    Directory of Open Access Journals (Sweden)

    Ning Xia

    2014-03-01

    Full Text Available Artichoke (Cynara scolymus L. is one of the world’s oldest medicinal plants with multiple health benefits. We have previously shown that artichoke leaf extracts and artichoke flavonoids upregulate the gene expression of endothelial-type nitric oxide synthase (eNOS in human endothelial cells. Whereas NO produced by the eNOS is a vasoprotective molecule, NO derived from the inducible iNOS plays a pro-inflammatory role in the vasculature. The present study was aimed to investigate the effects of artichoke on iNOS expression in human coronary artery smooth muscle cells (HCASMC. Incubation of HCASMC with a cytokine mixture led to an induction of iNOS mRNA expression. This iNOS induction was concentration- and time-dependently inhibited by an artichoke leaf extract (1–100 µg/mL, 6 h or 24 h. Consistently, the artichoke leaf extract also reduced cytokine-induced iNOS promoter activation and iNOS protein expression. In addition, treatment of HCASMC with four well-known artichoke compounds (cynarin > cyanidin > luteolin ≈ cynaroside led to a downregulation iNOS mRNA and protein expression, with cynarin being the most potent one. In conclusion, artichoke contains both eNOS-upregulating and iNOS-downregulating compounds. Such compounds may contribute to the beneficial effects of artichoke and may per se have therapeutic potentials.

  13. Artichoke, cynarin and cyanidin downregulate the expression of inducible nitric oxide synthase in human coronary smooth muscle cells.

    Science.gov (United States)

    Xia, Ning; Pautz, Andrea; Wollscheid, Ursula; Reifenberg, Gisela; Förstermann, Ulrich; Li, Huige

    2014-03-24

    Artichoke (Cynara scolymus L.) is one of the world's oldest medicinal plants with multiple health benefits. We have previously shown that artichoke leaf extracts and artichoke flavonoids upregulate the gene expression of endothelial-type nitric oxide synthase (eNOS) in human endothelial cells. Whereas NO produced by the eNOS is a vasoprotective molecule, NO derived from the inducible iNOS plays a pro-inflammatory role in the vasculature. The present study was aimed to investigate the effects of artichoke on iNOS expression in human coronary artery smooth muscle cells (HCASMC). Incubation of HCASMC with a cytokine mixture led to an induction of iNOS mRNA expression. This iNOS induction was concentration- and time-dependently inhibited by an artichoke leaf extract (1-100 µg/mL, 6 h or 24 h). Consistently, the artichoke leaf extract also reduced cytokine-induced iNOS promoter activation and iNOS protein expression. In addition, treatment of HCASMC with four well-known artichoke compounds (cynarin > cyanidin > luteolin ≈ cynaroside) led to a downregulation iNOS mRNA and protein expression, with cynarin being the most potent one. In conclusion, artichoke contains both eNOS-upregulating and iNOS-downregulating compounds. Such compounds may contribute to the beneficial effects of artichoke and may per se have therapeutic potentials.

  14. Histone deacetylases 1 and 3 but not 2 mediate cytokine-induced beta cell apoptosis in INS-1 cells and dispersed primary islets from rats and are differentially regulated in the islets of type 1 diabetic children

    DEFF Research Database (Denmark)

    Lundh, M; Christensen, D P; Damgaard Nielsen, M

    2012-01-01

    onset, HDAC1 was upregulated in beta cells whereas HDAC2 and -3 were downregulated in comparison with five paediatric controls. CONCLUSIONS/INTERPRETATION: These data demonstrate non-redundant functions of islet class I HDACs and suggest that targeting HDAC1 and HDAC3 would provide optimal protection......AIMS/HYPOTHESIS: Histone deacetylases (HDACs) are promising pharmacological targets in cancer and autoimmune diseases. All 11 classical HDACs (HDAC1-11) are found in the pancreatic beta cell, and HDAC inhibitors (HDACi) protect beta cells from inflammatory insults. We investigated which HDACs...... of HDAC1, -2 and -3 rescued INS-1 cells from inflammatory damage. Small hairpin RNAs against HDAC1 and -3, but not HDAC2, reduced pro-inflammatory cytokine-induced beta cell apoptosis in INS-1 and primary rat islets. The protective properties of specific HDAC knock-down correlated with attenuated cytokine...

  15. Calcium-mediated signaling and calmodulin-dependent kinase regulate hepatocyte-inducible nitric oxide synthase expression.

    Science.gov (United States)

    Zhang, Baochun; Crankshaw, Will; Nesemeier, Ryan; Patel, Jay; Nweze, Ikenna; Lakshmanan, Jaganathan; Harbrecht, Brian G

    2015-02-01

    Induced nitric oxide synthase (iNOS) is induced in hepatocytes by shock and inflammatory stimuli. Excessive NO from iNOS mediates shock-induced hepatic injury and death, so understanding the regulation of iNOS will help elucidate the pathophysiology of septic shock. In vitro, cytokines induce iNOS expression through activation of signaling pathways including mitogen-activated protein kinases and nuclear factor κB. Cytokines also induce calcium (Ca(2+)) mobilization and activate calcium-mediated intracellular signaling pathways, typically through activation of calmodulin-dependent kinases (CaMK). Calcium regulates NO production in macrophages but the role of calcium and calcium-mediated signaling in hepatocyte iNOS expression has not been defined. Primary rat hepatocytes were isolated, cultured, and induced to produce NO with proinflammatory cytokines. Calcium mobilization and Ca(2+)-mediated signaling were altered with ionophore, Ca(2+) channel blockers, and inhibitors of CaMK. The Ca(2+) ionophore A23187 suppressed cytokine-stimulated NO production, whereas Ethylene glycol tetraacetic acid and nifedipine increased NO production, iNOS messenger RNA, and iNOS protein expression. Inhibition of CaMK with KN93 and CBD increased NO production but the calcineurin inhibitor FK 506 decreased iNOS expression. These data demonstrate that calcium-mediated signaling regulates hepatocyte iNOS expression and does so through a mechanism independent of calcineurin. Changes in intracellular calcium levels may regulate iNOS expression during hepatic inflammation induced by proinflammatory cytokines. Copyright © 2015 Elsevier Inc. All rights reserved.

  16. Regulation of embryonic hematopoiesis by a cytokine-inducible SH2 domain homolog in zebrafish.

    Science.gov (United States)

    Lewis, Rowena S; Noor, Suzita M; Fraser, Fiona W; Sertori, Robert; Liongue, Clifford; Ward, Alister C

    2014-06-15

    Cytokine-inducible SH2 domain-containing protein (CISH), a member of the suppressor of cytokine signaling family of negative feedback regulators, is induced by cytokines that activate STAT5 and can inhibit STAT5 signaling in vitro. However, demonstration of a definitive in vivo role for CISH during development has remained elusive. This study employed expression analysis and morpholino-mediated knockdown in zebrafish in concert with bioinformatics and biochemical approaches to investigate CISH function. Two zebrafish CISH paralogs were identified, cish.a and cish.b, with high overall conservation (43-46% identity) with their mammalian counterparts. The cish.a gene was maternally derived, with transcripts present throughout embryogenesis, and increasing at 4-5 d after fertilization, whereas cish.b expression commenced at 8 h after fertilization. Expression of cish.a was regulated by the JAK2/STAT5 pathway via conserved tetrameric STAT5 binding sites (TTCN3GAA) in its promoter. Injection of morpholinos targeting cish.a, but not cish.b or control morpholinos, resulted in enhanced embryonic erythropoiesis, myelopoiesis, and lymphopoiesis, including a 2- 3-fold increase in erythrocytic markers. This occurred concomitantly with increased activation of STAT5. This study indicates that CISH functions as a conserved in vivo target and regulator of STAT5 in the control of embryonic hematopoiesis. Copyright © 2014 by The American Association of Immunologists, Inc.

  17. Clinical Studies Applying Cytokine-Induced Killer Cells for the Treatment of Renal Cell Carcinoma

    Directory of Open Access Journals (Sweden)

    Clara E. Jäkel

    2012-01-01

    Full Text Available Metastatic renal cell carcinoma (RCC seems to be resistant to conventional chemo- and radiotherapy and the general treatment regimen of cytokine therapy produces only modest responses while inducing severe side effects. Nowadays standard of care is the treatment with VEGF-inhibiting agents or mTOR inhibition; nevertheless, immunotherapy can induce complete remissions and long-term survival in selected patients. Among different adoptive lymphocyte therapies, cytokine-induced killer (CIK cells have a particularly advantageous profile as these cells are easily available, have a high proliferative rate, and exhibit a high antitumor activity. Here, we reviewed clinical studies applying CIK cells, either alone or with standard therapies, for the treatment of RCC. The adverse events in all studies were mild, transient, and easily controllable. In vitro studies revealed an increased antitumor activity of peripheral lymphocytes of participants after CIK cell treatment and CIK cell therapy was able to induce complete clinical responses in RCC patients. The combination of CIK cell therapy and standard therapy was superior to standard therapy alone. These studies suggest that CIK cell immunotherapy is a safe and competent treatment strategy for RCC patients and further studies should investigate different treatment combinations and schedules for optimal application of CIK cells.

  18. Cytokine-induced killer cells eradicate bone and soft-tissue sarcomas.

    Science.gov (United States)

    Sangiolo, Dario; Mesiano, Giulia; Gammaitoni, Loretta; Leuci, Valeria; Todorovic, Maja; Giraudo, Lidia; Cammarata, Cristina; Dell'Aglio, Carmine; D'Ambrosio, Lorenzo; Pisacane, Alberto; Sarotto, Ivana; Miano, Sara; Ferrero, Ivana; Carnevale-Schianca, Fabrizio; Pignochino, Ymera; Sassi, Francesco; Bertotti, Andrea; Piacibello, Wanda; Fagioli, Franca; Aglietta, Massimo; Grignani, Giovanni

    2014-01-01

    Unresectable metastatic bone sarcoma and soft-tissue sarcomas (STS) are incurable due to the inability to eradicate chemoresistant cancer stem-like cells (sCSC) that are likely responsible for relapses and drug resistance. In this study, we investigated the preclinical activity of patient-derived cytokine-induced killer (CIK) cells against autologous bone sarcoma and STS, including against putative sCSCs. Tumor killing was evaluated both in vitro and within an immunodeficient mouse model of autologous sarcoma. To identify putative sCSCs, autologous bone sarcoma and STS cells were engineered with a CSC detector vector encoding eGFP under the control of the human promoter for OCT4, a stem cell gene activated in putative sCSCs. Using CIK cells expanded from 21 patients, we found that CIK cells efficiently killed allogeneic and autologous sarcoma cells in vitro. Intravenous infusion of CIK cells delayed autologous tumor growth in immunodeficient mice. Further in vivo analyses established that CIK cells could infiltrate tumors and that tumor growth inhibition occurred without an enrichment of sCSCs relative to control-treated animals. These results provide preclinical proof-of-concept for an effective strategy to attack autologous sarcomas, including putative sCSCs, supporting the clinical development of CIK cells as a novel class of immunotherapy for use in settings of untreatable metastatic disease.

  19. Revving up Natural Killer Cells and Cytokine-Induced Killer Cells Against Hematological Malignancies.

    Science.gov (United States)

    Pittari, Gianfranco; Filippini, Perla; Gentilcore, Giusy; Grivel, Jean-Charles; Rutella, Sergio

    2015-01-01

    Natural killer (NK) cells belong to innate immunity and exhibit cytolytic activity against infectious pathogens and tumor cells. NK-cell function is finely tuned by receptors that transduce inhibitory or activating signals, such as killer immunoglobulin-like receptors, NK Group 2 member D (NKG2D), NKG2A/CD94, NKp46, and others, and recognize both foreign and self-antigens expressed by NK-susceptible targets. Recent insights into NK-cell developmental intermediates have translated into a more accurate definition of culture conditions for the in vitro generation and propagation of human NK cells. In this respect, interleukin (IL)-15 and IL-21 are instrumental in driving NK-cell differentiation and maturation, and hold great promise for the design of optimal NK-cell culture protocols. Cytokine-induced killer (CIK) cells possess phenotypic and functional hallmarks of both T cells and NK cells. Similar to T cells, they express CD3 and are expandable in culture, while not requiring functional priming for in vivo activity, like NK cells. CIK cells may offer some advantages over other cell therapy products, including ease of in vitro propagation and no need for exogenous administration of IL-2 for in vivo priming. NK cells and CIK cells can be expanded using a variety of clinical-grade approaches, before their infusion into patients with cancer. Herein, we discuss GMP-compliant strategies to isolate and expand human NK and CIK cells for immunotherapy purposes, focusing on clinical trials of adoptive transfer to patients with hematological malignancies.

  20. Revving up natural killer cells and cytokine-induced killer cells against hematological malignancies

    Directory of Open Access Journals (Sweden)

    Gianfranco ePittari

    2015-05-01

    Full Text Available Natural killer (NK cells belong to innate immunity and exhibit cytolytic activity against infectious pathogens and tumor cells. NK-cell function is finely tuned by receptors that transduce inhibitory or activating signals, such as killer immunoglobulin-like receptors (KIR, NK Group 2 member D (NKG2D, NKG2A/CD94, NKp46 and others, and recognize both foreign and self-antigens expressed by NK-susceptible targets. Recent insights into NK-cell developmental intermediates have translated into a more accurate definition of culture conditions for the in vitro generation and propagation of human NK cells. In this respect, interleukin (IL-15 and IL-21 are instrumental in driving NK-cell differentiation and maturation, and hold great promise for the design of optimal NK-cell culture protocols.Cytokine-induced killer (CIK cells possess phenotypic and functional hallmarks of both T cells and NK cells. Similar to T cells, they express CD3 and are expandable in culture, while not requiring functional priming for in vivo activity, like NK cells. CIK cells may offer some advantages over other cell therapy products, including ease of in vitro propagation and no need for exogenous administration of IL-2 for in vivo priming.NK cells and CIK cells can be expanded using a variety of clinical-grade approaches, before their infusion into patients with cancer. Herein, we discuss GMP-compliant strategies to isolate and expand human NK and CIK cells for immunotherapy purposes, focusing on clinical trials of adoptive transfer to patients with hematological malignancies.

  1. Insulin-Like growth factor-II (IGF-II) prevents proinflammatory cytokine-induced apoptosis and significantly improves islet survival after transplantation.

    Science.gov (United States)

    Hughes, Amy; Mohanasundaram, Daisy; Kireta, Svjetlana; Jessup, Claire F; Drogemuller, Chris J; Coates, P Toby H

    2013-03-15

    The early loss of functional islet mass (50-70%) due to apoptosis after clinical transplantation contributes to islet allograft failure. Insulin-like growth factor (IGF)-II is an antiapoptotic protein that is highly expressed in β-cells during development but rapidly decreases in postnatal life. We used an adenoviral (Ad) vector to overexpress IGF-II in isolated rat islets and investigated its antiapoptotic action against exogenous cytokines interleukin-1β- and interferon-γ-induced islet cell death in vitro. Using an immunocompromised marginal mass islet transplant model, the ability of Ad-IGF-II-transduced rat islets to restore euglycemia in nonobese diabetic/severe combined immunodeficient diabetic recipients was assessed. Ad-IGF-II transduction did not affect islet viability or function. Ad-IGF-II cytokine-treated islets exhibited decreased cell death (40% ± 2.8%) versus Ad-GFP and untransduced control islets (63.2% ± 2.5% and 53.6% ± 2.3%, respectively). Ad-IGF-II overexpression during cytokine treatment resulted in a marked reduction in terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive apoptotic cells (8.3% ± 1.4%) versus Ad-GFP control (41% ± 4.2%) and untransduced control islets (46.5% ± 6.2%). Western blot analysis confirmed that IGF-II inhibits apoptosis via activation of the phosphatidylinositol 3-kinase/Akt signaling pathway. Transplantation of IGF-II overexpressing islets under the kidney capsule of diabetic mice restored euglycemia in 77.8% of recipients compared with 18.2% and 47.5% of Ad-GFP and untransduced control islet recipients, respectively (Pislet transplant outcomes in vivo. Antiapoptotic gene transfer is a potentially powerful tool to improve islet survival after transplantation.

  2. Oxygen, nitric oxide and articular cartilage

    Directory of Open Access Journals (Sweden)

    B Fermor

    2007-04-01

    Full Text Available Molecular oxygen is required for the production of nitric oxide (NO, a pro-inflammatory mediator that is associated with osteoarthritis and rheumatoid arthritis. To date there has been little consideration of the role of oxygen tension in the regulation of nitric oxide production associated with arthritis. Oxygen tension may be particularly relevant to articular cartilage since it is avascular and therefore exists at a reduced oxygen tension. The superficial zone exists at approximately 6% O2, while the deep zone exists at less than 1% O2. Furthermore, oxygen tension can alter matrix synthesis, and the material properties of articular cartilage in vitro.The increase in nitric oxide associated with arthritis can be caused by pro-inflammatory cytokines and mechanical stress. Oxygen tension significantly alters endogenous NO production in articular cartilage, as well as the stimulation of NO in response to both mechanical loading and pro-inflammatory cytokines. Mechanical loading and pro-inflammatory cytokines also increase the production of prostaglandin E2 (PGE2. There is a complex interaction between NO and PGE2, and oxygen tension can alter this interaction. These findings suggest that the relatively low levels of oxygen within the joint may have significant influences on the metabolic activity, and inflammatory response of cartilage as compared to ambient levels. A better understanding of the role of oxygen in the production of inflammatory mediators in response to mechanical loading, or pro-inflammatory cytokines, may aid in the development of strategies for therapeutic intervention in arthritis.

  3. The TWEAK-Fn14 system: breaking the silence of cytokine-induced skeletal muscle wasting.

    Science.gov (United States)

    Bhatnagar, S; Kumar, A

    2012-01-01

    The occurrence of skeletal muscle atrophy, a devastating complication of a large number of disease states and inactivity/disuse conditions, provides a never ending quest to identify novel targets for its therapy. Proinflammatory cytokines are considered the mediators of muscle wasting in chronic diseases; however, their role in disuse atrophy has just begun to be elucidated. An inflammatory cytokine, tumor necrosis factor (TNF)- like weak inducer of apoptosis (TWEAK), has recently been identified as a potent inducer of skeletal muscle wasting. TWEAK activates various proteolytic pathways and stimulates the degradation of myofibril protein both in vitro and in vivo. Moreover, TWEAK mediates the loss of skeletal muscle mass and function in response to denervation, a model of disuse atrophy. Adult skeletal muscle express very low to minimal levels of TWEAK receptor, Fn14. Specific catabolic conditions such as denervation, immobilization, or unloading rapidly increase the expression of Fn14 in skeletal muscle which in turn stimulates the TWEAK activation of various catabolic pathways leading to muscle atrophy. In this article, we have discussed the emerging roles and the mechanisms of action of TWEAK-Fn14 system in skeletal muscle with particular reference to different models of muscle atrophy and injury and its potential to be used as a therapeutic target for prevention of muscle loss.

  4. Dual Functional Capability of Dendritic Cells - Cytokine-Induced Killer Cells in Improving Side Effects of Colorectal Cancer Therapy.

    Science.gov (United States)

    Mosińska, Paula; Gabryelska, Agata; Zasada, Malwina; Fichna, Jakub

    2017-01-01

    The aim of cancer therapy is to eradicate cancer without affecting healthy tissues. Current options available for treating colorectal cancer (CRC), including surgery, chemotherapy or radiotherapy, usually elicit multiple adverse effects and frequently fail to completely remove the tumor cells. Thus, there is a constant need for seeking cancer cell-specific therapeutics to improve the course of cancer therapy and reduce the risk of relapse. In this review we elaborate on the mechanisms underlying the immunotherapy with dendritic cells (DCs) and cytokine-induced killer (CIK) cells, and summarize their effectiveness and tolerability available clinical studies. Finally, we discuss the up-to-date combinatorial adoptive anti-cancer immunotherapy with CIK cells co-cultured with DCs that recently showed encouraging efficacy and usefulness in treating malignant disease, including CRC.

  5. Sunitinib indirectly enhanced anti-tumor cytotoxicity of cytokine-induced killer cells and CD3⁺CD56⁺ subset through the co-culturing dendritic cells.

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    Adisak Wongkajornsilp

    Full Text Available Cytokine-induced killer (CIK cells have reached clinical trials for leukemia and solid tumors. Their anti-tumor cytotoxicity had earlier been shown to be intensified after the co-culture with dendritic cells (DCs. We observed markedly enhanced anti-tumor cytotoxicity activity of CIK cells after the co-culture with sunitinib-pretreated DCs over that of untreated DCs. This cytotoxicity was reliant upon DC modulation by sunitinib because the direct exposure of CIK cells to sunitinib had no significant effect. Sunitinib promoted Th1-inducing and pro-inflammatory phenotypes (IL-12, IFN-γ and IL-6 in DCs at the expense of Th2 inducing phenotype (IL-13 and regulatory phenotype (PD-L1, IDO. Sunitinib-treated DCs subsequently induced the upregulation of Th1 phenotypic markers (IFN-γ and T-bet and the downregulation of the Th2 signature (GATA-3 and the Th17 marker (RORC on the CD3⁺CD56⁺ subset of CIK cells. It concluded that sunitinib-pretreated DCs drove the CD3⁺CD56⁺ subset toward Th1 phenotype with increased anti-tumor cytotoxicity.

  6. The role of germline promoters and I exons in cytokine-induced gene-specific class switch recombination.

    Science.gov (United States)

    Dunnick, Wesley A; Shi, Jian; Holden, Victoria; Fontaine, Clinton; Collins, John T

    2011-01-01

    Germline transcription precedes class switch recombination (CSR). The promoter regions and I exons of these germline transcripts include binding sites for activation- and cytokine-induced transcription factors, and the promoter regions/I exons are essential for CSR. Therefore, it is a strong hypothesis that the promoter/I exons regions are responsible for much of cytokine-regulated, gene-specific CSR. We tested this hypothesis by swapping the germline promoter and I exons for the murine γ1 and γ2a H chain genes in a transgene of the entire H chain C-region locus. We found that the promoter/I exon for γ1 germline transcripts can direct robust IL-4-induced recombination to the γ2a gene. In contrast, the promoter/I exon for the γ2a germline transcripts works poorly in the context of the γ1 H chain gene, resulting in expression of γ1 H chains that is level. Nevertheless, the small amount of recombination to the chimeric γ1 gene is induced by IFN-γ. These results suggest that cytokine regulation of CSR, but not the magnitude of CSR, is regulated by the promoter/I exons.

  7. Characterization of porcine cytokine inducible SH2-containing protein gene and its association with piglet diarrhea traits

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    Buyue Niu

    2017-12-01

    Full Text Available Objective The cytokine inducible SH2-containing protein (CISH, which might play a role in porcine intestine immune responses, was one of the promising candidate genes for piglet anti-disease traits. An experiment was conducted to characterize the porcine CISH (pCISH gene and to evaluate its genetic effects on pig anti-disease breeding. Methods Both reverse transcription polymerase chain reaction (RT-PCR and PCR were performed to obtain the sequence of pCISH gene. A pEGFP-C1-CISH vector was constructed and transfected into PK-15 cells to analysis the distribution of pCISH. The sequences of individuals were compared with each other to find the polymorphisms in pCISH gene. The association analysis was performed in Min pigs and Landrace pigs to evaluate the genetic effects on piglet diarrhea traits. Results In the present research, the coding sequence and genomic sequence of pCISH gene was obtained. Porcine CISH was mainly localized in cytoplasm. TaqI and HaeIII PCR restriction fragment length polymorphism (RFLP assays were established to detect single nucleotide polymorphisms (SNPs; A-1575G in promoter region and A2497C in Intron1, respectively. Association studies indicated that SNP A-1575G was significantly associated with diarrhea index of Min piglets (p<0.05 and SNP A2497C was significantly associated with the diarrhea trait of both Min pig and Landrace piglets (p<0.05. Conclusion This study suggested that the pCISH gene might be a novel candidate gene for pig anti-disease traits, and further studies are needed to confirm the results of this preliminary research.

  8. Characterization of STAT5B phosphorylation correlating with expression of cytokine-inducible SH2-containing protein (CIS).

    Science.gov (United States)

    Cooper, John C; Boustead, Jared N; Yu, Chao-Lan

    2006-06-01

    Cytokine-inducible SH2-containing protein (CIS) is the first identified member of genes encoding for the suppressor of cytokine signaling (SOCS). CIS is also a well-known target gene of signal transducer and activator of transcription 5 (STAT5) pathways, providing normal negative feedback control of signaling by cytokines and growth factors. Three other SOCS genes, SOCS1, SOCS2, and SOCS3, can be silenced by DNA hypermethylation in human cancers, suggesting a potential mechanism for constitutive STAT activation. However, it is not known whether CIS expression is similarly perturbed in tumor cells. We report here the absence of CIS expression in T lymphoma LSTRA that overexpresses the Lck protein tyrosine kinase and exhibits elevated STAT5 activity. Pervanadate-induced CIS expression and STAT5 binding to the CIS promoter in vivo over a short time course implies that mechanisms other than DNA hypermethylation may contribute to defective CIS expression in LSTRA cells. Comparison with cytokine-dependent BaF3 cells stimulated with interleukin-3 (IL-3) further reveals that CIS induction correlates with specific STAT5b post-translational modifications. It exhibits as the slowest migrating form through SDS-polyacrylamide gel electrophoresis (SDS-PAGE) analysis. This distinctly modified STAT5b is the predominant form that binds to the consensus STAT5 sites in the CIS promoter and accumulates in the nucleus. In vitro phosphatase assays and phosphoamino acid analysis suggest the involvement of phosphorylation on residues other than the highly conserved tyrosine and serine sites in this distinct STAT5b mobility shift. All together, our results provide a novel link between incomplete STAT5b phosphorylation and defective SOCS gene expression in cancer cells.

  9. Characterization of porcine cytokine inducible SH2-containing protein gene and its association with piglet diarrhea traits.

    Science.gov (United States)

    Niu, Buyue; Guo, Dongchun; Liu, Zhiran; Han, Xiaofei; Wang, Xibiao

    2017-12-01

    The cytokine inducible SH2-containing protein (CISH), which might play a role in porcine intestine immune responses, was one of the promising candidate genes for piglet anti-disease traits. An experiment was conducted to characterize the porcine CISH (pCISH) gene and to evaluate its genetic effects on pig anti-disease breeding. Both reverse transcription polymerase chain reaction (RT-PCR) and PCR were performed to obtain the sequence of pCISH gene. A pEGFP-C1-CISH vector was constructed and transfected into PK-15 cells to analysis the distribution of pCISH. The sequences of individuals were compared with each other to find the polymorphisms in pCISH gene. The association analysis was performed in Min pigs and Landrace pigs to evaluate the genetic effects on piglet diarrhea traits. In the present research, the coding sequence and genomic sequence of pCISH gene was obtained. Porcine CISH was mainly localized in cytoplasm. TaqI and HaeIII PCR restriction fragment length polymorphism (RFLP) assays were established to detect single nucleotide polymorphisms (SNPs); A-1575G in promoter region and A2497C in Intron1, respectively. Association studies indicated that SNP A-1575G was significantly associated with diarrhea index of Min piglets (p<0.05) and SNP A2497C was significantly associated with the diarrhea trait of both Min pig and Landrace piglets (p<0.05). This study suggested that the pCISH gene might be a novel candidate gene for pig anti-disease traits, and further studies are needed to confirm the results of this preliminary research.

  10. Phase II/III Study of Radiofrequency Ablation Combined with Cytokine-Induced Killer Cells Treating Colorectal Liver Metastases

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    Xiaodong Li

    2016-11-01

    Full Text Available Purpose: This phase II/III, non-randomized clinical trial aimed to determine the efficacy and safety of the combination of radiofrequency ablation (RFA and cytokine-induced killer (CIK cells transfusion for patients with colorectal liver metastases (CRLMs. Experimental Design: A total of 60 eligible patients with CRLMs were enrolled and divided into Group A (RFA alone, n = 30 and Group B (RFA plus CIK, n = 30, and following enzyme-linked immunosorbent spot assay was performed in 8 patients with CEA > 50 ng/mL pre-RFA and 7 days post-RFA and CIK treatment, respectively. Results: The median progression-free survival (PFS times of Group A and Group B were 18.5 months and 23 months, respectively (P = 0.0336. The 3-year progression-free rates were 13.3% in Group A and 20.3% in Group B, respectively. The median overall survival time was 43 months in Group A, and not reached in Group B. The 3-year survival rates were 64.6% in Group A and 81.0% in Group B, respectively (P = 0.1187. Among the 8 patients with CEA > 50ng/mL, 6 had increase of circulating CEA-specific T cells after RFA (P = 0.010. After CIK cell therapy, the number of CEA-specific T cells increased in all the 8 patients comparing with that pre-treatment (P = 0.001 and in 7 patients comparing with that post-RFA (P = 0.028. Conclusions: We firstly confirm that the combination of RFA and CIK cells boosts CEA-specific T cell response and shows to be an efficacious and safe treatment modality for patients with CRLMs.

  11. Role of Cytokine-Induced Glycosylation Changes in Regulating Cell Interactions and Cell Signaling in Inflammatory Diseases and Cancer

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    Justine H. Dewald

    2016-11-01

    Full Text Available Glycosylation is one of the most important modifications of proteins and lipids, and cell surface glycoconjugates are thought to play important roles in a variety of biological functions including cell-cell and cell-substrate interactions, bacterial adhesion, cell immunogenicity and cell signaling. Alterations of glycosylation are observed in number of diseases such as cancer and chronic inflammation. In that context, pro-inflammatory cytokines have been shown to modulate cell surface glycosylation by regulating the expression of glycosyltransferases involved in the biosynthesis of carbohydrate chains. These changes in cell surface glycosylation are also known to regulate cell signaling and could contribute to disease pathogenesis. This review summarizes our current knowledge of the glycosylation changes induced by pro-inflammatory cytokines, with a particular focus on cancer and cystic fibrosis, and their consequences on cell interactions and signaling.

  12. Comparison of Growth and the Cytokines Induced by Pathogenic Yersinia enterocolitica Bio-Serotypes 3/O: 3 and 2/O: 9.

    Science.gov (United States)

    Yang, Haoshu; Gu, Wenpeng; Qiu, Haiyan; Sun, Guixiang; Liang, Junrong; Li, Kewei; Xiao, Yuchun; Duan, Ran; Jing, Huaiqi; Wang, Xin

    2017-01-01

    Pathogenic Yersinia enterocolitica is widely distributed in China where the primary bio-serotypes are 3/O: 3 and 2/O: 9. Recently, the distribution of 2/O: 9 strains are being gradually replaced by 3/O: 3 strains where presently 3/O: 3 strains are the major pathogenic Y. enterocolitica in China. To identify the growth conditions and cytokines induced by Y. enterocolitica and providing some clues for this shift, we performed competitive growth in vitro and in vivo for these two bio-serotype strains; and we also compared the cytokines induced by them in infected BALB/C mice. We found 2/O: 9 strains grew more in vitro , while 3/O: 3 strains grew more in vivo regardless of using single cultures or mixed cultures. The cytokines induced by the two strains were similar: interleukin-6 (IL-6), IL-9, IL-13, granulocyte colony-stimulating factor (G-CSF), chemokines (KC), monocyte chemotactic protein 1 (MCP-1), macrophage inflammation protein-1α (MIP-1α), tumor necrosis factor-α (TNF-α), and RANTES were statistically up-regulated upon activation of normal T cells compared to the control. The cytokine values were higher in mixed infections than in single infections except for IL-6, G-CSF, and KC. The data illustrated the different growth of pathogenic Y. enterocolitica bio-serotype 3/O: 3 and 2/O: 9 in vitro and in vivo , and the cytokine changes induced by the two strains in infected BALB/C mice. The growth comparisons of two strains maybe reflect the higher pathogenic ability or resistance to host immune response for Y. enterocolitica bio-serotype 3/O: 3 and maybe it as one of the reason for bacteria shift.

  13. Comparison of Growth and the Cytokines Induced by Pathogenic Yersinia enterocolitica Bio-Serotypes 3/O: 3 and 2/O: 9

    Directory of Open Access Journals (Sweden)

    Haoshu Yang

    2017-05-01

    Full Text Available Pathogenic Yersinia enterocolitica is widely distributed in China where the primary bio-serotypes are 3/O: 3 and 2/O: 9. Recently, the distribution of 2/O: 9 strains are being gradually replaced by 3/O: 3 strains where presently 3/O: 3 strains are the major pathogenic Y. enterocolitica in China. To identify the growth conditions and cytokines induced by Y. enterocolitica and providing some clues for this shift, we performed competitive growth in vitro and in vivo for these two bio-serotype strains; and we also compared the cytokines induced by them in infected BALB/C mice. We found 2/O: 9 strains grew more in vitro, while 3/O: 3 strains grew more in vivo regardless of using single cultures or mixed cultures. The cytokines induced by the two strains were similar: interleukin-6 (IL-6, IL-9, IL-13, granulocyte colony-stimulating factor (G-CSF, chemokines (KC, monocyte chemotactic protein 1 (MCP-1, macrophage inflammation protein-1α (MIP-1α, tumor necrosis factor-α (TNF-α, and RANTES were statistically up-regulated upon activation of normal T cells compared to the control. The cytokine values were higher in mixed infections than in single infections except for IL-6, G-CSF, and KC. The data illustrated the different growth of pathogenic Y. enterocolitica bio-serotype 3/O: 3 and 2/O: 9 in vitro and in vivo, and the cytokine changes induced by the two strains in infected BALB/C mice. The growth comparisons of two strains maybe reflect the higher pathogenic ability or resistance to host immune response for Y. enterocolitica bio-serotype 3/O: 3 and maybe it as one of the reason for bacteria shift.

  14. Progesterone receptor membrane component 1 as the mediator of the inhibitory effect of progestins on cytokine-induced matrix metalloproteinase 9 activity in vitro.

    Science.gov (United States)

    Allen, Terrence K; Feng, Liping; Grotegut, Chad A; Murtha, Amy P

    2014-02-01

    Progesterone (P4) and the progestin, 17α-hydroxyprogesterone caproate, are clinically used to prevent preterm births (PTBs); however, their mechanism of action remains unclear. Cytokine-induced matrix metalloproteinase 9 (MMP-9) activity plays a key role in preterm premature rupture of the membranes and PTB. We demonstrated that the primary chorion cells and the HTR8/SVneo cells (cytotrophoblast cell line) do not express the classical progesterone receptor (PGR) but instead a novel progesterone receptor, progesterone receptor membrane component 1 (PGRMC1), whose role remains unclear. Using HTR8/SVneo cells in culture, we further demonstrated that 6 hours pretreatment with medroxyprogesterone acetate (MPA) and dexamethasone (Dex) but not P4 or 17α-hydroxyprogesterone hexanoate significantly attenuated tumor necrosis factor α-induced MMP-9 activity after a 24-hour incubation period. The inhibitory effect of MPA, but not Dex, was attenuated when PGRMC1 expression was successfully reduced by PGRMC1 small interfering RNA. Our findings highlight a possible novel role of PGRMC1 in mediating the effects of MPA and in modulating cytokine-induced MMP-9 activity in cytotrophoblast cells in vitro.

  15. Efficacy of cytokine-induced killer cell infusion as an adjuvant immunotherapy for hepatocellular carcinoma: a systematic review and meta-analysis

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    Yu R

    2017-03-01

    Full Text Available Ruili Yu,1 Bo Yang,2 Xiaohua Chi,3 Lili Cai,4 Cui Liu,5 Lei Yang,6 Xueyan Wang,1 Peifeng He,7 Xuechun Lu2 1Department of Allergy, Beijing Shijitan Hospital, Affiliated to Capital Medical University, 2Department of Geriatric Hematology, Chinese PLA General Hospital, 3Department of Pharmacy, Chinese PLA Rocket Force General Hospital, 4Department of Geriatric Laboratory Medicine, 5Department of Geriatric Ultrasound, 6Medical Department, Nanlou Clinic, Chinese PLA General Hospital, Beijing, 7School of Medical Information Management, Shanxi Medical University, Taiyuan, People’s Republic of China Abstract: This study was designed to evaluate the efficacy and safety of cytokine-induced killer (CIK cell-based immunotherapy as an adjuvant therapy for hepatocellular carcinoma (HCC. Published studies were identified by searching Medline, Cochrane, EMBASE, and Google Scholar databases with the keywords: cytokine-induced killer cell, hepatocellular carcinoma, and immunotherapy. The outcomes of interest were overall survival, progression-free survival, and disease-free survival. Eight randomized controlled trials (RCTs, six prospective studies, and three retrospective studies were included. The overall analysis revealed that patients in the CIK cell-treatment group had a higher survival rate (pooled hazard ratio (HR =0.594, 95% confidence interval [CI] =0.501–0.703, P<0.001. Patients treated with CIK cells in non-RCTs had a higher progression-free survival rate (pooled HR =0.613, 95% CI =0.510–0.738, P<0.001. However, CIK cell-treated patients in RCTs had progression-free survival rates similar to those of the control group (pooled HR =0.700, 95% CI =0.452–1.084, P=0.110. The comparison between pooled results of RCTs and non-RCTs regarding the progression-free survival rate did not reach statistical significance. Patients in the CIK cell-treatment group had lower rates of relapse in RCTs (pooled HR =0.635, 95% CI =0.514–0.784, P<0.001. Similar

  16. Alcoholism: a systemic proinflammatory condition.

    Science.gov (United States)

    González-Reimers, Emilio; Santolaria-Fernández, Francisco; Martín-González, María Candelaria; Fernández-Rodríguez, Camino María; Quintero-Platt, Geraldine

    2014-10-28

    Excessive ethanol consumption affects virtually any organ, both by indirect and direct mechanisms. Considerable research in the last two decades has widened the knowledge about the paramount importance of proinflammatory cytokines and oxidative damage in the pathogenesis of many of the systemic manifestations of alcoholism. These cytokines derive primarily from activated Kupffer cells exposed to Gram-negative intestinal bacteria, which reach the liver in supra-physiological amounts due to ethanol-mediated increased gut permeability. Reactive oxygen species (ROS) that enhance the inflammatory response are generated both by activation of Kupffer cells and by the direct metabolic effects of ethanol. The effects of this increased cytokine secretion and ROS generation lie far beyond liver damage. In addition to the classic consequences of endotoxemia associated with liver cirrhosis that were described several decades ago, important research in the last ten years has shown that cytokines may also induce damage in remote organs such as brain, bone, muscle, heart, lung, gonads, peripheral nerve, and pancreas. These effects are even seen in alcoholics without significant liver disease. Therefore, alcoholism can be viewed as an inflammatory condition, a concept which opens the possibility of using new therapeutic weapons to treat some of the complications of this devastating and frequent disease. In this review we examine some of the most outstanding consequences of the altered cytokine regulation that occurs in alcoholics in organs other than the liver.

  17. Requirement for C-X-C chemokines (macrophage inflammatory protein-2 and cytokine-induced neutrophil chemoattractant) in IgG immune complex-induced lung injury

    DEFF Research Database (Denmark)

    Shanley, T P; Schmal, H; Warner, R L

    1997-01-01

    chemokines, macrophage inflammatory protein-2 (MIP-2) and cytokine-induced neutrophil chemoattractant (CINC). Both mRNA and protein for MIP-2 and CINC appeared in a time-dependent manner after initiation of IgG immune complex deposition in lung. There exists a 69% homology between the amino acid sequences...... for these proteins, and we found cross-reactivity between polyclonal Abs raised to these chemokines. By purifying the blocking Abs using double affinity methods (with Ag-immobilized beads), this cross-reactivity was removed. Individually, anti-MIP-2 and anti-CINC Ab significantly reduced lung injury (as measured...... activity in BAL fluids collected 2 h after injury from animals undergoing immune complex deposition could be shown to be chiefly due to the combined contributions of MIP-2 (39%), CINC (28%), and C5a (21%). When either MIP-2 or CINC was blocked in vivo, up-regulation of Mac-1 expression on neutrophils...

  18. Pertussis toxin, an inhibitor of G(αi PCR, inhibits bile acid- and cytokine-induced apoptosis in primary rat hepatocytes.

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    Golnar Karimian

    Full Text Available Excessive hepatocyte apoptosis is a common event in acute and chronic liver diseases leading to loss of functional liver tissue. Approaches to prevent apoptosis have therefore high potential for the treatment of liver disease. G-protein coupled receptors (GPCR play crucial roles in cell fate (proliferation, cell death and act through heterotrimeric G-proteins. G(αiPCRs have been shown to regulate lipoapoptosis in hepatocytes, but their role in inflammation- or bile acid-induced apoptosis is unknown. Here, we analyzed the effect of inhibiting G(αiPCR function, using pertussis toxin (PT, on bile acid- and cytokine-induced apoptosis in hepatocytes. Primary rat hepatocytes, HepG2-rNtcp cells (human hepatocellular carcinoma cells or H-4-II-E cells (rat hepatoma cells were exposed to glycochenodeoxycholic acid (GCDCA or tumor necrosis factor-α (TNFα/actinomycin D (ActD. PT (50-200 nmol/L was added 30 minutes prior to the apoptotic stimulus. Apoptosis (caspase-3 activity, acridine orange staining and necrosis (sytox green staining were assessed. PT significantly reduced GCDCA- and TNFα/ActD-induced apoptosis in rat hepatocytes (-60%, p<0.05 in a dose-dependent manner (with no shift to necrosis, but not in HepG2-rNtcp cells or rat H-4-II-E cells. The protective effect of pertussis toxin was independent of the activation of selected cell survival signal transduction pathways, including ERK, p38 MAPK, PI3K and PKC pathways, as specific protein kinase inhibitors did not reverse the protective effects of pertussis toxin in GCDCA-exposed hepatocytes.Pertussis toxin, an inhibitor of G(αiPCRs, protects hepatocytes, but not hepatocellular carcinoma cells, against bile acid- and cytokine-induced apoptosis and has therapeutic potential as primary hepatoprotective drug, as well as adjuvant in anti-cancer therapy.

  19. Nitric oxide: a physiologic messenger.

    Science.gov (United States)

    Lowenstein, C J; Dinerman, J L; Snyder, S H

    1994-02-01

    To review the physiologic role of nitric oxide, an unusual messenger molecule that mediates blood vessel relaxation, neurotransmission, and pathogen suppression. A MEDLINE search of articles published from 1987 to 1993 that addressed nitric oxide and the enzyme that synthesizes it, nitric oxide synthase. Animal and human studies were selected from 3044 articles to analyze the clinical importance of nitric oxide. Descriptions of the structure and function of nitric oxide synthase were selected to show how nitric oxide acts as a biological messenger molecule. Biochemical and physiologic studies were analyzed if the same results were found by three or more independent observers. Two major classes of nitric oxide synthase enzymes produce nitric oxide. The constitutive isoforms found in endothelial cells and neurons release small amounts of nitric oxide for brief periods to signal adjacent cells, whereas the inducible isoform found in macrophages releases large amounts of nitric oxide continuously to eliminate bacteria and parasites. By diffusing into adjacent cells and binding to enzymes that contain iron, nitric oxide plays many important physiologic roles. It regulates blood pressure, transmits signals between neurons, and suppresses pathogens. Excess amounts, however, can damage host cells, causing neurotoxicity during strokes and causing the hypotension associated with sepsis. Nitric oxide is a simple molecule with many physiologic roles in the cardiovascular, neurologic, and immune systems. Although the general principles of nitric oxide synthesis are known, further research is necessary to determine what role it plays in causing disease.

  20. Clinical applications of dendritic cells–cytokine-induced killer cells mediated immunotherapy for pancreatic cancer: an up-to-date meta-analysis

    Directory of Open Access Journals (Sweden)

    Zhang YC

    2017-08-01

    Full Text Available Yucai Zhang,1 Xiaorui Zhang,1 Anqi Zhang,2 Ke Li,2 Kai Qu3 1Department of Health, 2Department of Central Laboratory, Liaocheng People’s Hospital of Taishan Medical University, Liaocheng, Shandong, 3Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China Purpose: This study aimed to systematically evaluate the efficacy and safety of dendritic cells–cytokine-induced killer (DC–CIK cells immunotherapy in treating pancreatic cancer (PC patients. Methods: Data were collected from published articles of clinical trials. Databases including Web of Science, EMBASE, PubMed, Cochrane Library, Wanfang, and CNKI were searched. The main outcome measures in this research included the overall response rate (ORR, disease control rate (DCR, overall survival (OS, patients’ quality of life (QoL, immune function, and adverse events. Comparative analysis was conducted between DC–CIK immunotherapy and chemotherapy (combined therapy and chemotherapy alone. Results: This analysis covered 14 trials with 1,088 PC patients involved. The combined therapy showed advantages over chemotherapy alone in ORR (odds ratio [OR] =1.69, 95% confidence interval [CI] =1.20–2.38, P=0.003, DCR (OR =2.33, 95% CI =1.63–3.33, P<0.00001, OS (1-year OS, OR =3.61, 95% CI =2.41–5.40, P<0.00001; 3-year OS, OR =2.65, 95% CI =1.56–4.50, P=0.0003 and patients’ QoL (P<0.01 with statistical significance. After immunotherapy, lymphocyte subsets’ percentages of CD3+ (P<0.00001, CD4+ (P=0.01, CD3+CD56+ (P<0.00001, and cytokine levels of IFN-γ (P<0.00001 were significantly increased, and the percentages of CD4+CD25+CD127low (P<0.00001 and levels of IL-4 (P<0.0001 were significantly decreased, whereas analysis on CD8+ (P=0.59 and CD4+/CD8+ ratio (P=0.64 did not show a significant difference. Conclusion: The combination of DC–CIK immunotherapy and chemotherapy is effective for PC treatment, indicated by prolonging

  1. Activation of farnesoid X receptor increases the expression of cytokine inducible SH2-containing protein in HepG2 cells.

    Science.gov (United States)

    Xu, Zhizhen; Huang, Gang; Gong, Wei; Zhao, Yuanyin; Zhou, Peng; Zeng, Yijun; He, Fengtian

    2012-11-01

    Cytokine inducible SH2-containing protein (CISH), which negatively regulates cytokine signaling by inhibiting JAK2/STAT5 activity, is regarded as a therapeutic target for inflammatory diseases. Farnesoid X receptor (FXR), a ligand-activated transcription factor, has been proposed to play a protective function in the inflammatory responses. However, the role of FXR in modulation of CISH expression is unknown. In the present study, we for the first time identified that in human hepatoma cell line HepG2 the activation of FXR by the natural agonist chenodeoxycholic acid (CDCA) and the synthetic specific agonist GW4064 upregulated CISH at both transcriptional and translational levels, and inhibited interleukin (IL)6-induced STAT5 activation. Moreover, the in vivo experiment demonstrated that gavaging mice with CDCA increased CISH expression and reduced basal STAT5 phosphorylation in liver tissues. Reporter assay showed that FXR agonists enhanced the transcriptional activity of CISH promoter. These data suggest that FXR may serve as a novel molecular target for manipulating CISH expression in hepatocytes. FXR-mediated upregulation of CISH may play an important role in the homeostasis of cytokine signal networks and be beneficial to control cytokine-associated inflammatory diseases.

  2. Retrospective Comparative Study of the Effects of Dendritic Cell Vaccine and Cytokine-Induced Killer Cell Immunotherapy with that of Chemotherapy Alone and in Combination for Colorectal Cancer

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    Jingxiu Niu

    2014-01-01

    Full Text Available Purpose. This retrospective study determined the delayed-type hypersensitivity (DTH skin test and safety of dendritic cell (DC vaccine and cytokine-induced killer (CIK cell immunotherapy and the survival compared to chemotherapy in 239 colorectal cancer (CRC patients. Methods. DTH and safety of the immunotherapy were recorded. The overall survival (OS and disease free survival curves were compared according to the immunotherapy and/or chemotherapy received with Kaplan-Meier estimates. Results. Of the 70 patients who received immunotherapy, 62.86% had a positive DTH skin test, 38.57% developed fever, 47.14% developed insomnia, 38.57% developed anorexia, 4.29% developed joint soreness, and 11.43% developed skin rash. For 204 resectable CRC patients, median survival time (MST (198.00 days was significantly longer in patients with immunotherapy plus chemotherapy than with chemotherapy alone (106.00 days (P=0.02. For 35 patients with unresectable or postsurgery relapsed CRC and who were confirmed to be dead, no statistical difference was observed in the MST between the patients treated with immunotherapy and with chemotherapy (P=0.41. MST in the patients treated with chemotherapy plus immunotherapy was 154 days longer than that of patients treated with chemotherapy alone (P=0.41. Conclusions. DC vaccination and CIK immunotherapy did not cause severe adverse effects, induce immune response against CRC, and prolong OS.

  3. Ascorbic acid deficiency stimulates hepatic expression of inflammatory chemokine, cytokine-induced neutrophil chemoattractant-1, in scurvy-prone ODS rats.

    Science.gov (United States)

    Horio, Fumihiko; Kiyama, Keiichiro; Kobayashi, Misato; Kawai, Kaori; Tsuda, Takanori

    2006-02-01

    ODS rat has a hereditary defect in ascorbic acid biosynthesis and is a useful animal model for elucidating the physiological role of ascorbic acid. We previously demonstrated by using ODS rats that ascorbic acid deficiency changes the hepatic gene expression of acute phase proteins, as seen in acute inflammation. In this study, we investigated the effects of ascorbic acid deficiency on the production of inflammatory chemokine, cytokine-induced neutrophil chemoattractant-1 (CINC-1), in ODS rats. Male ODS rats (6 wk of age) were fed a basal diet containing ascorbic acid (300 mg/kg diet) or a diet without ascorbic acid for 14 d. Obvious symptoms of scurvy were not observed in the ascorbic acid-deficient rats. Ascorbic acid deficiency significantly elevated the serum concentration of CINC-1 on d 14. The liver and spleen CINC-1 concentrations in the ascorbic acid-deficient rats were significantly elevated to 600% and 180% of the respective values in the control rats. However, the lung concentration of CINC-1 was not affected by ascorbic acid deficiency. Ascorbic acid deficiency significantly elevated the hepatic mRNA level of CINC-1 (to 480% of the value in the control rats), but not the lung mRNA level. These results demonstrate that ascorbic acid deficiency elevates the serum, liver and spleen concentrations of CINC-1 as seen in acute inflammation, and suggest that ascorbic acid deficiency stimulate the hepatic CINC-1 gene expression.

  4. Cytokine-induced oxidative stress in cardiac inflammation and heart failure – how the ubiquitin proteasome system targets this vicious cycle

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    Antje eVoigt

    2013-03-01

    Full Text Available The ubiquitin proteasome system (UPS is critical for the regulation of many intracellular processes necessary for cell function and survival. The absolute requirement of the UPS for the maintenance of protein homeostasis and thereby for the regulation of protein quality control is reflected by the fact that deviation of proteasome function from the norm was reported in cardiovascular pathologies. Inflammation is a major factor contributing to cardiac pathology. Herein, cytokines induce protein translation and the production of free radicals, thereby challenging the cellular protein equilibrium. Here, we discuss current knowledge on the mechanisms of UPS-functional adaptation in response to oxidative stress in cardiac inflammation. The increasing pool of oxidant-damaged degradation-prone proteins in cardiac pathology accounts for the need for enhanced protein turnover by the UPS. This process is accomplished by an up-regulation of the ubiquitylation machinery and the induction of immunoproteasomes. Thereby, the inflamed heart muscle is cleared from accumulating misfolded proteins. Current advances on immunoproteasome-specific inhibitors in this field question the impact of the proteasome as a therapeutic target in heart failure.

  5. A possible way to assess tidal exhaled nitric oxide in neonates and infants treated with nasal continuous positive airway pressure

    DEFF Research Database (Denmark)

    Schmidt, Birgitte Johanne; Reim, Pauline Schibler; Pedersen, Ole Find

    2018-01-01

    The endogenous compound nitric oxide (NO) is released into the airways via inducible NO synthase (1),which has the capacity to produce NO when up-regulated by pro-inflammatory cytokines or exogenous factors, like hypoxia, bacterial toxins and viruses (2). Prematurely born infants are susceptible...

  6. Dendritic cells decreased the concomitant expanded Tregs and Tregs related IL-35 in cytokine-induced killer cells and increased their cytotoxicity against leukemia cells.

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    Ying Pan

    Full Text Available Regulatory T cells (Tregs are potent immunosuppressive cells and essential for inducing immune tolerance. Recent studies have reported that Tregs and Tregs related cytokines can inhibit the antitumor activity of cytokine-induced killer (CIK cells, but dendritic cells co-cultured CIK (DC-CIK cells can be used for induction of a specific immune response by blocking of Tregs and TGF-β, IL-10. As a novel identified cytokine, IL-35 is specially produced by Tregs and plays an essential role in immune regulation. However, it remains unknown whether IL-35 roles in tumor immunotherapy mediated by CIK and DC-CIK cells. In this study, we cultured CIK and DC-CIK cells from the same healthy adult samples, and investigated their phenotype, proliferation, cytotoxic activity against leukemia cell lines K562 and NB4 by FCM and CCK-8, measured IL-35, TGF-β and IL-10 protein by ELISA, detected Foxp3, IL-35 and IL-35 receptor mRNA by Real-time PCR, respectively. We found Tregs and IL-35 concomitantly expanded by a time-dependent way during the generation of CIK cells, but DC significantly down-regulated the expression of them and simultaneously up-regulated the proliferation ability as well as cytotoxic activity of CIK cells against leukemia cell lines. Therefore, our data suggested that DC decreased concomitant expanded Tregs and Tregs related IL-35 in CIK cells and might contribute to improve their cytotoxicity against leukemia cells in vitro.

  7. Co-Expansion of Cytokine-Induced Killer Cells and Vγ9Vδ2 T Cells for CAR T-Cell Therapy.

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    Shou-Hui Du

    Full Text Available Gamma delta (γδ T cells and cytokine-induced killer (CIK cells, which are a heterogeneous population of T lymphocytes and natural killer T (NKT cells, have been separately expanded ex vivo and shown to be capable of targeting and mediating cytotoxicity against various tumor cells in a major histocompatibility complex-unrestricted manner. However, the co-expansion and co-administration of these immune cells have not been explored. In this study we describe an efficient method to expand simultaneously both CIK and Vγ9Vδ2 T cells, termed as CIKZ cells, from human peripheral blood mononuclear cells (PBMCs using Zometa, interferon-gamma (IFN-γ, interleukin 2 (IL-2, anti-CD3 antibody and engineered K562 feeder cells expressing CD64, CD137L and CD86. A 21-day culture of PBMCs with this method yielded nearly 20,000-fold expansion of CIKZ cells with γδ T cells making up over 20% of the expanded population. The expanded CIKZ cells exhibited antitumor cytotoxicity and could be modified to express anti-CD19 chimeric antigen receptor (CAR, anti-CEA CAR, and anti-HER2 CAR to enhance their specificity and cytotoxicity against CD19-, CEA-, or HER2-positive tumor cells. The tumor inhibitory activity of anti-CD19 CAR-modified CIKZ cells was further demonstrated in vivo in a Raji tumor mouse model. The findings herein substantiate the feasibility of co-expanding CIK and γδ cells for adoptive cellular immunotherapy applications such as CAR T-cell therapy against cancer.

  8. Dendritic Cell/Cytokine-Induced Killer Cell Immunotherapy Combined with S-1 in Patients with Advanced Pancreatic Cancer: A Prospective Study.

    Science.gov (United States)

    Jiang, Ni; Qiao, Guoliang; Wang, Xiaoli; Morse, Michael A; Gwin, William R; Zhou, Lei; Song, Yuguang; Zhao, Yanjie; Chen, Feng; Zhou, Xinna; Huang, Lefu; Hobeika, Amy; Yi, Xin; Xia, Xuefeng; Guan, Yanfang; Song, Jin; Ren, Jun; Lyerly, H Kim

    2017-09-01

    Purpose: Advanced pancreatic cancer has remained challenging to treat effectively. This study aimed to investigate the clinical effects and safety of immunotherapy with dendritic cells and cytokine-induced killer cells (DC-CIK) administered with the chemotherapy (CT) S-1 in this malignancy. Experimental Design: Consecutive patients ( n = 47) with advanced pancreatic cancer were treated with either DC-CIK + S-1, DC-CIK alone, S-1 alone, or best supportive care. Results: DC-CIK plus S-1 produced significantly longer median OS and PFS (212 and 136 days) compared with DC-CIK (128 and 85 days), CT (141 and 92 days), or supportive care only (52 and 43 days; P < 0.001). After adjusting for competing risk factors, DC-CIK combined with S-1 and receipt of 2 or more cycles of DC-CIK treatment remained independent predictors of disease-free and overall survival ( P < 0.05). Phenotypic analysis of PBMCs demonstrated that the CD3 + , CD3 + /CD4 + , and CD8 + /CD28 + T-cell subsets were elevated ( P < 0.05), while the CD3 + /CD8 + , CD3 + /CD16 + /CD56 + and CD4 + /CD25 + cell subsets were significantly decreased after DC-CIK cell therapy ( P < 0.05). There were no grade 3 or 4 toxicities. In addition, the mutational frequency in cell-free tumor DNA (cfDNA) declined in 4 of 14 patients who received DC-CIK, and was associated with a more favorable survival. Conclusions: Treatment of advanced pancreatic cancer with combined DC-CIK infusions and S-1 was safe, resulted in favorable PFS and OS, and modulated the peripheral blood immune repertoire. Clin Cancer Res; 23(17); 5066-73. ©2017 AACR . ©2017 American Association for Cancer Research.

  9. Effects of dendritic cell-activated and cytokine-induced killer cell therapy on 22 children with acute myeloid leukemia after chemotherapy.

    Science.gov (United States)

    Bai, Yan; Zheng, Jin-e; Wang, Nan; Cai, He-hua; Zhai, Li-na; Wu, Yao-hui; Wang, Fang; Jin, Run-ming; Zhou, Dong-feng

    2015-10-01

    The efficiency of dendritic cell-activated and cytokine-induced killer cell (DC-CIK) therapy on children with acute myeloid leukemia (AML) after chemotherapy was investigated. Mononuclear cells were collected from children achieving complete remission after chemotherapy, cultured in vitro and transfused back into the same patient. Interleukin-2 (IL-2) was injected subcutaneously every other day 10 times at the dose of 1 × 10(6) units. Peripheral blood lymphocyte subsets and minimal residual disease (MRD) were detected by flow cytometry. Function of bone marrow was monitored by methods of morphology, immunology, cytogenetics and molecular biology. The side effects were also observed during the treatment. The average follow-up period for all the 22 patients was 71 months and relapse occurred in two AML patients (9.1%). The percentage of CD3(+)/CD8(+) cells in peripheral blood of 15 patients at the 3rd month after DC-CIK treatment (36.73% ± 12.51%) was dramatically higher than that before treatment (29.20% ± 8.34%, P 0.1% in 5 patients before the treatment, and became lower than 0.1% 3 months after the treatment. During the transfusion of DC-CIK, side effects including fever, chills and hives appeared in 7 out of 22 (31.82%) cases but disappeared quickly after symptomatic treatments. There were no changes in electrocardiography and liver-renal functions after the treatment. MRD in children with AML can be eliminated by DC-CIK therapy which is safe and has fewer side effects.

  10. Transferrin-derived synthetic peptide induces highly conserved pro-inflammatory responses of macrophages.

    Science.gov (United States)

    Haddad, George; Belosevic, Miodrag

    2009-02-01

    We examined the induction of macrophage pro-inflammatory responses by transferrin-derived synthetic peptide originally identified following digestion of transferrin from different species (murine, bovine, human N-lobe and goldfish) using elastase. The mass spectrometry analysis of elastase-digested murine transferrin identified a 31 amino acid peptide located in the N2 sub-domain of the transferrin N-lobe, that we named TMAP. TMAP was synthetically produced and shown to induce a number of pro-inflammatory genes by quantitative PCR. TMAP induced chemotaxis, a potent nitric oxide response, and TNF-alpha secretion in different macrophage populations; P338D1 macrophage-like cells, mouse peritoneal macrophages, mouse bone marrow-derived macrophages (BMDM) and goldfish macrophages. The treatment of BMDM cultures with TMAP stimulated the production of nine cytokines and chemokines (IL-6, MCP-5, MIP-1 alpha, MIP-1 gamma, MIP-2, GCSF, KC, VEGF, and RANTES) that was measured using cytokine antibody array and confirmed by Western blot. Our results indicate that transferrin-derived peptide, TMAP, is an immunomodulating molecule capable of inducing pro-inflammatory responses in lower and higher vertebrates.

  11. Zirconium for nitric acid solutions

    International Nuclear Information System (INIS)

    Yau, T.L.

    1984-01-01

    The excellent corrosion resistance of zirconium in nitric acid has been known for over 30 years. Recently, there is an increasing interest in using zirconium for nitric acid services. Therefore, an extensive research effort has been carried out to achieve a better understanding of the corrosion properties of zirconium in nitric acid. Particular attention is paid to the effect of concentration, temperature, structure, solution impurities, and stress. Immersion, autoclave, U-bend, and constant strain-rate tests were used in this study. Results of this study indicate that the corrosion resistance of zirconium in nitric acid is little affected by changes in temperature and concentration, and the presence of common impurities such as seawater, sodium chloride, ferric chloride, iron, and stainless steel. Moreover, the presence of seawater, sodium chloride, ferric chloride, and stainless steel has little effect on the stress corrosion craking (SCC) susceptibility of zirconium in 70% nitric acid at room temperatures. However, zirconium could be attacked by fluoride-containing nitric acid and the vapors of chloride-containing nitric acid. Also, high sustained tensile stresses should be avoided when zirconium is used to handle 70% nitric acid at elevated temperatures or > 70% nitric acid

  12. Effects of IFN-β1a and IFN-β1b treatment on the expression of cytokines, inducible NOS (NOS type II), and myelin proteins in animal model of multiple sclerosis.

    Science.gov (United States)

    Lubina-Dąbrowska, Natalia; Stepień, Adam; Sulkowski, Grzegorz; Dąbrowska-Bouta, Beata; Langfort, Józef; Chalimoniuk, Małgorzata

    2017-08-01

    The aim of this study was to investigate the effects of interferon (IFN)-β1a and IFN-β1b treatment on inflammatory factors and myelin protein levels in the brain cortex of the Lewis rat experimental autoimmune encephalomyelitis (EAE), animal model of multiple sclerosis. To induce EAE, rat were immunized with inoculums containing spinal cord guinea pig homogenized in phosphate-buffered saline and emulsified in Freund's complete adjuvant containing 110 µg of the appropriate antigen in 100 µl of an emulsion and additionally 4-mg/ml Mycobacterium tuberculosis (H37Ra). The rats were treated three times per week with subcutaneous applications of 300,000 units IFN-β1a or IFN-β1b. The treatments were started 8 days prior to immunization and continued until day 14 after immunization. The rats were killed on the 14th day of the experiment. EAE induced dramatic increase in interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-concentrations and inducible nitric oxide synthase (iNOS) expression in the brain, which closely corresponded to the course of neurological symptoms and the loss of weight. Both IFN-β1b and IFN-β1a treatments inhibited the pro-inflammatory cytokines (IL-6, IL-1β, TNF-α and IFN-γ), decreased the activation of astrocytes, increased the myelin protein level in the brain cortex, and improved the neurological status of EAE rats by different mechanisms; IFN-β1a reduced iNOS expression, at least in part, by the enhancement of IL-10, while IFN-β1b diminished IL-10 concentration and did not decrease EAE-induced iNOS expression.

  13. All-trans retinoic acid results in irregular repair of septa and fails to inhibit proinflammatory macrophages.

    Science.gov (United States)

    Seifart, C; Muyal, J P; Plagens, A; Yildirim, A Ö; Kohse, K; Grau, V; Sandu, S; Reinke, C; Tschernig, T; Vogelmeier, C; Fehrenbach, H

    2011-08-01

    All-trans retinoic acid (ATRA) is controversially discussed in emphysema therapy. We re-evaluated ATRA in the elastase model and hypothesised that beneficial effects should be reflected by increased alveolar surface area, elastin expression and downregulation of inflammatory mediators and matrix metalloproteinases (MMPs). Emphysema was induced by porcine pancreatic elastase versus saline in Sprague-Dawley rats. On days 26-37, rats received daily intraperitoneal injections with ATRA (500 μg · kg(-1) body weight) versus olive oil. Lungs were removed at day 38. Rat alveolar epithelial L2 cells were incubated with/without elastase followed by ATRA- or vehicle-treatment, respectively. ATRA only partially ameliorated structural defects. Alveolar walls exhibited irregular architecture: increased arithmetic mean thickness, reduction in surface coverage by alveolar epithelial cells type II. ATRA only partially restored reduced soluble elastin. It tended to increase the ratio of ED1(+):ED2(+) macrophages. Bronchoalveolar lavage (BAL) cells exhibited a proinflammatory state and high expression of interleukin-1β, cytokine-induced neutrophil chemoattractant-1, tumour necrosis factor-α, nuclear factor-κB, MMP-2, MMP-9, MMP-12, tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 in emphysema, with ATRA exerting only few effects. MMP-7 was highly induced by ATRA in healthy but not in emphysematous lungs. ATRA reduced both MMP-2 and TIMP-1 activity in BAL fluid of emphysematous lungs. ATRA-therapy may bear the risk of unwanted side-effects on alveolar septal architecture in emphysematous lungs.

  14. Cytokine-induced loss of glucocorticoid function: effect of kinase inhibitors, long-acting β(2-adrenoceptor [corrected] agonist and glucocorticoid receptor ligands.

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    Christopher F Rider

    Full Text Available Acting on the glucocorticoid receptor (NR3C1, glucocorticoids are widely used to treat inflammatory diseases. However, glucocorticoid resistance often leads to suboptimal asthma control. Since glucocorticoid-induced gene expression contributes to glucocorticoid activity, the aim of this study was to use a 2 × glucocorticoid response element (GRE reporter and glucocorticoid-induced gene expression to investigate approaches to combat cytokine-induced glucocorticoid resistance. Pre-treatment with tumor necrosis factor-α (TNF or interleukin-1β inhibited dexamethasone-induced mRNA expression of the putative anti-inflammatory genes RGS2 and TSC22D3, or just TSC22D3, in primary human airway epithelial and smooth muscle cells, respectively. Dexamethasone-induced DUSP1 mRNA was unaffected. In human bronchial epithelial BEAS-2B cells, dexamethasone-induced TSC22D3 and CDKN1C expression (at 6 h was reduced by TNF pre-treatment, whereas DUSP1 and RGS2 mRNAs were unaffected. TNF pre-treatment also reduced dexamethasone-dependent 2×GRE reporter activation. This was partially reversed by PS-1145 and c-jun N-terminal kinase (JNK inhibitor VIII, inhibitors of IKK2 and JNK, respectively. However, neither inhibitor affected TNF-dependent loss of dexamethasone-induced CDKN1C or TSC22D3 mRNA. Similarly, inhibitors of the extracellular signal-regulated kinase, p38, phosphoinositide 3-kinase or protein kinase C pathways failed to attenuate TNF-dependent repression of the 2×GRE reporter. Fluticasone furoate, fluticasone propionate and budesonide were full agonists relative to dexamethasone, while GSK9027, RU24858, des-ciclesonide and GW870086X were partial agonists on the 2×GRE reporter. TNF reduced reporter activity in proportion with agonist efficacy. Full and partial agonists showed various degrees of agonism on RGS2 and TSC22D3 expression, but were equally effective at inducing CDKN1C and DUSP1, and did not affect the repression of CDKN1C or TSC22D3

  15. Evaluation on the Clinical Efficacy of Dendritic Cell-Activated Cytokine-Induced Killer Cells Combined with Conventional Therapy in the Treatment of Malignant Tumors

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    Hong WEI

    2016-06-01

    Full Text Available Objective: To evaluate the clinical efficacy of dendritic cell-activated cytokine-induced killer (DC-CIK cells combined with conventional therapy in the treatment of malignant tumors.Methods: A total of 100 patients with malignant tumors were randomly divided into two groups. Treatment group received conventional therapy combined with DC-CIK while control group received conventional therapy alone. The short-term efficacy, adverse reactions and changes of lymphocyte subpopulation were all compared between two groups after treatment.Results: The overall response rate (ORR was higher in treatment group (86.00% than in control group (54.00%, the difference was statistically significant (P<0.05. White blood cell count (WBC reduced after treatment when compared with treatment before (P=0.001, but liver and kidney function had no obvious change in treatment group (P>0.05. WBC reduced markedly, but the level of alanine aminotransferase (ALT increased obviously after treatment in control group (P<0.001. WBC was higher, but the level of ALT was lower in treatment group than in control group (P<0.001. However, there was no difference between two groups regarding serum creatinine (Scr and blood urea nitrogen (BUN (P>0.05. In treatment group, the levels of CD3+, CD3+CD4+, CD3+CD8+, and CD3+CD56+ increased (P<0.05, but the level of CD4+/CD8+ had no significant change (P>0.05. In control group, the levels of CD3+ and CD3+CD4+ reduced (P<0.05, while the levels of CD3+CD8+, CD3+CD56+ and CD4+/CD8+ had no significant change (P>0.05. The levels of CD3+, CD3+CD4+, CD3+CD8+ and CD3+CD56+ in treatment group were higher than those in control group (P<0.01, whereas CD4+/CD8+ was lower than that in control group (P<0.01.Conclusion: DC-CIK combined with conventional therapy, safe and effective, is capable of promoting the recovery of leukocytes and liver and kidney function, and improving the cellular immune function, which may provide a new therapeutic regimen for

  16. Cytotoxic capacity of IL-15-stimulated cytokine-induced killer cells against human acute myeloid leukemia and rhabdomyosarcoma in humanized preclinical mouse models

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    Eva eRettinger

    2012-04-01

    Full Text Available Allogeneic stem cell transplantation (allo-SCT has become an important treatment modality for patients with high risk acute myeloid leukemia (AML and is also under investigation for soft tissue sarcomas. The therapeutic success is still limited by minimal residual disease (MRD status ultimately leading to patients’ relapse. Adoptive donor lymphocyte infusions (DLI based on MRD status using IL-15-expanded cytokine-induced killer (CIK cells may prevent relapse without causing graft-versus-host-disease (GvHD. To generate preclinical data we developed mouse models to study anti-leukemic- and anti-tumor-potential of CIK cells in vivo. Immunodeficient mice (NOD/SCID/IL2Rγc-, NSG were injected intravenously with human leukemic cell lines THP-1, SH-2 and with human rhabdomyosarcoma (RMS cell lines RH41 and RH30 at minimal doses required for leukemia or tumor engraftment. Mice transplanted with THP-1 or RH41 cells were randomly assigned for analysis of CIK cell treatment. Organs of mice were analyzed by flow cytometry as well as quantitative polymerase chain reaction (qPCR for engraftment of malignant cells and CIK cells. Potential of CIK cells to induce GvHD was determined by histological analysis. Tissues of the highest degree of THP-1 cell expansion included bone marrow (BM followed by liver, lung, spleen, peripheral blood (PB, and brain. RH30 and RH41 engraftment mainly took place in liver and lung, but was also detectable in spleen and PB. In spite of delayed CIK cell expansion compared with malignant cells, CIK cells injected at an effector to target cell (E:T ratio of 1:1 were sufficient for significant reduction of RH41 cells, whereas against fast-expanding THP-1 cells an E:T ratio of 250:1 was needed to achieve comparable results. Our preclinical in vivo mouse models showed a reliably 100% engraftment of malignant cells which is essential for analysis of anti-cancer therapy. Furthermore our data demonstrated that IL-15-activated CIK cells

  17. Cytotoxic Capacity of IL-15-Stimulated Cytokine-Induced Killer Cells Against Human Acute Myeloid Leukemia and Rhabdomyosarcoma in Humanized Preclinical Mouse Models

    Energy Technology Data Exchange (ETDEWEB)

    Rettinger, Eva; Meyer, Vida; Kreyenberg, Hermann [Department of Pediatric Hematology, Oncology and Hemostaseology, University Children’s Hospital of Frankfurt/Main, Goethe-University Frankfurt/Main, Frankfurt/Main (Germany); Volk, Andreas [Chemotherapeutisches Forschungsinstitut, Georg-Speyer-Haus, Frankfurt/Main (Germany); Kuçi, Selim; Willasch, Andre [Department of Pediatric Hematology, Oncology and Hemostaseology, University Children’s Hospital of Frankfurt/Main, Goethe-University Frankfurt/Main, Frankfurt/Main (Germany); Koscielniak, Ewa [Department of Pediatric Oncology and Hematology, Olgahospital Stuttgart, Stuttgart (Germany); Fulda, Simone [Institute for Experimental Cancer Research in Pediatrics, Goethe-University Frankfurt/Main, Frankfurt/Main (Germany); Wels, Winfried S. [Chemotherapeutisches Forschungsinstitut, Georg-Speyer-Haus, Frankfurt/Main (Germany); Boenig, Halvard [Institute for Transfusion Medicine and Immunohematology, Goethe-University Frankfurt/Main, Division for Cell Processing, German Red Cross Blood Donor Service Baden-Württemberg-Hessen, Frankfurt/Main (Germany); Klingebiel, Thomas; Bader, Peter, E-mail: eva.rettinger@kgu.de, E-mail: peter.bader@kgu.de [Department of Pediatric Hematology, Oncology and Hemostaseology, University Children’s Hospital of Frankfurt/Main, Goethe-University Frankfurt/Main, Frankfurt/Main (Germany)

    2012-04-09

    Allogeneic stem cell transplantation (allo-SCT) has become an important treatment modality for patients with high-risk acute myeloid leukemia (AML) and is also under investigation for soft tissue sarcomas. The therapeutic success is still limited by minimal residual disease (MRD) status ultimately leading to patients’ relapse. Adoptive donor lymphocyte infusions based on MRD status using IL-15-expanded cytokine-induced killer (CIK) cells may prevent relapse without causing graft-versus-host-disease (GvHD). To generate preclinical data we developed mouse models to study anti-leukemic- and anti-tumor-potential of CIK cells in vivo. Immunodeficient mice (NOD/SCID/IL-2Rγc{sup −}, NSG) were injected intravenously with human leukemic cell lines THP-1, SH-2 and with human rhabdomyosarcoma (RMS) cell lines RH41 and RH30 at minimal doses required for leukemia or tumor engraftment. Mice transplanted with THP-1 or RH41 cells were randomly assigned for analysis of CIK cell treatment. Organs of mice were analyzed by flow cytometry as well as quantitative polymerase chain reaction for engraftment of malignant cells and CIK cells. Potential of CIK cells to induce GvHD was determined by histological analysis. Tissues of the highest degree of THP-1 cell expansion included bone marrow followed by liver, lung, spleen, peripheral blood (PB), and brain. RH30 and RH41 engraftment mainly took place in liver and lung, but was also detectable in spleen and PB. In spite of delayed CIK cell expansion compared with malignant cells, CIK cells injected at equal amounts were sufficient for significant reduction of RH41 cells, whereas against fast-expanding THP-1 cells 250 times more CIK than THP-1 cells were needed to achieve comparable results. Our preclinical in vivo mouse models showed a reliable 100% engraftment of malignant cells which is essential for analysis of anti-cancer therapy. Furthermore our data demonstrated that IL-15-activated CIK cells have potent cytotoxic capacity

  18. Difference in Pro-Inflammatory Cytokine Responses Induced in THP1 Cells by Particulate Matter Collected on Days with and without ASIAN Dust Storms

    Directory of Open Access Journals (Sweden)

    Masanari Watanabe

    2015-07-01

    Full Text Available The associations between particulate matter from Asian dust storms (ADS and health disorders differ among studies, and the underlying mechanisms remain unclear. In this study, ADS and non-ADS particles were tested for their potential to induce pro-inflammatory cytokines associated with adverse respiratory effects. Particulate matter was collected in Japan during four periods in 2013 (2 × ADS periods; 2 × non-ADS. THP1 cells were exposed to this particulate matter, and the levels of various interleukins (ILs, and tumor necrosis factor (TNF-α were measured. Levels of IL-2 increased significantly following exposure to all particulate matter samples (compared to levels in a solvent control. Increased levels of IL-10 and TNF-α were also observed following exposure to particles collected during three (one ADS and two non-ADS and two (one ADS and one non-ADS collection periods, respectively. Thus, the effects of particulate matter on cytokine responses differed according to collection period, and the effects of ADS particles differed for each ADS event. Additionally, the levels of pro-inflammatory cytokines induced by ADS particles were not always higher than those induced by non-ADS particles.

  19. Oxidative stress and proinflammatory cytokines contribute to demyelination and axonal damage in a cerebellar culture model of neuroinflammation.

    Science.gov (United States)

    di Penta, Alessandra; Moreno, Beatriz; Reix, Stephanie; Fernandez-Diez, Begoña; Villanueva, Maite; Errea, Oihana; Escala, Nagore; Vandenbroeck, Koen; Comella, Joan X; Villoslada, Pablo

    2013-01-01

    Demyelination and axonal damage are critical processes in the pathogenesis of multiple sclerosis (MS). Oxidative stress and pro-inflammatory cytokines elicited by inflammation mediates tissue damage. To monitor the demyelination and axonal injury associated with microglia activation we employed a model using cerebellar organotypic cultures stimulated with lipopolysaccharide (LPS). Microglia activated by LPS released pro-inflammatory cytokines (IL-1β, IL-6 and TNFα), and increased the expression of inducible nitric oxide synthase (iNOS) and production of reactive oxygen species (ROS). This activation was associated with demyelination and axonal damage in cerebellar cultures. Axonal damage, as revealed by the presence of non-phosphorylated neurofilaments, mitochondrial accumulation in axonal spheroids, and axonal transection, was associated with stronger iNOS expression and concomitant increases in ROS. Moreover, we analyzed the contribution of pro-inflammatory cytokines and oxidative stress in demyelination and axonal degeneration using the iNOS inhibitor ethyl pyruvate, a free-scavenger and xanthine oxidase inhibitor allopurinol, as well as via blockage of pro-inflammatory cytokines using a Fc-TNFR1 construct. We found that blocking microglia activation with ethyl pyruvate or allopurinol significantly decreased axonal damage, and to a lesser extent, demyelination. Blocking TNFα significantly decreased demyelination but did not prevented axonal damage. Moreover, the most common therapy for MS, interferon-beta, was used as an example of an immunomodulator compound that can be tested in this model. In vitro, interferon-beta treatment decreased oxidative stress (iNOS and ROS levels) and the release of pro-inflammatory cytokines after LPS stimulation, reducing axonal damage. The model of neuroinflammation using cerebellar culture stimulated with endotoxin mimicked myelin and axonal damage mediated by the combination of oxidative stress and pro-inflammatory cytokines

  20. Oxidative Stress and Proinflammatory Cytokines Contribute to Demyelination and Axonal Damage in a Cerebellar Culture Model of Neuroinflammation

    Science.gov (United States)

    di Penta, Alessandra; Moreno, Beatriz; Reix, Stephanie; Fernandez-Diez, Begoña; Villanueva, Maite; Errea, Oihana; Escala, Nagore; Vandenbroeck, Koen; Comella, Joan X.; Villoslada, Pablo

    2013-01-01

    Background Demyelination and axonal damage are critical processes in the pathogenesis of multiple sclerosis (MS). Oxidative stress and pro-inflammatory cytokines elicited by inflammation mediates tissue damage. Methods/Principal Findings To monitor the demyelination and axonal injury associated with microglia activation we employed a model using cerebellar organotypic cultures stimulated with lipopolysaccharide (LPS). Microglia activated by LPS released pro-inflammatory cytokines (IL-1β, IL-6 and TNFα), and increased the expression of inducible nitric oxide synthase (iNOS) and production of reactive oxygen species (ROS). This activation was associated with demyelination and axonal damage in cerebellar cultures. Axonal damage, as revealed by the presence of non-phosphorylated neurofilaments, mitochondrial accumulation in axonal spheroids, and axonal transection, was associated with stronger iNOS expression and concomitant increases in ROS. Moreover, we analyzed the contribution of pro-inflammatory cytokines and oxidative stress in demyelination and axonal degeneration using the iNOS inhibitor ethyl pyruvate, a free-scavenger and xanthine oxidase inhibitor allopurinol, as well as via blockage of pro-inflammatory cytokines using a Fc-TNFR1 construct. We found that blocking microglia activation with ethyl pyruvate or allopurinol significantly decreased axonal damage, and to a lesser extent, demyelination. Blocking TNFα significantly decreased demyelination but did not prevented axonal damage. Moreover, the most common therapy for MS, interferon-beta, was used as an example of an immunomodulator compound that can be tested in this model. In vitro, interferon-beta treatment decreased oxidative stress (iNOS and ROS levels) and the release of pro-inflammatory cytokines after LPS stimulation, reducing axonal damage. Conclusion The model of neuroinflammation using cerebellar culture stimulated with endotoxin mimicked myelin and axonal damage mediated by the combination of

  1. Proinflammatory Cytokines as Regulators of Vaginal Microbiota.

    Science.gov (United States)

    Kremleva, E A; Sgibnev, A V

    2016-11-01

    It was shown that IL-1β, IL-8, and IL-6 in concentrations similar to those in the vagina of healthy women stimulated the growth of normal microflora (Lactobacillus spp.) and suppressed the growth and biofilm production by S. aureus and E. coli. On the contrary, these cytokines in higher concentrations typical of vaginal dysbiosis suppressed normal microflora and stimulated the growth of opportunistic microorganisms. TGF-β1 in both doses produced a stimulating effects on study vaginal microsymbionts. It is hypothesized that pro-inflammatory cytokines serve as the molecules of interspecies communication coordinating the interactions of all components of the vaginal symbiotic system.

  2. Proinflammatory cytokines in open versus laparoscopic cholecystectomy

    International Nuclear Information System (INIS)

    Abu-Eshy, Saeed A.; Al-Rofaidi, Abdallah A.; Al-Faki, Ahmed S.; Ghalib, Hashim W.; Moosa, Riyadh A.; Sadik, Ali A.; Salati, Mohammad I.

    2002-01-01

    Laparoscopic cholecystectomy, a minimal access surgery, is fast replacing open cholecystectomy and is being associated with less trauma. The objective of this study was to compare the proinflammatory cytokine levels in both laparoscopic cholecystectomy and open cholecystectomy. This study was carried out at Aseer Central Hospital, Aseer region, Abha Private Hospital and the College of Medicine and Medical Sciences, King Khalid University, Abha, Kingdom of Saudi Arabia, during the time period October 1998 through to November 2000. Sixty-one patients were included in the study, 27 of them had laparoscopic cholecystectomy and 34 had open cholecystectomy. Cytokines [Interleukin-6 Interleukin-1b, Tumor necrosis factor -a and Interleukin- 8] were measured in blood samples collected from the patients before, at and 24 hours post surgery, using commercially available kits. Interleukin-6 levels were significantly increased at 24 hours post surgery in the open cholecystectomy group of patients compared to the laparoscopic cholecystectomy group (P<0.04). No differences were found in the other cytokines levels (Interleukin-1b, tumor necrosis factor -a and Interleukin-8) between the open cholecystectomy and laparoscopic cholecystectomy groups. Laparoscopic cholecystectomy, a minimal access surgery, is associated with lower levels of the proinflammatory interleukin-6 cytokine compared to open cholecystectomy. (author)

  3. Nitric oxide nanoparticles

    Science.gov (United States)

    Schairer, David O.; Martinez, Luis R.; Blecher, Karin; Chouake, Jason S.; Nacharaju, Parimala; Gialanella, Philip; Friedman, Joel M.; Nosanchuk, Joshua D.; Friedman, Adam J.

    2012-01-01

    Nitric oxide (NO) is a critical component of host defense against invading pathogens; however, its therapeutic utility is limited due to a lack of practical delivery systems. Recently, a NO-releasing nanoparticulate platform (NO-np) was shown to have in vitro broad-spectrum antimicrobial activity and in vivo pre-clinical efficacy in a dermal abscess model. To extend these findings, both topical (TP) and intralesional (IL) NO-np administration was evaluated in a MRSA intramuscular murine abscess model and compared with vancomycin. All treatment arms accelerated abscess clearance clinically, histologically, and by microbiological assays on both days 4 and 7 following infection. However, abscesses treated with NO-np via either route demonstrated a more substantial, statistically significant decrease in bacterial survival based on colony forming unit assays and histologically revealed less inflammatory cell infiltration and preserved muscular architecture. These data suggest that the NO-np may be an effective addition to our armament for deep soft tissue infections. PMID:22286699

  4. An intervertebral disc whole organ culture system to investigate proinflammatory and degenerative disc disease condition.

    Science.gov (United States)

    Lang, Gernot; Liu, Yishan; Geries, Janna; Zhou, Zhiyu; Kubosch, David; Südkamp, Norbert; Richards, R Geoff; Alini, Mauro; Grad, Sibylle; Li, Zhen

    2018-04-01

    The aim of this study was to compare the effect of different disease initiators of degenerative disc disease (DDD) within an intervertebral disc (IVD) organ culture system and to understand the interplay between inflammation and degeneration in the early stage of DDD. Bovine caudal IVDs were cultured within a bioreactor for up to 11 days. Control group was cultured under physiological loading (0.02-0.2 MPa; 0.2 Hz; 2 hr/day) and high glucose (4.5 g/L) medium. Detrimental loading (0.32-0.5 MPa, 5 Hz; 2 hr/day) and low glucose (2 g/L) medium were applied to mimic the condition of abnormal mechanical stress and limited nutrition supply. Tumour necrosis factor alpha (TNF-α) was injected into the nucleus pulposus (100 ng per IVD) as a proinflammatory trigger. TNF-α combined with detrimental loading and low glucose medium up-regulated interleukin 1β (IL-1β), IL-6, and IL-8 gene expression in disc tissue, nitric oxide, and IL-8 release from IVD, which indicate a proinflammatory effect. The combined initiators up-regulated matrix metalloproteinase 1 gene expression, down-regulated gene expression of Type I collagen in annulus fibrosus and Type II collagen in nucleus pulposus, and reduced the cell viability. Furthermore, the combined initiators induced a degradative effect, as indicated by markedly higher glycosaminoglycan release into conditioned medium. The combination of detrimental dynamic loading, nutrient deficiency, and TNF-α intradiscal injection can synergistically simulate the proinflammatory and degenerative disease condition within DDD. This model will be of high interest to screen therapeutic agents in further preclinical studies for early intervention and treatment of DDD. Copyright © 2018 John Wiley & Sons, Ltd.

  5. Minocycline counter-regulates pro-inflammatory microglia responses in the retina and protects from degeneration.

    Science.gov (United States)

    Scholz, Rebecca; Sobotka, Markus; Caramoy, Albert; Stempfl, Thomas; Moehle, Christoph; Langmann, Thomas

    2015-11-17

    Microglia reactivity is a hallmark of retinal degenerations and overwhelming microglial responses contribute to photoreceptor death. Minocycline, a semi-synthetic tetracycline analog, has potent anti-inflammatory and neuroprotective effects. Here, we investigated how minocycline affects microglia in vitro and studied its immuno-modulatory properties in a mouse model of acute retinal degeneration using bright white light exposure. LPS-treated BV-2 microglia were stimulated with 50 μg/ml minocycline for 6 or 24 h, respectively. Pro-inflammatory gene transcription was determined by real-time RT-PCR and nitric oxide (NO) secretion was assessed using the Griess reagent. Caspase 3/7 levels were determined in 661W photoreceptors cultured with microglia-conditioned medium in the absence or presence of minocycline supplementation. BALB/cJ mice received daily intraperitoneal injections of 45 mg/kg minocycline, starting 1 day before exposure to 15.000 lux white light for 1 hour. The effect of minocycline treatment on microglial reactivity was analyzed by immunohistochemical stainings of retinal sections and flat-mounts, and messenger RNA (mRNA) expression of microglia markers was determined using real-time RT-PCR and RNA-sequencing. Optical coherence tomography (OCT) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) stainings were used to measure the extent of retinal degeneration and photoreceptor apoptosis. Stimulation of LPS-activated BV-2 microglia with minocycline significantly diminished the transcription of the pro-inflammatory markers CCL2, IL6, and inducible nitric oxide synthase (iNOS). Minocycline also reduced the production of NO and dampened microglial neurotoxicity on 661W photoreceptors. Furthermore, minocycline had direct protective effects on 661W photoreceptors by decreasing caspase 3/7 activity. In mice challenged with white light, injections of minocycline strongly decreased the number of amoeboid alerted microglia in the outer

  6. Nitrogen isotope exchange between nitric oxide and nitric acid

    International Nuclear Information System (INIS)

    Axente, D.; Abrudean, M.; Baldea, A.

    1996-01-01

    The rate of nitrogen isotope exchange between NO and HNO 3 has been measured as a function of nitric acid concentration of 1.5-4M x 1 -1 . The exchange rate law is shown to be R=k[HNO 3 ] 2 [N 2 O 3 ] and the measured activation energy is E=67.78 kJ x M -1 (16.2 kcal x M -1 ). It is concluded that N 2 O 3 participates in 15 N/ 14 N exchange between NO and HNO 3 at nitric acid concentrations higher than 1.5M x 1 -1 . (author). 7 refs., 3 figs., 4 tabs

  7. Nitric Acid Poisoning: Case Report

    International Nuclear Information System (INIS)

    Quintero Giraldo, Maria Paulina; Quiceno Calderon, William de Jesus; Melo Arango Catalina

    2011-01-01

    Nitric acid (HNO 3 ) is a corrosive fluid that, when in contact with reducing agents, generates nitrogen oxides that are responsible for inhalation poisoning. We present two cases of poisoning from nitric acid gas inhalation resulting from occupational exposure. Imaging findings were similar in both cases, consistent with adult respiratory distress syndrome (ARDS): bilaterally diffuse alveolar opacities on the chest X-ray and a cobblestone pattern on computed tomography (CT).one of the patients died while the other evolved satisfactorily after treatment with n-acetyl cysteine and mechanical ventilation. The diagnosis of nitric acid poisoning was made on the basis of the history of exposure and the way in which the radiological findings evolved.

  8. IL-15 improves the cytotoxicity of cytokine-induced killer cells against leukemia cells by upregulating CD3+CD56+ cells and downregulating regulatory T cells as well as IL-35.

    Science.gov (United States)

    Tao, Qianshan; Chen, Tianping; Tao, Lili; Wang, Huiping; Pan, Ying; Xiong, Shudao; Zhai, Zhimin

    2013-01-01

    Cytokine-induced killer (CIK) cells are usually generated from peripheral blood mononuclear cells with the stimulation of IL-2 in vitro. Unlike the conventional IL-2-stimulated CIK cells (IL-2-CIK cells), we investigated the characteristics and potential mechanism of IL-15-stimulated CIK cells (IL-15-CIK cells) in this study. Compared with IL-2-CIK cells, the percentage of CD3CD56 cells was significantly increased in IL-15-CIK cells, but the expression of regulatory T (Treg) cells and IL-35 was significantly decreased in IL-15-CIK cells. Meanwhile, the in vitro cytotoxicity against human myeloid leukemia cells K562 of IL-15-CIK cells was significantly augmented compared with IL-2-CIK cells. These data suggest that IL-15 may improve the cytotoxicity of CIK cells against leukemia cells by upregulating CD3CD56 cells and downregulating Treg cells and IL-35.

  9. Nitric Oxide Synthases Reveal a Role for Calmodulin in Controlling Electron Transfer

    Science.gov (United States)

    Abu-Soud, Husam M.; Stuehr, Dennis J.

    1993-11-01

    Nitric oxide (NO) is synthesized within the immune, vascular, and nervous systems, where it acts as a wide-ranging mediator of mammalian physiology. The NO synthases (EC 1.14.13.39) isolated from neurons or endothelium are calmodulin dependent. Calmodulin binds reversibly to neuronal NO synthase in response to elevated Ca2+, triggering its NO production by an unknown mechanism. Here we show that calmodulin binding allows NADPH-derived electrons to pass onto the heme group of neuronal NO synthase. Calmodulin-triggered electron transfer to heme was independent of substrate binding, caused rapid enzymatic oxidation of NADPH in the presence of O_2, and was required for NO synthesis. An NO synthase isolated from cytokine-induced macrophages that contains tightly bound calmodulin catalyzed spontaneous electron transfer to its heme, consistent with bound calmodulin also enabling electron transfer within this isoform. Together, these results provide a basis for how calmodulin may regulate NO synthesis. The ability of calmodulin to trigger electron transfer within an enzyme is unexpected and represents an additional function for calcium-binding proteins in biology.

  10. Corrosion resistance of zirconium in nitric acid

    International Nuclear Information System (INIS)

    Kajimura, H.; Morikawa, H.; Nagano, H.

    1987-01-01

    Slow strain rate tests are effected on zirconium in boiling nitric acid to study the influence of nitric acid concentration, of oxidizing ions (Cr and Ce) and of electric potential. Corrosion resistance is excellent and stress corrosion cracking occurs only for severe conditions: 350 mV over electric potential for corrosion with nitric acid concentration of 40 % [fr

  11. Rescue of proinflammatory cytokine-inhibited chondrogenesis by the antiarthritic effect of melatonin in synovium mesenchymal stem cells via suppression of reactive oxygen species and matrix metalloproteinases.

    Science.gov (United States)

    Liu, Xiaozhen; Xu, Yong; Chen, Sijin; Tan, Zifang; Xiong, Ke; Li, Yan; Ye, Yun; Luo, Zong-Ping; He, Fan; Gong, Yihong

    2014-03-01

    Cartilage repair by mesenchymal stem cells (MSCs) often occurs in diseased joints in which the inflamed microenvironment impairs chondrogenic maturation and causes neocartilage degradation. In this environment, melatonin exerts an antioxidant effect by scavenging free radicals. This study aimed to investigate the anti-inflammatory and chondroprotective effects of melatonin on human MSCs in a proinflammatory cytokine-induced arthritic environment. MSCs were induced toward chondrogenesis in the presence of interleukin-1β (IL-1β) or tumor necrosis factor α (TNF-α) with or without melatonin. Levels of intracellular reactive oxygen species (ROS), hydrogen peroxide, antioxidant enzymes, and cell viability were then assessed. Deposition of glycosaminoglycans and collagens was also determined by histological analysis. Gene expression of chondrogenic markers and matrix metalloproteinases (MMPs) was assessed by real-time polymerase chain reaction. In addition, the involvement of the melatonin receptor and superoxide dismutase (SOD) in chondrogenesis was investigated using pharmacologic inhibitors. The results showed that melatonin significantly reduced ROS accumulation and increased SOD expression. Both IL-1β and TNF-α had an inhibitory effect on the chondrogenesis of MSCs, but melatonin successfully restored the low expression of cartilage matrix and chondrogenic genes. Melatonin prevented cartilage degradation by downregulating MMPs. The addition of luzindole and SOD inhibitors abrogated the protective effect of melatonin associated with increased levels of ROS and MMPs. These results demonstrated that proinflammatory cytokines impair the chondrogenesis of MSCs, which was rescued by melatonin treatment. This chondroprotective effect was potentially correlated to decreased ROS, preserved SOD, and suppressed levels of MMPs. Thus, melatonin provides a new strategy for promoting cell-based cartilage regeneration in diseased or injured joints. Copyright © 2013 Elsevier

  12. Krüppel-Like Factor 4 Is a Regulator of Proinflammatory Signaling in Fibroblast-Like Synoviocytes through Increased IL-6 Expression

    Directory of Open Access Journals (Sweden)

    Xinjing Luo

    2016-01-01

    Full Text Available Human fibroblast-like synoviocytes play a vital role in joint synovial inflammation in rheumatoid arthritis (RA. Proinflammatory cytokines induce fibroblast-like synoviocyte activation and dysfunction. The inflammatory mediator Krüppel-like factor 4 is upregulated during inflammation and plays an important role in endothelial and macrophage activation during inflammation. However, the role of Krüppel-like factor 4 in fibroblast-like synoviocyte activation and RA inflammation remains to be defined. In this study, we identify the notion that Krüppel-like factor 4 is higher expressed in synovial tissues and fibroblast-like synoviocytes from RA patients than those from osteoarthritis patients. In vitro, the expression of Krüppel-like factor 4 in RA fibroblast-like synoviocytes is induced by proinflammatory cytokine tumor necrosis factor-α. Overexpression of Krüppel-like factor 4 in RA fibroblast-like synoviocytes robustly induced interleukin-6 production in the presence or absence of tumor necrosis factor-α. Conversely, knockdown of Krüppel-like factor 4 markedly attenuated interleukin-6 production in the presence or absence of tumor necrosis factor-α. Krüppel-like factor 4 not only can bind to and activate the interleukin-6 promoter, but also may interact directly with nuclear factor-kappa B. These results suggest that Krüppel-like factor 4 may act as a transcription factor mediating the activation of fibroblast-like synoviocytes in RA by inducing interleukin-6 expression in response to tumor necrosis factor-α.

  13. Proinflammatory Cytokines IL-6 and TNF-α Increased Telomerase Activity through NF-κB/STAT1/STAT3 Activation, and Withaferin A Inhibited the Signaling in Colorectal Cancer Cells

    Directory of Open Access Journals (Sweden)

    Seyung S. Chung

    2017-01-01

    Full Text Available There are increasing evidences of proinflammatory cytokine involvement in cancer development. Here, we found that two cytokines, IL-6 and TNF-α, activated colorectal cancer cells to be more invasive and stem-like. Combined treatment of IL-6 and TNF-α phosphorylated transcription factors STAT3 in a synergistic manner. STAT3, STAT1, and NF-κB physically interacted upon the cytokine stimulation. STAT3 was bound to the promoter region of human telomerase reverse transcriptase (hTERT. IL-6 and TNF-α stimulation further enhanced STAT3 binding affinity. Stem cell marker Oct-4 was upregulated in colorectal cancer cells upon IL-6 and TNF-α stimulation. Withaferin A, an anti-inflammatory steroidal lactone, inhibited the IL-6- and TNF-α-induced cancer cell invasion and decreased colonosphere formation. Notably, withaferin A inhibited STAT3 phosphorylation and abolished the STAT3, STAT1, and NF-κB interactions. Oct-4 expression was also downregulated by withaferin A inhibition. The binding of STAT3 to the hTERT promoter region and telomerase activity showed reduction with withaferin A treatments. Proinflammatory cytokine-induced cancer cell invasiveness is mediated by a STAT3-regulated mechanism in colorectal cancer cells. Our data suggest that withaferin A could be a promising anticancer agent that effectively inhibits the progression of colorectal cancer.

  14. Photoperiodic Regulation of Behavioral Responsiveness to Proinflammatory Cytokines

    OpenAIRE

    Wen, Jarvi C.; Prendergast, Brian J.

    2007-01-01

    Symptoms of bacterial infection include decreases in body mass (cachexia), induction of depressive-like hedonic tone (anhedonia), decreases in food intake (anorexia), and increases in body temperature (fever). Recognition of bacteria by the innate immune system triggers the release of proinflammatory cytokines which induce these sickness behaviors via central and peripheral substrates. In Siberian hamsters, exposure to short day lengths decreases both the production of proinflammatory cytokin...

  15. Bioactive Extract from Moringa oleifera Inhibits the Pro-inflammatory Mediators in Lipopolysaccharide Stimulated Macrophages

    Science.gov (United States)

    Fard, Masoumeh Tangestani; Arulselvan, Palanisamy; Karthivashan, Govindarajan; Adam, Siti Khadijah; Fakurazi, Sharida

    2015-01-01

    Introduction: Inflammation is a well-known physiological response to protect the body against infection and restore tissue injury. Nevertheless, the chronic inflammation can trigger various inflammatory associated diseases/disorder. Moringa oleifera is a widely grown plant in most tropical countries and it has been recognized traditionally for several medicinal benefits. Objectives: The objective of this study was to investigate the anti-inflammatory properties of M. oleifera extract on lipopolysaccharide (LPS) - stimulated macrophages. Materials and Methods: The anti-inflammatory effect of M. oleifera hydroethanolic bioactive leaves extracts was evaluated by assessing the inhibition of nitric oxide (NO) production during Griess reaction and the expression of pro-inflammatory mediators in macrophages. Results: Interestingly, we found that M. oleifera hydroethanolic bioactive leaves extract significantly inhibited the secretion of NO production and other inflammatory markers such as prostaglandin E2, tumor necrosis factor alpha, interleukin (IL)-6, and IL-1β. Meanwhile, the bioactive extract has induced the production of IL-10 in a dose-dependent manner. In addition, M. oleifera hydroethanolic bioactive leaves extract effectively suppressed the protein expression of inflammatory markers inducible NO synthase, cyclooxygenase-2, and nuclear factor kappa-light-chain-enhancer of activated B-cells p65 in LPS-induced RAW264.7 macrophages in a dose-dependent manner. Conclusion: These findings support the traditional use of M. oleifera plant as an effective treatment for inflammation associated diseases/disorders. SUMMARY Hydroethanolic extracts of Moringa oleifera effectively inhibit the NO production in LPS induced inflammatory model.M. oleifera crude extracts successfully modulate the production of pro-inflammatory mediators in LPS stimulated macrophages.M. oleifera extracts suppressed the expression of inflammatory mediators in LPS stimulated macrophages. PMID:27013794

  16. Angiopoietin-like protein 2 induces proinflammatory responses in peritoneal cells

    Energy Technology Data Exchange (ETDEWEB)

    Umikawa, Masato, E-mail: umikawa@med.u-ryukyu.ac.jp [Department of Medical Biochemistry, Graduate School of Medicine, University of the Ryukyus, Okinawa (Japan); Umikawa, Asako; Asato, Tsuyoshi; Takei, Kimiko [Department of Medical Biochemistry, Graduate School of Medicine, University of the Ryukyus, Okinawa (Japan); Matsuzaki, Goro [Department of Tropical Infectious Diseases, COMB, Tropical Biosphere Research Center, University of the Ryukyus, Okinawa (Japan); Kariya, Ken-ichi [Department of Medical Biochemistry, Graduate School of Medicine, University of the Ryukyus, Okinawa (Japan); Zhang, Cheng Cheng, E-mail: alec.zhang@utsouthwestern.edu [Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX (United States)

    2015-11-13

    Monocytes and macrophages are important effectors and regulators of inflammation, and both their differentiation and activation are regulated strictly in response to environmental cues. Angiopoietin-like protein 2 (Angptl2) is a multifaceted protein, displaying many physiological and pathological functions in inflammation, angiogenesis, hematopoiesis, and tumor development. Although recent studies implicate Angptl2 in chronic inflammation, the mechanisms of inflammation caused by Angptl2 remain unclear. The purpose of the present study was to elucidate the role of Angptl2 in inflammation by understanding the effects of Angptl2 on monocytes/macrophages. We showed that Angptl2 directly activates resident murine peritoneal monocytes and macrophages and induces a drastic upregulation of the transcription of several inflammatory genes including nitric oxide synthase 2 and prostaglandin-endoperoxide synthase 2, and several proinflammatory cytokine genes such as interleukin (IL)-1β, IL-6, TNFα, and CSF2, along with activation of ERK, JNK, p38, and nuclear factor kappa B signaling pathways. Concordantly, proinflammatory cytokines IL-1β, IL-6, TNFα, and GM-CSF, were rapidly elevated from murine peritoneal monocytes and macrophages. These results demonstrate a novel role for Angptl2 in inflammation via the direct activation of peritoneal monocytes and macrophages. - Highlights: • Angptl2 directly activates resident murine peritoneal monocytes and macrophages. • Angptl2 induces a drastic upregulation of expression of inflammatory genes. • Angptl2 induces activation of ERK, JNK, p38, and nuclear factor kappa B signaling pathways. • Angptl2 does not activate bone marrow derived macrophages or macrophage cell lines.

  17. Acute cadmium administration to rats exerts both immunosuppressive and proinflammatory effects in spleen

    International Nuclear Information System (INIS)

    Demenesku, Jelena; Mirkov, Ivana; Ninkov, Marina; Popov Aleksandrov, Aleksandra; Zolotarevski, Lidija; Kataranovski, Dragan; Kataranovski, Milena

    2014-01-01

    Highlights: • The effect of cadmium on splenic T and innate immune cells in rats is explored. • Differential effects of 1 mg/kg on T cell and innate immune activities were shown. • Lower Cd dose (0.5 mg/kg) cause less pronounced immunosuppressive effects. • Proinflammatory effects on innate immune activities were seen at that dose. • Presented data depict complexity of immunomodulatory potential of this metal. - Abstract: Conflicting data (both suppression and augmentation as well as lack of the effect) exist in respect to cadmium (Cd) and splenic T cell-based immune cell activity. Spleen is also the site of innate immune responses but impact of Cd on this type of immunity has been less explored. In the present study the effects of acute Cd administration on basic aspects of both T cell-based and innate immune spleen cell activity were examined in rats. Intraperitoneal injection of 1 mg of Cd/kg resulted in decrease in concanavalin A (ConA) induced proliferation which seems to be more related to altered spleen cells responsiveness to IL-2 than to apoptosis. Differential effects on proinflammatory T cell derived cytokines were observed (decreases of IFN-γ gene expression and ConA-stimulated production, but increases in IL-17 mRNA levels with no effect on concentrations of protein product). Reduction of IFN-γ production seemed not to rely on IL-4 and IL-10, but at least partly on nitric oxide (NO). Increased activity relevant for innate immunity (granulocyte and CD11b + cell accumulation in the spleen, inducible nitric oxide synthase/iNOS expression and NO production by spleen cells) was observed, but there was a decrease in respiratory burst (dihydrorhodamine/DHR oxidation and nitroblue tetrazolium/NBT reduction). Increases of TNF-α and IL-1β gene expression and IL-1β protein product were noted as well. Administration of 0.5 mg Cd/kg resulted in less pronounced (ConA-induced proliferation) or lack of the effect (IFN-γ production) on spleen T cell

  18. Alternative to Nitric Acid Passivation

    Science.gov (United States)

    Kessel, Kurt R.

    2016-01-01

    Corrosion is an extensive problem that affects the National Aeronautics and Space Administration (NASA) and European Space Agency (ESA). The deleterious effects of corrosion result in steep costs, asset downtime affecting mission readiness, and safety risks to personnel. It is vital to reduce corrosion costs and risks in a sustainable manner. The primary objective of this effort is to qualify citric acid as an environmentally-preferable alternative to nitric acid for passivation of stainless steel alloys.

  19. Lysine deacetylases are produced in pancreatic beta cells and are differentially regulated by proinflammatory cytokines

    DEFF Research Database (Denmark)

    Lundh, M; Christensen, D P; Rasmussen, D N

    2010-01-01

    Cytokine-induced beta cell toxicity is abrogated by non-selective inhibitors of lysine deacetylases (KDACs). The KDAC family consists of 11 members, namely histone deacetylases HDAC1 to HDAC11, but it is not known which KDAC members play a role in cytokine-mediated beta cell death. The aim...

  20. Inhibition of Pro-inflammatory Mediators and Cytokines by Chlorella Vulgaris Extracts.

    Science.gov (United States)

    Sibi, G; Rabina, Santa

    2016-01-01

    The aim of this study was to determine the in vitro anti-inflammatory activities of solvent fractions from Chlorella vulgaris by inhibiting the production of pro-inflammatory mediators and cytokines. Methanolic extracts (80%) of C. vulgaris were prepared and partitioned with solvents of increasing polarity viz., n-hexane, chloroform, ethanol, and water. Various concentrations of the fractions were tested for cytotoxicity in RAW 264.7 cells using 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, and the concentrations inducing cell growth inhibition by about 50% (IC50) were chosen for further studies. Lipopolysaccharide (LPS) stimulated RAW 264.7 cells were treated with varying concentrations of C. vulgaris fractions and examined for its effects on nitric oxide (NO) production by Griess assay. The release of prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), and interleukin 6 (IL-6) were quantified using enzyme-linked immunosorbent assay using Celecoxib and polymyxin B as positive controls. MTT assay revealed all the solvent fractions that inhibited cell growth in a dose-dependent manner. Of all the extracts, 80% methanolic extract exhibited the strongest anti-inflammatory activity by inhibiting NO production (P < 0.01), PGE2 (P < 0.05), TNF-α, and IL-6 (P < 0.001) release in LPS induced RAW 264.7 cells. Both hexane and chloroform fractions recorded a significant (P < 0.05) and dose-dependent inhibition of LPS induced inflammatory mediators and cytokines in vitro. The anti-inflammatory effect of ethanol and aqueous extracts was not significant in the study. The significant inhibition of inflammatory mediators and cytokines by fractions from C. vulgaris suggests that this microalga would be a potential source of developing anti-inflammatory agents and a good alternate for conventional steroidal and nonsteroidal anti-inflammatory drugs. C. vulgaris extracts have potential anti-inflammatory activitySolvent extraction using methanol

  1. Proinflammatory cytokine levels in patients with conversion disorder.

    Science.gov (United States)

    Tiyekli, Utkan; Calıyurt, Okan; Tiyekli, Nimet Dilek

    2013-06-01

    It was aimed to evaluate the relationship between proinflammatory cytokine levels and conversion disorder both commonly known as stress regulated. Baseline proinflammatory cytokine levels-[Tumour necrosis factor alpha (TNF-α), Interleukin-1 beta (IL-1β), Interleukin-6 (IL-6)]-were evaluated with enzyme-linked immunosorbent assay in 35 conversion disorder patients and 30 healthy controls. Possible changes in proinflammatory cytokine levels were evaluated again, after their acute phase in conversion disorder patients. Statistically significant decreased serum TNF-α levels were obtained in acute phase of conversion disorder. Those levels increased after acute conversion phase. There were no statistically significant difference observed between groups in serum IL-1β and (IL-6) levels. Stress associated with conversion disorder may suppress immune function in acute conversion phase and may have diagnostic and therapeutic value.

  2. Isoeugenin, a Novel Nitric Oxide Synthase Inhibitor Isolated from the Rhizomes of Imperata cylindrica

    Directory of Open Access Journals (Sweden)

    Hyo-Jin An

    2015-12-01

    Full Text Available Phytochemical studies on the constituents of the rhizomes of Imperata cylindrica (Gramineae were performed using high-performance liquid chromatography (HPLC. We also aimed to search for any biologically active substance capable of inhibiting nitric oxide (NO formation in lipopolysaccharide (LPS-activated macrophage 264.7 cells, by testing four compounds isolated from this plant. Four compounds, including a new chromone, isoeugenin, along with ferulic acid, p-coumaric acid, and caffeic acid were isolated and identified by NMR spectroscopy. The structure of isoeugenin was determined as 7-hydroxy-5-methoxy-2-methylchromone by the 2D-NMR technique. Among the four compounds, isoeugenin has the lowest IC50 value on the inhibition of NO production in LPS-activated macrophage RAW264.7 cells (IC50, 9.33 μg/mL. In addition, isoeugenin significantly suppressed the LPS-induced expressions of inducible nitric oxide synthase (iNOS, cyclooxygenase-2 (COX-2, and proinflammatory cytokines mRNA levels. Taken together, these results suggest that the anti-inflammatory activity of isoeugenin is associated with the down-regulation of iNOS, COX-2, and pro-inflammatory cytokines in RAW264.7 cells. Accordingly, our results suggest that the new chromone isoegenin should be considered a potential treatment for inflammatory disease.

  3. Isoeugenin, a Novel Nitric Oxide Synthase Inhibitor Isolated from the Rhizomes of Imperata cylindrica.

    Science.gov (United States)

    An, Hyo-Jin; Nugroho, Agung; Song, Byong-Min; Park, Hee-Juhn

    2015-12-01

    Phytochemical studies on the constituents of the rhizomes of Imperata cylindrica (Gramineae) were performed using high-performance liquid chromatography (HPLC). We also aimed to search for any biologically active substance capable of inhibiting nitric oxide (NO) formation in lipopolysaccharide (LPS)-activated macrophage 264.7 cells, by testing four compounds isolated from this plant. Four compounds, including a new chromone, isoeugenin, along with ferulic acid, p-coumaric acid, and caffeic acid were isolated and identified by NMR spectroscopy. The structure of isoeugenin was determined as 7-hydroxy-5-methoxy-2-methylchromone by the 2D-NMR technique. Among the four compounds, isoeugenin has the lowest IC50 value on the inhibition of NO production in LPS-activated macrophage RAW264.7 cells (IC50, 9.33 μg/mL). In addition, isoeugenin significantly suppressed the LPS-induced expressions of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and proinflammatory cytokines mRNA levels. Taken together, these results suggest that the anti-inflammatory activity of isoeugenin is associated with the down-regulation of iNOS, COX-2, and pro-inflammatory cytokines in RAW264.7 cells. Accordingly, our results suggest that the new chromone isoegenin should be considered a potential treatment for inflammatory disease.

  4. Costunolide inhibits proinflammatory cytokines and iNOS in activated murine BV2 microglia.

    Science.gov (United States)

    Rayan, Nirmala Arul; Baby, Nimmi; Pitchai, Daisy; Indraswari, Fransisca; Ling, Eng-Ang; Lu, Jia; Dheen, Thameem

    2011-06-01

    Costunolide, a sesquiterpene lactone present in Costus speciosus root exerts a variety of pharmacological activity but its effects on neuroinflammation have not been studied. Microglia, the resident phagocytic cells in the central nervous system respond to neuroinflammation and their overwhelming response in turn aggravate brain damage during infection, ischemia and neurodegenerative diseases. In this study, we report the effect of Costunolide on the production of proinflammatory mediators and mechanisms involved in BV2 microglial cells stimulated with LPS. Costunolide attenuated the expression of tumour necrosis factor-alpha, interleukin-1,6, inducible nitric oxide synthase, monocyte chemotactic protein 1 and cyclooxygenase 2 in activated microglia. This Costunolide-mediated inhibition was correspondent with the inhibition of NFkappaB activation. It has been further shown that Costunolide suppressed MAPK pathway activation by inducing MKP-1 production. Collectively our results suggest that Costunolide shows an ability to inhibit expression of multiple neuroinflammatory mediators and this is attributable to the compounds inhibition of NFkappaB and MAPK activation. This novel role of Costunolide upon investigation may aid in developing better therapeutic strategies for treatment of neuroinflammatory diseases.

  5. Cancer as a Proinflammatory Environment: Metastasis and Cachexia

    Science.gov (United States)

    Inácio Pinto, Nelson; Carnier, June; Oyama, Lila M.; Otoch, Jose Pinhata; Alcântara, Paulo Sergio; Tokeshi, Flavio; Nascimento, Claudia M.

    2015-01-01

    The development of the syndrome of cancer cachexia and that of metastasis are related with a poor prognostic for cancer patients. They are considered multifactorial processes associated with a proinflammatory environment, to which tumour microenvironment and other tissues from the tumour bearing individuals contribute. The aim of the present review is to address the role of ghrelin, myostatin, leptin, HIF, IL-6, TNF-α, and ANGPTL-4 in the regulation of energy balance, tumour development, and tumoural cell invasion. Hypoxia induced factor plays a prominent role in tumour macro- and microenvironment, by modulating the release of proinflammatory cytokines. PMID:26508818

  6. Cancer as a Proinflammatory Environment: Metastasis and Cachexia

    Directory of Open Access Journals (Sweden)

    Nelson Inácio Pinto

    2015-01-01

    Full Text Available The development of the syndrome of cancer cachexia and that of metastasis are related with a poor prognostic for cancer patients. They are considered multifactorial processes associated with a proinflammatory environment, to which tumour microenvironment and other tissues from the tumour bearing individuals contribute. The aim of the present review is to address the role of ghrelin, myostatin, leptin, HIF, IL-6, TNF-α, and ANGPTL-4 in the regulation of energy balance, tumour development, and tumoural cell invasion. Hypoxia induced factor plays a prominent role in tumour macro- and microenvironment, by modulating the release of proinflammatory cytokines.

  7. Minocycline attenuates experimental colitis in mice by blocking expression of inducible nitric oxide synthase and matrix metalloproteinases

    International Nuclear Information System (INIS)

    Huang, T.-Y.; Chu, H.-C.; Lin, Y.-L.; Lin, C.-K.; Hsieh, T.-Y.; Chang, W.-K.; Chao, Y.-C.; Liao, C.-L.

    2009-01-01

    In addition to its antimicrobial activity, minocycline exerts anti-inflammatory effects in several disease models. However, whether minocycline affects the pathogenesis of inflammatory bowel disease has not been determined. We investigated the effects of minocycline on experimental colitis and its underlying mechanisms. Acute and chronic colitis were induced in mice by treatment with dextran sulfate sodium (DSS) or trinitrobenzene sulfonic acid (TNBS), and the effect of minocycline on colonic injury was assessed clinically and histologically. Prophylactic and therapeutic treatment of mice with minocycline significantly diminished mortality rate and attenuated the severity of DSS-induced acute colitis. Mechanistically, minocycline administration suppressed inducible nitric oxide synthase (iNOS) expression and nitrotyrosine production, inhibited proinflammatory cytokine expression, repressed the elevated mRNA expression of matrix metalloproteinases (MMPs) 2, 3, 9, and 13, diminished the apoptotic index in colonic tissues, and inhibited nitric oxide production in the serum of mice with DSS-induced acute colitis. In DSS-induced chronic colitis, minocycline treatment also reduced body weight loss, improved colonic histology, and blocked expression of iNOS, proinflammatory cytokines, and MMPs from colonic tissues. Similarly, minocycline could ameliorate the severity of TNBS-induced acute colitis in mice by decreasing mortality rate and inhibiting proinflammatory cytokine expression in colonic tissues. These results demonstrate that minocycline protects mice against DSS- and TNBS-induced colitis, probably via inhibition of iNOS and MMP expression in intestinal tissues. Therefore, minocycline is a potential remedy for human inflammatory bowel diseases.

  8. Data showing levels of interleukin-1β and nitric oxide in the plasma of uropathogenic E. coli infected UTI patients.

    Science.gov (United States)

    Verma, Vivek; Arora, Renu; Dhanda, Rakesh Singh; Gaind, Rajni; Yadav, Manisha

    2018-08-01

    Urinary tract infections (UTI) are a major cause of morbidity, affecting at least four million women worldwide, 65-75% of these infections are caused by Uropathogenic Escherichia coli (UPEC) (Foxman, 2010) [1]. Repertoire of virulence factors carried by UPEC provides the ability to precede urinary tract and additionally they provoke pro-inflammatory responses (Cirl et al., 2008; Verma et al., 2016) [2], [3]. In context to UPEC infected UTI patients, the levels of pro-inflammatory cytokine IL-1β and enzymatic antioxidant nitric oxide (NO) have not been reported worldwide till date, including India. In this data article, we report for the first time the levels of IL-1β and nitric oxide in the plasma of UPEC infected UTI patients. Data includes a profile of pro-inflammatory cytokine IL-1β and NO in the plasma of the confirmed UPEC infected UTI patients ( N  = 30) versus healthy controls ( N  = 40) from the present pilot study. The levels of IL-1β in plasma were significantly higher ( p  UTI patients (60.29 ± 1.1 μM) as compared to healthy controls (106.3 ± 8.75 μM).

  9. A novel immune-to-CNS communication pathway: cells of the meninges surrounding the spinal cord CSF space produce proinflammatory cytokines in response to an inflammatory stimulus.

    Science.gov (United States)

    Wieseler-Frank, Julie; Jekich, Brian M; Mahoney, John H; Bland, Sondra T; Maier, Steven F; Watkins, Linda R

    2007-07-01

    Pain is enhanced in response to elevations of proinflammatory cytokines in spinal cerebrospinal fluid (CSF), following either intrathecal injection of these cytokines or intrathecal immune challenge with HIV-1 gp120 that induces cytokine release. Spinal cord glia have been assumed to be the source of endogenous proinflammatory cytokines that enhance pain. However, assuming that spinal cord glia are the sole source of CSF cytokines may be an underestimate, as the cellular composition of the meninges surrounding the spinal cord CSF space includes several cell types known to produce proinflammatory cytokines. The present experiments provide the first investigation of the immunocompetent nature of the spinal cord meninges. Here, we explore whether rat meninges are responsive to intrathecal gp120. These studies demonstrate that: (a) intrathecal gp120 upregulates meningeal gene expression of proinflammatory signals, including tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), interleukin 6 (IL-6), and inducible nitric oxide synthase (iNOS), and (b) intrathecal gp120 induces meningeal release of TNF-alpha, IL-1beta, and IL-6. In addition, stimulation of isolated meninges in vitro with gp120 induced the release of TNF-alpha and IL-1beta, indicating that the resident cells of the meninges are able to respond without immune cell recruitment. Taken together, these data document that the meninges are responsive to immunogenic stimuli in the CSF and that the meninges may be a source of immune products detected in CSF. The ability of the meninges to release to proinflammatory signals suggests a potential role in the modulation of pain.

  10. Melatonin mitigates thioacetamide-induced hepatic fibrosis via antioxidant activity and modulation of proinflammatory cytokines and fibrogenic genes.

    Science.gov (United States)

    Lebda, Mohamed A; Sadek, Kadry M; Abouzed, Tarek K; Tohamy, Hossam G; El-Sayed, Yasser S

    2018-01-01

    The potential antifibrotic effects of melatonin against induced hepatic fibrosis were explored. Rats were allocated into four groups: placebo; thioacetamide (TAA) (200mg/kg bwt, i.p twice weekly for two months); melatonin (5mg/kgbwt, i.p daily for a week before TAA and continued for an additional two months); and melatonin plus TAA. Hepatic fibrotic changes were evaluated biochemically and histopathologically. Hepatic oxidative/antioxidative indices were assessed. The expression of hepatic proinflammatory cytokines (tumor necrosis factor-α, and interleukin-1β), fibrogenic-related genes (transforming growth factor-1β, collagen I, collagen, III, laminin, and autotaxin) and an antioxidant-related gene (thioredoxin-1) were detected by qRT-PCR. In fibrotic rats, melatonin lowered serum aspartate aminotransferase, alanine aminotransferase, and autotaxin activities, bilirubin, hepatic hydroxyproline and plasma ammonia levels. Melatonin displayed hepatoprotective and antifibrotic potential as indicated by mild hydropic degeneration of some hepatocytes and mild fibroplasia. In addition, TAA induced the depletion of glutathione, glutathione s-transferase, glutathione peroxidase, superoxide dismutase, catalase, and paraoxonase-1 (PON-1), while inducing the accumulation of malondialdehyde, protein carbonyl (C=O) and nitric oxide (NO), and DNA fragmentation. These effects were restored by melatonin pretreatment. Furthermore, melatonin markedly attenuated the expression of proinflammatory cytokines and fibrogenic genes via the upregulation of thioredoxin-1 mRNA transcripts. Melatonin exhibits potent anti-inflammatory, antioxidant and fibrosuppressive activities against TAA-induced hepatic fibrogenesis via the suppression of oxidative stress, DNA damage, proinflammatory cytokines and fibrogenic gene transcripts. In addition, we demonstrate that the antifibrotic activity of melatonin is mediated by the induction of thioredoxin-1 with attenuation of autotaxin expressions

  11. Dysregulated proinflammatory and fibrogenic phenotype of fibroblasts in cystic fibrosis.

    Directory of Open Access Journals (Sweden)

    François Huaux

    Full Text Available Morbi-mortality in cystic fibrosis (CF is mainly related to chronic lung infection and inflammation, uncontrolled tissue rearrangements and fibrosis, and yet the underlying mechanisms remain largely unknown. We evaluated inflammatory and fibrosis responses to bleomycin in F508del homozygous and wild-type mice, and phenotype of fibroblasts explanted from mouse lungs and skin. The effect of vardenafil, a cGMP-specific phosphodiesterase type 5 inhibitor, was tested in vivo and in culture. Responses of proinflammatory and fibrotic markers to bleomycin were enhanced in lungs and skin of CF mice and were prevented by treatment with vardenafil. Purified lung and skin fibroblasts from CF mice proliferated and differentiated into myofibroblasts more prominently and displayed higher sensitivity to growth factors than those recovered from wild-type littermates. Under inflammatory stimulation, mRNA and protein expression of proinflammatory mediators were higher in CF than in wild-type fibroblasts, in which CFTR expression reached similar levels to those observed in other non-epithelial cells, such as macrophages. Increased proinflammatory responses in CF fibroblasts were reduced by half with submicromolar concentrations of vardenafil. Proinflammatory and fibrogenic functions of fibroblasts are upregulated in CF and are reduced by vardenafil. This study provides compelling new support for targeting cGMP signaling pathway in CF pharmacotherapy.

  12. Tenocytes, pro-inflammatory cytokines and leukocytes: a relationship?

    OpenAIRE

    Al-Sadi, Onays; Schulze-Tanzil, Gundula; Kohl, Benjamin; Lohan, Anke; Lemke, Marion; Ertel, Wolfgang; John, Thilo

    2012-01-01

    Leukocyte derived pro-inflammatory mediators could be involved in tendon healing and scar formation. Hence, the effect of autologous leukocytes (PBMCs, peripheral blood mononuclear cells and neutrophils) on primary rabbit Achilles tenocytes gene expression was tested in insert assisted co-cultures.

  13. Adaptive T cell responses induced by oncolytic Herpes Simplex Virus-granulocyte macrophage-colony-stimulating factor therapy expanded by dendritic cell and cytokine-induced killer cell adoptive therapy.

    Science.gov (United States)

    Ren, Jun; Gwin, William R; Zhou, Xinna; Wang, Xiaoli; Huang, Hongyan; Jiang, Ni; Zhou, Lei; Agarwal, Pankaj; Hobeika, Amy; Crosby, Erika; Hartman, Zachary C; Morse, Michael A; H Eng, Kevin; Lyerly, H Kim

    2017-01-01

    Purpose : Although local oncolytic viral therapy (OVT) may enhance tumor lysis, antigen release, and adaptive immune responses, systemic antitumor responses post-therapy are limited. Adoptive immunotherapy with autologous dendritic cells (DC) and cytokine-induced killer cells (DC-CIK) synergizes with systemic therapies. We hypothesized that OVT with Herpes Simplex Virus-granulocyte macrophage-colony-stimulating factor (HSV-GM-CSF) would induce adaptive T cell responses that could be expanded systemically with sequential DC-CIK therapy. Patients and Methods : We performed a pilot study of intratumoral HSV-GM-CSF OVT followed by autologous DC-CIK cell therapy. In addition to safety and clinical endpoints, we monitored adaptive T cell responses by quantifying T cell receptor (TCR) populations in pre-oncolytic therapy, post-oncolytic therapy, and after DC-CIK therapy. Results : Nine patients with advanced malignancy were treated with OVT (OrienX010), of whom seven experienced stable disease (SD). Five of the OVT treated patients underwent leukapheresis, generation, and delivery of DC-CIKs, and two had SD, whereas three progressed. T cell receptor sequencing of TCR β sequences one month after OVT therapy demonstrates a dynamic TCR repertoire in response to OVT therapy in the majority of patients with the systematic expansion of multiple T cell clone populations following DC-CIK therapy. This treatment was well tolerated and long-term event free and overall survival was observed in six of the nine patients. Conclusions : Strategies inducing the local activation of tumor-specific immune responses can be combined with adoptive cellular therapies to expand the adaptive T cell responses systemically and further studies are warranted.

  14. Influence of the number and interval of treatment cycles on cytokine-induced killer cells and their adjuvant therapeutic effects in advanced non-small-cell lung cancer (NSCLC).

    Science.gov (United States)

    Gu, Yuanlong; Lv, Huimin; Zhao, Juan; Li, Qi; Mu, Guannan; Li, Jiade; Wuyang, Jiazi; Lou, Ge; Wang, Ruitao; Zhang, Yanqiao; Huang, Xiaoyi

    2017-09-01

    Cytokine-induced killer (CIK) cells have important therapeutic effects in adoptive cell transfer (ACT) for the treatment of various malignancies. In this study, we focused on in vitro expansion of CIK cells and their clinical efficacy in combination with chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC). A total of 64 patients with NSCLC (enrolled from 2011 to 2012), including 32 patients who received chemotherapy alone or with sequential radiotherapy (conventional treatment, control group) and 32 patients who received conventional treatment and sequential CIK infusion (study group), were retrospectively analyzed. The time to progression (TTP), overall survival (OS) and adverse effects were analyzed and the phenotype of lymphocytes in CIK population was also determined by flow cytometry. After in vitro expansion, the average percentage of CIK cells was 26.35%. During the 54-month follow up, the median OS and TTP were significantly longer in the study group than in the control group (P=0.0189 and P=0.0129, respectively). The median OS of the ACT≥4cycles subgroup was significantly longer than that of the ACTcells in patients who received ≥4cycles of ACT was higher than that in patients treated with cells were difficult to expand in vitro in some patients after the first ACT cycle but became much easier as the treatment cycles increased monthly. Longer treatment interval negatively impacted the expansion of CIK cells. Systematic immune levels can be increasingly boosted by reinfusion of ACT. Conventional treatment plus CIK cells is an effective therapeutic strategy to prevent progression and prolong survival of patients with advanced NSCLC. Copyright © 2017. Published by Elsevier B.V.

  15. Resveratrol and Endothelial Nitric Oxide

    Directory of Open Access Journals (Sweden)

    Ning Xia

    2014-10-01

    Full Text Available Nitric oxide (NO derived from the endothelial NO synthase (eNOS has antihypertensive, antithrombotic, anti-atherosclerotic and antiobesogenic properties. Resveratrol is a polyphenol phytoalexin with multiple cardiovascular and metabolic effects. Part of the beneficial effects of resveratrol are mediated by eNOS. Resveratrol stimulates NO production from eNOS by a number of mechanisms, including upregulation of eNOS expression, stimulation of eNOS enzymatic activity and reversal of eNOS uncoupling. In addition, by reducing oxidative stress, resveratrol prevents oxidative NO inactivation by superoxide thereby enhancing NO bioavailability. Molecular pathways underlying these effects of resveratrol involve SIRT1, AMPK, Nrf2 and estrogen receptors.

  16. Nanocarriers for Nitric Oxide Delivery

    Directory of Open Access Journals (Sweden)

    Juliana Saraiva

    2011-01-01

    Full Text Available Nitric oxide (NO is a promising pharmaceutical agent that has vasodilative, antibacterial, and tumoricidal effects. To study the complex and wide-ranging roles of NO and to facilitate its therapeutic use, a great number of synthetic compounds (e.g., nitrosothiols, nitrosohydroxyamines, N-diazeniumdiolates, and nitrosyl metal complexes have been developed to chemically stabilize and release NO in a controlled manner. Although NO is currently being exploited in many biomedical applications, its use is limited by several factors, including a short half-life, instability during storage, and potential toxicity. Additionally, efficient methods of both localized and systemic in vivo delivery and dose control are needed. One strategy for addressing these limitations and thus increasing the utility of NO donors is based on nanotechnology.

  17. Nitric oxide and chronic colitis

    Directory of Open Access Journals (Sweden)

    Matthew B Grisham

    1996-01-01

    Full Text Available Nitric oxide (NO is thought to play an important role in modulating the inflammatory response by virtue of its ability to affect bloodflow, leukocyte function and cell viability. The objective of this study was to assess the role that NO may play in mediating the mucosal injury and inflammation in a model of chronic granulomatous colitis using two pharmacologically different inhibitors of nitric oxide synthase (NOS. Chronic granulomatous colitis with liver and spleen inflammation was induced in female Lewis rats via the subserosal (intramural injection of peptidoglycan/polysaccharide (PG/PS derived from group A streptococci. Chronic NOS inhibition by oral administration of NG-nitro-L-arginine methyl ester (L-NAME (15 µmol/kg/day or amino-guanidine (AG (15 µmol/ kg/day was found to attenuate the PG/PS-induced increases in macroscopic colonic inflammation scores and colonic myeloperoxidase activity. Only AG -- not L-NAME – attenuated the PG/PS-induced increases in colon dry weight. Both L-NAME and AG significantly attenuated the PG/PS-induced increases in spleen weight whereas neither was effective at significantly attenuating the PG/PS-induced increases in liver weight. Although both L-NAME and AG inhibited NO production in vivo, as measured by decreases in plasma nitrite and nitrate levels, only AG produced significantly lower values (38±3 versus 83±8 µM, respectively, P<0.05. Finally, L-NAME, but not AG, administration significantly increased mean arterial pressure from 83 mmHg in colitic animals to 105 mmHg in the PG/PS+ L-NAME-treated animals (P<0.05. It is concluded that NO may play an important role in mediating some of the pathophysiology associated with this model of chronic granulomatous colitis.

  18. Artichoke, Cynarin and Cyanidin Downregulate the Expression of Inducible Nitric Oxide Synthase in Human Coronary Smooth Muscle Cells

    OpenAIRE

    Ning Xia; Andrea Pautz; Ursula Wollscheid; Gisela Reifenberg; Ulrich Förstermann; Huige Li

    2014-01-01

    Artichoke (Cynara scolymus L.) is one of the world’s oldest medicinal plants with multiple health benefits. We have previously shown that artichoke leaf extracts and artichoke flavonoids upregulate the gene expression of endothelial-type nitric oxide synthase (eNOS) in human endothelial cells. Whereas NO produced by the eNOS is a vasoprotective molecule, NO derived from the inducible iNOS plays a pro-inflammatory role in the vasculature. The present study was aimed to investigate the effects ...

  19. 21 CFR 862.3080 - Breath nitric oxide test system.

    Science.gov (United States)

    2010-04-01

    ... Systems § 862.3080 Breath nitric oxide test system. (a) Identification. A breath nitric oxide test system... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Breath nitric oxide test system. 862.3080 Section... fractional nitric oxide concentration in expired breath aids in evaluating an asthma patient's response to...

  20. Gemfibrozil, a Lipid-lowering Drug, Inhibits the Induction of Nitric-oxide Synthase in Human Astrocytes*

    Science.gov (United States)

    Pahan, Kalipada; Jana, Malabendu; Liu, Xiaojuan; Taylor, Bradley S.; Wood, Charles; Fischer, Susan M.

    2007-01-01

    Gemfibrozil, a lipid-lowering drug, inhibited cytokine-induced production of NO and the expression of inducible nitric-oxide synthase (iNOS) in human U373MG astroglial cells and primary astrocytes. Similar to gemfibrozil, clofibrate, another fibrate drug, also inhibited the expression of iNOS. Inhibition of human iNOS promoter-driven luciferase activity by gemfibrozil in cytokine-stimulated U373MG astroglial cells suggests that this compound inhibits the transcription of iNOS. Since gemfibrozil is known to activate peroxisome proliferator-activated receptor-α (PPAR-α), we investigated the role of PPAR-α in gemfibrozil-mediated inhibition of iNOS. Gemfibrozil induced peroxisome proliferator-responsive element (PPRE)-dependent luciferase activity, which was inhibited by the expression of ΔhPPAR-α, the dominant-negative mutant of human PPAR-α. However, ΔhPPAR-α was unable to abrogate gemfibrozil-mediated inhibition of iNOS suggesting that gemfibrozil inhibits iNOS independent of PPAR-α. The human iNOS promoter contains consensus sequences for the binding of transcription factors, including interferon-γ (IFN-γ) regulatory factor-1 (IRF-1) binding to interferon-stimulated responsive element (ISRE), signal transducer and activator of transcription (STAT) binding to γ-activation site (GAS), nuclear factor-κB (NF-κB), activator protein-1 (AP-1), and CCAAT/enhancer-binding protein β (C/EBPβ); therefore, we investigated the effect of gemfibrozil on the activation of these transcription factors. The combination of interleukin (IL)-1β and IFN-γ induced the activation of NF-κB, AP-1, C/EBPβ, and GAS but not that of ISRE, suggesting that IRF-1 may not be involved in cytokine-induced expression of iNOS in human astrocytes. Interestingly, gemfibrozil strongly inhibited the activation of NF-κB, AP-1, and C/EBPβ but not that of GAS in cytokine-stimulated astroglial cells. These results suggest that gemfibrozil inhibits the induction of iNOS probably by

  1. Aqueous proinflammatory cytokines in acute primary angle-closure eyes

    Directory of Open Access Journals (Sweden)

    Yao-Ming Liu

    2017-05-01

    Full Text Available AIM: To evaluate changes of proinflammatory cytokines in aqueous humor of patients with acute primary angle-closure (APAC and age-related cataracts. METHODS: Twenty eyes of 20 APAC patients and 15 eyes of 15 age-related cataract patients were included in this cross-sectional study. Aqueous humor samples were collected prospectively. The levels of 20 proinflammatory cytokines were evaluated in the aqueous humor of the APAC and cataract patients using the multiplex bead immunoassay technique. Clinical data were collected for correlation analysis. RESULTS: Seven of the 20 proinflammatory cytokines included in the magnetic bead panel were detectable in both APAC eyes and cataract eyes: interleukin (IL-10, IL-12, IL-15, IL-21, IL-6, chemokine (C-C motif ligand 20, and tumor necrosis factor alpha (TNF-α. IL-27 was only detectable in APAC eyes. Compared with the cataract eyes, the APAC eyes had significantly elevated concentrations of IL-12 (P=0.036, IL-15 (P=0.001, IL-6 (P=0.012, and IL-27 (only detectable in APAC eyes. Age was positively correlated with IL-12 (P=0.022 and IL-6 (P=0.037, and time elapsed between APAC onset and aqueous humor samples collection was positively correlated with IL-15 (P=0.037, IL-27 (P=0.040, and TNF-α (P=0.042. CONCLUSION: Several proinflammatory cytokines including IL-12,IL-15, IL-6 and IL-27, were elevated in the APAC eyes and may be implicated in its pathologic mechanism.

  2. The Pro-inflammatory Effects of Glucocorticoids in the Brain

    Science.gov (United States)

    Duque, Erica de Almeida; Munhoz, Carolina Demarchi

    2016-01-01

    Glucocorticoids are a class of steroid hormones derived from cholesterol. Their actions are mediated by the glucocorticoid and mineralocorticoid receptors, members of the superfamily of nuclear receptors, which, once bound to their ligands, act as transcription factors that can directly modulate gene expression. Through protein–protein interactions with other transcription factors, they can also regulate the activity of many genes in a composite or tethering way. Rapid non-genomic signaling was also demonstrated since glucocorticoids can act through membrane receptors and activate signal transduction pathways, such as protein kinases cascades, to modulate other transcriptions factors and activate or repress various target genes. By all these different mechanisms, glucocorticoids regulate numerous important functions in a large variety of cells, not only in the peripheral organs but also in the central nervous system during development and adulthood. In general, glucocorticoids are considered anti-inflammatory and protective agents due to their ability to inhibit gene expression of pro-inflammatory mediators and other possible damaging molecules. Nonetheless, recent studies have uncovered situations in which these hormones can act as pro-inflammatory agents depending on the dose, chronicity of exposure, and the structure/organ analyzed. In this review, we will provide an overview of the conditions under which these phenomena occur, a discussion that will serve as a basis for exploring the mechanistic foundation of glucocorticoids pro-inflammatory gene regulation in the brain. PMID:27445981

  3. Endothelial nitric oxide synthase gene polymorphisms associated ...

    African Journals Online (AJOL)

    STORAGESEVER

    2010-05-24

    May 24, 2010 ... chronic periodontitis (CP), 31 with gingivitis (G) and 50 healthy controls. Probing depth ..... Periodontal disease in pregnancy I. Prevalence and severity. ... endothelial nitric oxide synthase gene in premenopausal women with.

  4. Flavonoids as scavengers of nitric oxide radical.

    NARCIS (Netherlands)

    van Acker, S.A.B.E.; Tromp, M.N.J.L.; Haenen, G.R.M.M.; van der Vijgh, W.J.F.; Bast, A.

    1995-01-01

    Flavonoids are a group of naturally occurring compounds used, e.g., in the treatment of vascular endothelial damage. They are known to be excellent scavengers of oxygen free radicals. Since the nitric oxide radical (

  5. DMPD: Post-transcriptional regulation of proinflammatory proteins. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 15075353 Post-transcriptional regulation of proinflammatory proteins. Anderson P, P...l) (.csml) Show Post-transcriptional regulation of proinflammatory proteins. PubmedID 15075353 Title Post-tr...anscriptional regulation of proinflammatory proteins. Authors Anderson P, Phillip

  6. Nitric oxide in the stress axis

    OpenAIRE

    Lopez-Figueroa, M.O.; Day, H.E.W.; Akil, H.; Watson, S.J.

    1998-01-01

    In recent years nitric oxide (NO) has emerged as a unique biological messenger. NO is a highly diffusible gas, synthesized from L-arginine by the enzyme nitric oxide synthase (NOS). Three unique subtypes of NOS have been described, each with a specific distribution profile in the brain and periphery. NOS subtype I is present, among other areas, in the hippocampus, hypothalamus, pituitary and adrenal gland. Together these structures form the limbichypothalamic- ...

  7. The molecular basis for development of proinflammatory autoantibodies to progranulin.

    Science.gov (United States)

    Thurner, Lorenz; Fadle, Natalie; Regitz, Evi; Kemele, Maria; Klemm, Philipp; Zaks, Marina; Stöger, Elisabeth; Bette, Birgit; Carbon, Gabi; Zimmer, Vincent; Assmann, Gunter; Murawski, Niels; Kubuschok, Boris; Held, Gerhard; Preuss, Klaus-Dieter; Pfreundschuh, Michael

    2015-07-01

    Recently we identified in a wide spectrum of autoimmune diseases frequently occurring proinflammatory autoantibodies directed against progranulin, a direct inhibitor of TNFR1 & 2 and of DR3. In the present study we investigated the mechanisms for the breakdown of self-tolerance against progranulin. Isoelectric focusing identified a second, differentially electrically charged progranulin isoform exclusively present in progranulin-antibody-positive patients. Alkaline phosphatase treatment revealed this additional progranulin isoform to be hyperphosphorylated. Subsequently Ser81, which is located within the epitope region of progranulin-antibodies, was identified as hyperphosphorylated serine residue by site directed mutagenesis of candidate phosphorylation sites. Hyperphosphorylated progranulin was detected exclusively in progranulin-antibody-positive patients during the courses of their diseases. The occurrence of hyperphosphorylated progranulin preceded seroconversions of progranulin-antibodies, indicating adaptive immune response. Utilizing panels of kinase and phosphatase inhibitors, PKCβ1 was identified as the relevant kinase and PP1 as the relevant phosphatase for phosphorylation and dephosphorylation of Ser81. In contrast to normal progranulin, hyperphosphorylated progranulin interacted exclusively with inactivated (pThr320) PP1, suggesting inactivated PP1 to cause the detectable occurrence of phosphorylated Ser81 PGRN. Investigation of possible functional alterations of PGRN due to Ser81 phosphorylation revealed, that hyperphosphorylation prevents the interaction and thus direct inhibition of TNFR1, TNFR2 and DR3, representing an additional direct proinflammatory effect. Finally phosphorylation of Ser81 PGRN alters the conversion pattern of PGRN. In conclusion, inactivated PP1 induces hyperphosphorylation of progranulin in a wide spectrum of autoimmune diseases. This hyperphosphorylation prevents direct inhibition of TNFR1, TNFR2 and DR3 by PGRN, alters the

  8. Etiogenic factors present in the cerebrospinal fluid from amyotrophic lateral sclerosis patients induce predominantly pro-inflammatory responses in microglia.

    Science.gov (United States)

    Mishra, Pooja-Shree; Vijayalakshmi, K; Nalini, A; Sathyaprabha, T N; Kramer, B W; Alladi, Phalguni Anand; Raju, T R

    2017-12-16

    Microglial cell-associated neuroinflammation is considered as a potential contributor to the pathophysiology of sporadic amyotrophic lateral sclerosis. However, the specific role of microglia in the disease pathogenesis remains to be elucidated. We studied the activation profiles of the microglial cultures exposed to the cerebrospinal fluid from these patients which recapitulates the neurodegeneration seen in sporadic amyotrophic lateral sclerosis. This was done by investigating the morphological and functional changes including the expression levels of prostaglandin E2 (PGE2), cyclooxygenase-2 (COX-2), TNF-α, IL-6, IFN-γ, IL-10, inducible nitric oxide synthase (iNOS), arginase, and trophic factors. We also studied the effect of chitotriosidase, the inflammatory protein found upregulated in the cerebrospinal fluid from amyotrophic lateral sclerosis patients, on these cultures. We report that the cerebrospinal fluid from amyotrophic lateral sclerosis patients could induce an early and potent response in the form of microglial activation, skewed primarily towards a pro-inflammatory profile. It was seen in the form of upregulation of the pro-inflammatory cytokines and factors including IL-6, TNF-α, iNOS, COX-2, and PGE2. Concomitantly, a downregulation of beneficial trophic factors and anti-inflammatory markers including VEGF, glial cell line-derived neurotrophic factor, and IFN-γ was seen. In addition, chitotriosidase-1 appeared to act specifically via the microglial cells. Our findings demonstrate that the cerebrospinal fluid from amyotrophic lateral sclerosis patients holds enough cues to induce microglial inflammatory processes as an early event, which may contribute to the neurodegeneration seen in the sporadic amyotrophic lateral sclerosis. These findings highlight the dynamic role of microglial cells in the pathogenesis of the disease, thus suggesting the need for a multidimensional and temporally guarded therapeutic approach targeting the inflammatory

  9. Low-Dose Ribavirin Treatments Attenuate Neuroinflammatory Activation of BV-2 Cells by Interfering with Inducible Nitric Oxide Synthase

    Directory of Open Access Journals (Sweden)

    Iva Bozic

    2015-01-01

    Full Text Available Microglia play a key role in defending central nervous system from various internal and external threats. However, their excessive and/or chronic activation is associated with deleterious effects in a variety of neurodegenerative diseases. Previously, we have shown that ribavirin when applied in clinically relevant dosage (10 μM modulates activated microglia in complex fashion inducing both anti- and proinflammatory effects, simultaneously causing cytotoxicity. Here, we examined potential of low-dose ribavirin (0.1 and 1 μM to modulate activated BV-2 microglia. Morphological and functional activation of BV-2 cells was achieved with lipopolysaccharide (LPS stimulation. Our results demonstrated that low-dose ribavirin did not induce cell death, while 10 μM ribavirin promoted LPS induced apoptosis. We determined that 1 μM ribavirin was equally efficient in deactivation of LPS induced morphological changes as 10 μM ribavirin treatment. Ribavirin showed halfway success in reducing markers of functional activation of microglia. Namely, none of the doses had effect on LPS triggered production of proinflammatory cytokine tumor necrosis factor alpha. On the other hand, low-dose ribavirin proved its effectiveness in reduction of another inflammatory mediator, nitric oxide, by inhibiting inducible form of nitric oxide synthase. Our results imply that low-dose ribavirin may alleviate nitrosative stress during neuroinflammation.

  10. Low-Dose Ribavirin Treatments Attenuate Neuroinflammatory Activation of BV-2 Cells by Interfering with Inducible Nitric Oxide Synthase

    Science.gov (United States)

    Bozic, Iva; Savic, Danijela; Jovanovic, Marija; Bjelobaba, Ivana; Laketa, Danijela; Nedeljkovic, Nadezda; Stojiljkovic, Mirjana; Pekovic, Sanja; Lavrnja, Irena

    2015-01-01

    Microglia play a key role in defending central nervous system from various internal and external threats. However, their excessive and/or chronic activation is associated with deleterious effects in a variety of neurodegenerative diseases. Previously, we have shown that ribavirin when applied in clinically relevant dosage (10 μM) modulates activated microglia in complex fashion inducing both anti- and proinflammatory effects, simultaneously causing cytotoxicity. Here, we examined potential of low-dose ribavirin (0.1 and 1 μM) to modulate activated BV-2 microglia. Morphological and functional activation of BV-2 cells was achieved with lipopolysaccharide (LPS) stimulation. Our results demonstrated that low-dose ribavirin did not induce cell death, while 10 μM ribavirin promoted LPS induced apoptosis. We determined that 1 μM ribavirin was equally efficient in deactivation of LPS induced morphological changes as 10 μM ribavirin treatment. Ribavirin showed halfway success in reducing markers of functional activation of microglia. Namely, none of the doses had effect on LPS triggered production of proinflammatory cytokine tumor necrosis factor alpha. On the other hand, low-dose ribavirin proved its effectiveness in reduction of another inflammatory mediator, nitric oxide, by inhibiting inducible form of nitric oxide synthase. Our results imply that low-dose ribavirin may alleviate nitrosative stress during neuroinflammation. PMID:26413464

  11. Protective effects of agmatine on lipopolysaccharide-injured microglia and inducible nitric oxide synthase activity.

    Science.gov (United States)

    Ahn, Soo Kyung; Hong, Samin; Park, Yu Mi; Choi, Ja Yong; Lee, Won Taek; Park, Kyung Ah; Lee, Jong Eun

    2012-12-17

    Proinflammatory factors released from activated microglia contribute to maintaining homeostasis against various noxious stimuli in the central nervous system. If excessive, however, they may initiate a pathologic neuroinflammatory process. In this investigation, we evaluated whether agmatine, a primary polyamine known to protect neurons, reduces lipopolysaccharide (LPS)-induced damage to microglia in vitro and in vivo. For in vitro study, BV2-immortalized murine microglia were exposed to LPS with agmatine treatment. After 24hours, cell viability and the amount of nitrite generated were determined. For in vivo study, LPS was microinjected into the corpus callosum of adult male albino mice. Agmatine was intraperitoneally administered at the time of injury. Brains were evaluated 24hours after LPS microinjection to check for immunoreactivity with a microglial marker of ionized calcium binding adaptor molecule 1 (Iba1) and inducible nitric oxide synthase (iNOS). Using western blot analysis, protein expression of iNOS as well as that of the proinflammatory cytokines, tumor necrosis factor (TNF)-α and interleukin (IL)-1β, was determined. Agmatine significantly reduced the LPS-induced BV2 microglial cytotoxicity from over 80% to less than 60% (pAgmatine also decreased the activities of microglia and iNOS induced by LPS microinjection into corpus callosum. Our findings reveal that agmatine attenuates LPS-induced microglial damage and suggest that agmatine may serve as a novel therapeutic strategy for neuroinflammatory diseases. Copyright © 2012 Elsevier Inc. All rights reserved.

  12. Anti-Inflammatory and Gastroprotective Roles of Rabdosia inflexa through Downregulation of Pro-Inflammatory Cytokines and MAPK/NF-κB Signaling Pathways

    Directory of Open Access Journals (Sweden)

    Md Rashedunnabi Akanda

    2018-02-01

    Full Text Available Globally, gastric ulcer is a vital health hazard for a human. Rabdosia inflexa (RI has been used in traditional medicine for inflammatory diseases. The present study aimed to investigate the protective effect and related molecular mechanism of RI using lipopolysaccharide (LPS-induced inflammation in RAW 246.7 cells and HCl/EtOH-induced gastric ulcer in mice. We applied 3-(4,5-dimethyl-thiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT, nitric oxide (NO, reactive oxygen species (ROS, histopathology, malondialdehyde (MDA, quantitative real-time polymerase chain reaction (qPCR, immunohistochemistry (IHC, and Western blot analyses to evaluate the protective role of RI. Study revealed that RI effectively attenuated LPS-promoted NO and ROS production in RAW 246.7 cells. In addition, RI mitigated gastric oxidative stress by inhibiting lipid peroxidation, elevating NO, and decreasing gastric inflammation. RI significantly halted elevated gene expression of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α, interleukin-1β (IL-1β, interleukin-6 (IL-6, inducible nitric oxide synthetase (iNOS, and cyclooxygenase-2 (COX-2 in gastric tissue. Likewise, RI markedly attenuated the mitogen-activated protein kinases (MAPKs phosphorylation, COX-2 expression, phosphorylation and degradation of inhibitor kappa B (IκBα and activation of nuclear factor kappa B (NF-κB. Thus, experimental findings suggested that the anti-inflammatory and gastroprotective activities of RI might contribute to regulating pro-inflammatory cytokines and MAPK/NF-κB signaling pathways.

  13. Nitric Oxide Mediates Crosstalk between Interleukin 1β and WNT Signaling in Primary Human Chondrocytes by Reducing DKK1 and FRZB Expression.

    Science.gov (United States)

    Zhong, Leilei; Schivo, Stefano; Huang, Xiaobin; Leijten, Jeroen; Karperien, Marcel; Post, Janine N

    2017-11-22

    Interleukin 1 beta (IL1β) and Wingless-Type MMTV Integration Site Family (WNT) signaling are major players in Osteoarthritis (OA) pathogenesis. Despite having a large functional overlap in OA onset and development, the mechanism of IL1β and WNT crosstalk has remained largely unknown. In this study, we have used a combination of computational modeling and molecular biology to reveal direct or indirect crosstalk between these pathways. Specifically, we revealed a mechanism by which IL1β upregulates WNT signaling via downregulating WNT antagonists, DKK1 and FRZB. In human chondrocytes, IL1β decreased the expression of Dickkopf-1 (DKK1) and Frizzled related protein (FRZB) through upregulation of nitric oxide synthase (iNOS), thereby activating the transcription of WNT target genes. This effect could be reversed by iNOS inhibitor 1400W, which restored DKK1 and FRZB expression and their inhibitory effect on WNT signaling. In addition, 1400W also inhibited both the matrix metalloproteinase (MMP) expression and cytokine-induced apoptosis. We concluded that iNOS/NO play a pivotal role in the inflammatory response of human OA through indirect upregulation of WNT signaling. Blocking NO production may inhibit the loss of the articular phenotype in OA by preventing downregulation of the expression of DKK1 and FRZB.

  14. The Hierarchy of Proinflammatory Cytokines in Ocular Inflammation.

    Science.gov (United States)

    Da Cunha, A P; Zhang, Q; Prentiss, M; Wu, X Q; Kainz, V; Xu, Y Y; Vrouvlianis, J; Li, H; Rangaswamy, N; Leehy, B; McGee, T L; Bell, C L; Bigelow, C E; Kansara, V; Medley, Q; Huang, Q; Wu, H Y

    2018-04-01

    The concept of tissue-dependent cytokine hierarchy has been demonstrated in a number of diseases, but it has not been investigated in ophthalmic diseases. Here, we evaluated the functional hierarchy of interleukin-1β (IL-1β), IL-6, IL-17A, and tumor necrosis factor (TNF) in the induction of ocular inflammation. We delivered adeno-associated virus (AAV) vectors expressing IL-1β, IL-6, IL-17A, or TNF intravitreally in naïve C57/BL6 mice and compared and contrasted the inflammatory effects in the eye 5 weeks after AAV-mediated gene transfer. We also used an in vitro human system to test the effect of cytokines on barrier function. We found that IL-1β had the highest ability to initiate ocular inflammation. The continuous overexpression of IL-1β resulted in a significant upregulation of additional proinflammatory mediators in the eye. Using scanning laser ophthalmoscope and optical coherence tomography imaging techniques, we showed that a low dose of AAVIL-1β was sufficient and was as pathogenic as a high dose of TNF in inducing vascular leakage, retinal degeneration, and cellular infiltration. Furthermore, only a marginal increase in IL-1β was enough to cause cellular infiltration, thus confirming the highly pathogenic nature of IL-1β in the eye. Contrary to our expectation, IL-6 or IL-17A had minimal or no effect in the eye. To examine the clinical relevance of our findings, we used an impedance assay to show that IL-1β alone or TNF alone was able to cause primary human retinal endothelial cell barrier dysfunction in vitro. Again, IL-6 alone or IL-17A alone had no effect on barrier function; however, in the presence of IL-1β or TNF, IL-17A but not IL-6 may provide additive proinflammatory effects. Our studies demonstrate the existence of a functional hierarchy of proinflammatory cytokines in the eye, and we show that IL-1β is the most pathogenic when it is continuously expressed in the eye.

  15. 21 CFR 868.5165 - Nitric oxide administration apparatus.

    Science.gov (United States)

    2010-04-01

    ... apparatus. (a) Identification. The nitric oxide administration apparatus is a device used to add nitric oxide to gases that are to be breathed by a patient. The nitric oxide administration apparatus is to be used in conjunction with a ventilator or other breathing gas administration system. (b) Classification...

  16. Containment of Nitric Acid Solutions of Plutonium-238

    International Nuclear Information System (INIS)

    Reimus, M.A.H.; Silver, G.L.; Pansoy-Hjelvik, L.; Ramsey, K.

    1999-01-01

    The corrosion of various metals that could be used to contain nitric acid solutions of Pu-238 has been studied. Tantalum and tantalum/2.5% tungsten resisted the test solvent better than 304L stainless steel and several INCONEL alloys. The solvent used to imitate nitric acid solutions of Pu-238 contained 70% nitric acid, hydrofluoric acid, and ammonium hexanitratocerate

  17. Electroreduction of nitric acid to hydroxylamine

    International Nuclear Information System (INIS)

    Haque, I.U.; Saima, W.

    2008-01-01

    This article reviews recent studies concerned with the synthesis of hydroxylamine Hydroxylamine plays a significant role in agriculture, photographic developing, as a component in liquid propellants and as a reducing agent etc. In this regard modification of carbon electrode surface greatly increases hydrogen overpotential in nitric acid solutions and allows electrochemical generation of hydroxylamine with good current efficiency. (author)

  18. ORIGINAL ARTICLE Relationship between endothelial nitric oxide ...

    African Journals Online (AJOL)

    salah

    The haplotype analysis confirmed ... hand, no consistent association was shown between the two SNPs and SBP or. DBP. ... Endothelial nitric oxide synthase gene polymorphisms and risk of MI .... type (-786T*+894G), the haplotypes ... Tests adjusted for age, BMI, diabetes, current smoking and alcohol consumption.

  19. Endothelial nitric oxide synthase gene polymorphisms associated ...

    African Journals Online (AJOL)

    Endothelial nitric oxide synthase (NOS3) is involved in key steps of immune response. Genetic factors predispose individuals to periodontal disease. This study's aim was to explore the association between NOS3 gene polymorphisms and clinical parameters in patients with periodontal disease. Genomic DNA was obtained ...

  20. Nitric oxide enhances osmoregulation of tobacco ( Nicotiana ...

    African Journals Online (AJOL)

    This study was carried out to investigate the effect of the intracellular signaling molecule nitric oxide (NO) on osmoregulation of tobacco cells under osmotic stress caused by phenylethanoid glycosides 6000 (PEG 6000). The results show that the PEG stress induced a specific pattern of endogenous NO production with two ...

  1. An ethanol extract of Piper betle Linn. mediates its anti-inflammatory activity via down-regulation of nitric oxide.

    Science.gov (United States)

    Ganguly, Sudipto; Mula, Soumyaditya; Chattopadhyay, Subrata; Chatterjee, Mitali

    2007-05-01

    The leaves of Piper betle (locally known as Paan) have long been in use in the Indian indigenous system of medicine for the relief of pain; however, the underlying molecular mechanisms of this effect have not been elucidated. The anti-inflammatory and immunomodulatory effects of an ethanolic extract of the leaves of P. betle (100 mg kg(-1); PB) were demonstrated in a complete Freund's adjuvant-induced model of arthritis in rats with dexamethasone (0.1 mg kg(-1)) as the positive control. At non-toxic concentrations of PB (5-25 microg mL(-1)), a dose-dependent decrease in extracellular production of nitric oxide in murine peritoneal macrophages was measured by the Griess assay and corroborated by flow cytometry using the nitric oxide specific probe, 4,5-diaminofluorescein-2 diacetate. This decreased generation of reactive nitrogen species was mediated by PB progressively down-regulating transcription of inducible nitric oxide synthase in macrophages, and concomitantly causing a dose-dependent decrease in the expression of interleukin-12 p40, indicating the ability of PB to down-regulate T-helper 1 pro-inflammatory responses. Taken together, the anti-inflammatory and anti-arthrotic activity of PB is attributable to its ability to down-regulate the generation of reactive nitrogen species, thus meriting further pharmacological investigation.

  2. Proinflammatory effects of cookstove emissions on human bronchial epithelial cells.

    Science.gov (United States)

    Hawley, B; Volckens, J

    2013-02-01

    Approximately half of the world's population uses biomass fuel for indoor cooking and heating. This form of combustion typically occurs in open fires or primitive stoves. Human exposure to emissions from indoor biomass combustion is a global health concern, causing an estimated 1.5 million premature deaths each year. Many 'improved' stoves have been developed to address this concern; however, studies that examine exposure-response with cleaner-burning, more efficient stoves are few. The objective of this research was to evaluate the effects of traditional and cleaner-burning stove emissions on an established model of the bronchial epithelium. We exposed well-differentiated, normal human bronchial epithelial cells to emissions from a single biomass combustion event using either a traditional three-stone fire or one of two energy-efficient stoves. Air-liquid interface cultures were exposed using a novel, aerosol-to-cell deposition system. Cellular expression of a panel of three pro-inflammatory markers was evaluated at 1 and 24 h following exposure. Cells exposed to emissions from the cleaner-burning stoves generated significantly fewer amounts of pro-inflammatory markers than cells exposed to emissions from a traditional three-stone fire. Particulate matter emissions from each cookstove were substantially different, with the three-stone fire producing the largest concentrations of particles (by both number and mass). This study supports emerging evidence that more efficient cookstoves have the potential to reduce respiratory inflammation in settings where solid fuel combustion is used to meet basic domestic needs. Emissions from more efficient, cleaner-burning cookstoves produced less inflammation in well-differentiated bronchial lung cells. The results support evidence that more efficient cookstoves can reduce the health burden associated with exposure to indoor pollution from the combustion of biomass. © 2012 John Wiley & Sons A/S.

  3. Macrophage elastase (MMP-12: a pro-inflammatory mediator?

    Directory of Open Access Journals (Sweden)

    Soazig Nénan

    2005-03-01

    Full Text Available As many metalloproteinases (MMPs, macrophage elastase (MMP-12 is able to degrade extracellular matrix components such as elastin and is involved in tissue remodeling processes. Studies using animal models of acute and chronic pulmonary inflammatory diseases, such as pulmonary fibrosis and chronic obstrutive pulmonary disease (COPD, have given evidences that MMP-12 is an important mediator of the pathogenesis of these diseases. However, as very few data regarding the direct involvement of MMP-12 in inflammatory process in the airways were available, we have instilled a recombinant form of human MMP-12 (rhMMP-12 in mouse airways. Hence, we have demonstrated that this instillation induced a severe inflammatory cell recruitment characterized by an early accumulation of neutrophils correlated with an increase in proinflammatory cytokines and in gelatinases and then by a relatively stable recruitment of macrophages in the lungs over a period of ten days. Another recent study suggests that resident alveolar macrophages and recruited neutrophils are not involved in the delayed macrophage recruitment. However, epithelial cells could be one of the main targets of rhMMP-12 in our model. We have also reported that a corticoid, dexamethasone, phosphodiesterase 4 inhibitor, rolipram and a non-selective MMP inhibitor, marimastat could reverse some of these inflammatory events. These data indicate that our rhMMP-12 model could mimic some of the inflammatory features observed in COPD patients and could be used for the pharmacological evaluation of new anti-inflammatory treatment. In this review, data demonstrating the involvement of MMP-12 in the pathogenesis of pulmonary fibrosis and COPD as well as our data showing a pro-inflammatory role for MMP-12 in mouse airways will be summarized.

  4. miR-296-3p, miR-298-5p and their downstream networks are causally involved in the higher resistance of mammalian pancreatic α cells to cytokine-induced apoptosis as compared to β cells

    Directory of Open Access Journals (Sweden)

    Barbagallo Davide

    2013-01-01

    Full Text Available Abstract Background The molecular bases of mammalian pancreatic α cells higher resistance than β to proinflammatory cytokines are very poorly defined. MicroRNAs are master regulators of cell networks, but only scanty data are available on their transcriptome in these cells and its alterations in diabetes mellitus. Results Through high-throughput real-time PCR, we analyzed the steady state microRNA transcriptome of murine pancreatic α (αTC1-6 and β (βTC1 cells: their comparison demonstrated significant differences. We also characterized the alterations of αTC1-6 cells microRNA transcriptome after treatment with proinflammatory cytokines. We focused our study on two microRNAs, miR-296-3p and miR-298-5p, which were: (1 specifically expressed at steady state in αTC1-6, but not in βTC1 or INS-1 cells; (2 significantly downregulated in αTC1-6 cells after treatment with cytokines in comparison to untreated controls. These microRNAs share more targets than expected by chance and were co-expressed in αTC1-6 during a 6–48 h time course treatment with cytokines. The genes encoding them are physically clustered in the murine and human genome. By exploiting specific microRNA mimics, we demonstrated that experimental upregulation of miR-296-3p and miR-298-5p raised the propensity to apoptosis of transfected and cytokine-treated αTC1-6 cells with respect to αTC1-6 cells, treated with cytokines after transfection with scramble molecules. Both microRNAs control the expression of IGF1Rβ, its downstream targets phospho-IRS-1 and phospho-ERK, and TNFα. Our computational analysis suggests that MAFB (a transcription factor exclusively expressed in pancreatic α cells within adult rodent islets of Langerhans controls the expression of miR-296-3p and miR-298-5p. Conclusions Altogether, high-throughput microRNA profiling, functional analysis with synthetic mimics and molecular characterization of modulated pathways strongly suggest that specific

  5. Nitric oxide in the rat cerebellum after hypoxia/ischemia.

    Science.gov (United States)

    Rodrigo, José; Fernández, Ana Patricia; Alonso, David; Serrano, Julia; Fernández-Vizarra, Paula; Martínez-Murillo, Ricardo; Bentura, María Luisa; Martinez, Alfredo

    2004-01-01

    Nitric oxide is a regulatory biological substance and an important intracellular messenger that acts as a specific mediator of various neuropathological disorders. In mammals and invertebrates, nitric oxide is synthesized from L-arginine in the central and peripheral neural structures by the endothelial, neuronal and inducible enzymatic isoforms of nitric oxide synthase. Nitric oxide may affect the function of various neurotransmitter-specific systems, and is involved in neuromodulation, reproductive function, immune response, and regulation of the cerebral blood circulation. This makes nitric oxide the main candidate in brain responses to brain ischemia/hypoxia. The cerebellum has been reported to be the area of the brain that has the highest nitric oxide synthase activity and the highest concentration of glutamate and aspartate. By glutamate receptors and physiological action of nitric oxide, cyclic guanisine-5'-monophosphate may be rapidly increased. The cerebellum significantly differs with respect to ischemia and hypoxia, this response being directly related to the duration and intensity of the injury. The cerebellum could cover the eventual need for nitric oxide during the hypoxia, boosting the nitric oxide synthase activity, but overall ischemia would require de novo protein synthesis, activating the inducible nitric oxide synthase to cope with the new situation. The specific inhibitors of nitric oxide synthesis show neuroprotective effects.

  6. Downregulation of blood-brain barrier phenotype by proinflammatory cytokines involves NADPH oxidase-dependent ROS generation: consequences for interendothelial adherens and tight junctions.

    Directory of Open Access Journals (Sweden)

    Keith D Rochfort

    Full Text Available Blood-brain barrier (BBB dysfunction is an integral feature of neurological disorders and involves the action of multiple proinflammatory cytokines on the microvascular endothelial cells lining cerebral capillaries. There is still however, considerable ambiguity throughout the scientific literature regarding the mechanistic role(s of cytokines in this context, thereby warranting a comprehensive in vitro investigation into how different cytokines may cause dysregulation of adherens and tight junctions leading to BBB permeabilization.The present study employs human brain microvascular endothelial cells (HBMvECs to compare/contrast the effects of TNF-α and IL-6 on BBB characteristics ranging from the expression of interendothelial junction proteins (VE-cadherin, occludin and claudin-5 to endothelial monolayer permeability. The contribution of cytokine-induced NADPH oxidase activation to altered barrier phenotype was also investigated.In response to treatment with either TNF-α or IL-6 (0-100 ng/ml, 0-24 hrs, our studies consistently demonstrated significant dose- and time-dependent decreases in the expression of all interendothelial junction proteins examined, in parallel with dose- and time-dependent increases in ROS generation and HBMvEC permeability. Increased expression and co-association of gp91 and p47, pivotal NADPH oxidase subunits, was also observed in response to either cytokine. Finally, cytokine-dependent effects on junctional protein expression, ROS generation and endothelial permeability could all be attenuated to a comparable extent using a range of antioxidant strategies, which included ROS depleting agents (superoxide dismutase, catalase, N-acetylcysteine, apocynin and targeted NADPH oxidase blockade (gp91 and p47 siRNA, NSC23766.A timely and wide-ranging investigation comparing the permeabilizing actions of TNF-α and IL-6 in HBMvECs is presented, in which we demonstrate how either cytokine can similarly downregulate the

  7. Proinflammatory Cytokine Responses in Extra-Respiratory Tissues During Severe Influenza

    NARCIS (Netherlands)

    Short, Kirsty R; Veeris, Rebecca; Leijten, Lonneke M; van den Brand, Judith M; Jong, Victor L; Stittelaar, Koert J; Osterhaus, Ab D M E|info:eu-repo/dai/nl/074960172; Andeweg, Arno C; van Riel, Debby

    2017-01-01

    Severe influenza is often associated with disease manifestations outside the respiratory tract. While proinflammatory cytokines can be detected in the lungs and blood of infected patients, the role of extra-respiratory organs in the production of proinflammatory cytokines is unknown. Here, we show

  8. Proinflammatory Cytokine Responses in Extra-Respiratory Tissues during Severe Influenza

    NARCIS (Netherlands)

    Short, Kirsty R.; Veeris, Rebecca; Leijten, Lonneke M.; van den Brand, Judith M A; Jong, Victor L.; Stittelaar, Koert; Osterhaus, Ab D.M.E.; Andeweg, Arno C; Van Riel, Debby

    2017-01-01

    Severe influenza is often associated with disease manifestations outside the respiratory tract. While proinflammatory cytokines can be detected in the lungs and blood of infected patients, the role of extra-respiratory organs in the production of proinflammatory cytokines is unknown. Here, we show

  9. Therapeutic strategies to address neuronal nitric oxide synthase deficiency and the loss of nitric oxide bioavailability in Duchenne Muscular Dystrophy.

    Science.gov (United States)

    Timpani, Cara A; Hayes, Alan; Rybalka, Emma

    2017-05-25

    Duchenne Muscular Dystrophy is a rare and fatal neuromuscular disease in which the absence of dystrophin from the muscle membrane induces a secondary loss of neuronal nitric oxide synthase and the muscles capacity for endogenous nitric oxide synthesis. Since nitric oxide is a potent regulator of skeletal muscle metabolism, mass, function and regeneration, the loss of nitric oxide bioavailability is likely a key contributor to the chronic pathological wasting evident in Duchenne Muscular Dystrophy. As such, various therapeutic interventions to re-establish either the neuronal nitric oxide synthase protein deficit or the consequential loss of nitric oxide synthesis and bioavailability have been investigated in both animal models of Duchenne Muscular Dystrophy and in human clinical trials. Notably, the efficacy of these interventions are varied and not always translatable from animal model to human patients, highlighting a complex interplay of factors which determine the downstream modulatory effects of nitric oxide. We review these studies herein.

  10. A plasma needle generates nitric oxide

    International Nuclear Information System (INIS)

    Stoffels, E; Gonzalvo, Y Aranda; Whitmore, T D; Seymour, D L; Rees, J A

    2006-01-01

    Generation of nitric oxide (NO) by a plasma needle is studied by means of mass spectrometry. The plasma needle is an atmospheric glow generated by a radio-frequency excitation in a mixture of helium and air. This source is used for the treatment of living tissues, and nitric oxide may be one of the most important active agents in plasma therapy. Efficient NO generation is of particular importance in the treatment of cardiovascular diseases. Mass spectrometric measurements have been performed under various plasma conditions; gas composition in the plasma and conversion of feed gases (nitrogen and oxygen) into other species has been studied. Up to 30% of the N 2 and O 2 input is consumed in the discharge, and NO has been identified as the main conversion product

  11. Interactions between cytokines and nitric oxide.

    Science.gov (United States)

    Liew, F Y

    1995-01-01

    There is now an impressive range of evidence supporting the important role of cytokines in sleep regulation (see Krueger et al., 1995; De Simoni et al., 1995). It has also been reported that inhibition of nitric oxide (NO) synthesis suppresses sleep in rabbits (Kapás et al., 1994). This is not surprising, since NO is closely involved in neurotransmission (Garthwaite, 1991; Schuman and Madison, 1994) and cytokines are the major inducers of NO synthesis (Hibbs et al., 1990). Further, it is now clear that NO plays an important role in modulating immune responses, possibly through the differential regulation of cytokine synthesis (Taylor-Robinson et al., 1994). In this article, I will provide evidence for the interactions between cytokines and nitric oxide, and discuss their implications in the regulation of immune responses. I shall illustrate these mainly with results from my coworkers and I, from our laboratory rather than attempting an exhaustive review of the subject.

  12. Alternative to Nitric Acid Passivation Project Overview

    Science.gov (United States)

    Lewis, Pattie L.

    2013-01-01

    The standard practice for protection of stainless steel is a process called passivation. This procedure results in the formation of a metal oxide layer to prevent corrosion. Typical passivation procedures call for the use of nitric acid which exhibits excellent corrosion performance; however, there are a number of environmental, worker safety, and operational issues associated with its use. The longtime military specification for the passivation of stainless steel was cancelled in favor of newer specifications which allow for the use of citric acid in place of nitric acid. Citric acid offers a variety of benefits that include increased safety for personnel, reduced environmental impact, and reduced operational costs. There have been few studies, however, to determine whether citric acid is an acceptable alternative for NASA and DoD. This paper details activities to date including development of the joint test plan, on-going and planned testing, and preliminary results.

  13. On hydrazine oxidation in nitric acid media

    International Nuclear Information System (INIS)

    Zil'berman, B.Ya.; Lelyuk, G.A.; Mashkin, A.N.; Yasnovitskaya, A.L.

    1988-01-01

    Yield of products of radiolytic ( 60 Co gamma radiation) and chemical hydrazine (HZ) oxidation in nitric acid media is studied. Under radiolyte HZ oxidation by nitric acid hydrazoic acid, ammonia and nitrogen appear to be the reaction products. HN 3 yield maximum under HZN oxidation makes up ∼ 0.35 mol per a mol of oxiduzed HZN. Under chemical oxidation HZN is oxidized by HNO 3 according to reaction catalysed by technetium HN 3 yield makes up ∼ 0.35 mol per a mol of oxidized HZN. Radiation-chemical oxidation of HN 3 proceeds up to its complete decomposition, decomposition rate is comparable with HZ oxidation rate. Under the chemical oxidation HN 3 is more stable, it is slowly decomposed after complete HZ decomposition

  14. Removal of fluoride from aqueous nitric acid

    International Nuclear Information System (INIS)

    Pruett, D.J.; Howerton, W.B.; Mailen, J.C.

    1981-06-01

    Several methods for removing fluoride from aqueous nitric acid were investigated and compared with the frequently used aluminum nitrate-calcium nitrate (Ca 2+ -Al 3+ ) chemical trap-distillation system. Zirconium oxynitrate solutions were found to be superior in preventing volatilization of fluoride during distillation of the nitric acid, producing decontamination factors (DFs) on the order of 2 x 10 3 (vs approx. 500 for the Ca 2+ -Al 3+ system). Several other metal nitrate systems were tested, but they were less effective. Alumina and zirconia columns proved highly effective in removing HF from HF-HNO 3 vapors distilled through the columns; fluoride DFs on the order of 10 6 and 10 4 , respectively, were obtained. A silica gel column was very effective in adsorbing HF from HF-HNO 3 solutions, producing a fluoride DF of approx. 10 4

  15. Radiation, nitric oxide and cellular death

    International Nuclear Information System (INIS)

    Dubner, D.; Perez, M.R. Del; Michelin, S.C.; Gisone, P.A.

    1997-01-01

    The mechanisms of radiation induced cellular death constitute an objective of research ever since the first biological effects of radiation were first observed. The explosion of information produced in the last 20 years calls for a careful analysis due to the apparent contradictory data related to the cellular system studied and the range of doses used. This review focuses on the role of the active oxygen species, in particular the nitric oxides, in its relevance as potential mediator of radiation induced cellular death

  16. Cannula sensor for nitric oxide detection

    Energy Technology Data Exchange (ETDEWEB)

    Glazier, S.A. [National Institute of Standard and Technology, Gaithersburg, MD (United States)

    1995-12-31

    Nitric oxide (NO) has received much attention because of its numerous roles in mammalian systems. It has been found in the brain and nervous system to act as a neurotransmitter, in blood vessels as a blood pressure regulator, in the immune system to act as a bactericide and tumorcide, and in other postulated roles as well. Nitric oxide is produced in mammalian cells by the enzyme nitric oxide synthetase. Once produced, NO is oxidized or reacts rapidly with components in living systems and hence has a short half-life. Only a few sensors have been constructed which can detect NO at nanomolar to micromolar levels found in these systems. We are currently examining the use of a cannula sensor employing oxyhemoglobin for NO detection. This sensor continuously draws in liquid sample at a low rate and immediately reacts it with oxyhemoglobin. The absorbance changes which accompany the reaction are monitored. The sensor has a linear response range from approximately 50 to 1000 nM of NO in aqueous solution. Its utility in monitoring NO produced by stimulated murine macrophage cells (RAW 264.7) in culture is currently being examined. The sensor design is generic in that it can also employ fluorescence and chemiluminescence detection chemistries which may allow lower detection limits to be achieved. Details of the sensor`s performance will be given.

  17. Improved Metabolic Control in Diabetes, HSP60, and Proinflammatory Mediators

    Directory of Open Access Journals (Sweden)

    Claudio Blasi

    2012-01-01

    Full Text Available The diabetes-atherosclerosis relationship remains to be fully defined. Repeated prolonged hyperglycemia, increased ROS production and endothelial dysfunction are important factors. One theory is that increased blood levels of heat shock protein (HSP60 are proinflammatory, through activation of innate immunity, and contribute to the progression of vascular disease. It was hypothesized that improvement of diabetes control in patients presenting with metabolic syndrome would lower HSP60, and anti-HSP60 antibody levels and decrease inflammatory markers. Paired sera of 17 Italian patients, before and after intensive treatment, were assayed for cytokines, HSP60 and anti-HSP60 antibodies. As expected, intensive treatment was associated with a decrease in HgbA1C (P<0.001 and BMI (P<0.001. After treatment, there was a significant decrease in IL-6 (P<0.05. HSP60 levels were before treatment −6.9+1.9, after treatment −7.1+2.0 ng/mL (P=ns. Overall HSP60 concentrations were lower than published reports. Anti-HSP60 antibody titers were high and did not decrease with treatment. In conclusion, improvement of diabetic control did not alter HSP60 concentrations or antiHSP60 antibody titers, but led to a reduction of IL-6 levels.

  18. The Staphyloccous aureus Eap protein activates expression of proinflammatory cytokines.

    Science.gov (United States)

    Scriba, Thomas J; Sierro, Sophie; Brown, Eric L; Phillips, Rodney E; Sewell, Andrew K; Massey, Ruth C

    2008-05-01

    The extracellular adhesion protein (Eap) secreted by the major human pathogen Staphylococcus aureus is known to have several effects on human immunity. We have recently added to knowledge of these roles by demonstrating that Eap enhances interactions between major histocompatibility complex molecules and human leukocytes. Several studies have indicated that Eap can induce cytokine production by human peripheral blood mononuclear cells (PBMCs). To date, there has been no rigorous attempt to identify the breadth of cytokines produced by Eap stimulation or to identify the cell subsets that respond. Here, we demonstrate that Eap induces the secretion of the proinflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) by CD14(+) leukocytes (monocytes and macrophages) within direct ex vivo PBMC populations (note that granulocytes are also CD14(+) but are largely depleted from PBMC preparations). Anti-intercellular adhesion molecule 1 (CD54) antibodies inhibited this induction and implicated a role for this known Eap binding protein in cellular activation. IL-6 and TNF-alpha secretion by murine cells exposed to Eap was also observed. The activation of CD14(+) cells by Eap suggests that it could play a significant role in both septic shock and fever, two of the major pathological features of S. aureus infections.

  19. Riboflavin Reduces Pro-Inflammatory Activation of Adipocyte-Macrophage Co-culture. Potential Application of Vitamin B2 Enrichment for Attenuation of Insulin Resistance and Metabolic Syndrome Development.

    Science.gov (United States)

    Mazur-Bialy, Agnieszka Irena; Pocheć, Ewa

    2016-12-15

    Due to the progressive increase in the incidence of obese and overweight individuals, cardiometabolic syndrome has become a worldwide pandemic in recent years. Given the immunomodulatory properties of riboflavin, the current study was performed to investigate the potency of riboflavin in reducing obesity-related inflammation, which is the main cause of insulin resistance, diabetes mellitus 2 or arteriosclerosis. We determined whether pretreatment with a low dose of riboflavin (10.4-1000 nM) affected the pro-inflammatory activity of adipocyte-macrophage co-culture (3T3 L1-RAW 264.7) following lipopolysaccharide stimulation (LPS; 100 ng/mL) which mimics obesity-related inflammation. The apoptosis of adipocytes and macrophages as well as tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), interleukin 1beta (IL-1β), monocyte chemotactic protein 1 (MCP-1), high-mobility group box 1 (HMGB1), transforming growth factor-beta 1 (TGFβ), interleukin 10 (IL-10), inducible nitric oxide synthase (iNOS), nitric oxide (NO), matrix metalloproteinase 9 (MMP-9), tissue inhibitor of metalloproteinases-1 (TIMP-1) expression and release, macrophage migration and adipokines (adiponectin and leptin) were determined. Our results indicated an efficient reduction in pro-inflammatory factors (TNFα, IL-6, MCP-1, HMGB1) upon culture with riboflavin supplementation (500-1000 nM), accompanied by elevation in anti-inflammatory adiponectin and IL-10. Moreover, macrophage migration was reduced by the attenuation of chemotactic MCP-1 release and degradation of the extracellular matrix by MMP-9. In conclusion, riboflavin effectively inhibits the pro-inflammatory activity of adipocyte and macrophage co-cultures, and therefore we can assume that its supplementation may reduce the likelihood of conditions associated with the mild inflammation linked to obesity.

  20. Riboflavin Reduces Pro-Inflammatory Activation of Adipocyte-Macrophage Co-culture. Potential Application of Vitamin B2 Enrichment for Attenuation of Insulin Resistance and Metabolic Syndrome Development

    Directory of Open Access Journals (Sweden)

    Agnieszka Irena Mazur-Bialy

    2016-12-01

    Full Text Available Due to the progressive increase in the incidence of obese and overweight individuals, cardiometabolic syndrome has become a worldwide pandemic in recent years. Given the immunomodulatory properties of riboflavin, the current study was performed to investigate the potency of riboflavin in reducing obesity-related inflammation, which is the main cause of insulin resistance, diabetes mellitus 2 or arteriosclerosis. We determined whether pretreatment with a low dose of riboflavin (10.4–1000 nM affected the pro-inflammatory activity of adipocyte-macrophage co-culture (3T3 L1-RAW 264.7 following lipopolysaccharide stimulation (LPS; 100 ng/mL which mimics obesity-related inflammation. The apoptosis of adipocytes and macrophages as well as tumor necrosis factor-alpha (TNF-α, interleukin 6 (IL-6, interleukin 1beta (IL-1β, monocyte chemotactic protein 1 (MCP-1, high-mobility group box 1 (HMGB1, transforming growth factor–beta 1 (TGFβ, interleukin 10 (IL-10, inducible nitric oxide synthase (iNOS, nitric oxide (NO, matrix metalloproteinase 9 (MMP-9, tissue inhibitor of metalloproteinases-1 (TIMP-1 expression and release, macrophage migration and adipokines (adiponectin and leptin were determined. Our results indicated an efficient reduction in pro-inflammatory factors (TNFα, IL-6, MCP-1, HMGB1 upon culture with riboflavin supplementation (500–1000 nM, accompanied by elevation in anti-inflammatory adiponectin and IL-10. Moreover, macrophage migration was reduced by the attenuation of chemotactic MCP-1 release and degradation of the extracellular matrix by MMP-9. In conclusion, riboflavin effectively inhibits the pro-inflammatory activity of adipocyte and macrophage co-cultures, and therefore we can assume that its supplementation may reduce the likelihood of conditions associated with the mild inflammation linked to obesity.

  1. Neuroprotective properties of nitric oxide and S-nitrosoglutathione

    International Nuclear Information System (INIS)

    Rauhala, Pekka; Andoh, Tsugunobu; Chiueh, C.C.

    2005-01-01

    Oxidative stress and apoptosis may play an important role in the neurodegeneration. The present paper outlines antioxidative and antiapototic mechanisms of nitric oxide and S-nitrosothiols, which could mediate neuroprotection. Nitric oxide generated by nitric oxide synthase or released from an endogenous S-nitrosothiol, S-nitrosoglutathione may up-regulate antioxidative thioredoxin system and antiapototic Bcl-2 protein through a cGMP-dependent mechanism. Moreover, nitric oxide radicals have been shown to have direct antioxidant effect through their reaction with free radicals and iron-oxygen complexes. In addition to serving as a stabilizer and carrier of nitric oxide, S-nitrosoglutathione may have protective effect through transnitrosylation reactions. Based on these new findings, a hypothesis arises that the homeostasis of nitric oxide, S-nitrosothiols, glutathione, and thioredoxin systems is important for protection against oxidative stress, apoptosis, and related neurodegenerative disorders

  2. Nitric oxide synthase gene G298 allele

    International Nuclear Information System (INIS)

    Nagib El-Kilany, Galal E.; Nayel, Ehab; Hazzaa, Sahar

    2004-01-01

    Background: Nitric oxide (NO) has an important effect on blood pressure, arterial wall, and the basal release of endothelial NO in hypertension (HPN) may be reduced. Until now, there is no solid data revealing the potential role of the polymorphism of the nitric oxide synthase gene (NOS) in patients with HPN and microvascular angina. Aim: The aim of the present study is to investigate the gene of endothelial nitric oxide synthase (eNOS), as the polymorphism of this gene may be a putative candidate for HPN and initiate the process of atherosclerosis. Methods: Sixty participants were recruited for this study; 50 were hypertensive patients complaining of chest pain [30 of them have electrocardiogram (EKG) changes of ischemia], 20 had isolated HPN, and 10 healthy volunteers served as control. All patients underwent stress myocardial perfusion imaging (MPI) and coronary angiography. Genotyping of eNOS for all patients and controls was performed. The linkages between HPN, microvascular angina and eNOS gene polymorphism were investigated. Results: MPI and coronary angiography revealed that 15 patients had chest pain with true ischemia and reversible myocardial perfusion defects (multiple and mild) but normal epicardial coronary arteries (microvascular angina), while 15 patients had significant coronary artery disease (CAD), and 20 hypertensive patients showed normal perfusion scan and coronary angiography. The prevalence of the NOS G 298 allele was higher in the hypertensive group with microvascular angina (documented by MPI) than it was among the control participants (P<.005). The eNOS allele was significantly higher in the hypertensive group than in the control participants, but there was no significant difference in homozygote mutants among hypertensive participants, x-syndrome and patients with CAD. Conclusion: eNOS gene polymorphism is proved to be an important etiology in microvascular angina (x-syndrome) among hypertensive patients. In addition, the eNOS mutant

  3. HIV-1 Myristoylated Nef Treatment of Murine Microglial Cells Activates Inducible Nitric Oxide Synthase, NO2 Production and Neurotoxic Activity.

    Directory of Open Access Journals (Sweden)

    Giorgio Mangino

    Full Text Available The potential role of the human immunodeficiency virus-1 (HIV-1 accessory protein Nef in the pathogenesis of neuroAIDS is still poorly understood. Nef is a molecular adapter that influences several cellular signal transduction events and membrane trafficking. In human macrophages, Nef expression induces the production of extracellular factors (e.g. pro-inflammatory chemokines and cytokines and the recruitment of T cells, thus favoring their infection and its own transfer to uninfected cells via exosomes, cellular protrusions or cell-to-cell contacts. Murine cells are normally not permissive for HIV-1 but, in transgenic mice, Nef is a major disease determinant. Both in human and murine macrophages, myristoylated Nef (myr+Nef treatment has been shown to activate NF-κB, MAP kinases and interferon responsive factor 3 (IRF-3, thereby inducing tyrosine phosphorylation of signal transducers and activator of transcription (STAT-1, STAT-2 and STAT-3 through the production of proinflammatory factors.We report that treatment of BV-2 murine microglial cells with myr+Nef leads to STAT-1, -2 and -3 tyrosine phosphorylation and upregulates the expression of inducible nitric oxide synthase (iNOS with production of nitric oxide. We provide evidence that extracellular Nef regulates iNOS expression through NF-κB activation and, at least in part, interferon-β (IFNβ release that acts in concert with Nef. All of these effects require both myristoylation and a highly conserved acidic cluster in the viral protein. Finally, we report that Nef induces the release of neurotoxic factors in the supernatants of microglial cells.These results suggest a potential role of extracellular Nef in promoting neuronal injury in the murine model. They also indicate a possible interplay between Nef and host factors in the pathogenesis of neuroAIDS through the production of reactive nitrogen species in microglial cells.

  4. Circulating nitric oxide products do not solely reflect nitric oxide release in cirrhosis and portal hypertension

    DEFF Research Database (Denmark)

    Afzelius, Pia; Bazeghi, Nassim; Bie, Peter

    2011-01-01

    Patients with cirrhosis often develop a systemic vasodilatation and a hyperdynamic circulation with activation of vasoconstrictor systems such as the renin-angiotensin-aldosterone system (RAAS), and vasopressin. Increased nitric oxide (NO) synthesis has been implicated in the development of this ...

  5. Nitric oxide synthase inhibition and cerebrovascular regulation

    DEFF Research Database (Denmark)

    Iadecola, C; Pelligrino, D A; Moskowitz, M A

    1994-01-01

    tone and may play an important role in selected vasodilator responses of the cerebral circulation. Furthermore, evidence has been presented suggesting that NO participates in the mechanisms of cerebral ischemic damage. Despite the widespread attention that NO has captured in recent years and the large......There is increasing evidence that nitric oxide (NO) is an important molecular messenger involved in a wide variety of biological processes. Recent data suggest that NO is also involved in the regulation of the cerebral circulation. Thus, NO participants in the maintenance of resting cerebrovascular...

  6. Nitric oxide turnover in permeable river sediment

    DEFF Research Database (Denmark)

    Schreiber, Frank; Stief, Peter; Kuypers, Marcel M M

    2014-01-01

    We measured nitric oxide (NO) microprofiles in relation to oxygen (O2) and all major dissolved N-species (ammonium, nitrate, nitrite, and nitrous oxide [N2O]) in a permeable, freshwater sediment (River Weser, Germany). NO reaches peak concentrations of 0.13 μmol L-1 in the oxic zone and is consumed......-nitroso-N-acetylpenicillamine (SNAP) (1) confirmed denitrification as the main NO consumption pathway, with N2O as its major product, (2) showed that denitrification combines one free NO molecule with one NO molecule formed from nitrite to produce N2O, and (3) suggested that NO inhibits N2O reduction....

  7. Processes regulating nitric oxide emissions from soils

    DEFF Research Database (Denmark)

    Pilegaard, Kim

    2013-01-01

    , the net result is complex and dependent on several factors such as nitrogen availability, organic matter content, oxygen status, soil moisture, pH and temperature. This paper reviews recent knowledge on processes forming NO in soils and the factors controlling its emission to the atmosphere. Schemes......Nitric oxide (NO) is a reactive gas that plays an important role in atmospheric chemistry by influencing the production and destruction of ozone and thereby the oxidizing capacity of the atmosphere. NO also contributes by its oxidation products to the formation of acid rain. The major sources...

  8. A Comparison of the Effects of Neuronal Nitric Oxide Synthase and Inducible Nitric Oxide Synthase Inhibition on Cartilage Damage

    Directory of Open Access Journals (Sweden)

    Nevzat Selim Gokay

    2016-01-01

    Full Text Available The objective of this study was to investigate the effects of selective inducible nitric oxide synthase and neuronal nitric oxide synthase inhibitors on cartilage regeneration. The study involved 27 Wistar rats that were divided into five groups. On Day 1, both knees of 3 rats were resected and placed in a formalin solution as a control group. The remaining 24 rats were separated into 4 groups, and their right knees were surgically damaged. Depending on the groups, the rats were injected with intra-articular normal saline solution, neuronal nitric oxide synthase inhibitor 7-nitroindazole (50 mg/kg, inducible nitric oxide synthase inhibitor amino-guanidine (30 mg/kg, or nitric oxide precursor L-arginine (200 mg/kg. After 21 days, the right and left knees of the rats were resected and placed in formalin solution. The samples were histopathologically examined by a blinded evaluator and scored on 8 parameters. Although selective neuronal nitric oxide synthase inhibition exhibited significant (P=0.044 positive effects on cartilage regeneration following cartilage damage, it was determined that inducible nitric oxide synthase inhibition had no statistically significant effect on cartilage regeneration. It was observed that the nitric oxide synthase activation triggered advanced arthrosis symptoms, such as osteophyte formation. The fact that selective neuronal nitric oxide synthase inhibitors were observed to have mitigating effects on the severity of the damage may, in the future, influence the development of new agents to be used in the treatment of cartilage disorders.

  9. Iodinated contrast media alter immune responses in pro-inflammatory states.

    LENUS (Irish Health Repository)

    O'Donnell, David H

    2010-07-01

    Hypertonic saline causes a transient elevation of blood osmolality and has been shown to alter cellular inflammatory responses in pro-inflammatory states. Intravascular administration of iodine contrast media also causes a transient elevation of blood osmolarity.

  10. Pro-inflammatory cytokine single nucleotide polymorphisms in Kawasaki disease.

    Science.gov (United States)

    Assari, Raheleh; Aghighi, Yahya; Ziaee, Vahid; Sadr, Maryam; Rahmani, Farzaneh; Rezaei, Arezou; Sadr, Zeinab; Moradinejad, Mohammad Hassan; Raeeskarami, Seyed Reza; Rezaei, Nima

    2016-07-25

    Kawasaki disease (KD) is a systemic vasculitis of children associated with cardiovascular sequelae. Proinflammatory cytokines play a major role in KD pathogenesis. However, their role is both influenced and modified by regulatory T-cells. IL-1 gene cluster, IL-6 and TNF-α polymorphisms have shown significant associations with some vasculitides. Herein we investigated their role in KD. Fifty-five patients with KD who were randomly selected from referrals to the main pediatric hospital were enrolled in this case-control study. Single nucleotide polymorphisms (SNPs) of the following genes were assessed in patients and 140 healthy subjects as control group: IL-1α at -889 (rs1800587), IL-1β at -511 (rs16944), IL-1β at +3962 (rs1143634), IL-1R at Pst-I 1970 (rs2234650), IL-1RN/A at Mspa-I 11100 (rs315952), TNF-α at -308 (rs1800629), TNF-α at -238, IL-6 at -174 (rs1800795) and IL-6 at +565. Twenty-one percent of the control group had A allele at TNF-α -238 while only 8% of KD patients had A allele at this position (P = 0.003, OR [95%CI] = 0.32 [0.14-0.71]). Consistently, TNF-α genotype GG at -238 had significant association with KD (OR [95% CI] = 4.31 [1.79-10.73]). Most controls carried the CG genotype at IL-6 -174 (n = 93 [66.9%]) while GG genotype was the most common genotype (n = 27 [49%]) among patients. Carriers of the GG haplotype at TNF-α (-308, -238) were significantly more prevalent among the KD group. No association was found between IL-1 gene cluster, allelic or haplotypic variants and KD. TNF-α GG genotype at -238 and GG haplotype at positions -308 and -238 were associated with KD in an Iranian population. © 2016 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.

  11. EFFECTS OF NITRIC ACID ON CRITICALITY SAFETY ANALYSIS

    Energy Technology Data Exchange (ETDEWEB)

    Williamson, B.

    2011-08-18

    As nitric acid molarity is increased, there are two competing phenomena affecting the reactivity of the system. First, there is interaction between each of the 10 wells in the basket-like insert. As the molarity of the nitric acid solution is increased (it moves from 100% water to 100% HNO{sub 3}), the hydrogen atom density decreases by about 80%. However, it remains a relatively efficient moderator. The moderating ratio of nitric acid is about 90% that of water. As the media between the wells is changed from 100% water to 100% nitric acid, the density of the media increases by 50%. A higher density typically leads to a better reflector. However, when the macroscopic scattering cross sections are considered, nitric acid is a much worse reflector than water. The effectiveness of nitric acid as a reflector is about 40% that of water. Since the media between the wells become a worse reflector and still remains an effective moderator, interaction between the wells increases. This phenomenon will cause reactivity to increase as nitric acid molarity increases. The seond phenomenon is due to the moderating ratio changing in the high concentration fissile-nitric acid solution in the 10 wells. Since the wells contain relatively small volumes of high concentration solutions, a small decrease in moderating power has a large effect on reactivity. This is due to the fact that neutrons are more likely to escape the high concentration fissile solution before causing another fission event. The result of this phenomenon is that as nitric acid molarity increases, reactivity decreases. Recent studies have shown that the second phenomenon is indeed the dominating force in determining reactivity changes in relation to nitric acid molarity changes. When considering the system as a whole, as nitric acid molarity increases, reactivity decreases.

  12. Nitric oxide synthase modulates CFA-induced thermal hyperalgesia through cytokine regulation in mice.

    Science.gov (United States)

    Chen, Yong; Boettger, Michael K; Reif, Andreas; Schmitt, Angelika; Uçeyler, Nurcan; Sommer, Claudia

    2010-03-02

    Although it has been largely demonstrated that nitric oxide synthase (NOS), a key enzyme for nitric oxide (NO) production, modulates inflammatory pain, the molecular mechanisms underlying these effects remain to be clarified. Here we asked whether cytokines, which have well-described roles in inflammatory pain, are downstream targets of NO in inflammatory pain and which of the isoforms of NOS are involved in this process. Intraperitoneal (i.p.) pretreatment with 7-nitroindazole sodium salt (7-NINA, a selective neuronal NOS inhibitor), aminoguanidine hydrochloride (AG, a selective inducible NOS inhibitor), L-N(G)-nitroarginine methyl ester (L-NAME, a non-selective NOS inhibitor), but not L-N(5)-(1-iminoethyl)-ornithine (L-NIO, a selective endothelial NOS inhibitor), significantly attenuated thermal hyperalgesia induced by intraplantar (i.pl.) injection of complete Freund's adjuvant (CFA). Real-time reverse transcription-polymerase chain reaction (RT-PCR) revealed a significant increase of nNOS, iNOS, and eNOS gene expression, as well as tumor necrosis factor-alpha (TNF), interleukin-1 beta (IL-1beta), and interleukin-10 (IL-10) gene expression in plantar skin, following CFA. Pretreatment with the NOS inhibitors prevented the CFA-induced increase of the pro-inflammatory cytokines TNF and IL-1beta. The increase of the anti-inflammatory cytokine IL-10 was augmented in mice pretreated with 7-NINA or L-NAME, but reduced in mice receiving AG or L-NIO. NNOS-, iNOS- or eNOS-knockout (KO) mice had lower gene expression of TNF, IL-1beta, and IL-10 following CFA, overall corroborating the inhibitor data. These findings lead us to propose that inhibition of NOS modulates inflammatory thermal hyperalgesia by regulating cytokine expression.

  13. Nitric oxide synthase modulates CFA-induced thermal hyperalgesia through cytokine regulation in mice

    Directory of Open Access Journals (Sweden)

    Üçeyler Nurcan

    2010-03-01

    Full Text Available Abstract Background Although it has been largely demonstrated that nitric oxide synthase (NOS, a key enzyme for nitric oxide (NO production, modulates inflammatory pain, the molecular mechanisms underlying these effects remain to be clarified. Here we asked whether cytokines, which have well-described roles in inflammatory pain, are downstream targets of NO in inflammatory pain and which of the isoforms of NOS are involved in this process. Results Intraperitoneal (i.p. pretreatment with 7-nitroindazole sodium salt (7-NINA, a selective neuronal NOS inhibitor, aminoguanidine hydrochloride (AG, a selective inducible NOS inhibitor, L-N(G-nitroarginine methyl ester (L-NAME, a non-selective NOS inhibitor, but not L-N(5-(1-iminoethyl-ornithine (L-NIO, a selective endothelial NOS inhibitor, significantly attenuated thermal hyperalgesia induced by intraplantar (i.pl. injection of complete Freund's adjuvant (CFA. Real-time reverse transcription-polymerase chain reaction (RT-PCR revealed a significant increase of nNOS, iNOS, and eNOS gene expression, as well as tumor necrosis factor-alpha (TNF, interleukin-1 beta (IL-1β, and interleukin-10 (IL-10 gene expression in plantar skin, following CFA. Pretreatment with the NOS inhibitors prevented the CFA-induced increase of the pro-inflammatory cytokines TNF and IL-1β. The increase of the anti-inflammatory cytokine IL-10 was augmented in mice pretreated with 7-NINA or L-NAME, but reduced in mice receiving AG or L-NIO. NNOS-, iNOS- or eNOS-knockout (KO mice had lower gene expression of TNF, IL-1β, and IL-10 following CFA, overall corroborating the inhibitor data. Conclusion These findings lead us to propose that inhibition of NOS modulates inflammatory thermal hyperalgesia by regulating cytokine expression.

  14. Fisetin Inhibits Hyperglycemia-Induced Proinflammatory Cytokine Production by Epigenetic Mechanisms

    OpenAIRE

    Hye Joo Kim; Seong Hwan Kim; Jung-Mi Yun

    2012-01-01

    Diabetes is characterized by a proinflammatory state, and several inflammatory processes have been associated with both type 1 and type 2 diabetes and the resulting complications. High glucose levels induce the release of proinflammatory cytokines. Fisetin, a flavonoid dietary ingredient found in the smoke tree (Cotinus coggygria), and is also widely distributed in fruits and vegetables. Fisetin is known to exert anti-inflammatory effects via inhibition of the NF-?B signaling pathway. In this...

  15. Proinflammatory cytokine levels in fibromyalgia patients are independent of body mass index

    OpenAIRE

    Hernandez, Maria E; Becerril, Enrique; Perez, Mayra; Leff, Philippe; Anton, Benito; Estrada, Sergio; Estrada, Iris; Sarasa, Manuel; Serrano, Enrique; Pavon, Lenin

    2010-01-01

    Abstract Background Fibromyalgia (FM) is characterized by chronic, widespread muscular pain and tenderness and is generally associated with other somatic and psychological symptoms. Further, circulatory levels of proinflammatory cytokines (IL-1β, TNF-α, and IL-6) may be altered in FM patients, possibly in association with their symptoms. Recently, rises in BMI have been suggested to contribute to increased circulating levels of proinflammatory cytokines in FM patients. Our aim was to measure ...

  16. Nitric oxide in the stress axis.

    Science.gov (United States)

    López-Figueroa, M O; Day, H E; Akil, H; Watson, S J

    1998-10-01

    In recent years nitric oxide (NO) has emerged as a unique biological messenger. NO is a highly diffusible gas, synthesized from L-arginine by the enzyme nitric oxide synthase (NOS). Three unique subtypes of NOS have been described, each with a specific distribution profile in the brain and periphery. NOS subtype I is present, among other areas, in the hippocampus, hypothalamus, pituitary and adrenal gland. Together these structures form the limbic-hypothalamic-pituitary-adrenal (LHPA) or stress axis, activation of which is one of the defining features of a stress response. Evidence suggests that NO may modulate the release of the stress hormones ACTH and corticosterone, and NOS activity and transcription is increased in the LHPA axis following various stressful stimuli. Furthermore, following activation of the stress axis, glucocorticoids are thought to down-regulate the transcription and activity of NOS via a feedback mechanism. Taken together, current data indicate a role for NO in the regulation of the LHPA axis, although at present this role is not well defined. It has been suggested that NO may act as a cellular communicator in plasticity and development, to facilitate the activation or the release of other neurotransmitters, to mediate immune responses, and/or as a vasodilator in the regulation of blood flow. In the following review we summarize some of the latest insights into the function of NO, with special attention to its relationship with the LHPA axis.

  17. Vascular nitric oxide: Beyond eNOS

    Directory of Open Access Journals (Sweden)

    Yingzi Zhao

    2015-10-01

    Full Text Available As the first discovered gaseous signaling molecule, nitric oxide (NO affects a number of cellular processes, including those involving vascular cells. This brief review summarizes the contribution of NO to the regulation of vascular tone and its sources in the blood vessel wall. NO regulates the degree of contraction of vascular smooth muscle cells mainly by stimulating soluble guanylyl cyclase (sGC to produce cyclic guanosine monophosphate (cGMP, although cGMP-independent signaling [S-nitrosylation of target proteins, activation of sarco/endoplasmic reticulum calcium ATPase (SERCA or production of cyclic inosine monophosphate (cIMP] also can be involved. In the blood vessel wall, NO is produced mainly from l-arginine by the enzyme endothelial nitric oxide synthase (eNOS but it can also be released non-enzymatically from S-nitrosothiols or from nitrate/nitrite. Dysfunction in the production and/or the bioavailability of NO characterizes endothelial dysfunction, which is associated with cardiovascular diseases such as hypertension and atherosclerosis.

  18. Catalytic abatement of nitrous oxide from nitric and production

    NARCIS (Netherlands)

    Oonk, J.

    1998-01-01

    Nitric acid production is identified as a main source of nitrous oxide. Options for emission reduction however are not available. TNO and Hydro Agri studied the technological and economic feasibility of catalytic decomposition of nitrous oxide in nitric acid tail-gases. Although in literature

  19. Influence of nitric oxide on histamine and carbachol – induced ...

    African Journals Online (AJOL)

    The study aimed to determine the influence of nitric oxide (NO) on the action of histamine and carbachol on acid secretion in the common African toad – Bufo regularis. Gastric acidity was determined by titration method. The acid secretion was determined when nitric oxide was absent following administration of NO synthase ...

  20. The correlation between total antioxidant capacity and nitric oxide ...

    African Journals Online (AJOL)

    DNA damage was measured by comet assay and nitric oxide concentration was evaluated by Griess assay. TAC was measured in seminal plasma based on the generation of peroxyl radicals from 2,2-azinobis (2-amidino propane) dihydrochlorid (AAPH). Our results show that the means of DNA damage and nitric oxide ...

  1. Defective bone formation and anabolic response to exogenous estrogen in mice with targeted disruption of endothelial nitric oxide synthase.

    Science.gov (United States)

    Armour, K E; Armour, K J; Gallagher, M E; Gödecke, A; Helfrich, M H; Reid, D M; Ralston, S H

    2001-02-01

    Nitric oxide (NO) is a pleiotropic signaling molecule that is produced by bone cells constitutively and in response to diverse stimuli such as proinflammatory cytokines, mechanical strain, and sex hormones. Endothelial nitric oxide synthase (eNOS) is the predominant NOS isoform expressed in bone, but its physiological role in regulating bone metabolism remains unclear. Here we studied various aspects of bone metabolism in female mice with targeted disruption of the eNOS gene. Mice with eNOS deficiency (eNOS KO) had reduced bone mineral density, and cortical thinning when compared with WT controls and histomorphometric analysis of bone revealed profound abnormalities of bone formation, with reduced osteoblast numbers, surfaces and mineral apposition rate. Studies in vitro showed that osteoblasts derived from eNOS KO mice had reduced rates of growth when compared with WT and were less well differentiated as reflected by lower levels of alkaline phosphatase activity. Mice with eNOS deficiency lost bone normally following ovariectomy but exhibited a significantly blunted anabolic response to high dose exogenous estrogen. We conclude that the eNOS pathway plays an essential role in regulating bone mass and bone turnover by modulating osteoblast function.

  2. Nitric Oxide Metabolites and Asymmetric Dimethylarginine Concentrations in Breast Milk

    Directory of Open Access Journals (Sweden)

    Hakan Öztürk

    2017-04-01

    Full Text Available Objective: Nitric oxide plays a preventive role in the development of necrotizing enterocolitis. Oral nitrite and nitrate intake has gained importance with the discovery of the conversion of nitrite to nitric oxide in acidic medium out of the synthesis of nitric oxide from L-arginine. Objective of this study was to examine the breast milk concentrations of nitric oxide and asymmetric dimethylarginine which is a competitive inhibitor of nitric oxide and to compare these concentrations in terms of gestational age and maturity of breast milk. Study Design: Forty-one women were included in the study. Milk samples were collected from 3 groups of mothers as term, late preterm and preterm on the postpartum days 3, 7 and 28. Results: When breast milk concentrations of nitric oxide were compared according to the postnatal day of the milk independently from gestational age; nitric oxide concentration was higher in the colostrum than in the transition milk and mature milk (p=0,035; p=0,001; respectively. For the comparison of asymmetric dimethylarginine concentrations among these groups and days; no statistically significant difference was observed in terms of gestational age and maturity of the milk (p=0.865, p=0.115; respectively. Conclusion: The highest nitric oxide concentration was found in the colostrum, suggesting that colostrum is a valuable food for newborns. Plasma concentrations of asymmetric dimethylarginine were negatively correlated with nitric oxide and did not show a correlation with breast milk, suggesting that asymmetric dimethylargininedoesn’t make nitric oxide inhibition in breast milk.

  3. Cancer Associated Fibroblasts express pro-inflammatory factors in human breast and ovarian tumors

    Energy Technology Data Exchange (ETDEWEB)

    Erez, Neta, E-mail: netaerez@post.tau.ac.il [Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel-Aviv 69978 (Israel); Glanz, Sarah [Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel-Aviv 69978 (Israel); Raz, Yael [Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel-Aviv 69978 (Israel); Department of Obstetrics and Gynecology, LIS Maternity Hospital, Tel Aviv Sourasky Medical Center, affiliated with Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv (Israel); Avivi, Camilla [Department of Pathology, Sheba Medical Center, Tel Hashomer, affiliated with Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv (Israel); Barshack, Iris [Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel-Aviv 69978 (Israel); Department of Pathology, Sheba Medical Center, Tel Hashomer, affiliated with Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv (Israel)

    2013-08-02

    Highlights: •CAFs in human breast and ovarian tumors express pro-inflammatory factors. •Expression of pro-inflammatory factors correlates with tumor invasiveness. •Expression of pro-inflammatory factors is associated with NF-κb activation in CAFs. -- Abstract: Inflammation has been established in recent years as a hallmark of cancer. Cancer Associated Fibroblasts (CAFs) support tumorigenesis by stimulating angiogenesis, cancer cell proliferation and invasion. We previously demonstrated that CAFs also mediate tumor-enhancing inflammation in a mouse model of skin carcinoma. Breast and ovarian carcinomas are amongst the leading causes of cancer-related mortality in women and cancer-related inflammation is linked with both these tumor types. However, the role of CAFs in mediating inflammation in these malignancies remains obscure. Here we show that CAFs in human breast and ovarian tumors express high levels of the pro-inflammatory factors IL-6, COX-2 and CXCL1, previously identified to be part of a CAF pro-inflammatory gene signature. Moreover, we show that both pro-inflammatory signaling by CAFs and leukocyte infiltration of tumors are enhanced in invasive ductal carcinoma as compared with ductal carcinoma in situ. The pro-inflammatory genes expressed by CAFs are known NF-κB targets and we show that NF-κB is up-regulated in breast and ovarian CAFs. Our data imply that CAFs mediate tumor-promoting inflammation in human breast and ovarian tumors and thus may be an attractive target for stromal-directed therapeutics.

  4. Cancer Associated Fibroblasts express pro-inflammatory factors in human breast and ovarian tumors

    International Nuclear Information System (INIS)

    Erez, Neta; Glanz, Sarah; Raz, Yael; Avivi, Camilla; Barshack, Iris

    2013-01-01

    Highlights: •CAFs in human breast and ovarian tumors express pro-inflammatory factors. •Expression of pro-inflammatory factors correlates with tumor invasiveness. •Expression of pro-inflammatory factors is associated with NF-κb activation in CAFs. -- Abstract: Inflammation has been established in recent years as a hallmark of cancer. Cancer Associated Fibroblasts (CAFs) support tumorigenesis by stimulating angiogenesis, cancer cell proliferation and invasion. We previously demonstrated that CAFs also mediate tumor-enhancing inflammation in a mouse model of skin carcinoma. Breast and ovarian carcinomas are amongst the leading causes of cancer-related mortality in women and cancer-related inflammation is linked with both these tumor types. However, the role of CAFs in mediating inflammation in these malignancies remains obscure. Here we show that CAFs in human breast and ovarian tumors express high levels of the pro-inflammatory factors IL-6, COX-2 and CXCL1, previously identified to be part of a CAF pro-inflammatory gene signature. Moreover, we show that both pro-inflammatory signaling by CAFs and leukocyte infiltration of tumors are enhanced in invasive ductal carcinoma as compared with ductal carcinoma in situ. The pro-inflammatory genes expressed by CAFs are known NF-κB targets and we show that NF-κB is up-regulated in breast and ovarian CAFs. Our data imply that CAFs mediate tumor-promoting inflammation in human breast and ovarian tumors and thus may be an attractive target for stromal-directed therapeutics

  5. Pharmacological Effect of Caulophyllum robustum on Collagen-Induced Arthritis and Regulation of Nitric Oxide, NF-κB, and Proinflammatory Cytokines In Vivo and In Vitro

    Directory of Open Access Journals (Sweden)

    Qiu-hong Wang

    2017-01-01

    Full Text Available Caulophyllum robustum Maxim (C. robustum has commonly been used as traditional Chinese medicine for the treatment of rheumatic pain and rheumatoid arthritis (RA in China. This paper first investigated the anti-inflammation effect of C. robustum extraction (CRME on RAW264.7 cells stimulated by lipopolysaccharide (LPS and gene expression levels of inflammatory factors. Moreover, we first evaluated the anti-RA effects of CRME using collagen-induced arthritis (CIA in DBA/1J mice, and the incidence, clinical score, and joint histopathology were evaluated. The levels of IL-1, IL-6, TNF-α, and PGE2 inflammatory factors in sera of mice were detected by enzyme-linked immunosorbent assay. The expression of NF-κB p65 in the joint was tested by immune histochemical technique. The results showed that, compared with the model group, CRME significantly improved symptoms of the arthritis index, limb swelling, and histological findings by decreasing synovial membrane damage, the extent of inflammatory cell infiltration, and the expansion of capillaries in CIA mice. The results also showed that CRME can reduce the levels of IL-1, IL-6, TNF-α, and PGE2 and inhibit the expression of NF-κB p65. All these results indicated the anti-inflammatory efficacy of CRME as a novel botanical extraction for the treatment of RA.

  6. Activation of the inducible nitric oxide synthase pathway contributes to inflammation-induced osteoporosis by suppressing bone formation and causing osteoblast apoptosis.

    Science.gov (United States)

    Armour, K J; Armour, K E; van't Hof, R J; Reid, D M; Wei, X Q; Liew, F Y; Ralston, S H

    2001-12-01

    Osteoporosis is a major clinical problem in chronic inflammatory diseases such as rheumatoid arthritis. The mechanism of bone loss in this condition remains unclear, but previous studies have indicated that depressed bone formation plays a causal role. Since cytokine-induced nitric oxide (NO) production has been shown to inhibit osteoblast growth and differentiation in vitro, this study was undertaken to investigate the role of the inducible NO synthase (iNOS) pathway in the pathogenesis of inflammation-mediated osteoporosis (IMO) by studying mice with targeted inactivation of the iNOS gene (iNOS knockout [iNOS KO] mice). IMO was induced in wild-type (WT) and iNOS KO mice by subcutaneous injections of magnesium silicate. The skeletal response was assessed at the tibial metaphysis by measurements of bone mineral density (BMD), using peripheral quantitative computed tomography, by bone histomorphometry, and by measurements of bone cell apoptosis. NO production increased 2.5-fold (P < 0.005) in WT mice with IMO, but did not change significantly in iNOS KO mice. Total BMD values decreased by a mean +/- SEM of 14.4+/-2.0% in WT mice with IMO, compared with a decrease of 8.6+/-1.2% in iNOS KO mice with IMO (P < 0.01). Histomorphometric analysis confirmed that trabecular bone volume was lower in WT mice with IMO compared with iNOS KO mice with IMO (16.2+/-1.5% versus 23.4+/-2.6%; P < 0.05) and showed that IMO was associated with reduced bone formation and a 320% increase in osteoblast apoptosis (P < 0.005) in WT mice. In contrast, iNOS KO mice with IMO showed less inhibition of bone formation than WT mice and showed no significant increase in osteoblast apoptosis. Inducible NOS-mediated osteoblast apoptosis and depressed bone formation play important roles in the pathogenesis of IMO.

  7. Nitric oxide, human diseases and the herbal products that affect the nitric oxide signalling pathway.

    Science.gov (United States)

    Achike, Francis I; Kwan, Chiu-Yin

    2003-09-01

    1. Nitric oxide (NO) is formed enzymatically from l-arginine in the presence of nitric oxide synthase (NOS). Nitric oxide is generated constitutively in endothelial cells via sheer stress and blood-borne substances. Nitric oxide is also generated constitutively in neuronal cells and serves as a neurotransmitter and neuromodulator in non-adrenergic, non-cholinergic nerve endings. Furthermore, NO can also be formed via enzyme induction in many tissues in the presence of cytokines. 2. The ubiquitous presence of NO in the living body suggests that NO plays an important role in the maintenance of health. Being a free radical with vasodilatory properties, NO exerts dual effects on tissues and cells in various biological systems. At low concentrations, NO can dilate the blood vessels and improve the circulation, but at high concentrations it can cause circulatory shock and induce cell death. Thus, diseases can arise in the presence of the extreme ends of the physiological concentrations of NO. 3. The NO signalling pathway has, in recent years, become a target for new drug development. The high level of flavonoids, catechins, tannins and other polyphenolic compounds present in vegetables, fruits, soy, tea and even red wine (from grapes) is believed to contribute to their beneficial health effects. Some of these compounds induce NO formation from the endothelial cells to improve circulation and some suppress the induction of inducible NOS in inflammation and infection. 4. Many botanical medicinal herbs and drugs derived from these herbs have been shown to have effects on the NO signalling pathway. For example, the saponins from ginseng, ginsenosides, have been shown to relax blood vessels (probably contributing to the antifatigue and blood pressure-lowering effects of ginseng) and corpus cavernosum (thus, for the treatment of men suffering from erectile dysfunction; however, the legendary aphrodisiac effect of ginseng may be an overstatement). Many plant extracts or

  8. Inhaled nitric oxide augments nitric oxide transport on sickle cell hemoglobin without affecting oxygen affinity

    OpenAIRE

    Gladwin, Mark T.; Schechter, Alan N.; Shelhamer, James H.; Pannell, Lewis K.; Conway, Deirdre A.; Hrinczenko, Borys W.; Nichols, James S.; Pease-Fye, Margaret E.; Noguchi, Constance T.; Rodgers, Griffin P.; Ognibene, Frederick P.

    1999-01-01

    Nitric oxide (NO) inhalation has been reported to increase the oxygen affinity of sickle cell erythrocytes. Also, proposed allosteric mechanisms for hemoglobin, based on S-nitrosation of β-chain cysteine 93, raise the possibilty of altering the pathophysiology of sickle cell disease by inhibiting polymerization or by increasing NO delivery to the tissue. We studied the effects of a 2-hour treatment, using varying concentrations of inhaled NO. Oxygen affinity, as measured by P50, did not respo...

  9. Serum nitric oxide metabolites and disease activity in patients with systemic sclerosis.

    Science.gov (United States)

    Mok, Mo Yin; Fung, Peter Chin Wah; Ooi, Clara; Tse, Hung Fat; Wong, Yik; Lam, Yui Ming; Wong, Woon Sing; Lau, Chak Sing

    2008-03-01

    There is no surrogate marker in serum for defining disease activity in scleroderma (SSc). Nitric oxide (NO), which regulates vasodilation and possesses pro-inflammatory actions, has been implicated in the pathogenesis of SSc. We compared serum NO(x) (total nitrate and nitrite) level in SSc patients to healthy controls and evaluated its correlation with detailed symptomatology and scoring systems for various organ involvement. Symptoms and physical findings that suggested disease activity in regard to various organs were documented. Lung function test, high-resolution computed tomographic (HRCT) scan of thorax and echocardiography were performed. Serum NO(x) was measured by chemiluminescence. Serum NO(x) levels in SSc (n = 43) were significantly higher (72.4 +/- 47.8 microM) than age- and sex-matched controls (n = 41; 37.1 +/- 13.5 microM; p n = 9; OR 145.3, p = 0.01) were predictive factors for elevated serum NO(x). Prednisolone use was associated with lower serum NO(x) level (OR 0.06, p = 0.04). Elevated PAP of increasing severity was found to be associated with higher level of serum NO(x) (p = 0.004 by trend). Serum NO(x) in SSc patients were elevated compared to healthy controls. Serum NO(x) level was determined by multiple factors including age, prednisolone use, and elevated PAP.

  10. Involvement of Syk kinase in TNF-induced nitric oxide production by airway epithelial cells

    International Nuclear Information System (INIS)

    Ulanova, Marina; Marcet-Palacios, Marcelo; Munoz, Samira; Asfaha, Samuel; Kim, Moo-Kyung; Schreiber, Alan D.; Befus, A. Dean

    2006-01-01

    We have recently found that Syk is widely expressed in lung epithelial cells (EC) and participates in β1 integrin signaling. In this study, we assessed the role of Syk in regulation of NO production. Stimulation of human bronchial EC line HS-24 by TNF caused an increased expression of inducible nitric oxide synthase (iNOS). Inhibition of Syk using siRNA or piceatannol down-regulated the iNOS expression and reduced NO production. This effect occurred in EC simultaneously stimulated via β1 integrins, suggesting that TNF and β1 integrins provide co-stimulatory signals. Inhibition of Syk down-regulated TNF-induced p38 and p44/42 MAPK phosphorylation and nuclear translocation of p65 NF-κB. Thus, TNF-induced activation of pro-inflammatory signaling in EC leading to enhanced expression of iNOS and NO production was dependent on Syk. Syk-mediated signaling regulates NO production at least partly via activating the MAPK cascade. Understanding the role of Syk in airway EC may help in developing new therapeutic tools for inflammatory lung disorders

  11. Oxygen binding to nitric oxide marked hemoglobin

    International Nuclear Information System (INIS)

    Louro, S.R.W.; Ribeiro, P.C.; Bemski, G.

    1979-04-01

    Electron spin resonance spectra of organic phosphate free human hemoglobin marked with nitric oxide at the sixth coordination position of one of the four hemes allow to observe the transition from the tense (T) to the relaxed (R) conformation, as a function of parcial oxygen pressure. The spectra are composites of contributions from α sub(T), α sub(R) and β chains spectra, showing the presence of only two conformations: T and R. In the absence of organic phosphates NO binds to α and β chains with the same probability, but in the presence of phosphates NO combines preferentially with α chains. The dissociation of NO proceeds at least an order of magnitude faster in T than in R configuration. (author) [pt

  12. Nitric oxide: cancer target or anticancer agent?

    Science.gov (United States)

    Mocellin, Simone

    2009-03-01

    Despite the improved understanding of nitric oxide (NO) biology and the large amount of preclinical experiments testing its role in cancer development and progression, it is still debated whether NO should be considered a potential anticancer agent or instead a carcinogen. The complexity of NO effects within a cell and the variability of the final biological outcome depending upon NO levels makes it highly challenging to determine the therapeutic value of interfering with the activity of this intriguing gaseous messenger. This uncertainty has so far halted the clinical implementation of NO-based therapeutics in the field of oncology. Accordingly, only an in depth knowledge of the mechanisms leading to experimental tumor regression or progression in response to NO will allow us to exploit this molecule to fight cancer.

  13. Citric Acid Alternative to Nitric Acid Passivation

    Science.gov (United States)

    Lewis, Pattie L. (Compiler)

    2013-01-01

    The Ground Systems Development and Operations GSDO) Program at NASA John F. Kennedy Space Center (KSC) has the primary objective of modernizing and transforming the launch and range complex at KSC to benefit current and future NASA programs along with other emerging users. Described as the launch support and infrastructure modernization program in the NASA Authorization Act of 2010, the GSDO Program will develop and implement shared infrastructure and process improvements to provide more flexible, affordable, and responsive capabilities to a multi-user community. In support of the GSDO Program, the purpose of this project is to demonstratevalidate citric acid as a passivation agent for stainless steel. Successful completion of this project will result in citric acid being qualified for use as an environmentally preferable alternative to nitric acid for passivation of stainless steel alloys in NASA and DoD applications.

  14. Nitric oxide and mitochondria in metabolic syndrome

    Science.gov (United States)

    Litvinova, Larisa; Atochin, Dmitriy N.; Fattakhov, Nikolai; Vasilenko, Mariia; Zatolokin, Pavel; Kirienkova, Elena

    2015-01-01

    Metabolic syndrome (MS) is a cluster of metabolic disorders that collectively increase the risk of cardiovascular disease. Nitric oxide (NO) plays a crucial role in the pathogeneses of MS components and is involved in different mitochondrial signaling pathways that control respiration and apoptosis. The present review summarizes the recent information regarding the interrelations of mitochondria and NO in MS. Changes in the activities of different NO synthase isoforms lead to the formation of metabolic disorders and therefore are highlighted here. Reduced endothelial NOS activity and NO bioavailability, as the main factors underlying the endothelial dysfunction that occurs in MS, are discussed in this review in relation to mitochondrial dysfunction. We also focus on potential therapeutic strategies involving NO signaling pathways that can be used to treat patients with metabolic disorders associated with mitochondrial dysfunction. The article may help researchers develop new approaches for the diagnosis, prevention and treatment of MS. PMID:25741283

  15. Radiolysis of concentrated nitric acid solutions

    International Nuclear Information System (INIS)

    Nagaishi, R.; Jiang, P.Y.; Katsumura, Y.; Domae, M.; Ishigure, K.

    1995-01-01

    A study on electron pulse- and 60 Co γ-radiolysis of concentrated nitric acid and nitrate solutions has been carried out to elucidate the radiation induced reactions taking place in the solutions. Dissociation into NO 2 - and O( 3 P) was proposed as a direct action of the radiation on nitrate and gave the G-values were dependent on the chemical forms of nitrate: g s2 (-NO 3 - )=1.6 and g s2 (-HNO 3 )=2.2 (molecules/100eV). Based on the experimental yields of HNO 2 and reduced Ce IV , the primary yields of radiolysis products of water, g w , were evaluated to clarify the effects of nitrate on spur reactions of water in various nitrate solutions. (author)

  16. The role of nitric oxide in reproduction

    Directory of Open Access Journals (Sweden)

    McCann S.M.

    1999-01-01

    Full Text Available Nitric oxide (NO plays a crucial role in reproduction at every level in the organism. In the brain, it activates the release of luteinizing hormone-releasing hormone (LHRH. The axons of the LHRH neurons project to the mating centers in the brain stem and by afferent pathways evoke the lordosis reflex in female rats. In males, there is activation of NOergic terminals that release NO in the corpora cavernosa penis to induce erection by generation of cyclic guanosine monophosphate (cGMP. NO also activates the release of LHRH which reaches the pituitary and activates the release of gonadotropins by activating neural NO synthase (nNOS in the pituitary gland. In the gonad, NO plays an important role in inducing ovulation and in causing luteolysis, whereas in the reproductive tract, it relaxes uterine muscle via cGMP and constricts it via prostaglandins (PG.

  17. Auroral nitric oxide concentration and infrared emission

    Science.gov (United States)

    Reidy, W. P.; Degges, T. C.; Hurd, A. G.; Stair, A. T., Jr.; Ulwick, J. C.

    1982-05-01

    Rocket-borne measurements of infrared auroral emission by nitric oxide are analyzed. Four rocket flights provided opportunities to measure 5.3- and 2.7-micron NO emission by means of infrared fixed band radiometers and CVF spectrometers, narrow band photometers, and incident energy spectra on various occasions. Analysis of infrared emission profiles and electron flux data indicates the NO density to be significantly enhanced with respect to midlatitude values. NO emission in the fundamental 5.3-micron band is attributed to resonance excitation by warm earth radiation, collisional excitation primarily by O atoms and chemiluminescence from the reaction of N with O2; with an energy efficiency of 0.015. The overtone band emission at 2.7 microns is accounted for by chemiluminescence produced with an energy efficiency of 0.0054. Total photon yield for the chemiluminescence reaction is estimated to range from 1.2 to 2.4 vibrational quanta per NO molecule.

  18. Studies of molybdenite interaction with nitric acid

    International Nuclear Information System (INIS)

    Potashnikov, Yu.M.; Lutsik, V.I.; Chursanov, Yu.V.

    1984-01-01

    Product composition and their effect on the reaction rate of molybdenite with nitric acid are specified. It is shown that alongside with NO NO 2 is included in the composition of the products of MoS 2 and HNO 3 interaction and it produces catalytic effect on the process considered. Under the conditions studied MoS 2 dissolution proceeds in the mixed regime, conditioned by similar values of molybdenite oxidation rate and reaction product diffusion into solution volume (Esub(act.=28.9 kJ/mol, K 298 =6.3x10 -7 , cmxs -1 ), at that due to catalytic effect of NO 2 the dependence V approximately αsup(-g.37) is observed

  19. Nitric oxide and plant iron homeostasis.

    Science.gov (United States)

    Buet, Agustina; Simontacchi, Marcela

    2015-03-01

    Like all living organisms, plants demand iron (Fe) for important biochemical and metabolic processes. Internal imbalances, as a consequence of insufficient or excess Fe in the environment, lead to growth restriction and affect crop yield. Knowledge of signals and factors affecting each step in Fe uptake from the soil and distribution (long-distance transport, remobilization from old to young leaves, and storage in seeds) is necessary to improve our understanding of plant mineral nutrition. In this context, the role of nitric oxide (NO) is discussed as a key player in maintaining Fe homeostasis through its cross talk with hormones, ferritin, and frataxin and the ability to form nitrosyl-iron complexes. © 2015 New York Academy of Sciences.

  20. Nitric oxide-induced calcium release: activation of type 1 ryanodine receptor by endogenous nitric oxide.

    Science.gov (United States)

    Kakizawa, Sho; Yamazawa, Toshiko; Iino, Masamitsu

    2013-01-01

    Ryanodine receptors (RyRs), located in the sarcoplasmic/endoplasmic reticulum (SR/ER) membrane, are required for intracellular Ca2+ release that is involved in a wide range of cellular functions. In addition to Ca2+-induced Ca2+ release in cardiac cells and voltage-induced Ca2+ release in skeletal muscle cells, we recently identified another mode of intracellular Ca2+ mobilization mediated by RyR, i.e., nitric oxide-induced Ca2+ release (NICR), in cerebellar Purkinje cells. NICR is evoked by neuronal activity, is dependent on S-nitrosylation of type 1 RyR (RyR1) and is involved in the induction of long-term potentiation (LTP) of cerebellar synapses. In this addendum, we examined whether peroxynitrite, which is produced by the reaction of nitric oxide with superoxide, may also have an effect on the Ca2+ release via RyR1 and the cerebellar LTP. We found that scavengers of peroxynitrite have no significant effect either on the Ca2+ release via RyR1 or on the cerebellar LTP. We also found that an application of a high concentration of peroxynitrite does not reproduce neuronal activity-dependent Ca2+ release in Purkinje cells. These results support that NICR is induced by endogenous nitric oxide produced by neuronal activity through S-nitrosylation of RyR1.

  1. Heterotrimeric G protein-dependent WNT-5A signaling to ERK1/2 mediates distinct aspects of microglia proinflammatory transformation

    Directory of Open Access Journals (Sweden)

    Halleskog Carina

    2012-05-01

    Full Text Available Abstract Background WNT-5A signaling in the central nervous system is important for morphogenesis, neurogenesis and establishment of functional connectivity; the source of WNT-5A and its importance for cellular communication in the adult brain, however, are mainly unknown. We have previously investigated the inflammatory effects of WNT/β-catenin signaling in microglia in Alzheimer's disease. WNT-5A, however, generally recruits β-catenin-independent signaling. Thus, we aim here to characterize the role of WNT-5A and downstream signaling pathways for the inflammatory transformation of the brain's macrophages, the microglia. Methods Mouse brain sections were used for immunohistochemistry. Primary isolated microglia and astrocytes were employed to characterize the WNT-induced inflammatory transformation and underlying intracellular signaling pathways by immunoblotting, quantitative mRNA analysis, proliferation and invasion assays. Further, measurements of G protein activation by [γ-35 S]GTP binding, examination of calcium fluxes and cyclic AMP production were used to define intracellular signaling pathways. Results Astrocytes in the adult mouse brain express high levels of WNT-5A, which could serve as a novel astroglia-microglia communication pathway. The WNT-5A-induced proinflammatory microglia response is characterized by increased expression of inducible nitric oxide synthase, cyclooxygenase-2, cytokines, chemokines, enhanced invasive capacity and proliferation. Mapping of intracellular transduction pathways reveals that WNT-5A activates heterotrimeric Gi/o proteins to reduce cyclic AMP levels and to activate a Gi/o protein/phospholipase C/calcium-dependent protein kinase/extracellular signal-regulated kinase 1/2 (ERK1/2 axis. We show further that WNT-5A-induced ERK1/2 signaling is responsible for distinct aspects of the proinflammatory transformation, such as matrix metalloprotease 9/13 expression, invasion and proliferation. Conclusions

  2. Nitric oxide in the psychobiology of mental disorders

    Directory of Open Access Journals (Sweden)

    Altan Eşsizoğlu

    2009-03-01

    Full Text Available Nitric oxide is in a gaseous form and is widespread in the human body. It functions by acting as a secondary messenger in the modulatory activities of neuronal functions of the central nervous system. Nitric oxide is the first identified neurotransmitter of the nontraditional neurotransmitter family.Studies conducted on experimental animals demonstrate that nitric oxide has a neuromodulatory efficacy on the secretions of other neurotransmitters and that it has an effect on learning and memory functions, and on various neuronal mechanisms. Many studies have been conducted to investigate the location of nitric oxide in the central nervous system, its effect on anxiety and depression, its relationship with other neurotransmitters, and also about its role on neurotoxicity. There are clinical studies concerning the level of nitrate, a product of nitric oxide metabolism, and also experimental studies concerning its rewarding effect of alcohol and substance use, in patients with depression and schizophrenia. However, limited studies have been conducted to investigate its relationship with stress, which is an important factor in the etiology of psychiatric disorders. These studies demonstrate that nitric oxide is closely related with stress physiology.Nitric oxide is a neuromodulator, which is frequently being mentioned about nowadays in psychiatry. Clinical and experimental studies play an important role in the psychobiology of psychiatric disorders.

  3. Proinflammatory Cytokines in Prostate Cancer Development and Progression Promoted by High-Fat Diet

    Directory of Open Access Journals (Sweden)

    Hua Xu

    2015-01-01

    Full Text Available Background. We aimed to examine whether proinflammatory cytokines participated in prostate cancer (PCa development and progression promoted by high-fat diet (HFD. Methods. TRAMP (transgenic adenocarcinoma mouse prostate mice were randomly divided into two groups: normal diet group and HFD group. Mortality rate and tumor formation rate were examined. TRAMP mice were sacrificed and sampled on the 20th, 24th, and 28th week, respectively. Levels of proinflammatory cytokines, including IL-1α, IL-1β, IL-6, and TNF-α, were tested by FlowCytomix. Prostate tissue of TRAMP mice was used for histology study. Results. A total of 13 deaths of TRAMP mice were observed, among which 3 (8.33% were from the normal diet group and 10 (27.78% from the HFD group. The mortality rate of TRAMP mice from HFD group was significantly higher than that of normal diet group (P=0.032. Tumor formation rate at 20th week of age of HFD group was significantly higher than that of normal diet group (P=0.045. Proinflammatory cytokines levels, including IL-1α, IL-1β, IL-6, and TNF-α, were significantly higher in HFD TRAMP mice. Conclusions. HFD could promote TRAMP mouse PCa development and progression with elevated proinflammatory cytokines levels. Proinflammatory cytokines could contribute to PCa development and progression promoted by HFD.

  4. Effects of transcutaneous electrical nerve stimulation (TENS) on proinflammatory cytokines: protocol for systematic review.

    Science.gov (United States)

    Almeida, Tábata Cristina do Carmo; Figueiredo, Francisco Winter Dos Santos; Barbosa Filho, Valter Cordeiro; de Abreu, Luiz Carlos; Fonseca, Fernando Luiz Affonso; Adami, Fernando

    2017-07-11

    Pain reduction can be achieved by lowering proinflammatory cytokine levels in the blood. Transcutaneous electrical nerve stimulation (TENS) is a non-invasive physiotherapeutic resource for pain management, but evidence on the effectiveness of this device at reducing proinflammatory cytokines in the blood is unclear. This study systematically reviews the literature on the effect of TENS on proinflammatory cytokines. A systematic review protocol was developed based on searches of articles in six electronic databases and references of retrieved articles, contact with authors, and repositories of clinical trials. Eligibility criteria: publication in peer-reviewed journals, randomized clinical trials, use of TENS in the experimental group, and pre- and post-measurements of proinflammatory cytokines in the blood. Selection of the studies and extraction of the data will be carried out by two reviewers independently. Characteristics of the study, participants, interventions and outcomes were extracted and described. Assessments were performed on the risk of bias, level of evidence and the size of the intervention effect in the studies, according to GRADE guidelines and the Cochrane Handbook for Systematic Reviews. Clinical and statistical assessments compared the effects of the interventions (meta-analysis), taking into consideration any influencing characteristics of the studies (e.g., methods and application sites). We anticipate that this review will strengthen evidence-based knowledge of the effect of TENS on proinflammatory cytokines and, as a result, direct new studies to benefit patients with specific pathologies. PROSPERO, CRD42017060379 .

  5. Proinflammatory cytokine levels in fibromyalgia patients are independent of body mass index

    Directory of Open Access Journals (Sweden)

    Estrada Iris

    2010-06-01

    Full Text Available Abstract Background Fibromyalgia (FM is characterized by chronic, widespread muscular pain and tenderness and is generally associated with other somatic and psychological symptoms. Further, circulatory levels of proinflammatory cytokines (IL-1β, TNF-α, and IL-6 may be altered in FM patients, possibly in association with their symptoms. Recently, rises in BMI have been suggested to contribute to increased circulating levels of proinflammatory cytokines in FM patients. Our aim was to measure the circulatory levels of proinflammatory cytokines to determine the influence of BMI on these levels in FM patients and healthy volunteers (HVs. In Spanish FM patients (n = 64 and HVs (n = 25, we measured BMI and serum concentrations of proinflammatory cytokines by capture ELISA. Findings There were significant differences in BMI levels between FM patients (26.40 ± 4.46 and HVs (23.64 ± 3.45 and significant increase in IL-6 in FM patients (16.28 ± 8.13 vs 0.92 ± 0.32 pg/ml (P Conclusions Our analysis in FM patients of BMI as a covariate of proinflammatory cytokines levels showed that serum TNF-α and IL-6 levels are independent of BMI. Further studies are necessary to dissect these findings and their implication in future therapeutic approaches for FM patients.

  6. Proinflammatory cytokine levels in fibromyalgia patients are independent of body mass index.

    Science.gov (United States)

    Hernandez, Maria E; Becerril, Enrique; Perez, Mayra; Leff, Philippe; Anton, Benito; Estrada, Sergio; Estrada, Iris; Sarasa, Manuel; Serrano, Enrique; Pavon, Lenin

    2010-06-03

    Fibromyalgia (FM) is characterized by chronic, widespread muscular pain and tenderness and is generally associated with other somatic and psychological symptoms. Further, circulatory levels of proinflammatory cytokines (IL-1beta, TNF-alpha, and IL-6) may be altered in FM patients, possibly in association with their symptoms. Recently, rises in BMI have been suggested to contribute to increased circulating levels of proinflammatory cytokines in FM patients. Our aim was to measure the circulatory levels of proinflammatory cytokines to determine the influence of BMI on these levels in FM patients and healthy volunteers (HVs). In Spanish FM patients (n = 64) and HVs (n = 25), we measured BMI and serum concentrations of proinflammatory cytokines by capture ELISA. There were significant differences in BMI levels between FM patients (26.40 +/- 4.46) and HVs (23.64 +/- 3.45) and significant increase in IL-6 in FM patients (16.28 +/- 8.13 vs 0.92 +/- 0.32 pg/ml) (P BMI and TNF-alpha (F = 0.098, p = 0.75) or IL-6 (F = 0.221, p = 0.63) levels in FM patients. Our analysis in FM patients of BMI as a covariate of proinflammatory cytokines levels showed that serum TNF-alpha and IL-6 levels are independent of BMI. Further studies are necessary to dissect these findings and their implication in future therapeutic approaches for FM patients.

  7. Dissolution behavior of PFBR MOX fuel in nitric acid

    International Nuclear Information System (INIS)

    Kelkar, Anoop; Kapoor, Y.S.; Singh, Mamta; Meena, D.L.; Pandey, Ashish; Bhatt, R.B.; Behere, P.G.

    2017-01-01

    Present paper describes the dissolution characteristics of PFBR MOX fuel (U,Pu)O 2 in nitric acid. An overview of batch dissolution experiments, studying the percentage dissolution of uranium and plutonium in (U, Pu)O 2 MOX sintered pellets with different percentage of PuO 2 with reference to time and nitric acid concentration are described. 90% of uranium and plutonium of PFBR MOX gets dissolves in 2 hrs and amount of residue increases with the decrease in nitric acid concentration. Overall variation in percentage residue in PFBR MOX fuel after dissolution test also described. (author)

  8. Thermal decomposition studies of aqueous and nitric solutions of hydroxyurea

    International Nuclear Information System (INIS)

    Shekhar Kumar; Pranay Kumar Sinha; Kamachi Mudali, U.; Natarajan, R.

    2012-01-01

    Hydroxyurea and its derivatives are important nonsalt forming reductants in partitioning of uranium and plutonium in the nuclear fuel reprocessing operations. There is no experimental data available in open literature describing pressurization due to the thermal decomposition of aqueous and nitric solutions of hydroxyurea at elevated temperatures. Authors studied thermal decomposition of hydroxyurea-nitric acid system and resultant pressurization at various concentrations of nitric acid in an adiabatic calorimeter in closed-vent conditions. During these experiments, pressurization was observed. In this paper, results of these experiments have been discussed. (author)

  9. Leaching of sodium carbonate cakes by nitric acid

    International Nuclear Information System (INIS)

    Troyanker, L.S.; Nikonov, V.N.

    1977-01-01

    The interaction has been studied of soda cakes of fluorite-rare-earth concentrate with nitric acid. The effect of a number of factors on extraction of REE into a nitric solution has been considered: the final acidity of the pulp, the duration of leaching, and the ratio between solid and liquid phases. The effect of adding aluminium nitrate into the pulp has also been studied. It has been shown that three-stage counterflow leaching of soda cakes with nitric acid increases REE extraction approximately by 10%

  10. Zeolites as catalyzer to environmental control. Nitric oxide removal

    International Nuclear Information System (INIS)

    Montes, C.; Zapata N, M; Villa H, A.L.

    1995-01-01

    Zeolites and the microporous materials related to them are a class of environmental catalysts, it which are used to remove the produced gases in combustion process (as mobile sources). In this work the importance that has catalysis for environment improvement is emphasized. A review of recent progress in the use of certain zeolitic material as catalysts for nitric oxide elimination of combustion systems is presented. More used nitric oxide removal methods are presented, as well as its advantages and disadvantages. Furthermore, it is emphasized on the need of accomplishing more investigation projects on the development of an active catalyst for the decomposition of the nitric oxide in its elements (N and O)

  11. 76 FR 63878 - New Source Performance Standards Review for Nitric Acid Plants

    Science.gov (United States)

    2011-10-14

    ... technologies. Nitric acid production is also one of the industrial sectors for which ``white papers'' were... standards (NSPS) for nitric acid plants. Nitric acid plants include one or more nitric acid production units. These proposed revisions include a change to the nitrogen oxides (NO X ) emission limit, which applies...

  12. INHALED NITRIC OXIDE: CLINICAL EFFECTS AND INFLUENCE ON THE PROFILE OF INFLAMMATORY MARKERS IN PATIENTS WITH IDIOPATHIC PULMONARY HYPERTENSION

    Directory of Open Access Journals (Sweden)

    T. V. Martynyuk

    2012-01-01

    Full Text Available Aim. To study the effect of treatment with inhaled nitric oxide (iNO on the clinical status of patients with idiopathic pulmonary hypertension (IPH, and the profile of proinflammatory cytokines in peripheral blood. Material and methods. Patients with IPH (n=48 were included into the study. Evaluation of the IPH functional class (FC, the 6-minute walk test (6MWT with the assessment of the Borg index, echocardiography , laboratory tests [blood count, evaluation of high-sensitivity C-reactive protein (hsCRP, interleukins (IL, interferon-γ (INFγ, tumor necrosis factor a (TNFa, macrophage inflammatory protein a (MIP1 a, soluble adhesion molecules (sICAM-1, sVCAM-1 in peripheral blood] were performed at baseline and on day 21 of iNO therapy course. The iNO course 40 ppm during 5 hours a day for 21 days was carried out additionally to the standard IPH therapy under the toxicity control by the PrinterNOx (England. Results. Increase in exercise tolerance, improvement of IPH FC (from 3.35±0.52 to 2.71±0.56; p=0.008, reduction in systolic pulmonary artery pressure (SPAP by Doppler echocardiography (from 96.23±23.65 to 82.36±20.92 mmHg; p<0.05 were found in IPH patients as a result of iNo therapy. The significance of inflammation in IPH pathogenesis was confirmed due to assessment of the initial levels of proinflammatory cytokines. iNO therapy resulted in significant decrease in proinflammatory cytokines-IL-1β, IL-6, IL-8, TNFa levels. iNO induced significant dynamics of IL-1β and sVCAM in patients with IPH FC II. It reduced IL-8 and TNFa and increase INFγ (p<0.05 in patients with IPH FC III-IV. Changes in IL-1β and sVCAM levels (ΔIL-1β and ΔsVCAM by the 21 day of iNO therapy in comparison with these at baseline correlated with ΔSPAP , and ΔIL-6 correlated with ΔFC and Δ6MWT distance (30.5 [21.0; 53.0] m; p<0.001. This allows considering these indicators as markers of iNO treatment efficacy. Conclusions. 21-day iNO therapy in IPH patients

  13. The nitric acid decomposition of calcined danburite concentrate of Ak-Arkhar Deposit

    International Nuclear Information System (INIS)

    Kurbonov, A.S.; Mamatov, E.D.; Suleymani, M.; Borudzherdi, A.; Mirsaidov, U.M.

    2011-01-01

    Present article is devoted to nitric acid decomposition of calcined danburite concentrate of Ak-Arkhar Deposit of Tajikistan. The obtaining of boric acid from pre backed danburite concentrate by decomposition of nitric acid was studied. The chemical composition of danburite concentrate was determined. The laboratory study of danburite leaching by nitric acid was conducted. The influence of temperature, process duration, nitric acid concentration on nitric acid decomposition of calcined danburite concentrate of Ak-Arkhar Deposit was studied as well. The optimal conditions of nitric acid decomposition of calcined danburite concentrate of Ak-Arkhar Deposit, including temperature, process duration, nitric acid concentration and particle size were proposed.

  14. Anti-inflammatory homoeopathic drug dilutions restrain lipopolysaccharide-induced release of pro-inflammatory cytokines: In vitro and in vivo evidence

    Directory of Open Access Journals (Sweden)

    Umesh B Mahajan

    2017-01-01

    Full Text Available Context: The lipopolysaccharide (LPS-induced cytokine release and oxidative stress are validated experimental parameters used to test anti-inflammatory activity. We investigated the effects of homoeopathic mother tinctures, 6 CH, 30 CH and 200 CH dilutions of Arnica montana, Thuja occidentalis and Bryonia alba against LPS (1 μg/ml-induced cytokine release from RAW-264.7 cells and human whole-blood culture. Materials and Methods: For in vivo evaluations, mice were orally treated with 0.1 ml drug dilutions twice a day for 5 days followed by an intraperitoneal injection of 0.5 mg/kg LPS. After 24 h, the mice were sacrificed and serum levels of pro-inflammatory cytokines and nitric oxide were determined. The extent of oxidative stress was determined in the liver homogenates as contents of reduced glutathione, malondialdehyde, superoxide dismutase and catalase. Results: The tested drug dilutions significantly reduced in vitro LPS-induced release of tumour necrosis factor-α, interleukin-1 (IL-1 and IL-6 from the RAW-264.7 cells and human whole blood culture. Similar suppression of cytokines was evident in mice serum samples. These drugs also protected mice from the LPS-induced oxidative stress in liver tissue. Conclusions: Our findings substantiate the protective effects of Arnica, Thuja and Bryonia homoeopathic dilutions against LPS-induced cytokine elevations and oxidative stress. This study authenticates the claims of anti-inflammatory efficacy of these homoeopathic drugs.

  15. Curative Effects of Thiacremonone against Acetaminophen-Induced Acute Hepatic Failure via Inhibition of Proinflammatory Cytokines Production and Infiltration of Cytotoxic Immune Cells and Kupffer Cells

    Directory of Open Access Journals (Sweden)

    Yu Ri Kim

    2013-01-01

    Full Text Available High doses of acetaminophen (APAP; N-acetyl-p-aminophenol cause severe hepatotoxicity after metabolic activation by cytochrome P450 2E1. This study was undertaken to examine the preventive effects of thiacremonone, a compound extracted from garlic, on APAP-induced acute hepatic failure in male C57BL/6J. Mice received with 500 mg/kg APAP after a 7-day pretreatment with thiacremonone (10–50 mg/kg. Thiacremonone inhibited the APAP-induced serum ALT and AST levels in a dose-dependent manner, and markedly reduced the restricted area of necrosis and inflammation by administration of APAP. Thiacremonone also inhibited the APAP-induced depletion of intracellular GSH, induction of nitric oxide, and lipid peroxidation as well as expression of P450 2E1. After APAP injection, the numbers of Kupffer cells, natural killer cells, and cytotoxic T cells were elevated, but the elevated cell numbers in the liver were reduced in thiacremonone pretreated mice. The expression levels of I-309, M-CSF, MIG, MIP-1α, MIP-1β, IL-7, and IL-17 were increased by APAP treatment, which were inhibited in thiacremonone pretreated mice. These data indicate that thiacremonone could be a useful agent for the treatment of drug-induced hepatic failure and that the reduction of cytotoxic immune cells as well as proinflammatory cytokine production may be critical for the prevention of APAP-induced acute liver toxicity.

  16. Egg ovotransferrin-derived ACE inhibitory peptide IRW increases ACE2 but decreases proinflammatory genes expression in mesenteric artery of spontaneously hypertensive rats.

    Science.gov (United States)

    Majumder, Kaustav; Liang, Guanxiang; Chen, Yanhong; Guan, LeLuo; Davidge, Sandra T; Wu, Jianping

    2015-09-01

    Egg ovotransferrin-derived angiotensin converting enzyme (ACE) inhibitory peptide IRW was previously shown to reduce blood pressure in spontaneously hypertensive rats through reduced vascular inflammation and increased nitric oxide-mediated vasorelaxation. The main objective of the present study was to investigate the molecular mechanism of this peptide through transcriptome analysis by RNAseq technique. Total RNA was extracted from kidney and mesenteric arteries; the RNAseq libraries (from untreated and IRW-treated groups) were constructed and subjected to sequence using HiSeq 2000 system (Illumina) system. A total of 12 764 and 13 352 genes were detected in kidney and mesenteric arteries, respectively. The differentially expressed (DE) genes between untreated and IRW-treated groups were identified and the functional analysis through ingenuity pathway analysis revealed a greater role of DE genes identified from mesenteric arteries than that of kidney in modulating various cardiovascular functions. Subsequent qPCR analysis further confirmed that IRW significantly increased the expression of ACE-2, ABCB-1, IRF-8, and CDH-1 while significantly decreased the expression ICAM-1 and VCAM-1 in mesenteric arteries. Our research showed for the first time that ACE inhibitory peptide IRW could contribute to its antihypertensive activity through increased ACE2 and decreased proinflammatory genes expression. © 2015 The Authors. Molecular Nutrition & Food Research published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  17. The importance of balanced pro-inflammatory and anti-inflammatory mechanisms in diffuse lung disease

    Directory of Open Access Journals (Sweden)

    Strieter Robert

    2002-01-01

    Full Text Available Abstract The lung responds to a variety of insults in a remarkably consistent fashion but with inconsistent outcomes that vary from complete resolution and return to normal to the destruction of normal architecture and progressive fibrosis. Increasing evidence indicates that diffuse lung disease results from an imbalance between the pro-inflammatory and anti-inflammatory mechanisms, with a persistent imbalance that favors pro-inflammatory mediators dictating the development of chronic diffuse lung disease. This review focuses on the mediators that influence this imbalance.

  18. Acute Respiratory Distress Syndrome (ARDS After Nitric Acid Inhalation

    Directory of Open Access Journals (Sweden)

    Gülay Kır

    2014-12-01

    Full Text Available Lung injury resulting from inhalation of chemical products continues to be associated with high morbidity and mortality. Concentrated nitric acids are also extremely corrosive fuming chemical liquids. Fumes of nitric acid (HNO3 and various oxides of nitrogen such as nitric oxide (NO and nitrogen dioxide (NO2 may cause fatal illnesses such as severe pulmonary edema and acute respiratory distress syndrome (ARDS when inhaled. Intensive respiratory management including mechanical ventilation with positive end expiratory pressure (PEEP, inverse ratio ventilation, replacement of surfactant and extracorporeal membrane oxygenation (ECMO, steroids and n-acetylcysteine (NAC may improve survival. In this case report we present the diagnosis and successful treatment of a 57 years old male patient who developed ARDS following pulmonary edema due to nitric acid fumes inhalation.

  19. Studies on the reaction of nitric acid and sugar

    International Nuclear Information System (INIS)

    MacDougall, C.S.; Bayne, C.K.; Roberson, R.B.

    1982-01-01

    The design of vessels and off-gas systems for denitrating acidic radioactive process solutions by reacting nitric acid with sugar requires a fairly accurate determination of the rate of the controlling step. Therefore, the reaction of sugar with concentrated nitric acid was closely examined at temperatures of 100 and 110 0 C and in the presence of low levels of iron )0 to 0.2 M Fe(III)). Efficiencies of the sugar destruction by nitric acid ranged from 2.56 to 2.93 mol of acid consumed per mole of carbon added. Product off-gases were examined throughout the reaction. Release of CO was fairly constant throughout the reaction, but amounts of CO 2 increased as the nitric acid began to attack the terminal carboxylic acids produced from the consumption of sucrose. Voluminous quantities of NO 2 were released at the beginning of the reaction, but larger relative concentrations of NO were observed toward the end

  20. Modulation of glucose uptake in adipose tissue by nitric oxide ...

    Indian Academy of Sciences (India)

    Madhu

    ion-dependent breakdown and trans-nitrosation reactions are ... [McGrowder D, Ragoobirsingh D and Brown P 2006 Modulation of glucose uptake in adipose tissue by nitric oxide-generating ... Briefly, nicotinamide (Sigma Chemical Co.,.

  1. Inhibition of Nitric Oxide and Prostaglandin E 2 Expression by ...

    African Journals Online (AJOL)

    Inhibition of Nitric Oxide and Prostaglandin E 2 Expression by Methanol Extract of Polyopes affinis in Lipopolysaccharide-stimulated BV2 Microglial Cells through Suppression of Akt-dependent NF-kB Activity and MAPK Pathway.

  2. Inducible nitric oxide synthase mediates bone loss in ovariectomized mice.

    NARCIS (Netherlands)

    Cuzzocrea, S.; Mazzon, E.; Dugo, L.; Genovese, T.; Paola, R. Di; Ruggeri, Z.; Vegeto, E.; Caputi, A.P.; Loo, F.A.J. van de; Puzzolo, D.; Maggi, A.

    2003-01-01

    Several clinical studies have shown that bone loss may be attributed to osteoclast recruitment induced by mediators of inflammation. In different experimental paradigms we have recently demonstrated that estrogen exhibits antiinflammatory activity by preventing the induction of inducible nitric

  3. Nitric oxide inhibits glycogen synthesis in isolated rat hepatocytes

    NARCIS (Netherlands)

    Sprangers, F.; Sauerwein, H. P.; Romijn, J. A.; van Woerkom, G. M.; Meijer, A. J.

    1998-01-01

    There is increasing evidence for the existence of intrahepatic regulation of glucose metabolism by Kupffer cell products. Nitric oxide (NO) is known to inhibit gluconeogenic flux through pyruvate carboxylase and phosphoenolpyruvate carboxykinase. However, NO may also influence glucose metabolism at

  4. Control of instability in nitric acid evaporators for plutonium processing

    International Nuclear Information System (INIS)

    1998-03-01

    Improved control of the nitric acid process evaporators requires the detection of spontaneously unstable operating conditions. This process reduces the volume of contaminated liquid by evaporating nitric acid and concentrating salt residues. If a instability is identified quickly, prompt response can avert distillate contamination. An algorithm applied to the runtime data was evaluated to detect this situation. A snapshot of data from a histogram in the old process control software was captured during the unstable conditions and modeled

  5. Acute chemical pneumonitis caused by nitric acid inhalation: case report

    Energy Technology Data Exchange (ETDEWEB)

    Choe, Hyung Shim; Lee, In Jae; Ko, Eun Young; Lee, Jae Young; Kim, Hyun Beom; Hwang, Dae Hyun; Lee, Kwan Seop; Lee, Yul; Bae, Sang Hoon [Hallym University Sacred Heart Hospital, Anyang (Korea, Republic of)

    2003-06-01

    Chemical pneumonitis induced by nitric acid inhalation is a rare clinical condition. The previously reported radiologic findings of this disease include acute permeability pulmonary edema, delayed bronchiolitis obliterans, and bronchiectasis. In very few published rare radiologic reports has this disease manifested as acute alveolar injury; we report a case of acute chemical pneumonitis induced by nitric acid inhalation which at radiography manifested as bilateral perihilar consolidation and ground-glass attenuation, suggesting acute alveolar injury.

  6. Formation of nitric acid hydrates - A chemical equilibrium approach

    Science.gov (United States)

    Smith, Roland H.

    1990-01-01

    Published data are used to calculate equilibrium constants for reactions of the formation of nitric acid hydrates over the temperature range 190 to 205 K. Standard enthalpies of formation and standard entropies are calculated for the tri- and mono-hydrates. These are shown to be in reasonable agreement with earlier calorimetric measurements. The formation of nitric acid trihydrate in the polar stratosphere is discussed in terms of these equilibrium constants.

  7. IL-1beta-induced chemokine and Fas expression are inhibited by suppressor of cytokine signalling-3 in insulin-producing cells

    DEFF Research Database (Denmark)

    Jacobsen, M L B; Rønn, S G; Bruun, C

    2008-01-01

    AIMS/HYPOTHESIS: Chemokines recruit activated immune cells to sites of inflammation and are important mediators of insulitis. Activation of the pro-apoptotic receptor Fas leads to apoptosis-mediated death of the Fas-expressing cell. The pro-inflammatory cytokines IL-1beta and IFN-gamma regulate...... the transcription of genes encoding the Fas receptor and several chemokines. We have previously shown that suppressor of cytokine signalling (SOCS)-3 inhibits IL-1beta- and IFN-gamma-induced nitric oxide production in a beta cell line. The aim of this study was to investigate whether SOCS-3 can influence cytokine......-induced Fas and chemokine expression in beta cells. METHODS: Using a beta cell line with inducible Socs3 expression or primary neonatal rat islet cells transduced with a Socs3-encoding adenovirus, we employed real-time RT-PCR analysis to investigate whether SOCS-3 affects cytokine-induced chemokine and Fas m...

  8. Nitric acid recycling and copper nitrate recovery from effluent.

    Science.gov (United States)

    Jô, L F; Marcus, R; Marcelin, O

    2014-01-01

    The recycling of nitric acid and copper nitrate contained in an industrial effluent was studied. The experiments conducted on such a medium showed that the presence of copper nitrate significantly improves nitric acid-water separation during distillation in an azeotropic medium. At the temperature of the azeotrope, however, this metal salt starts to precipitate, making the medium pasty, thus inhibiting the nitric acid extraction process. The optimisation of parameters such as column efficiency and adding water to the boiler at the azeotrope temperature are recommended in this protocol in order to collect the various components while avoiding the formation of by-products: NOx compounds. Thus, the absence of column, along with the addition of a small volume of water at a temperature of 118 °C, significantly increases the yield, allowing 94 % nitric acid to be recovered at the end of the process, along with the residual copper nitrate. The resulting distillate, however, is sufficiently dilute to not be used as is. Rectification is required to obtain concentrated nitric acid at 15 mol·l(-1), along with a weakly acidic distillate from the distillation front. This latter is quenched using potassium hydroxide and is used as a fertiliser solution for horticulture or sheltered market gardening. This process thus allows complete recycling of all the medium's components, including that of the distillate resulting from the nitric acid rectification operation.

  9. Cellular signaling with nitric oxide and cyclic GMP

    Directory of Open Access Journals (Sweden)

    F. Murad

    1999-11-01

    Full Text Available During the past two decades, nitric oxide signaling has been one of the most rapidly growing areas in biology. This simple free radical gas can regulate an ever growing list of biological processes. In most instances nitric oxide mediates its biological effects by activating guanylyl cyclase and increasing cyclic GMP synthesis. However, the identification of effects of nitric oxide that are independent of cyclic GMP is also growing at a rapid rate. The effects of nitric oxide can mediate important physiological regulatory events in cell regulation, cell-cell communication and signaling. Nitric oxide can function as an intracellular messenger, neurotransmitter and hormone. However, as with any messenger molecule, there can be too much or too little of the substance and pathological events ensue. Methods to regulate either nitric oxide formation, metabolism or function have been used therapeutically for more than a century as with nitroglycerin therapy. Current and future research should permit the development of an expanded therapeutic armamentarium for the physician to manage effectively a number of important disorders. These expectations have undoubtedly fueled the vast research interests in this simple molecule.

  10. Americium removal from nitric acid waste streams

    International Nuclear Information System (INIS)

    Muscatello, A.C.; Navratil, J.D.

    1986-01-01

    Separations research at the Rocky Flats Plant (RFP) has found ways to significantly improve americium removal from nitric acid (7M) waste streams generated by plutonium purification operations. Partial neutralization of the acid waste followed by solid supported liquid membranes (SLM) are useful in transferring and concentrating americium from nitrate solutions. Specifically, DHDECMP (dihexyl-N,N-diethylcarbamoylmethylphosphonate) supported on Accurel polypropylene hollow fibers assembled in modular form transfers >95% of the americium from high nitrate (6.9M), low acid (0.1M) feeds into 0.25M oxalic acid stripping solution. Maximum permeabilities were observed to be 0.001 cm/sec, consistent with typical values for other systems. The feed:strip volume ratio shows an inverse relationship to the fraction of metal ion transferred. Cation exchangers may be used to concentrate americium from the strip solution. Furthermore, O0D (iB)CMPO (or CMPO) (octylphenyl-N-N-diisobutylcarbamoylmethylphosphine oxide) has been tested in an extraction chromatography mode. Preliminary results show CMPO to be effective in removing americium if the feed is neutralized to 1.0M acidity and iron(III) is complexed with 0.20M oxalic acid. 3 figs

  11. Nitric oxide bioavailability dysfunction involves in atherosclerosis.

    Science.gov (United States)

    Chen, Jing-Yi; Ye, Zi-Xin; Wang, Xiu-Fen; Chang, Jian; Yang, Mei-Wen; Zhong, Hua-Hua; Hong, Fen-Fang; Yang, Shu-Long

    2018-01-01

    The pathological characteristics of atherosclerosis (AS) include lipid accumulation, fibrosis formation and atherosclerotic plaque produced in artery intima, which leads to vascular sclerosis, lumen stenosis and irritates the ischemic changes of corresponding organs. Endothelial dysfunction was closely associated with AS. Nitric oxide (NO) is a multifunctional signaling molecule involved in the maintenance of metabolic and cardiovascular homeostasis. NO is also a potent endogenous vasodilator and enters for the key processes that suppresses the formation vascular lesion even AS. NO bioavailability indicates the production and utilization of endothelial NO in organisms, its decrease is related to oxidative stress, lipid infiltration, the expressions of some inflammatory factors and the alteration of vascular tone, which plays an important role in endothelial dysfunction. The enhancement of arginase activity and the increase in asymmetric dimethylarginine and hyperhomocysteinemia levels all contribute to AS by intervening NO bioavailability in human beings. Diabetes mellitus, obesity, chronic kidney disease and smoking, etc., also participate in AS by influencing NO bioavailability and NO level. Here, we reviewed the relationship between NO bioavailability and AS according the newest literatures. Copyright © 2017. Published by Elsevier Masson SAS.

  12. Nasal nitric oxide in unilateral sinus disease.

    Directory of Open Access Journals (Sweden)

    Chia-Hsiang Fu

    Full Text Available Unilateral sinus disease (USD can sometimes be difficult to accurately diagnose before surgery. The application of nasal nitric oxide (nNO for USD diagnosis and its surgical outcome in USD has not been reported in the literature. We prospectively enrolled sixty-six USD patients who underwent endoscopic sinus surgery for fungal rhinosinusitis (n = 19, chronic rhinosinusitis (CRS without nasal polyps (n = 13, CRS with nasal polyps (n = 12 and sinonasal mass lesions (n = 22. nNO levels were measured preoperatively and at three and six months postoperatively. Correlations between nNO levels and potential clinical parameters, type of disease, disease severity, and disease-related quality of life (QOL were assessed. Unlike bilateral CRS, in USD, nNO levels did not correlate with disease severity or postoperative QOL improvements. Except for fungus group, there were no differences in nNO levels between lesion and non-lesion sides in all the other groups. nNO levels on both sides were significantly elevated six months postoperatively in all groups. Fungal rhinosinusitis patients had the lowest preoperative nNO levels, and a cutoff of 239.3 ppb had the best sensitivity (79.0% and specificity (87.2% for preoperative diagnosis. While preoperative nNO levels cannot serve as an alternative marker for disease severity of USD, they were lower in fungal rhinosinusitis patients than in other USD patients and may be useful for more accurate diagnosis prior to surgery.

  13. Nitric oxide and cardiovascular risk factors

    Directory of Open Access Journals (Sweden)

    Livio Dai Cas

    2007-06-01

    Full Text Available The endothelium is a dynamic organ with many properties that takes part in the regulation of the principal mechanisms of vascular physiology. Its principal functions include the control of blood-tissue exchange and permeability, the vascular tonus, and the modulation of inflammatory or coagulatory mechanisms. Many vasoactive molecules, produced by the endothelium, are involved in the control of these functions. The most important is nitric oxide (NO, a gaseous molecule electrically neutral with an odd number of electrons that gives the molecule chemically reactive radical properties. Already known in the twentieth century, NO, sometimes considered as a dangerous molecule, recently valued as an important endogenous vasodilator factor. Recently, it was discovered that it is involved in several physiological mechanisms of endothelial protection (Tab. I. In 1992, Science elected it as “molecule of the year”; 6 yrs later three American researchers (Louis Ignarro, Robert Furchgott and Fried Murad obtained a Nobel Prize for Medicine and Physiology “for their discoveries about NO as signal in the cardiovascular system”.

  14. Nitric acid adduct formation during crystallization of barium and strontium nitrates and their co-precipitation from nitric acid media

    International Nuclear Information System (INIS)

    Mishina, N.E.; Zilberman, B.Ya.; Lumpov, A.A.; Koltsova, T.I.; Puzikov, E.A.; Ryabkov, D.V.

    2015-01-01

    The molar solubilities of Ba, Sr and Pb nitrates in nitric acid as a function of total nitrate concentration is presented and described by the mass action law, indicating on formation of the adducts with nitric acid. Precipitates of Ba(NO 3 ) 2 and Sr(NO 3 ) 2 crystallized from nitric acid were studied by ISP OES and IR spectroscopy. The data obtained confirmed formation of metastable adducts with nitric acid. IR and X-ray diffraction studies of the mixed salt systems indicated conversion of the mixed salts into (Ba,Sr)(NO 3 ) 2 solid solution of discrete structure in range of total nitrate ion concentration ∼6 mol/L. (author)

  15. Inhibition of lipopolysaccharide-induced proinflammatory responses by Buddleja officinalis extract in BV-2 microglial cells via negative regulation of NF-kB and ERK1/2 signaling.

    Science.gov (United States)

    Oh, Won-Jun; Jung, Uhee; Eom, Hyun-Soo; Shin, Hee-June; Park, Hae-Ran

    2013-07-31

    Buddleja officinalis has been traditionally used in the supportive treatment of inflammatory and neuronal diseases in Korea and China. Although several reports have shown the anti-inflammatory effects of Buddleja officinalis, the anti-neuroinflammatory effect has remained unclear. In this study, we aimed to investigate the inhibitory effects of flower buds of B. officinalis Maximowicz water extract (BOWE) on LPS-induced inflammatory processes in BV-2 microglial cells. BOWE dose-dependently inhibited the production of nitric oxide as well as iNOS mRNA expression. Moreover, BOWE prevented IL-1β and IL-6 mRNA expression. However, BOWE had no effect on LPS-induced COX-2 or TNF-a mRNA expression. The extract also had no effect on LPS-stimulated p38 MAPK, JNK, and c-Jun phosphorylation, whereas ERK1/2 phosphorylation was strongly inhibited by BOWE. BOWE also inhibited the LPS-induced degradation of IkB-α, and LPS-induced phosphorylation of p65 NF-kB protein. These data indicate that BOWE inhibited the nitric oxide production and pro-inflammatory gene expression in BV-2 microglial cells, possibly through a negative regulation of the NF-kB and ERK1/2 pathways. Further identification of the direct target molecule(s) of BOWE is required to support its use as an anti-neuroinflammatory agent against the neurodegenerative disorders.

  16. Inhibition of Lipopolysaccharide-Induced Proinflammatory Responses by Buddleja officinalis Extract in BV-2 Microglial Cells via Negative Regulation of NF-kB and ERK1/2 Signaling

    Directory of Open Access Journals (Sweden)

    Hae-Ran Park

    2013-07-01

    Full Text Available Buddleja officinalis has been traditionally used in the supportive treatment of inflammatory and neuronal diseases in Korea and China. Although several reports have shown the anti-inflammatory effects of Buddleja officinalis, the anti-neuroinflammatory effect has remained unclear. In this study, we aimed to investigate the inhibitory effects of flower buds of B. officinalis Maximowicz water extract (BOWE on LPS-induced inflammatory processes in BV-2 microglial cells. BOWE dose-dependently inhibited the production of nitric oxide as well as iNOS mRNA expression. Moreover, BOWE prevented IL-1β and IL-6 mRNA expression. However, BOWE had no effect on LPS-induced COX-2 or TNF-a mRNA expression. The extract also had no effect on LPS-stimulated p38 MAPK, JNK, and c-Jun phosphorylation, whereas ERK1/2 phosphorylation was strongly inhibited by BOWE. BOWE also inhibited the LPS-induced degradation of IkB-α, and LPS-induced phosphorylation of p65 NF-kB protein. These data indicate that BOWE inhibited the nitric oxide production and pro-inflammatory gene expression in BV-2 microglial cells, possibly through a negative regulation of the NF-kB and ERK1/2 pathways. Further identification of the direct target molecule(s of BOWE is required to support its use as an anti-neuroinflammatory agent against the neurodegenerative disorders.

  17. Effect of caffeic acid phenethyl ester on Prevotella intermedia lipopolysaccharide-induced production of proinflammatory mediators in murine macrophages.

    Science.gov (United States)

    Choi, E-Y; Choe, S-H; Hyeon, J-Y; Choi, J-I; Choi, I S; Kim, S-J

    2015-12-01

    Caffeic acid phenethyl ester (CAPE) has numerous potentially beneficial properties, including antioxidant, immunomodulatory and anti-inflammatory activities. However, the effect of CAPE on periodontal disease has not been studied before. This study was designed to investigate the efficacy of CAPE in ameliorating the production of proinflammatory mediators in macrophages activated by lipopolysaccharide (LPS) from Prevotella intermedia, a pathogen implicated in periodontal disease. LPS from P. intermedia ATCC 25611 was isolated by using the standard hot phenol-water method. Culture supernatants were assayed for nitric oxide (NO), interleukin (IL)-1β and IL-6. We used real-time polymerase chain reaction to quantify inducible NO synthase, IL-1β, IL-6, heme oxygenase (HO)-1 and suppressors of cytokine signaling (SOCS) 1 mRNA expression. HO-1 protein expression and levels of signaling proteins were assessed by immunoblot analysis. DNA-binding activities of NF-κB subunits were analyzed by using the enzyme-linked immunosorbent assay-based kits. CAPE exerted significant inhibitory effects on P. intermedia LPS-induced production of NO, IL-1β and IL-6 as well as their mRNA expression in RAW264.7 cells. CAPE-induced HO-1 expression in cells activated with P. intermedia LPS, and selective inhibition of HO-1 activity by tin protoporphyrin IX attenuated the inhibitory effect of CAPE on LPS-induced NO production. CAPE did not interfere with IκB-α degradation induced by P. intermedia LPS. Instead, CAPE decreased nuclear translocation of NF-κB p65 and p50 subunits induced with LPS, and lessened LPS-induced p50 binding activity. Further, CAPE showed strong inhibitory effects on LPS-induced signal transducer and activator of transcription 1 and 3 phosphorylation. Besides, CAPE significantly elevated SOCS1 mRNA expression in P. intermedia LPS-stimulated cells. Modulation of host response by CAPE may represent an attractive strategy towards the treatment of periodontal disease

  18. Proinflammatory response during Ebola virus infection of primate models: possible involvement of the tumor necrosis factor receptor superfamily.

    Science.gov (United States)

    Hensley, Lisa E; Young, Howard A; Jahrling, Peter B; Geisbert, Thomas W

    2002-03-01

    Ebola virus (EBOV) infections are characterized by dysregulation of normal host immune responses. Insight into the mechanism came from recent studies in nonhuman primates, which showed that EBOV infects cells of the mononuclear phagocyte system (MPS), resulting in apoptosis of bystander lymphocytes. In this study, we evaluated serum levels of cytokines/chemokines in EBOV-infected nonhuman primates, as possible correlates of this bystander apoptosis. Increased levels of interferon (IFN)-alpha, IFN-beta, interleukin (IL)-6, IL-18, MIP-1alpha, and MIP-1beta were observed in all EBOV-infected monkeys, indicating the occurrence of a strong proinflammatory response. To investigate the mechanism(s) involved in lymphoid apoptosis, soluble Fas (sFas) and nitrate accumulation were measured. sFas was detected in 4/9 animals, while, elevations of nitrate accumulation occurred in 3/3 animals. To further evaluate the potential role of these factors in the observed bystander apoptosis and intact animals, in vitro cultures were prepared of adherent human monocytes/macrophages (PHM), and monocytes differentiated into immature dendritic cells (DC). These cultures were infected with EBOV and analyzed for cytokine/chemokine induction and expression of apoptosis-related genes. In addition, the in vitro EBOV infection of peripheral blood mononuclear cells (PBMC) resulted in strong cytokine/chemokine induction, a marked increase in lactate dehydrogenase (LDH) activity, and an increase in the number of apoptotic lymphocytes examined by electron microscopy. Increased levels of sFAS were detected in PHM cultures, although, 90% of EBOV-infected PHM were positive for tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) by immunohistochemistry, RNA analysis, and flow cytometry. Inactivated EBOV also effected increased TRAIL expression in PHM, suggesting that the TNF receptor superfamily may be involved in apoptosis of the host lymphoid cells, and that induction may occur

  19. Induction of Chemokine Secretion and Monocyte Migration by Human Choroidal Melanocytes in Response to Proinflammatory Cytokines

    DEFF Research Database (Denmark)

    Jehs, Tina; Faber, Carsten; Udsen, Maja S.

    2016-01-01

    of 10 HCM donors induced a high initial level of monocyte migration, which decreased upon stimulation with either TCM or IFN-γ and TNF-α. The supernatants from three HCM donors initially showed a low level of monocyte attraction, which increased after exposure to proinflammatory cytokines. Direct...

  20. Retracted: Effects of pro-inflammatory cytokines on mineralization potential of rat dental pulp stem cells

    NARCIS (Netherlands)

    Yang, X.; Walboomers, X.F.; Bian, Z.; Jansen, J.A.; Fan, M.

    2011-01-01

    The following article from the Journal of Tissue Engineering and Regenerative Medicine, 'Effects of Pro-inflammatory Cytokines on Mineralization Potential of Rat Dental Pulp Stem Cells' by Yang X, Walboomers XF, Bian Z, Jansen JA, Fan M, published online on 11 July 2011 in Wiley Online Library

  1. Pro-inflammatory delipidizing cytokines reduce adiponectin secretion from human adipocytes without affecting adiponectin oligomerization

    NARCIS (Netherlands)

    Simons, Peter J.; van den Pangaart, Petra S.; Aerts, Johannes M. F. G.; Boon, Louis

    2007-01-01

    Adiponectin and, especially, its oligomeric complex composition have been suggested to be critical in determining insulin sensitivity. Pro-inflammatory cytokines play an important role in the development of insulin resistance in obesity and associated diseases. Therefore, we investigated the effect

  2. Chronic disruptions of circadian sleep regulation induce specific proinflammatory responses in the rat colon

    Czech Academy of Sciences Publication Activity Database

    Polidarová, Lenka; Houdek, Pavel; Sumová, Alena

    2017-01-01

    Roč. 34, č. 9 (2017), s. 1273-1287 ISSN 0742-0528 R&D Projects: GA ČR(CZ) GA14-07711S Institutional support: RVO:67985823 Keywords : aging * colon * constant light * melatonin * proinflammatory cytokine * Rgs16 * sleep disruption Subject RIV: ED - Physiology OBOR OECD: Physiology (including cytology) Impact factor: 2.562, year: 2016

  3. Efficient Maturation and Cytokine Production of Neonatal DCs Requires Combined Proinflammatory Signals

    Directory of Open Access Journals (Sweden)

    Doreen Krumbiegel

    2005-01-01

    Full Text Available Specific functional properties of dendritic cells (DCs have been suspected as being responsible for the impaired specific immune responses observed in human neonates. To analyze stimulatory requirements for the critical transition from immature, antigen-processing DCs to mature, antigen-presenting DCs, we investigated the effect of different proinflammatory mediators and antigens on phenotype and cytokine secretion of human neonatal DCs derived from hematopoietic progenitor cells (HPCs. Whereas single proinflammatory mediators were unable to induce the maturation of neonatal DCs, various combinations of IFNγ, CD40L, TNFα, LPS and antigens, induced the maturation of neonatal DCs documented by up-regulation of HLA-DR, CD83 and CD86. Combinations of proinflammatory mediators also increased cytokine secretion by neonatal DCs. Especially combined stimulation with LPS and IFNγ proved to be very efficient in inducing maturation and cytokine synthesis of neonatal DCs. In conclusion, neonatal DCs can be stimulated to express maturation as well as costimulatory surface molecules. However, induction of maturation requires combined stimulation with multiple proinflammatory signals.

  4. Flavonoids inhibit histamine release and expression of proinflammatory cytokines in mast cells.

    Science.gov (United States)

    Park, Hyo-Hyun; Lee, Soyoung; Son, Hee-Young; Park, Seung-Bin; Kim, Mi-Sun; Choi, Eun-Ju; Singh, Thoudam S K; Ha, Jeoung-Hee; Lee, Maan-Gee; Kim, Jung-Eun; Hyun, Myung Chul; Kwon, Taeg Kyu; Kim, Yeo Hyang; Kim, Sang-Hyun

    2008-10-01

    Mast cells participate in allergy and inflammation by secreting inflammatory mediators such as histamine and proinflammatory cytokines. Flavonoids are naturally occurring molecules with antioxidant, cytoprotective, and antiinflammatory actions. However, effect of flavonoids on the release of histamine and proinflammatory mediator, and their comparative mechanism of action in mast cells were not well defined. Here, we compared the effect of six flavonoids (astragalin, fisetin, kaempferol, myricetin, quercetin, and rutin) on the mast cell-mediated allergic inflammation. Fisetin, kaempferol, myricetin, quercetin, and rutin inhibited IgE or phorbol-12-myristate 13-acetate and calcium ionophore A23187 (PMACI)-mediated histamine release in RBL-2H3 cells. These five flavonoids also inhibited elevation of intracellular calcium. Gene expressions and secretion of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, IL-6, and IL-8 were assessed in PMACI-stimulated human mast cells (HMC-1). Fisetin, quercetin, and rutin decreased gene expression and production of all the proinflammatory cytokines after PMACI stimulation. Myricetin attenuated TNF-alpha and IL-6 but not IL-1beta and IL-8. Fisetin, myricetin, and rutin suppressed activation of NF-kappaB indicated by inhibition of nuclear translocation of NF-kappaB, NF-kappaB/DNA binding, and NF-kappaB-dependent gene reporter assay. The pharmacological actions of these flavonoids suggest their potential activity for treatment of allergic inflammatory diseases through the down-regulation of mast cell activation.

  5. Involvement of Pro-Inflammatory Macrophages in Liver Pathology of Pirital Virus-Infected Syrian Hamsters

    Directory of Open Access Journals (Sweden)

    Corey L. Campbell

    2018-05-01

    Full Text Available New World arenaviruses cause fatal hemorrhagic disease in South America. Pirital virus (PIRV, a mammarenavirus hosted by Alston’s cotton rat (Sigmodon alstoni, causes a disease in Syrian golden hamsters (Mesocricetus auratus (biosafety level-3, BSL-3 that has many pathologic similarities to the South American hemorrhagic fevers (BSL-4 and, thus, is considered among the best small-animal models for human arenavirus disease. Here, we extend in greater detail previously described clinical and pathological findings in Syrian hamsters and provide evidence for a pro-inflammatory macrophage response during PIRV infection. The liver was the principal target organ of the disease, and signs of Kupffer cell involvement were identified in mortally infected hamster histopathology data. Differential expression analysis of liver mRNA revealed signatures of the pro-inflammatory response, hematologic dysregulation, interferon pathway and other host response pathways, including 17 key transcripts that were also reported in two non-human primate (NHP arenavirus liver-infection models, representing both Old and New World mammarenavirus infections. Although antigen presentation may differ among rodent and NHP species, key hemostatic and innate immune-response components showed expression parallels. Signatures of pro-inflammatory macrophage involvement in PIRV-infected livers included enrichment of Ifng, Nfkb2, Stat1, Irf1, Klf6, Il1b, Cxcl10, and Cxcl11 transcripts. Together, these data indicate that pro-inflammatory macrophage M1 responses likely contribute to the pathogenesis of acute PIRV infection.

  6. Extraction of nitric acid, uranyl nitrate, and bismuth nitrate from aqueous nitric acid solutions with CMPO

    Energy Technology Data Exchange (ETDEWEB)

    Spencer, B.B.

    1995-08-01

    DOE sponsored development of the transuranium extraction (TRUEX) process for removing actinides from radioactive wastes. The solvent is a mixture of CMPO and TBP. Since the extraction characteristics of CMPO are not as well understood as those of TBP, the extraction of nitric acid, uranyl nitrate, and bismuth nitrate with CMPO (dissolved in n-dodecane) were studied. Results indicate that CMPO extracts nitric acid with a 1:1 stoichiometry; equilibrium constant is 2. 660{plus_minus}0.092 at 25 C, and extraction enthalpy is -5. 46{plus_minus}0.46 kcal/mol. Slope analysis indicates that uranyl nitrate extracts with a mixed equilibria of 1:1 and 2:1 stoichiometries in nearly equal proportion. Equil. constant of the 2: 1 extraction was 1.213 {times} 10{sup 6}{plus_minus}3.56 {times} 10{sup 4} at 25 C; reaction enthalpy was -9.610{plus_minus}0.594 kcal/mol. Nitration complexation constant is 8.412{plus_minus}0.579, with an enthalpy of -10.72{plus_minus}1.87 kcal/mol. Bismuth nitrate also extracts with a mixed equilibria of (perhaps) 1:1 and 2:1 stoichiometries. A 2:1 extraction equilibrium and a nitrate complexation adequately model the data. Kinetics and enthalpies were also measured.

  7. Extraction of nitric acid, uranyl nitrate, and bismuth nitrate from aqueous nitric acid solutions with CMPO

    International Nuclear Information System (INIS)

    Spencer, B.B.

    1995-08-01

    DOE sponsored development of the transuranium extraction (TRUEX) process for removing actinides from radioactive wastes. The solvent is a mixture of CMPO and TBP. Since the extraction characteristics of CMPO are not as well understood as those of TBP, the extraction of nitric acid, uranyl nitrate, and bismuth nitrate with CMPO (dissolved in n-dodecane) were studied. Results indicate that CMPO extracts nitric acid with a 1:1 stoichiometry; equilibrium constant is 2. 660±0.092 at 25 C, and extraction enthalpy is -5. 46±0.46 kcal/mol. Slope analysis indicates that uranyl nitrate extracts with a mixed equilibria of 1:1 and 2:1 stoichiometries in nearly equal proportion. Equil. constant of the 2: 1 extraction was 1.213 x 10 6 ±3.56 x 10 4 at 25 C; reaction enthalpy was -9.610±0.594 kcal/mol. Nitration complexation constant is 8.412±0.579, with an enthalpy of -10.72±1.87 kcal/mol. Bismuth nitrate also extracts with a mixed equilibria of (perhaps) 1:1 and 2:1 stoichiometries. A 2:1 extraction equilibrium and a nitrate complexation adequately model the data. Kinetics and enthalpies were also measured

  8. Atypical antipsychotics induce both proinflammatory and adipogenic gene expression in human adipocytes in vitro

    International Nuclear Information System (INIS)

    Sárvári, Anitta K.; Veréb, Zoltán; Uray, Iván P.; Fésüs, László; Balajthy, Zoltán

    2014-01-01

    Highlights: • Antipsychotics modulate the expression of adipogenic genes in human adipocytes. • Secretion of proinflammatory cytokine IL8 and MCP-1 is induced by antipsychotics. • Adipocyte-dependent inflammatory abnormality could develop during chronic treatment. • Infiltrated macrophages would further enhance proinflammatory cytokine production. - Abstract: Schizophrenia requires lifelong treatment, potentially causing systemic changes in metabolic homeostasis. In the clinical setting, antipsychotic treatment may differentially lead to weight gain among individual patients, although the molecular determinants of such adverse effects are currently unknown. In this study, we investigated changes in the expression levels of critical regulatory genes of adipogenesis, lipid metabolism and proinflammatory genes during the differentiation of primary human adipose-derived stem cells (ADSCs). These cells were isolated from patients with body mass indices <25 and treated with the second-generation antipsychotics olanzapine, ziprasidone, clozapine, quetiapine, aripiprazole and risperidone and the first-generation antipsychotic haloperidol. We found that antipsychotics exhibited a marked effect on key genes involved in the regulation of cell cycle, signal transduction, transcription factors, nuclear receptors, differentiation markers and metabolic enzymes. In particular, we observed an induction of the transcription factor NF-KB1 and NF-KB1 target genes in adipocytes in response to these drugs, including the proinflammatory cytokines TNF-α, IL-1β, IL-8 and MCP-1. In addition, enhanced secretion of both IL8 and MCP-1 was observed in the supernatant of these cell cultures. In addition to their remarkable stimulatory effects on proinflammatory gene transcription, three of the most frequently prescribed antipsychotic drugs, clozapine, quetiapine and aripiprazole, also induced the expression of essential adipocyte differentiation genes and the adipocyte hormones leptin

  9. Atypical antipsychotics induce both proinflammatory and adipogenic gene expression in human adipocytes in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Sárvári, Anitta K., E-mail: anittasarvari@med.unideb.hu [Department of Biochemistry and Molecular Biology, Medical and Health Science Center, University of Debrecen, Debrecen (Hungary); Veréb, Zoltán, E-mail: jzvereb@gmail.com [Department of Biochemistry and Molecular Biology, Medical and Health Science Center, University of Debrecen, Debrecen (Hungary); Uray, Iván P., E-mail: ipuray@mdanderson.org [Clinical Cancer Prevention Department, The University of Texas, MD Anderson Cancer Center, Houston, TX (United States); Fésüs, László, E-mail: fesus@med.unideb.hu [Department of Biochemistry and Molecular Biology, Medical and Health Science Center, University of Debrecen, Debrecen (Hungary); MTA DE Apoptosis, Genomics and Stem Cell Research Group of the Hungarian Academy of Sciences (Hungary); Balajthy, Zoltán, E-mail: balajthy@med.unideb.hu [Department of Biochemistry and Molecular Biology, Medical and Health Science Center, University of Debrecen, Debrecen (Hungary)

    2014-08-08

    Highlights: • Antipsychotics modulate the expression of adipogenic genes in human adipocytes. • Secretion of proinflammatory cytokine IL8 and MCP-1 is induced by antipsychotics. • Adipocyte-dependent inflammatory abnormality could develop during chronic treatment. • Infiltrated macrophages would further enhance proinflammatory cytokine production. - Abstract: Schizophrenia requires lifelong treatment, potentially causing systemic changes in metabolic homeostasis. In the clinical setting, antipsychotic treatment may differentially lead to weight gain among individual patients, although the molecular determinants of such adverse effects are currently unknown. In this study, we investigated changes in the expression levels of critical regulatory genes of adipogenesis, lipid metabolism and proinflammatory genes during the differentiation of primary human adipose-derived stem cells (ADSCs). These cells were isolated from patients with body mass indices <25 and treated with the second-generation antipsychotics olanzapine, ziprasidone, clozapine, quetiapine, aripiprazole and risperidone and the first-generation antipsychotic haloperidol. We found that antipsychotics exhibited a marked effect on key genes involved in the regulation of cell cycle, signal transduction, transcription factors, nuclear receptors, differentiation markers and metabolic enzymes. In particular, we observed an induction of the transcription factor NF-KB1 and NF-KB1 target genes in adipocytes in response to these drugs, including the proinflammatory cytokines TNF-α, IL-1β, IL-8 and MCP-1. In addition, enhanced secretion of both IL8 and MCP-1 was observed in the supernatant of these cell cultures. In addition to their remarkable stimulatory effects on proinflammatory gene transcription, three of the most frequently prescribed antipsychotic drugs, clozapine, quetiapine and aripiprazole, also induced the expression of essential adipocyte differentiation genes and the adipocyte hormones leptin

  10. Pro-inflammatory cytokines upregulate sympathoexcitatory mechanisms in the subfornical organ of the rat

    Science.gov (United States)

    Wei, Shun-Guang; Yu, Yang; Zhang, Zhi-Hua; Felder, Robert B.

    2015-01-01

    Our previous work indicated that the subfornical organ (SFO) is an important brain sensor of blood-borne pro-inflammatory cytokines, mediating their central effects on autonomic and cardiovascular function. However, the mechanisms by which SFO mediates the central effects of circulating pro-inflammatory cytokines remain unclear. We hypothesized that pro-inflammatory cytokines act within the SFO to upregulate the expression of excitatory and inflammatory mediators that drive sympathetic nerve activity. In urethane-anesthetized Sprague-Dawley rats, direct microinjection of TNF-α (25 ng) or IL-1β (25 ng) into SFO increased mean blood pressure, heart rate and renal sympathetic nerve activity within 15–20 minutes, mimicking the response to systemically administered pro-inflammatory cytokines. Pretreatment of SFO with microinjections of the angiotensin II type 1 receptor (AT1R) blocker losartan (1 µg), angiotensin-converting enzyme (ACE) inhibitor captopril (1 µg) or cyclooxygenase (COX)-2 inhibitor NS-398 (2 µg) attenuated those responses. Four hours after the SFO microinjection of TNF-α (25 ng) or IL-1β (25 ng), mRNA for ACE, AT1R, TNF-α and the p55 TNF-α receptor TNFR1, IL-1β and the IL-1R receptor, and COX-2 had increased in SFO, and mRNA for ACE, AT1R and COX-2 had increased downstream in the hypothalamic paraventricular nucleus. Confocal immunofluorescent images revealed that immunoreactivity for TNFR1 and the IL-1 receptor accessory protein, a subunit of the IL-1 receptor, co-localized with ACE, AT1R-like, COX-2 and prostaglandin E2 EP3 receptor immunoreactivity in SFO neurons. These data suggest that pro-inflammatory cytokines act within the SFO to upregulate the expression of inflammatory and excitatory mediators that drive sympathetic excitation. PMID:25776070

  11. Nitric oxide amplifies the rat electroretinogram.

    Science.gov (United States)

    Vielma, Alex; Delgado, Luz; Elgueta, Claudio; Osorio, Rodrigo; Palacios, Adrián G; Schmachtenberg, Oliver

    2010-11-01

    It is well established that nitric oxide (NO) participates in retinal signal processing through stimulation of its receptor enzyme, soluble guanylyl cyclase (sGC). However, under pathological conditions such as uveoretinitis, diabetic or ischemic retinopathy, elevated NO concentrations may cause protein S-nitrosation and peroxynitrite formation in the retina, promoting cellular injury and apoptosis. Previous electroretinogram (ERG) studies demonstrated deleterious effects of NO on the retinal light response, but showed no evidence for a role in normal signal processing. To better understand the function of NO in ocular physiology, we investigated the effects of exogenous NO, produced by NO donors with different release kinetics, on the flash ERG of the rat. Within a limited concentration range, NO strongly amplified ERG a- and b-waves, oscillatory potentials, and the scotopic threshold response. Amplification exceeded 100% under dark adaptation, whereas the photopic ERG and the isolated cone response were increased by less than 50%. Blocking photoreceptor-bipolar cell synapses by AP-4 demonstrated a significant increase of the isolated a-wave by NO, and modeling the ERG generator PIII supported photoreceptors as primary NO targets. The sGC inhibitors ODQ and NS2028 did not reduce NO-dependent ERG amplification, ruling out an involvement of the classical NO effector cyclic GMP. Using immunohistochemistry, we show that illumination and exogenous NO altered the S-nitrosation level of the photoreceptor layer, suggesting that direct protein modifications caused by elevated levels of NO may be responsible for the observed phenomenon. Copyright © 2010 Elsevier Ltd. All rights reserved.

  12. Genetic responses against nitric oxide toxicity

    Directory of Open Access Journals (Sweden)

    B. Demple

    1999-11-01

    Full Text Available The threat of free radical damage is opposed by coordinated responses that modulate expression of sets of gene products. In mammalian cells, 12 proteins are induced by exposure to nitric oxide (NO levels that are sub-toxic but exceed the level needed to activate guanylate cyclase. Heme oxygenase 1 (HO-1 synthesis increases substantially, due to a 30- to 70-fold increase in the level of HO-1 mRNA. HO-1 induction is cGMP-independent and occurs mainly through increased mRNA stability, which therefore indicates a new NO-signaling pathway. HO-1 induction contributes to dramatically increased NO resistance and, together with the other inducible functions, constitutes an adaptive resistance pathway that also defends against oxidants such as H2O2. In E. coli, an oxidative stress response, the soxRS regulon, is activated by direct exposure of E. coli to NO, or by NO generated in murine macrophages after phagocytosis of the bacteria. This response is governed by the SoxR protein, a homodimeric transcription factor (17-kDa subunits containing [2Fe-2S] clusters essential for its activity. SoxR responds to superoxide stress through one-electron oxidation of the iron-sulfur centers, but such oxidation is not observed in reactions of NO with SoxR. Instead, NO nitrosylates the iron-sulfur centers of SoxR both in vitro and in intact cells, which yields a form of the protein with maximal transcriptional activity. Although nitrosylated SoxR is very stable in purified form, the spectroscopic signals for the nitrosylated iron-sulfur centers disappear rapidly in vivo, indicating an active process to reverse or eliminate them.

  13. Myeloperoxidase potentiates nitric oxide-mediated nitrosation.

    Science.gov (United States)

    Lakshmi, Vijaya M; Nauseef, William M; Zenser, Terry V

    2005-01-21

    Nitrosation is an important reaction elicited by nitric oxide (NO). To better understand how nitrosation occurs in biological systems, we assessed the effect of myeloperoxidase (MPO), a mediator of inflammation, on nitrosation observed during NO autoxidation. Nitrosation of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ; 10 mum) to 2-nitrosoamino-3-methylimidazo[4,5-f]quinoline (N-NO-IQ) was monitored by HPLC. Using the NO donor spermine NONOate at pH 7.4, MPO potentiated N-NO-IQ formation. The minimum effective quantity of necessary components was 8.5 nm MPO, 0.25 mum H(2)O(2)/min, and 0.024 mum NO/min. Autoxidation was only detected at >/=1.2 mum NO/min. MPO potentiation was not affected by a 40-fold excess flux of H(2)O(2) over NO or less than a 2.4-fold excess flux of NO over H(2)O(2). Potentiation was due to an 8.8-fold increased affinity of MPO-derived nitrosating species for IQ. Autoxidation was inhibited by azide, suggesting involvement of the nitrosonium ion, NO(+). MPO potentiation was inhibited by NADH, but not azide, suggesting oxidative nitrosylation with NO(2)(.) or an NO(2)(.)-like species. MPO nonnitrosative oxidation of IQ with 0.3 mm NO(2)(-) at pH 5.5 was inhibited by azide, but not NADH, demonstrating differences between MPO oxidation of IQ with NO compared with NO(2)(-). Using phorbol ester-stimulated human neutrophils, N-NO-IQ formation was increased with superoxide dismutase and inhibited by catalase and NADH, but not NaN(3). This is consistent with nitrosation potentiation by MPO, not peroxynitrite. Increased N-NO-IQ formation was not detected with polymorphonuclear neutrophils from two unrelated MPO-deficient patients. Results suggest that the highly diffusible stable gas NO could initiate nitrosation at sites of neutrophil infiltration.

  14. Selections of appropriate regimen of high-dose chemotherapy combined with adoptive cellular therapy with dendritic and cytokine-induced killer cells improved progression-free and overall survival in patients with metastatic breast cancer: reargument of such contentious therapeutic preferences.

    Science.gov (United States)

    Ren, Jun; Di, Lijun; Song, Guohong; Yu, Jing; Jia, Jun; Zhu, Yuling; Yan, Ying; Jiang, Hanfang; Liang, Xu; Che, Li; Zhang, Jie; Wan, Fengling; Wang, Xiaoli; Zhou, Xinna; Lyerly, Herbert Kim

    2013-10-01

    We hypothesized that combination of dendritic cell (DC) with autologous cytokine-induced killer (CIK) immunotherapy in setting of high-dose chemotherapy (HDC) would be effective for selected metastatic breast cancer (MBC) patients. Our previous work showed thiotepa could eradicate breast cancer stem cells. From 2004 to 2009, 79 patients received standard dose chemotherapy (SDC) of 75 mg/m(2) docetaxel and 75 mg/m(2) thiotepa versus 87 patients of HDC + DC/CIK: 120 mg/m(2) docetaxel to mobilize peripheral CD34(+) progenitor cells, a sequence of HDC (120 mg/m(2) docetaxel, plus 175 mg/m(2) thiotepa) + DC/CIK, with or without 400 mg/m(2) carboplatin depending upon bone marrow function. The endpoints were response rates (RR), progression-free survival (PFS), and overall survival (OS). Compared with SDC, PFS and OS were improved in HDC + DC/CIK (median PFS 10.2 vs. 3.7 months, P < 0.001; median OS 33.1 vs. 15.2 months, P < 0.001). Patients of pre-menopausal, HDC as first-line treatment after metastasis, or with visceral metastasis showed prolonged PFS and OS. SDC group also achieved the similar response as previous reports. Our study demonstrated the novel combination of HDC with DC/CIK to be an effective choice for the selected MBC population, in which choosing appropriate chemo regimens played important roles, and also specific HDC regimen plus DC/CIK immunotherapy showed the clinical benefits compared with chemotherapy alone.

  15. Targeting Integrin-β1 Impedes Cytokine-Induced Osteoclast ...

    African Journals Online (AJOL)

    but not in RANKL pathway. Given that, inflammatory cytokine secretions such as TNF-α are progressively implicated in pathological osteolysis, targeting this pathway may .... RANKL or TNF-alpha treated culture systems ... universal PCR Master Mix (Life Technologies,. USA). ... and developed using Super Signal West Dura.

  16. Characterization and antagonism of cytokine-induced eosinophil priming

    NARCIS (Netherlands)

    Rosas Rosas, Ana Marcela

    2006-01-01

    Allergic asthma is an inflammatory disease characterized by bronchial hyper-responsiveness, airway inflammation, and reversible obstruction of the airways. In humans, cytokine activated eosinophils are thought to be important players in this process since they can release inflammatory mediators

  17. Inflammatory Cytokines Induce Podoplanin Expression at the Tumor Invasive Front.

    Science.gov (United States)

    Kunita, Akiko; Baeriswyl, Vanessa; Meda, Claudia; Cabuy, Erik; Takeshita, Kimiko; Giraudo, Enrico; Wicki, Andreas; Fukayama, Masashi; Christofori, Gerhard

    2018-05-01

    Tumor invasion is a critical first step in the organismic dissemination of cancer cells and the formation of metastasis in distant organs, the most important prognostic factor and the actual cause of death in most of the cancer patients. We report herein that the cell surface protein podoplanin (PDPN), a potent inducer of cancer cell invasion, is conspicuously expressed by the invasive front of squamous cell carcinomas (SCCs) of the cervix in patients and in the transgenic human papillomavirus/estrogen mouse model of cervical cancer. Laser capture microscopy combined with gene expression profiling reveals that the expression of interferon-responsive genes is up-regulated in PDPN-expressing cells at the tumor invasive front, which are exposed to CD45-positive inflammatory cells. Indeed, PDPN expression can be induced in cultured SCC cell lines by single or combined treatments with interferon-γ, transforming growth factor-β, and/or tumor necrosis factor-α. Notably, shRNA-mediated ablation of either PDPN or STAT1 in A431 SCC cells repressed cancer cell invasion on s.c. transplantation into immunodeficient mice. The results highlight the induction of tumor cell invasion by the inflammatory cytokine-stimulated expression of PDPN in the outermost cell layers of cervical SCC. Copyright © 2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  18. Inhibition of Pro-inflammatory Cytokines by Ethyl Acetate Extract of ...

    African Journals Online (AJOL)

    striata Boiss (Scrophulariaceae). Several species of this genus have been used since ancient times as folk remedies for ailments such as scrophulas, scabies, eczema, psoriasis, tumors, etc. We have previously demonstrated the inhibitory effect of S. striata extract on nitric oxide production in vitro and ex vivo model [5].

  19. The Mechanism of Activated Nitrogen-Containing Metabolites in the Respiratory Tract: Proinflammatory Effect (Part 3

    Directory of Open Access Journals (Sweden)

    O.Ye. Abaturov

    2016-03-01

    Full Text Available The literature review presents current data about modulating action of nitrogen monoxide on the inflammatory response and the apoptotic process depending on its concentration. There is demonstrated a dual action of nitric oxide in the respiratory tract — prevention of infection and strengthening the destruction of lung tissue.

  20. Mechanism of nitric acid generation on Ag-X Zeolite

    International Nuclear Information System (INIS)

    Kanazawa, T.; Kishimoto, T.; Haseba, S.; Mitoh, Y.; Itoh, S.; Nakai, I.

    1983-01-01

    When Ag-X Zeolite is used for the removal of iodine from the off gas streams of nuclear facilities, it is possible that nitric acid is formed on Ag-X Zeolite from co-existing nitrogen dioxide and water vapor. If nitric acid is formed on the surface of Ag-X zeolite, Ag-X zeolite is damaged and is not able to operate for a long time. When Ag-X zeolite is used in NO 2 -O 2 -H 2 O mixture, the nitric acid generation reaction is varied, depending upon the reaction temperature, and concentration of NO 2 and H 2 O. At a temperature of more than 40 deg. C, however, only the surface reaction will be progressed on the zeolite surface. The generation of nitric acid solution on the zeolite can be forecasted through the relationship between the concentration of nitric acid solution, equilibrium vapor pressure of H 2 O, and equilibrium vapor pressure of HNO 3 . Concerning the surface reaction caused on the zeolite, the adsorption water reacts on NO 2 , and the resulting HNO 3 is adsorbed firmly by the zeolite, which is thought to interfere with the surface reaction for generation of the HNO 3 . When the adsorption bed is long, the time required for adsorbed HNO 3 to saturate is increased in proportion to the bed length

  1. Mitochondrial dysfunction associated with nitric oxide pathways in glutamate neurotoxicity.

    Science.gov (United States)

    Manucha, Walter

    Multiple mechanisms underlying glutamate-induced neurotoxicity have recently been discussed. Likewise, a clear deregulation of the mitochondrial respiratory mechanism has been described in patients with neurodegeneration, oxidative stress, and inflammation. This article highlights nitric oxide, an atypical neurotransmitter synthesized and released on demand by the post-synaptic neurons, and has many important implications for nerve cell survival and differentiation. Consequently, synaptogenesis, synapse elimination, and neurotransmitter release, are nitric oxide-modulated. Interesting, an emergent role of nitric oxide pathways has been discussed as regards neurotoxicity from glutamate-induced apoptosis. These findings suggest that nitric oxide pathways modulation could prevent oxidative damage to neurons through apoptosis inhibition. This review aims to highlight the emergent aspects of nitric oxide-mediated signaling in the brain, and how they can be related to neurotoxicity, as well as the development of neurodegenerative diseases development. Copyright © 2016 Sociedad Española de Arteriosclerosis. Publicado por Elsevier España, S.L.U. All rights reserved.

  2. Nitric Oxide in Astrocyte-Neuron Signaling

    Energy Technology Data Exchange (ETDEWEB)

    Li, Nianzhen [Iowa State Univ., Ames, IA (United States)

    2002-01-01

    Astrocytes, a subtype of glial cell, have recently been shown to exhibit Ca2+ elevations in response to neurotransmitters. A Ca2+ elevation can propagate to adjacent astrocytes as a Ca2+ wave, which allows an astrocyte to communicate with its neighbors. Additionally, glutamate can be released from astrocytes via a Ca2+-dependent mechanism, thus modulating neuronal activity and synaptic transmission. In this dissertation, the author investigated the roles of another endogenous signal, nitric oxide (NO), in astrocyte-neuron signaling. First the author tested if NO is generated during astrocytic Ca2+ signaling by imaging NO in purified murine cortical astrocyte cultures. Physiological concentrations of a natural messenger, ATP, caused a Ca2+-dependent NO production. To test the roles of NO in astrocytic Ca2+ signaling, the author applied NO to astrocyte cultures via addition of a NO donor, S-nitrosol-N-acetylpenicillamine (SNAP). NO induced an influx of external Ca2+, possibly through store-operated Ca2+ channels. The NO-induced Ca2+ signaling is cGMP-independent since 8-Br-cGMP, an agonistic analog of cGMP, did not induce a detectable Ca2+ change. The consequence of this NO-induced Ca2+ influx was assessed by simultaneously monitoring of cytosolic and internal store Ca2+ using fluorescent Ca2+ indicators x-rhod-1 and mag-fluo-4. Blockage of NO signaling with the NO scavenger PTIO significantly reduced the refilling percentage of internal stores following ATP-induced Ca2+ release, suggesting that NO modulates internal store refilling. Furthermore, locally photo-release of NO to a single astrocyte led to a Ca2+ elevation in the stimulated astrocyte and a subsequent Ca2+ wave to neighbors. Finally, the author tested the role of NO inglutamate-mediated astrocyte-neuron signaling by

  3. Unintended inhalation of nitric oxide by contamination of compressed air: physiologic effects and interference with intended nitric oxide inhalation in acute lung injury.

    Science.gov (United States)

    Benzing, A; Loop, T; Mols, G; Geiger, K

    1999-10-01

    Compressed air from a hospital's central gas supply may contain nitric oxide as a result of air pollution. Inhaled nitric oxide may increase arterial oxygen tension and decrease pulmonary vascular resistance in patients with acute lung injury and acute respiratory distress syndrome. Therefore, the authors wanted to determine whether unintentional nitric oxide inhalation by contamination of compressed air influences arterial oxygen tension and pulmonary vascular resistance and interferes with the therapeutic use of nitric oxide. Nitric oxide concentrations in the compressed air of a university hospital were measured continuously by chemiluminescence during two periods (4 and 2 weeks). The effects of unintended nitric oxide inhalation on arterial oxygen tension (n = 15) and on pulmonary vascular resistance (n = 9) were measured in patients with acute lung injury and acute respiratory distress syndrome by changing the source of compressed air of the ventilator from the hospital's central gas supply to a nitric oxide-free gas tank containing compressed air. In five of these patients, the effects of an additional inhalation of 5 ppm nitric oxide were evaluated. During working days, compressed air of the hospital's central gas supply contained clinically effective nitric oxide concentrations (> 80 parts per billion) during 40% of the time. Change to gas tank-supplied nitric oxide-free compressed air decreased the arterial oxygen tension by 10% and increased pulmonary vascular resistance by 13%. The addition of 5 ppm nitric oxide had a minimal effect on arterial oxygen tension and pulmonary vascular resistance when added to hospital-supplied compressed air but improved both when added to tank-supplied compressed air. Unintended inhalation of nitric oxide increases arterial oxygen tension and decreases pulmonary vascular resistance in patients with acute lung injury and acute respiratory distress syndrome. The unintended nitric oxide inhalation interferes with the

  4. Attenuation of acute nitrogen mustard-induced lung injury, inflammation and fibrogenesis by a nitric oxide synthase inhibitor

    Energy Technology Data Exchange (ETDEWEB)

    Malaviya, Rama; Venosa, Alessandro [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854 (United States); Hall, LeRoy [Drug Safety Sciences, Johnson and Johnson, Raritan, NJ 08869 (United States); Gow, Andrew J. [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854 (United States); Sinko, Patrick J. [Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854 (United States); Laskin, Jeffrey D. [Department of Environmental and Occupational Medicine, UMDNJ-Robert Wood Johnson Medical School, Piscataway, NJ 08854 (United States); Laskin, Debra L., E-mail: laskin@eohsi.rutgers.edu [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854 (United States)

    2012-12-15

    Nitrogen mustard (NM) is a toxic vesicant known to cause damage to the respiratory tract. Injury is associated with increased expression of inducible nitric oxide synthase (iNOS). In these studies we analyzed the effects of transient inhibition of iNOS using aminoguanidine (AG) on NM-induced pulmonary toxicity. Rats were treated intratracheally with 0.125 mg/kg NM or control. Bronchoalveolar lavage fluid (BAL) and lung tissue were collected 1 d–28 d later and lung injury, oxidative stress and fibrosis assessed. NM exposure resulted in progressive histopathological changes in the lung including multifocal lesions, perivascular and peribronchial edema, inflammatory cell accumulation, alveolar fibrin deposition, bronchiolization of alveolar septal walls, and fibrosis. This was correlated with trichrome staining and expression of proliferating cell nuclear antigen (PCNA). Expression of heme oxygenase (HO)-1 and manganese superoxide dismutase (Mn-SOD) was also increased in the lung following NM exposure, along with levels of protein and inflammatory cells in BAL, consistent with oxidative stress and alveolar-epithelial injury. Both classically activated proinflammatory (iNOS{sup +} and cyclooxygenase-2{sup +}) and alternatively activated profibrotic (YM-1{sup +} and galectin-3{sup +}) macrophages appeared in the lung following NM administration; this was evident within 1 d, and persisted for 28 d. AG administration (50 mg/kg, 2 ×/day, 1 d–3 d) abrogated NM-induced injury, oxidative stress and inflammation at 1 d and 3 d post exposure, with no effects at 7 d or 28 d. These findings indicate that nitric oxide generated via iNOS contributes to acute NM-induced lung toxicity, however, transient inhibition of iNOS is not sufficient to protect against pulmonary fibrosis. -- Highlights: ► Nitrogen mustard (NM) induces acute lung injury and fibrosis. ► Pulmonary toxicity is associated with increased expression of iNOS. ► Transient inhibition of iNOS attenuates acute

  5. AIR POLLUTION INFLUENCES ON EXHALED NITRIC OXIDE AMONG PEOPLE WITH TYPE II DIABETES.

    Science.gov (United States)

    Peng, Cheng; Luttmann-Gibson, Heike; Zanobetti, Antonella; Cohen, Allison; De Souza, Celine; Coull, Brent A; Horton, Edward S; Schwartz, Joel; Koutrakis, Petros; Gold, Diane R

    2016-04-01

    In a population with type 2 diabetes mellitus (T2DM), we examined associations of short-term air pollutant exposures with pulmonary inflammation, measured as fraction of exhaled pulmonary nitric oxide (FeNO). Sixty-nine Boston Metropolitan residents with T2DM completed up to 5 bi-weekly visits with 321 offline FeNO measurements. We measured ambient concentrations of particle mass, number and components at our stationary central site. Ambient concentrations of gaseous air pollutants were obtained from state monitors. We used linear models with fixed effects for participants, adjusting for 24-hour mean temperature, 24-hour mean water vapor pressure, season, and scrubbed room NO the day of the visit, to estimate associations between FeNO and interquartile range increases in exposure. Interquartile increases in the 6-hour averages of black carbon (BC) (0.5 μg/m 3 ) and particle number (PN) (1,000 particles/cm 3 ) were associated with increases in FeNO of 3.84% (95% CI 0.60% to 7.18%) and 9.86 % (95% CI 3.59% to 16.52%), respectively. We also found significant associations of increases in FeNO with increases in 24-hour moving averages of BC, PN and nitrogen oxides (NOx). Recent studies have focused on FeNO as a marker for eosinophilic pulmonary inflammation in asthmatic populations. This study adds support to the relevance of FeNO as a marker for pulmonary inflammation in diabetic populations, whose underlying chronic inflammatory status is likely to be related to innate immunity and proinflammatory adipokines.

  6. Pentose Phosphate Shunt Modulates Reactive Oxygen Species and Nitric Oxide Production Controlling Trypanosoma cruzi in Macrophages

    Directory of Open Access Journals (Sweden)

    Sue-jie Koo

    2018-02-01

    Full Text Available Metabolism provides substrates for reactive oxygen species (ROS and nitric oxide (NO generation, which are a part of the macrophage (Mφ anti-microbial response. Mφs infected with Trypanosoma cruzi (Tc produce insufficient levels of oxidative species and lower levels of glycolysis compared to classical Mφs. How Mφs fail to elicit a potent ROS/NO response during infection and its link to glycolysis is unknown. Herein, we evaluated for ROS, NO, and cytokine production in the presence of metabolic modulators of glycolysis and the Krebs cycle. Metabolic status was analyzed by Seahorse Flux Analyzer and mass spectrometry and validated by RNAi. Tc infection of RAW264.7 or bone marrow-derived Mφs elicited a substantial increase in peroxisome proliferator-activated receptor (PPAR-α expression and pro-inflammatory cytokine release, and moderate levels of ROS/NO by 18 h. Interferon (IFN-γ addition enhanced the Tc-induced ROS/NO release and shut down mitochondrial respiration to the levels noted in classical Mφs. Inhibition of PPAR-α attenuated the ROS/NO response and was insufficient for complete metabolic shift. Deprivation of glucose and inhibition of pyruvate transport showed that Krebs cycle and glycolysis support ROS/NO generation in Tc + IFN-γ stimulated Mφs. Metabolic profiling and RNAi studies showed that glycolysis-pentose phosphate pathway (PPP at 6-phosphogluconate dehydrogenase was essential for ROS/NO response and control of parasite replication in Mφ. We conclude that IFN-γ, but not inhibition of PPAR-α, supports metabolic upregulation of glycolytic-PPP for eliciting potent ROS/NO response in Tc-infected Mφs. Chemical analogs enhancing the glucose-PPP will be beneficial in controlling Tc replication and dissemination by Mφs.

  7. Nitric oxide modulates the immunological response of bovine PBMCs in an in vitro BRDc infection model.

    Science.gov (United States)

    Sheridan, Michael Peter; Regev-Shoshani, Gilly; Martins, James; Vimalanathan, Selvarani; Miller, Chris

    2016-12-01

    Bovine respiratory disease complex (BRDc) is a multi-factorial disease, involving both viral and bacterial pathogens, that negatively impacts the cattle feedlot industry. A nitric oxide releasing solution (NORS) has been developed and shown to have potential in the prevention of BRDc. This study investigated the underlying immunological mechanisms through which the nitroslyating agent NORS provides protection against the development of BRDc in susceptible cattle. An in vitro BRDc experimental model was designed using bovine peripheral blood mononuclear cells (PBMCs) which were infected with bovine herpesvirus 1 (BHV-1) and subsequently cultured with lipopolysaccharides (LPS) extracted from Mannheimia haemolytica bacteria. The cells were treated with NORS following viral infection to reflect the timing of administering the NORS treatment in feedlots during initial processing. An expression and protein analysis of key genes involved in the innate immune response was carried out. The BRDc model produced significant increases in gene expression (p<0.01) and protein release (p<0.05) of the proinflammatory cytokines IL-1β and TNF. Treatment with NORS reduced the protein levels of IL-1β (0.39-fold↓) (p<0.05) and TNF (0.48-fold↓) (p<0.01) in the BRDc experimental group when compared against the non-treatment BRDc controls. TLR4 expression, having been significantly reduced under the BRDc experimental conditions (0.33-fold↓) (p<0.05), increased significantly (0.76-fold↑) (p<0.05) following NORS treatment. This study provides evidence suggesting that NO may protect against the development of BRDc by limiting deleterious inflammation while simultaneously increasing TLR4 expression and enhancing the ability of the host to detect and respond to bacterial pathogens. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. Photochemical reactions of neptunium in nitric acid solution containing photocatalyst

    International Nuclear Information System (INIS)

    Fukasawa, Tetsuo; Kawamura, Fumio

    1991-01-01

    Photochemical oxidation and reduction behaviors of neptunium were preliminarily investigated in 3 mol/l nitric acid solution. Nitric acid of 3 mol/l simulated the high level waste solution from a spent fuel reprocessing process. Concentrations of Np(V), Np(VI) and nitrous acid were determined with a photospectrometer, and solution potential with an electrode. Without additives, Np(VI) was reduced to Np(V) by nitrous acid which was photolytically generated from nitric acid. With a scavenger for nitrous acid, Np(V) was oxidized to extractable Np(VI) by a photolytically generated oxidizing reagent which were predicted by the solution potential measurement. The reduction rate was higher than the oxidation rate because of the larger quantity and higher reactivity of nitrous acid than an oxidizing reagent. Photocatalyst was proved to be effective for the oxidation of Np(V) to Np(VI). (author)

  9. Pain modulation by nitric oxide in the spinal cord.

    Directory of Open Access Journals (Sweden)

    Marco Aurelio M Freire

    2009-09-01

    Full Text Available Nitric oxide (NO is a versatile messenger molecule first associated with endothelial relaxing effects. In the central nervous system (CNS, NO synthesis is primarily triggered by activation of N-methyl-D-aspartate (NMDA receptors and has a Janus face, with both beneficial and harmful properties, depending on concentration and the identity of its synthetic enzyme isoform. There are three isoforms of the NO synthesizing enzyme nitric oxide synthase (NOS: neuronal (nNOS, endothelial (eNOS, and inducible nitric oxide synthase (iNOS, each one involved with specific events in the brain. In CNS, nNOS is involved with modulation of synaptic transmission through long-term potentiation in several regions, including nociceptive circuits in the spinal cord. Here, we review the role played by NO on central pain sensitization.

  10. Vapor-liquid equilibria for nitric acid-water and plutonium nitrate-nitric acid-water solutions

    International Nuclear Information System (INIS)

    Maimoni, A.

    1980-01-01

    The liquid-vapor equilibrium data for nitric acid and nitric acid-plutnonium nitrate-water solutions were examined to develop correlations covering the range of conditions encountered in nuclear fuel reprocessing. The scanty available data for plutonium nitrate solutions are of poor quality but allow an order of magnitude estimate to be made. A formal thermodynamic analysis was attempted initially but was not successful due to the poor quality of the data as well as the complex chemical equilibria involved in the nitric acid and in the plutonium nitrate solutions. Thus, while there was no difficulty in correlating activity coefficients for nitric acid solutions over relatively narrow temperature ranges, attempts to extend the correlations over the range 25 0 C to the boiling point were not successful. The available data were then analyzed using empirical correlations from which normal boiling points and relative volatilities can be obtained over the concentration ranges 0 to 700 g/l Pu, 0 to 13 M nitric acid. Activity coefficients are required, however, if estimates of individual component vapor pressures are needed. The required ternary activity coefficients can be approximated from the correlations

  11. Carnosol Inhibits Pro-Inflammatory and Catabolic Mediators of Cartilage Breakdown in Human Osteoarthritic Chondrocytes and Mediates Cross-Talk between Subchondral Bone Osteoblasts and Chondrocytes.

    Directory of Open Access Journals (Sweden)

    Christelle Sanchez

    Full Text Available The aim of this work was to evaluate the effects of carnosol, a rosemary polyphenol, on pro-inflammatory and catabolic mediators of cartilage breakdown in chondrocytes and via bone-cartilage crosstalk.Osteoarthritic (OA human chondrocytes were cultured in alginate beads for 4 days in presence or absence of carnosol (6 nM to 9 μM. The production of aggrecan, matrix metalloproteinase (MMP-3, tissue inhibitor of metalloproteinase (TIMP-1, interleukin (IL-6 and nitric oxide (NO and the expression of type II collagen and ADAMTS-4 and -5 were analyzed. Human osteoblasts from sclerotic (SC or non-sclerotic (NSC subchondral bone were cultured for 3 days in presence or absence of carnosol before co-culture with chondrocytes. Chondrocyte gene expression was analyzed after 4 days of co-culture.In chondrocytes, type II collagen expression was significantly enhanced in the presence of 3 μM carnosol (p = 0.008. MMP-3, IL-6, NO production and ADAMTS-4 expression were down-regulated in a concentration-dependent manner by carnosol (p<0.01. TIMP-1 production was slightly increased at 3 μM (p = 0.02 and ADAMTS-5 expression was decreased from 0.2 to 9 μM carnosol (p<0.05. IL-6 and PGE2 production was reduced in the presence of carnosol in both SC and NSC osteoblasts while alkaline phosphatase activity was not changed. In co-culture experiments preincubation of NSC and SC osteoblasts wih carnosol resulted in similar effects to incubation with anti-IL-6 antibody, namely a significant increase in aggrecan and decrease in MMP-3, ADAMTS-4 and -5 gene expression by chondrocytes.Carnosol showed potent inhibition of pro-inflammatory and catabolic mediators of cartilage breakdown in chondrocytes. Inhibition of matrix degradation and enhancement of formation was observed in chondrocytes cocultured with subchondral osteoblasts preincubated with carnosol indicating a cross-talk between these two cellular compartments, potentially mediated via inhibition of IL-6 in

  12. Unsymmetrical phosphate as extractant for the extraction of nitric acid

    International Nuclear Information System (INIS)

    Gaikwad, R.H.; Jayaram, R.V.

    2016-01-01

    Tri-n-butyl phosphate (TBP) was first used as an extractant in 1944, during Manhattan project for the separation of actinides and further explored by Warf in 1949 for the extraction of Ce(IV) from aqueous nitric acid. TBP was further used as an extractant in the Plutonium Uranium Recovery by Extraction (PUREX) process. To meet the stringent requirements of the nuclear industry TBP has been extensively investigated. In spite of its wide applicability, TBP suffers from various disadvantages such as high aqueous solubility, third phase formation, chemical and radiation degradation leading to the formation of undesired products. It also suffers from incomplete decontamination of the actinides from fission products. Various attempts have been made to overcome the problems associated with TBP by way of using higher homologues of TBP such as Tri-iso amyl phosphate (TiAP), Tri-secondary butyl phosphate (TsBP), Tri amyl phosphate (TAP). It was found that in some cases the results were considerably better than those obtained with TBP for uranium/thorium extraction. The extraction of nitric acid by TBP and its higher homologues which are symmetrical are well documented. However, no solvent has emerged clearly superior than TBP. Here in we report the extraction of nitric acid with neutral unsymmetrical phosphates and study them as extractants for the extraction of nitric acid. Dibutyl secbutyl phosphate, dibutyl pentyl phosphate and dibutyl heptyl phosphate were synthesised for this purpose and the extraction of nitric acid was studied in n-dodecane. The results indicate that the substitution of one of the alkyl groups of the symmetrical phosphate adjacent to the phosphoryl (P=O) group of the phosphate does not have any pronounced effect on the extraction capacity of nitric acid. (author)

  13. Kruppel-like factor 2 (KLF2) regulates proinflammatory activation of monocytes

    Science.gov (United States)

    Das, Hiranmoy; Kumar, Ajay; Lin, Zhiyong; Patino, Willmar D.; Hwang, Paul M.; Feinberg, Mark W.; Majumder, Pradip K.; Jain, Mukesh K.

    2006-01-01

    The mechanisms regulating activation of monocytes remain incompletely understood. Herein we provide evidence that Kruppel-like factor 2 (KLF2) inhibits proinflammatory activation of monocytes. In vitro, KLF2 expression in monocytes is reduced by cytokine activation or differentiation. Consistent with this observation, KLF2 expression in circulating monocytes is reduced in patients with chronic inflammatory conditions such as coronary artery disease. Adenoviral overexpression of KLF2 inhibits the LPS-mediated induction of proinflammatory factors, cytokines, and chemokines and reduces phagocytosis. Conversely, short interfering RNA-mediated reduction in KLF2 increased inflammatory gene expression. Reconstitution of immunodeficient mice with KLF2-overexpressing monocytes significantly reduced carrageenan-induced acute paw edema formation. Mechanistically, KLF2 inhibits the transcriptional activity of both NF-κB and activator protein 1, in part by means of recruitment of transcriptional coactivator p300/CBP-associated factor. These observations identify KLF2 as a novel negative regulator of monocytic activation. PMID:16617118

  14. Prediabetes and prehypertension in disease free obese adults correlate with an exacerbated systemic proinflammatory milieu

    Directory of Open Access Journals (Sweden)

    Johnson William D

    2010-07-01

    Full Text Available Abstract Background Obesity is a pro-inflammatory state frequently associated with widespread metabolic alterations that include insulin resistance and deregulation of blood pressure (BP. This cascade of events in some measure explains the susceptibility of obese adults for co-morbid conditions like diabetes mellitus and hypertension. Hypothesis We hypothesized that an elevated systemic proinflammatory burden correlates with dysglycemia and deregulated blood pressure. Methods We analyzed the screening anthropometric and laboratory measures from healthy disease free obese adults (n = 35; women (W 27, men (M 8 in a weight loss study. Results Healthy obese normoglycemic (fasting serum glucose: FSG Conclusions In otherwise healthy disease free obese adults, a higher degree of systemic inflammation is associated with prediabetes and prehypertension.

  15. Tumour-Derived Interleukin-1 Beta Induces Pro-inflammatory Response in Human Mesenchymal Stem Cells

    DEFF Research Database (Denmark)

    Alajez, Nehad M; Al-toub, Mashael; Almusa, Abdulaziz

    ’ secreted factors as represented by a panel of human cancer cell lines (breast (MCF7 and MDA-MB-231); prostate (PC-3); lung (NCI-H522); colon (HT-29) and head & neck (FaDu)) on the biological characteristics of MSCs. Background Over the past several years, significant amount of research has emerged......, the goal of this study was to assess the cellular and molecular changes in MSCs in response to secreted factors present in conditioned media (CM) from a panel of human tumor cell lines covering a spectrum of human cancers (Breast, Prostate, Lung, colon, and head and neck). Research Morphological changes...... with bipolar processes. In association with phenotypic changes, genome-wide gene expression and bioinformatics analysis revealed an enhanced pro-inflammatory response of those MSCs. Pharmacological inhibitions of FAK and MAPKK severely impaired the pro-inflammatory response of MSCs to tumor CM (~80-99%, and 55...

  16. Study of niobium V compounds in nitric medium

    International Nuclear Information System (INIS)

    Gue, J.-P.; Kikindai, Tivadar; CEA Centre d'Etudes Nucleaires de Fontenay-aux-Roses, 92

    1976-01-01

    Nitric solutions of niobium V were studied in the range of concentrations of 5.10 -6 M to 0,5.10 -3 M in niobium and 0,4 to 10N in nitric acid. Methods used were light scattering, electron microscopy, electrophoresis and ultracentrifugation. It is shown that niobium was in a colloidal hydroxide form. Solvent extraction studies were performed with dibutyl phosphoric acid diluted in dodecane. It appears that floculation of the sol occurs for weak organic acid concentrations. But if the concentration increases, the precipitated niobium compound is redissolved in the organic phase [fr

  17. Corrosion resistance of zirconium: general mechanisms, behaviour in nitric acid

    International Nuclear Information System (INIS)

    Pinard Legry, G.

    1990-01-01

    Corrosion resistance of zirconium results from the strong affinity of this metal for oxygen; as a result a thin protective oxide film is spontaneously formed in air or aqueous media, its thickness and properties depending on the physicochemical conditions at the interface. This film passivates the underlying metal but obviously if the passive film is partially or completely removed, localised or generalised corrosion phenomena will occur. In nitric acid, this depassivation may be chemical (fluorides) or mechanical (straining, creep, fretting). In these cases it is useful to determine the physicochemical conditions (concentration, temperature, potential, stress) which will have to be observed to use safely zirconium and its alloys in nitric acid solutions [fr

  18. Adrenoceptor-activated nitric oxide synthesis in salivary acinar cells

    DEFF Research Database (Denmark)

    Looms, Dagnia; Dissing, Steen; Tritsaris, Katerina

    2000-01-01

    We investigated the cellular regulation of nitric oxide synthase (NOS) activity in isolated acinar cells from rat parotid and human labial salivary glands, using the newly developed fluorescent nitric oxide (NO) indicator, DAF-2. We found that sympathetic stimulation with norepinephrine (NE) caused...... a strong increase in NO synthesis that was not seen after parasympathetic stimulation with acetylcholine. In rat parotid acinar cells, we furthermore investigated to which extent the NOS activity was dependent on the intracellular free Ca2+ concentration ([Ca2+]i) by simultaneously measuring NO synthesis...

  19. A nitric oxide donor (nitroglycerin) triggers genuine migraine attacks

    DEFF Research Database (Denmark)

    Thomsen, L L; Kruuse, C; Iversen, Helle Klingenberg

    1994-01-01

    Supersensitivity to induction of headache and arterial dilatation by a donor of nitric oxide (nitroglycerin) has recently been demonstrated in migraine sufferers. The aims of the present study were to examine whether the nitric oxide donor nitroglycerin may induce a typical migraine attack......, to exclude placebo-related effects and to describe the relation between middle cerebral artery dilatation and provoked migraine. Nitroglycerin (0.5 μg/kg/min for 20 min) or placebo was infused into 12 migraine patients in a double-blind cross-over trial. Blood velocity in the middle cerebral artery...

  20. Polybrominated diphenyl ethers enhance the production of proinflammatory cytokines by the placenta.

    Science.gov (United States)

    Peltier, M R; Klimova, N G; Arita, Y; Gurzenda, E M; Murthy, A; Chawala, K; Lerner, V; Richardson, J; Hanna, N

    2012-09-01

    Polybrominated diphenyl ether(s) (PBDE) are ubiquitous environmental contaminants that bind and cross the placenta but their effects on pregnancy outcome are unclear. It is possible that environmental contaminants increase the risk of inflammation-mediated pregnancy complications such as preterm birth by promoting a proinflammatory environment at the maternal-fetal interface. We hypothesized that PBDE would reduce IL-10 production and enhance the production of proinflammatory cytokines associated with preterm labor/birth by placental explants. Second-trimester placental explants were cultured in either vehicle (control) or 2 μM PBDE mixture of congers 47, 99 and 100 for 72 h. Cultures were then stimulated with 10(6) CFU/ml heat-killed Escherichia coli for a final 24 h incubation and conditioned medium was harvested for quantification of cytokines and PGE(2). COX-2 content and viability of the treated tissues were then quantified by tissue ELISA and MTT reduction activity, respectively. PBDE pre-treatment reduced E. coli-stimulated IL-10 production and significantly increased E. coli-stimulated IL-1β secretion. PBDE exposure also increased basal and bacteria-stimulated COX-2 expression. Basal, but not bacteria-stimulated PGE(2), was also enhanced by PBDE exposure. No effect of PBDE on viability of the explants cultures was detected. In summary, pre-exposure of placental explants to congers 47, 99, and 100 enhanced the placental proinflammatory response to infection. This may increase the risk of infection-mediated preterm birth by lowering the threshold for bacteria to stimulate a proinflammatory response(s). Copyright © 2012 Elsevier Ltd. All rights reserved.

  1. Globular adiponectin induces a pro-inflammatory response in human astrocytic cells

    International Nuclear Information System (INIS)

    Wan, Zhongxiao; Mah, Dorrian; Simtchouk, Svetlana; Klegeris, Andis; Little, Jonathan P.

    2014-01-01

    Highlights: • Adiponectin receptors are expressed in human astrocytes. • Globular adiponectin induces secretion of IL-6 and MCP-1 from cultured astrocytes. • Adiponectin may play a pro-inflammatory role in astrocytes. - Abstract: Neuroinflammation, mediated in part by activated brain astrocytes, plays a critical role in the development of neurodegenerative disorders, including Alzheimer’s disease (AD). Adiponectin is the most abundant adipokine secreted from adipose tissue and has been reported to exert both anti- and pro-inflammatory effects in peripheral tissues; however, the effects of adiponectin on astrocytes remain unknown. Shifts in peripheral concentrations of adipokines, including adiponectin, could contribute to the observed link between midlife adiposity and increased AD risk. The aim of the present study was to characterize the effects of globular adiponectin (gAd) on pro-inflammatory cytokine mRNA expression and secretion in human U373 MG astrocytic cells and to explore the potential involvement of nuclear factor (NF)-κB, p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK)1/2, c-Jun N-terminal kinase (JNK) and phosphatidylinositide 3-kinases (PI3 K) signaling pathways in these processes. We demonstrated expression of adiponectin receptor 1 (adipoR1) and adipoR2 in U373 MG cells and primary human astrocytes. gAd induced secretion of interleukin (IL)-6 and monocyte chemoattractant protein (MCP)-1, and gene expression of IL-6, MCP-1, IL-1β and IL-8 in U373 MG cells. Using specific inhibitors, we found that NF-κB, p38MAPK and ERK1/2 pathways are involved in gAd-induced induction of cytokines with ERK1/2 contributing the most. These findings provide evidence that gAd may induce a pro-inflammatory phenotype in human astrocytes

  2. Gene array analysis of PD-1H overexpressing monocytes reveals a pro-inflammatory profile

    Directory of Open Access Journals (Sweden)

    Preeti Bharaj

    2018-02-01

    Full Text Available We have previously reported that overexpression of Programmed Death -1 Homolog (PD-1H in human monocytes leads to activation and spontaneous secretion of multiple pro inflammatory cytokines. Here we evaluate changes in monocytes gene expression after enforced PD-1H expression by gene array. The results show that there are significant alterations in 51 potential candidate genes that relate to immune response, cell adhesion and metabolism. Genes corresponding to pro-inflammatory cytokines showed the highest upregulation, 7, 3.2, 3.0, 5.8, 4.4 and 3.1 fold upregulation of TNF-α, IL-1 β, IFN-α, γ, λ and IL-27 relative to vector control. The data are in agreement with cytometric bead array analysis showing induction of proinflammatory cytokines, IL-6, IL-1β and TNF-α by PD-1H. Other genes related to inflammation, include transglutaminase 2 (TG2, NF-κB (p65 and p50 and toll like receptors (TLR 3 and 4 were upregulated 5, 4.5 and 2.5 fold, respectively. Gene set enrichment analysis (GSEA also revealed that signaling pathways related to inflammatory response, such as NFκB, AT1R, PYK2, MAPK, RELA, TNFR1, MTOR and proteasomal degradation, were significantly upregulated in response to PD-1H overexpression. We validated the results utilizing a standard inflammatory sepsis model in humanized BLT mice, finding that PD-1H expression was highly correlated with proinflammatory cytokine production. We therefore conclude that PD-1H functions to enhance monocyte activation and the induction of a pro-inflammatory gene expression profile.

  3. A pro-inflammatory role for Th22 cells in Helicobacter pylori-associated gastritis.

    Science.gov (United States)

    Zhuang, Yuan; Cheng, Ping; Liu, Xiao-fei; Peng, Liu-sheng; Li, Bo-sheng; Wang, Ting-ting; Chen, Na; Li, Wen-hua; Shi, Yun; Chen, Weisan; Pang, Ken C; Zeng, Ming; Mao, Xu-hu; Yang, Shi-ming; Guo, Hong; Guo, Gang; Liu, Tao; Zuo, Qian-fei; Yang, Hui-jie; Yang, Liu-yang; Mao, Fang-yuan; Lv, Yi-pin; Zou, Quan-ming

    2015-09-01

    Helper T (Th) cell responses are critical for the pathogenesis of Helicobacter pylori-induced gastritis. Th22 cells represent a newly discovered Th cell subset, but their relevance to H. pylori-induced gastritis is unknown. Flow cytometry, real-time PCR and ELISA analyses were performed to examine cell, protein and transcript levels in gastric samples from patients and mice infected with H. pylori. Gastric tissues from interleukin (IL)-22-deficient and wild-type (control) mice were also examined. Tissue inflammation was determined for pro-inflammatory cell infiltration and pro-inflammatory protein production. Gastric epithelial cells and myeloid-derived suppressor cells (MDSC) were isolated, stimulated and/or cultured for Th22 cell function assays. Th22 cells accumulated in gastric mucosa of both patients and mice infected with H. pylori. Th22 cell polarisation was promoted via the production of IL-23 by dendritic cells (DC) during H. pylori infection, and resulted in increased inflammation within the gastric mucosa. This inflammation was characterised by the CXCR2-dependent influx of MDSCs, whose migration was induced via the IL-22-dependent production of CXCL2 by gastric epithelial cells. Under the influence of IL-22, MDSCs, in turn, produced pro-inflammatory proteins, such as S100A8 and S100A9, and suppressed Th1 cell responses, thereby contributing to the development of H. pylori-associated gastritis. This study, therefore, identifies a novel regulatory network involving H. pylori, DCs, Th22 cells, gastric epithelial cells and MDSCs, which collectively exert a pro-inflammatory effect within the gastric microenvironment. Efforts to inhibit this Th22-dependent pathway may therefore prove a valuable strategy in the therapy of H. pylori-associated gastritis. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  4. Proinflammatory effects of exogenously administered IL-10 in experimental autoimmune orchitis

    DEFF Research Database (Denmark)

    Kaneko, Tetsushi; Itoh, Masahiro; Nakamura, Yoichi

    2003-01-01

    We studied the effects of exogenously administered recombinant murine interleukin (IL)-10 on the development of experimental autoimmune orchitis (EAO) in C3H/He mice. IL-10 significantly augments histological signs of EAO when administered for 6 consecutive days from days 15 to 20 after primary...... immunisations with testicular germ cells. These data demonstrate that IL-10, in addition to its well-known antiinflammatory property, also has proinflammatory functions capable of up-regulating testicular immunoinflammatory processes in vivo....

  5. Globular adiponectin induces a pro-inflammatory response in human astrocytic cells

    Energy Technology Data Exchange (ETDEWEB)

    Wan, Zhongxiao; Mah, Dorrian; Simtchouk, Svetlana [School of Health and Exercise Sciences, University of British Columbia Okanagan, Kelowna, BC (Canada); Klegeris, Andis [Department of Biology, University of British Columbia Okanagan, Kelowna, BC (Canada); Little, Jonathan P., E-mail: jonathan.little@ubc.ca [School of Health and Exercise Sciences, University of British Columbia Okanagan, Kelowna, BC (Canada)

    2014-03-28

    Highlights: • Adiponectin receptors are expressed in human astrocytes. • Globular adiponectin induces secretion of IL-6 and MCP-1 from cultured astrocytes. • Adiponectin may play a pro-inflammatory role in astrocytes. - Abstract: Neuroinflammation, mediated in part by activated brain astrocytes, plays a critical role in the development of neurodegenerative disorders, including Alzheimer’s disease (AD). Adiponectin is the most abundant adipokine secreted from adipose tissue and has been reported to exert both anti- and pro-inflammatory effects in peripheral tissues; however, the effects of adiponectin on astrocytes remain unknown. Shifts in peripheral concentrations of adipokines, including adiponectin, could contribute to the observed link between midlife adiposity and increased AD risk. The aim of the present study was to characterize the effects of globular adiponectin (gAd) on pro-inflammatory cytokine mRNA expression and secretion in human U373 MG astrocytic cells and to explore the potential involvement of nuclear factor (NF)-κB, p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK)1/2, c-Jun N-terminal kinase (JNK) and phosphatidylinositide 3-kinases (PI3 K) signaling pathways in these processes. We demonstrated expression of adiponectin receptor 1 (adipoR1) and adipoR2 in U373 MG cells and primary human astrocytes. gAd induced secretion of interleukin (IL)-6 and monocyte chemoattractant protein (MCP)-1, and gene expression of IL-6, MCP-1, IL-1β and IL-8 in U373 MG cells. Using specific inhibitors, we found that NF-κB, p38MAPK and ERK1/2 pathways are involved in gAd-induced induction of cytokines with ERK1/2 contributing the most. These findings provide evidence that gAd may induce a pro-inflammatory phenotype in human astrocytes.

  6. Hemocyanins Stimulate Innate Immunity by Inducing Different Temporal Patterns of Proinflammatory Cytokine Expression in Macrophages.

    Science.gov (United States)

    Zhong, Ta-Ying; Arancibia, Sergio; Born, Raimundo; Tampe, Ricardo; Villar, Javiera; Del Campo, Miguel; Manubens, Augusto; Becker, María Inés

    2016-06-01

    Hemocyanins induce a potent Th1-dominant immune response with beneficial clinical outcomes when used as a carrier/adjuvant in vaccines and nonspecific immunostimulant in cancer. However, the mechanisms by which hemocyanins trigger innate immune responses, leading to beneficial adaptive immune responses, are unknown. This response is triggered by a proinflammatory signal from various components, of which macrophages are an essential part. To understand how these proteins influence macrophage response, we investigated the effects of mollusks hemocyanins with varying structural and immunological properties, including hemocyanins from Concholepas concholepas, Fissurella latimarginata, and Megathura crenulata (keyhole limpet hemocyanin), on cultures of peritoneal macrophages. Hemocyanins were phagocytosed and slowly processed. Analysis of this process showed differential gene expression along with protein levels of proinflammatory markers, including IL-1β, IL-6, IL-12p40, and TNF-α. An extended expression analysis of 84 cytokines during a 24-h period showed a robust proinflammatory response for F. latimarginata hemocyanin in comparison with keyhole limpet hemocyanin and C. concholepas hemocyanin, which was characterized by an increase in the transcript levels of M1 cytokines involved in leukocyte recruitment. These cytokine genes included chemokines (Cxcl1, Cxcl3, Cxcl5, Ccl2, and Ccl3), ILs (Il1b and Ifng), growth factors (Csf2 and Csf3), and TNF family members (Cd40lg). The protein levels of certain cytokines were increased. However, every hemocyanin maintains downregulated key M2 cytokine genes, including Il4 and Il5 Collectively, our data demonstrate that hemocyanins are able to trigger the release of proinflammatory factors with different patterns of cytokine expression, suggesting differential signaling pathways and transcriptional network mechanisms that lead to the activation of M1-polarized macrophages. Copyright © 2016 by The American Association of

  7. Proinflammatory gene polymorphisms are potentially associated with Korean non-Sjogren dry eye patients

    OpenAIRE

    Na, Kyung-Sun; Mok, Jee-Won; Kim, Ja Yeon; Joo, Choun-Ki

    2011-01-01

    Purpose To determine whether proinflammatory cytokine genes were potential susceptibility candidate genes for Korean patients with non-Sjogren dry eye, we investigated the association of the interleukin 1 beta (IL1B), interleukin 6 (IL6), and interleukin 6 receptor (IL6R) variations with this disease in Korean patients. Methods Genomic DNA was extracted from blood samples of unrelated non-Sjogren dry eye patients and healthy control individuals who visited the Eye Center and Health Promotion ...

  8. Fisetin Inhibits Hyperglycemia-Induced Proinflammatory Cytokine Production by Epigenetic Mechanisms

    Directory of Open Access Journals (Sweden)

    Hye Joo Kim

    2012-01-01

    Full Text Available Diabetes is characterized by a proinflammatory state, and several inflammatory processes have been associated with both type 1 and type 2 diabetes and the resulting complications. High glucose levels induce the release of proinflammatory cytokines. Fisetin, a flavonoid dietary ingredient found in the smoke tree (Cotinus coggygria, and is also widely distributed in fruits and vegetables. Fisetin is known to exert anti-inflammatory effects via inhibition of the NF-κB signaling pathway. In this study, we analyzed the effects of fisetin on proinflammatory cytokine secretion and epigenetic regulation, in human monocytes cultured under hyperglycemic conditions. Human monocytic (THP-1 cells were cultured under control (14.5 mmol/L mannitol, normoglycemic (NG, 5.5 mmol/L glucose, or hyperglycemic (HG, 20 mmol/L glucose conditions, in the absence or presence of fisetin. Fisetin was added (3–10 μM for 48 h. While the HG condition significantly induced histone acetylation, NF-κB activation, and proinflammatory cytokine (IL-6 and TNF-α release from THP-1 cells, fisetin suppressed NF-κB activity and cytokine release. Fisetin treatment also significantly reduced CBP/p300 gene expression, as well as the levels of acetylation and HAT activity of the CBP/p300 protein, which is a known NF-κB coactivator. These results suggest that fisetin inhibits HG-induced cytokine production in monocytes, through epigenetic changes involving NF-κB. We therefore propose that fisetin supplementation be considered for diabetes prevention.

  9. Histamine mediates the pro-inflammatory effect of latex of Calotropis procera in rats

    Directory of Open Access Journals (Sweden)

    Yatin M. Shivkar

    2003-01-01

    Full Text Available Introduction: Calotropis procera is known to produce contact dermatitis and the latex of this plant produces intense inflammation when injected locally. However, the precise mode of its pro-inflammatory effect is not known. In present study we have pharmacologically characterized the inflammation induced by latex of C. procera in a rat paw edema model and determined the role of histamine in latex-induced inflammation.

  10. Chitosan drives anti-inflammatory macrophage polarisation and pro-inflammatory dendritic cell stimulation

    Directory of Open Access Journals (Sweden)

    MI Oliveira

    2012-07-01

    Full Text Available Macrophages and dendritic cells (DC share the same precursor and play key roles in immunity. Modulation of their behaviour to achieve an optimal host response towards an implanted device is still a challenge. Here we compare the differentiation process and polarisation of these related cell populations and show that they exhibit different responses to chitosan (Ch, with human monocyte-derived macrophages polarising towards an anti-inflammatory phenotype while their DC counterparts display pro-inflammatory features. Macrophages and DC, whose interactions with biomaterials are frequently analysed using fully differentiated cells, were cultured directly on Ch films, rather than exposed to the polymer after complete differentiation. Ch was the sole stimulating factor and activated both macrophages and DC, without leading to significant T cell proliferation. After 10 d on Ch, macrophages significantly down-regulated expression of pro-inflammatory markers, CD86 and MHCII. Production of pro-inflammatory cytokines, particularly TNF-α, decreased with time for cells cultured on Ch, while anti-inflammatory IL-10 and TGF-β1, significantly increased. Altogether, these results suggest an M2c polarisation. Also, macrophage matrix metalloproteinase activity was augmented and cell motility was stimulated by Ch. Conversely, DC significantly enhanced CD86 expression, reduced IL-10 secretion and increased TNF-α and IL-1β levels. Our findings indicate that cells with a common precursor may display different responses, when challenged by the same biomaterial. Moreover, they help to further comprehend macrophage/DC interactions with Ch and the balance between pro- and anti-inflammatory signals associated with implant biomaterials. We propose that an overall pro-inflammatory reaction may hide the expression of anti-inflammatory cytokines, likely relevant for tissue repair/regeneration.

  11. Pro-inflammatory capacity of classically activated monocytes relates positively to muscle mass and strength.

    Science.gov (United States)

    Beenakker, Karel G M; Westendorp, Rudi G J; de Craen, Anton J M; Slagboom, Pieternella E; van Heemst, Diana; Maier, Andrea B

    2013-08-01

    In mice, monocytes that exhibit a pro-inflammatory profile enter muscle tissue after muscle injury and are crucial for clearance of necrotic tissue and stimulation of muscle progenitor cell proliferation and differentiation. The aim of this study was to test if pro-inflammatory capacity of classically activated (M1) monocytes relates to muscle mass and strength in humans. This study included 191 male and 195 female subjects (mean age 64.2 years (SD 6.4) and 61.9 ± 6.4, respectively) of the Leiden Longevity Study. Pro-inflammatory capacity of M1 monocytes was assessed by ex vivo stimulation of whole blood with Toll-like receptor (TLR) 4 agonist lipopolysaccharide (LPS) and TLR-2/1 agonist tripalmitoyl-S-glycerylcysteine (Pam₃Cys-SK₄), both M1 phenotype activators. Cytokines that stimulate M1 monocyte response (IFN-γ and GM-CSF) as well as cytokines that are secreted by M1 monocytes (IL-6, TNF-α, IL-12, and IL-1β) were measured. Analyses were adjusted for age, height, and body fat mass. Upon stimulation with LPS, the cytokine production capacity of INF-γ, GM-CSF, and TNF-α was significantly positively associated with lean body mass, appendicular lean mass and handgrip strength in men, but not in women. Upon stimulation with Pam₃Cys-SK₄, IL-6; TNF-α; and Il-1β were significantly positively associated with lean body mass and appendicular lean in women, but not in men. Taken together, this study shows that higher pro-inflammatory capacity of M1 monocytes upon stimulation is associated with muscle characteristics and sex dependent. © 2013 John Wiley & Sons Ltd and the Anatomical Society.

  12. Supplementation of xanthophylls decreased proinflammatory and increased anti-inflammatory cytokines in hens and chicks.

    Science.gov (United States)

    Gao, Yu-Yun; Xie, Qing-Mei; Jin, Ling; Sun, Bao-Li; Ji, Jun; Chen, Feng; Ma, Jing-Yun; Bi, Ying-Zuo

    2012-11-28

    The present study investigated the effects of xanthophylls (containing 40 % of lutein and 60 % of zeaxanthin) on proinflammatory cytokine (IL-1β, IL-6, interferon (IFN)-γ and lipopolysaccharide-induced TNF-α factor (LITAF)) and anti-inflammatory cytokine (IL-4 and IL-10) expression of breeding hens and chicks. In Expt 1, a total of 432 hens were fed diets supplemented with 0 (as the control group), 20 or 40 mg/kg xanthophylls (six replicates per treatment). The liver, duodenum, jejunum and ileum were sampled at 35 d of the trial. The results showed that both levels of xanthophyll addition decreased IL-1β mRNA in the liver and jejunum, IL-6 mRNA in the liver, IFN-γ mRNA in the jejunum and LITAF mRNA in the liver compared to the control group. Expt 2 was a 2 × 2 factorial design. Male chicks hatched from 0 or 40 mg/kg xanthophyll diet of hens were fed a diet containing either 0 or 40 mg/kg xanthophylls. The liver, duodenum, jejunum and ileum were collected at 0, 7, 14 and 21 d after hatching. The results showed that in ovo xanthophylls decreased proinflammatory cytokine expression (IL-1β, IL-6, IFN-γ and LITAF) in the liver, duodenum, jejunum and ileum and increased anti-inflammatory cytokine expression (IL-4 and IL-10) in the liver, jejunum and ileum mainly at 0-7 d after hatching. In ovo effects gradually vanished and dietary effects began to work during 1-2 weeks after hatching. Dietary xanthophylls modulated proinflammatory cytokines (IL-1β, IL-6 and IFN-γ) in the liver, duodenum, jejunum and ileum and anti-inflammatory cytokine (IL-10) in the liver and jejunum mainly from 2 weeks onwards. In conclusion, xanthophylls could regulate proinflammatory and anti-inflammatory cytokine expression in different tissues of hens and chicks.

  13. Murine Neonates Infected with Yersinia enterocolitica Develop Rapid and Robust Proinflammatory Responses in Intestinal Lymphoid Tissues

    Science.gov (United States)

    Siefker, David T.; Echeverry, Andrea; Brambilla, Roberta; Fukata, Masayuki; Schesser, Kurt

    2014-01-01

    Neonatal animals are generally very susceptible to infection with bacterial pathogens. However, we recently reported that neonatal mice are highly resistant to orogastric infection with Yersinia enterocolitica. Here, we show that proinflammatory responses greatly exceeding those in adults arise very rapidly in the mesenteric lymph nodes (MLN) of neonates. High-level induction of proinflammatory gene expression occurred in the neonatal MLN as early as 18 h postinfection. Marked innate phagocyte recruitment was subsequently detected at 24 h postinfection. Enzyme-linked immunosorbent spot assay (ELISPOT) analyses indicated that enhanced inflammation in neonatal MLN is contributed to, in part, by an increased frequency of proinflammatory cytokine-secreting cells. Moreover, both CD11b+ and CD11b− cell populations appeared to play a role in proinflammatory gene expression. The level of inflammation in neonatal MLN was also dependent on key bacterial components. Y. enterocolitica lacking the virulence plasmid failed to induce innate phagocyte recruitment. In contrast, tumor necrosis factor alpha (TNF-α) protein expression and neutrophil recruitment were strikingly higher in neonatal MLN after infection with a yopP-deficient strain than with wild-type Y. enterocolitica, whereas only modest increases occurred in adults. This hyperinflammatory response was associated with greater colonization of the spleen and higher mortality in neonates, while there was no difference in mortality among adults. This model highlights the dynamic levels of inflammation in the intestinal lymphoid tissues and reveals the protective (wild-type strain) versus harmful (yopP-deficient strain) consequences of inflammation in neonates. Moreover, these results reveal that the neonatal intestinal lymphoid tissues have great potential to rapidly mobilize innate components in response to infection with bacterial enteropathogens. PMID:24478090

  14. Anthocyanin prevents CD40-activated proinflammatory signaling in endothelial cells by regulating cholesterol distribution.

    Science.gov (United States)

    Xia, Min; Ling, Wenhua; Zhu, Huilian; Wang, Qing; Ma, Jing; Hou, Mengjun; Tang, Zhihong; Li, Lan; Ye, Qinyuan

    2007-03-01

    Intracellular tumor necrosis factor receptor-associated factors (TRAFs) translocation to lipid rafts is a key element in CD40-induced signaling. The purpose of this study was to investigate the influence of anthocyanin on CD40-mediated proinflammatory events in human endothelial cells and the underlying possible molecular mechanism. Treatment of endothelial cells with anthocyanin prevented from CD40-induced proinflammatory status, measured by production of IL-6, IL-8, and monocyte chemoattractant protein-1 through inhibiting CD40-induced nuclear factor-kappaB (NF-kappaB) activation. TRAF-2 played pivotal role in CD40-NF-kappaB pathway as TRAF-2 small interference RNA (siRNA) diminished CD40-induced NF-kappaB activation and inflammation. TRAF-2 overexpression increased CD40-mediated NF-kappaB activation. Moreover, TRAF-2 almost totally recruited to lipid rafts after stimulation by CD40 ligand and depletion of cholesterol diminished CD40-mediated NF-kappaB activation. Exposure to anthocyanin not only interrupted TRAF-2 recruitment to lipid rafts but also decreased cholesterol content in Triton X-100 insoluble lipid rafts. However, anthocyanin did not influence the interaction between CD40 ligand and CD40 receptor. Our findings suggest that anthocyanin protects from CD40-induced proinflammatory signaling by preventing TRAF-2 translocation to lipid rafts through regulation of cholesterol distribution, which thereby may represent a mechanism that would explain the anti-inflammatory response of anthocyanin.

  15. Ultraviolet Radiation and the Slug Transcription Factor Induce Proinflammatory and Immunomodulatory Mediator Expression in Melanocytes

    Directory of Open Access Journals (Sweden)

    Stephanie H. Shirley

    2012-01-01

    Full Text Available Despite extensive investigation, the precise contribution of the ultraviolet radiation (UVR component of sunlight to melanoma etiology remains unclear. UVR induces keratinocytes to secrete proinflammatory and immunomodulatory mediators that promote inflammation and skin tumor development; expression of the slug transcription factor in keratinocytes is required for maximal production of these mediators. In the present studies we examined the possibility that UVR-exposed melanocytes also produce proinflammatory mediators and that Slug is important in this process. Microarray studies revealed that both UVR exposure and Slug overexpression altered transcription of a variety of proinflammatory mediators by normal human melanocytes; some of these mediators are also known to stimulate melanocyte growth and migration. There was little overlap in the spectra of cytokines produced by the two stimuli. However IL-20 was similarly induced by both stimuli and the NFκB pathway appeared to be important in both circumstances. Further exploration of UVR-induced and Slug-dependent pathways of cytokine induction in melanocytes may reveal novel targets for melanoma therapy.

  16. Irradiation of existing atherosclerotic lesions increased inflammation by favoring pro-inflammatory macrophages

    International Nuclear Information System (INIS)

    Gabriels, Karen; Hoving, Saske; Gijbels, Marion J.; Pol, Jeffrey F.; Poele, Johannes A. te; Biessen, Erik A.; Daemen, Mat J.; Stewart, Fiona A.; Heeneman, Sylvia

    2014-01-01

    Background and purpose: Recent studies have shown an increased incidence of localized atherosclerosis and subsequent cardiovascular events in cancer patients treated with thoracic radiotherapy. We previously demonstrated that irradiation accelerated the development of atherosclerosis and predisposed to an inflammatory plaque phenotype in young hypercholesterolemic ApoE −/− mice. However, as older cancer patients already have early or advanced stages of atherosclerosis at the time of radiotherapy, we investigated the effects of irradiation on the progression of existing atherosclerotic lesions in vivo. Material and methods: ApoE −/− mice (28 weeks old) received local irradiation with 14 or 0 Gy (sham-treated) at the aortic arch and were examined after 4 and 12 weeks for atherosclerotic lesions, plaque size and phenotype. Moreover, we investigated the impact of irradiation on macrophage phenotype (pro- or anti-inflammatory) and function (efferocytotic capacity, i.e. clearance of apoptotic cells) in vitro. Results: Irradiation of existing lesions in the aortic arch resulted in smaller, macrophage-rich plaques with intraplaque hemorrhage and increased apoptosis. In keeping with the latter, in vitro studies revealed augmented polarization toward pro-inflammatory macrophages after irradiation and reduced efferocytosis by anti-inflammatory macrophages. In addition, considerably more lesions in irradiated mice were enriched in pro-inflammatory macrophages. Conclusions: Irradiation of existing atherosclerotic lesions led to smaller but more inflamed plaques, with increased numbers of apoptotic cells, most likely due to a shift toward pro-inflammatory macrophages in the plaque

  17. Identification of informative features for predicting proinflammatory potentials of engine exhausts.

    Science.gov (United States)

    Wang, Chia-Chi; Lin, Ying-Chi; Lin, Yuan-Chung; Jhang, Syu-Ruei; Tung, Chun-Wei

    2017-08-18

    The immunotoxicity of engine exhausts is of high concern to human health due to the increasing prevalence of immune-related diseases. However, the evaluation of immunotoxicity of engine exhausts is currently based on expensive and time-consuming experiments. It is desirable to develop efficient methods for immunotoxicity assessment. To accelerate the development of safe alternative fuels, this study proposed a computational method for identifying informative features for predicting proinflammatory potentials of engine exhausts. A principal component regression (PCR) algorithm was applied to develop prediction models. The informative features were identified by a sequential backward feature elimination (SBFE) algorithm. A total of 19 informative chemical and biological features were successfully identified by SBFE algorithm. The informative features were utilized to develop a computational method named FS-CBM for predicting proinflammatory potentials of engine exhausts. FS-CBM model achieved a high performance with correlation coefficient values of 0.997 and 0.943 obtained from training and independent test sets, respectively. The FS-CBM model was developed for predicting proinflammatory potentials of engine exhausts with a large improvement on prediction performance compared with our previous CBM model. The proposed method could be further applied to construct models for bioactivities of mixtures.

  18. Changes in proinflammatory cytokines and white matter in chronically stressed rats

    Directory of Open Access Journals (Sweden)

    Yang P

    2015-03-01

    Full Text Available Ping Yang,1 Zhenyong Gao,1 Handi Zhang,1 Zeman Fang,1 Cairu Wu,1 Haiyun Xu,1,2 Qing-Jun Huang1 1Mental Health Center, 2Department of Anatomy, Shantou University Medical College, Shantou, Guangdong, People’s Republic of China Abstract: Although the pathogenesis of depression, an incapacitating psychiatric ailment, remains largely unknown, previous human and animal studies have suggested that both proinflammatory cytokines and altered oligodendrocytes play important roles in the condition. This study examined these two factors in the brains of rats following unpredictable chronic mild stress for 4 weeks, with the hypothesis that chronic stress may affect oligodendrocytes and elevate proinflammatory cytokines in the brain. After suffering unpredictable stressors for 4 weeks, the rats showed depression-like behaviors, including decreased locomotion in the open field, increased immobility time in the forced swim test, and decreased sucrose consumption and less sucrose preference when compared with controls. Immunohistochemical staining of brain sections showed higher immunoreactivity of proinflammatory cytokines in certain brain regions of stressed rats compared with controls; lower immunoreactivity of myelin basic protein and fewer mature oligodendrocytes were seen in the prefrontal cortex, but no demyelination was detected. These results are interpreted and discussed in the context of recent findings from human and animal studies. Keywords: cytokines, depression, myelination, oligodendrocytes, stress 

  19. A Proinflammatory Effect of the β-Glucan from Pleurotus cornucopiae Mushroom on Macrophage Action

    Directory of Open Access Journals (Sweden)

    Ken-ichiro Minato

    2017-01-01

    Full Text Available PCPS from P. citrinopileatus mushroom extract is a β-1,6-glucan possessing a proinflammatory effect on innate immune cells. The PCPS stimulated THP-1 macrophages to secrete significant levels of TNF. Moreover, the mRNA expressions of TNF and IL-1β were significantly enhanced by PCPS treatment. However, the PCPS did not induce to express both IL-12 and IL-10 mRNA in the macrophages. Next, the P. cornucopiae extract (containing mainly PCPS treatment against mice showed significant increases in TNF and IL-1β mRNA expressions in the peritoneal macrophages of them. In this study, the expression levels of IFNγ mRNA in the spleen were almost the same between the extract- (PCPS- treated group and control group. However, the expression of IL-4 mRNA showed a lower level in the extract-treated group than that in the control. Our results suggested that the PCPS could induce proinflammatory action in the immune response. In addition, the proinflammatory effect of the PCPS on THP-1 was enhanced by 5′-GMP-Na, while it was reduced by vitamin D2. These two compounds are majorly contained in the P. citrinopileatus mushroom. Therefore, these results suggested that the P. citrinopileatus mushroom might contain other immune regulative compounds, such as vitamin D2, as well as PCPS.

  20. Herpesviruses viral loads and levels of proinflammatory cytokines in apical periodontitis.

    Science.gov (United States)

    Jakovljevic, A; Knezevic, A; Nikolic, N; Soldatovic, I; Jovanovic, T; Milasin, J; Andric, M

    2018-07-01

    This study aimed to analyse Epstein-Barr virus (EBV) and human cytomegalovirus (HCMV) viral loads in symptomatic and asymptomatic apical periodontitis lesions, to determine levels of TNF-α, IL-1β and IL-6 in these lesions and to investigate a possible correlation between herpesviral copy numbers and levels of proinflammatory cytokines. A total of 100 samples of apical periodontitis were subjected to HCMV and EBV copy numbers analysis by nested polymerase chain reaction (PCR) and TaqMan real-time PCR. The concentrations of TNF-α, IL-1β and IL-6 were determined by ELISA method. SPSS software was used for statistical analysis. There were no significant differences in the occurrence of EBV and HCMV between symptomatic and asymptomatic periapical lesions (p = .686, p = .879, respectively). Only 12 of 74 EBV (16.2%) and four of 54 HCMV (13.5%) nested PCR-positive samples showed increased viral copy numbers above the limit of 125 copies/ml. There was no significant correlation between the levels of analysed proinflammatory cytokines and herpesviral copy numbers in our sample. The observed low viral loads point to a relatively rare occurrence of active EBV and HCMV infection in our sample. Latent herpesviral infection does not enhance the production of investigated proinflammatory cytokines. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. All rights reserved.

  1. Intermittent fasting during Ramadan attenuates proinflammatory cytokines and immune cells in healthy subjects.

    Science.gov (United States)

    Faris, Mo'ez Al-Islam E; Kacimi, Safia; Al-Kurd, Ref'at A; Fararjeh, Mohammad A; Bustanji, Yasser K; Mohammad, Mohammad K; Salem, Mohammad L

    2012-12-01

    Intermittent fasting and caloric restriction have been shown to extend life expectancy and reduce inflammation and cancer promotion in animal models. It was hypothesized that intermittent prolonged fasting practiced during the month of Ramadan (RIF) could positively affect the inflammatory state. To investigate this hypothesis, a cross-sectional study was designed to investigate the impact of RIF on selected inflammatory cytokines and immune biomarkers in healthy subjects. Fifty (21 men and 29 women) healthy volunteers who practiced Ramadan fasting were recruited for the investigation of circulating proinflammatory cytokines (interleukin [IL]-1β, IL-6, and tumor necrosis factor α), immune cells (total leukocytes, monocytes, granulocytes, and lymphocytes), and anthropometric and dietary assessments. The investigations were conducted 1 week before Ramadan fasting, at the end of the third week of Ramadan, and 1 month after the cessation of Ramadan month. The proinflammatory cytokines IL-1β, IL-6, and tumor necrosis factor α; systolic and diastolic blood pressures; body weight; and body fat percentage were significantly lower (P fasting. Immune cells significantly decreased during Ramadan but still remained within the reference ranges. These results indicate that RIF attenuates inflammatory status of the body by suppressing proinflammatory cytokine expression and decreasing body fat and circulating levels of leukocytes. Copyright © 2012 Elsevier Inc. All rights reserved.

  2. Proinflammatory Soluble Interleukin-15 Receptor Alpha Is Increased in Rheumatoid Arthritis

    Directory of Open Access Journals (Sweden)

    Ana Cecilia Machado Diaz

    2012-01-01

    Full Text Available Rheumatoid arthritis (RA is an autoimmune and inflammatory disease in which many cytokines have been implicated. In particular, IL-15 is a cytokine involved in the inflammatory processes and bone loss. The aim of this study was to investigate the existence in synovial fluid of soluble IL-15Rα, a private receptor subunit for IL-15 which may act as an enhancer of IL-15-induced proinflammatory cytokines. Soluble IL-15Rα was quantified by a newly developed enzyme-linked immunosorbent assay (ELISA in samples of synovial fluid from patients with RA and osteoarthritis (OA. The levels of IL-15Rα were significantly increased in RA patients compared to OA patients. Also, we studied the presence of membrane-bound IL-15 in cells from synovial fluids, another element necessary to induce pro-inflammatory cytokines through reverse signaling. Interestingly, we found high levels of IL-6 related to high levels of IL-15Rα in RA but not in OA. Thus, our results evidenced presence of IL-15Rα in synovial fluids and suggested that its pro-inflammatory effect could be related to induction of IL-6.

  3. Detection of nitric acid and nitric oxides in the terrestrial atmosphere in the middle-infrared spectral region

    Directory of Open Access Journals (Sweden)

    M. I. Blecka

    1996-11-01

    Full Text Available A proposal for combined space and ground-based observations of the vertical distributions and the column densities of nitric acid and nitric oxide concentrations in the earth's atmosphere is discussed. We focus on the aspects that are particular to the idea of correlative measurements: geometrical considerations, simulations of the solar absorption spectra in the middle-infrared region corresponding to the different observational geometries, and the associated retrieval methods. These studies are done specifically for the Belgian-French experiment MIRAS (MIR Infrared Atmospheric Spectrometer onboard the Russian Space Station MIR and correlative ground-based FTIR measurements in the Tatra mountains.

  4. LYATK1 potently inhibits LPS-mediated pro-inflammatory response

    International Nuclear Information System (INIS)

    Xi, Feng; Liu, Yuan; Wang, Xiujuan; Kong, Wei; Zhao, Feng

    2016-01-01

    Lipopolysaccharide (LPS)-primed monocytes/macrophages produce pro-inflammatory cytokines, which could lead to endotoxin shock. TGF-β-activated kinase1 (TAK1) activation is involved in the process. In the current study, we studied the potential effect of a selective TAK1 inhibitor, LYTAK1, on LPS-stimulated response both in vitro and in vivo. We demonstrated that LYTAK1 inhibited LPS-induced mRNA expression and production of several pro-inflammatory cytokines [interleukin 1β (IL-1β), tumor necrosis factor-α (TNFα) and interleukin-6 (IL-6)] in RAW 264.7 macrophages. LYTAK1's activity was almost nullified with TAK1 shRNA-knockdown. Meanwhile, in both primary mouse bone marrow derived macrophages (BMDMs) and human peripheral blood mononuclear cells (PBMCs), LPS-induced pro-inflammatory cytokine production was again attenuated with LYTAK1 co-treatment. Molecularly, LYTAK1 dramatically inhibited LPS-induced TAK1-nuclear factor kappa B (NFκB) and mitogen-activated protein kinase (Erk, Jnk and p38) activation in RAW 264.7 cells, mouse BMDMs and human PBMCs. In vivo, oral administration of LYTAK1 inhibited LPS-induced activation of TAK1-NFκB-p38 in ex-vivo cultured PBMCs, and cytokine production and endotoxin shock in mice. Together, these results demonstrate that LYTAK1 inhibits LPS-induced production of several pro-inflammatory cytokines and endotoxin shock probably through blocking TAK1-regulated signalings. - Highlights: • LYTAK1 inhibits LPS-induced pro-inflammatory cytokine production in RAW 264.7 cells. • The effect by LYTAK1 is more potent than other known TAK1 inhibitors. • LYTAK1 inhibits LPS-induced cytokine production in primary macrophages/monocytes. • LYTAK1 inhibits LPS-induced TAK1-NFκB and MAPK activation in macrophages/monocytes. • LYTAK1 gavage inhibits LPS-induced endotoxin shock and cytokine production in mice.

  5. LYATK1 potently inhibits LPS-mediated pro-inflammatory response

    Energy Technology Data Exchange (ETDEWEB)

    Xi, Feng [Department of Intensive Care Unit, Taixing People" ' s Hospital, Taixing, Jiangsu Province, 225400 (China); Liu, Yuan [Department of Ophthalmology, Nanjing First Hospital, Nanjing Medical University, Nanjing (China); Wang, Xiujuan; Kong, Wei [Department of Intensive Care Unit, Taixing People" ' s Hospital, Taixing, Jiangsu Province, 225400 (China); Zhao, Feng, E-mail: taixingzhaofeng163@163.com [Department of Intensive Care Unit, Taixing People" ' s Hospital, Taixing, Jiangsu Province, 225400 (China)

    2016-01-29

    Lipopolysaccharide (LPS)-primed monocytes/macrophages produce pro-inflammatory cytokines, which could lead to endotoxin shock. TGF-β-activated kinase1 (TAK1) activation is involved in the process. In the current study, we studied the potential effect of a selective TAK1 inhibitor, LYTAK1, on LPS-stimulated response both in vitro and in vivo. We demonstrated that LYTAK1 inhibited LPS-induced mRNA expression and production of several pro-inflammatory cytokines [interleukin 1β (IL-1β), tumor necrosis factor-α (TNFα) and interleukin-6 (IL-6)] in RAW 264.7 macrophages. LYTAK1's activity was almost nullified with TAK1 shRNA-knockdown. Meanwhile, in both primary mouse bone marrow derived macrophages (BMDMs) and human peripheral blood mononuclear cells (PBMCs), LPS-induced pro-inflammatory cytokine production was again attenuated with LYTAK1 co-treatment. Molecularly, LYTAK1 dramatically inhibited LPS-induced TAK1-nuclear factor kappa B (NFκB) and mitogen-activated protein kinase (Erk, Jnk and p38) activation in RAW 264.7 cells, mouse BMDMs and human PBMCs. In vivo, oral administration of LYTAK1 inhibited LPS-induced activation of TAK1-NFκB-p38 in ex-vivo cultured PBMCs, and cytokine production and endotoxin shock in mice. Together, these results demonstrate that LYTAK1 inhibits LPS-induced production of several pro-inflammatory cytokines and endotoxin shock probably through blocking TAK1-regulated signalings. - Highlights: • LYTAK1 inhibits LPS-induced pro-inflammatory cytokine production in RAW 264.7 cells. • The effect by LYTAK1 is more potent than other known TAK1 inhibitors. • LYTAK1 inhibits LPS-induced cytokine production in primary macrophages/monocytes. • LYTAK1 inhibits LPS-induced TAK1-NFκB and MAPK activation in macrophages/monocytes. • LYTAK1 gavage inhibits LPS-induced endotoxin shock and cytokine production in mice.

  6. Production of nitric oxide using a microwave plasma torch and its application to fungal cell differentiation

    International Nuclear Information System (INIS)

    Na, Young Ho; Kang, Min-Ho; Cho, Guang Sup; Choi, Eun Ha; Park, Gyungsoon; Uhm, Han Sup; Kumar, Naresh

    2015-01-01

    The generation of nitric oxide by a microwave plasma torch is proposed for its application to cell differentiation. A microwave plasma torch was developed based on basic kinetic theory. The analytical theory indicates that nitric oxide density is nearly proportional to oxygen molecular density and that the high-temperature flame is an effective means of generating nitric oxide. Experimental data pertaining to nitric oxide production are presented in terms of the oxygen input in units of cubic centimeters per minute. The apparent length of the torch flame increases as the oxygen input increases. The various levels of nitric oxide are observed depending on the flow rate of nitrogen gas, the mole fraction of oxygen gas, and the microwave power. In order to evaluate the potential of nitric oxide as an activator of cell differentiation, we applied nitric oxide generated from the microwave plasma torch to a model microbial cell (Neurospora crassa: non-pathogenic fungus). Germination and hyphal differentiation of fungal cells were not dramatically changed but there was a significant increase in spore formation after treatment with nitric oxide. In addition, the expression level of a sporulation related gene acon-3 was significantly elevated after 24 h upon nitric oxide treatment. Increase in the level of nitric oxide, nitrite and nitrate in water after nitric oxide treatment seems to be responsible for activation of fungal sporulation. Our results suggest that nitric oxide generated by plasma can be used as a possible activator of cell differentiation and development. (paper)

  7. Reproducibility of exhaled nitric oxide measurements in overweight and obese adults

    NARCIS (Netherlands)

    Thijs, Willemien; de Mutsert, Renée; le Cessie, Saskia; Hiemstra, Pieter S.; Rosendaal, Frits R.; Middeldorp, Saskia; Rabe, Klaus F.

    2014-01-01

    Exhaled nitric oxide is a noninvasive measure of airway inflammation that can be detected by a handheld device. Obesity may influence the reproducibility of exhaled nitric oxide measurements, by - for instance - decreased expiratory reserve volume. We analyzed triple exhaled nitric oxide

  8. The angiotensin-(1-7/Mas axis counteracts angiotensin II-dependent and –independent pro-inflammatory signaling in human vascular smooth muscle cells

    Directory of Open Access Journals (Sweden)

    Laura A Villalobos

    2016-12-01

    Full Text Available Background and aims: Targeting inflammation is nowadays considered as a challenging pharmacological strategy to prevent or delay the development of vascular diseases. Angiotensin-(1-7 is a member of the renin-angiotensin system (RAS that binds Mas receptors and has gained growing attention in the last years as a regulator of vascular homeostasis. Here, we explored the capacity of Ang-(1-7 to counteract human aortic smooth muscle cell (HASMC inflammation triggered by RAS-dependent and –independent stimuli, such as Ang II or interleukin (IL-1.Methods and Results: In cultured HASMC, the expression of iNOS and the release of nitric oxide were stimulated by both Ang II and IL-1, as determined by Western blot and indirect immunofluorescence or the Griess method, respectively. iNOS induction was inhibited by Ang-(1-7 in a concentration-dependent manner. This effect was equally blocked by two different Mas receptor antagonists, A779 and D-Pro7-Ang-(1-7, suggesting the participation of a unique Mas receptor subtype. Using pharmacological inhibitors, the induction of iNOS was proven to rely on the consecutive upstream activation of NADPH oxidase and NF-B. Indeed, Ang-(1-7 markedly inhibited the activation of the NADPH oxidase and subsequently of NF-B, as determined by lucigenin-derived chemiluminiscence and electromobility shift assay, respectively.Conclusion: Ang-(1-7 can act as a counter-regulator of the inflammation of vascular smooth muscle cells triggered by Ang II, but also by other stimuli beyond the RAS. Activating or mimicking the Ang-(1-7/Mas axis may represent a pharmacological opportunity to attenuate the pro-inflammatory environment that promotes and sustains the development of vascular diseases.

  9. Variation of nitric oxide levels in imported Plasmodium falciparum ...

    African Journals Online (AJOL)

    SERVER

    2008-03-18

    Mar 18, 2008 ... ISSN 1684–5315 © 2008 Academic Journals. Full Length Research Paper. Variation of nitric oxide levels in imported Plasmodium falciparum malaria episodes. De Sousa, Karina*, Silva, Marcelo S. and Tavira, Luís T. Instituto de Higiene e Medicina Tropical, Centro de Malária e outras Doenças Tropicais, ...

  10. Methanol Extract of Codonopsis pilosula Inhibits Inducible Nitric ...

    African Journals Online (AJOL)

    Purpose: To evaluate the mechanism of antioxidant activity of the methanol extract of Codonopsis pilosula. Methods: Anti-oxidative properties were assessed by measuring free radical scavenging activity, nitric oxide (NO) levels, protein oxidation and reducing power, while the mechanism of antioxidative effect of ...

  11. Nitric oxide radical scavenging potential of some Elburz medicinal ...

    African Journals Online (AJOL)

    Some plants scavenge nitric oxide (NO) with high affinity. For this purpose, forty extracts from 26 medicinal plants, growing extensively in Elburz mountains, were evaluated for their NO scavenging activity. Total phenolic and flavonoid contents of these extracts were also measured by Folin Ciocalteu and AlCl3 colorimetric ...

  12. On EPR detection of nitric oxide in vivo

    NARCIS (Netherlands)

    van Faassen, E.E.H.

    2008-01-01

    Nitric oxide (NO ) is a peculiar radical: Ground state is not paramagnetic (g = 0 since orbital and spin magnetic moments cancel); low reactivity with other molecules except superoxide (O2 ); thermodynamically unstable; dimerizes to N2O2; difficult to detect in-vivo.

  13. Estimation of the nitric oxide formed from hydroxylamine by Nitrosomonas

    Science.gov (United States)

    Anderson, J. H.

    1965-01-01

    1. Nitric oxide that was produced by reducing nitrite with an excess of acidified potassium iodide under nitrogen in Warburg respirometer flasks was rapidly absorbed by a solution of permanganate in sodium hydroxide held in the side arm. A small amount of nitrous oxide (or nitrogen) that was also produced was not absorbed. 2. By using a quantitative method for the recovery of nitrite from samples of the alkaline permanganate, it was found that the sum of the nitrite N formed and the residual nitrous oxide N was equivalent to the nitrite N used to generate the gases. These results showed that alkaline permanganate completely oxidized nitric oxide to nitrite. The method was suitable for determining 0·4–20 μmoles of nitric oxide. 3. The technique was used to determine the nitric oxide content of the nitrogenous gas that was produced anaerobically from hydroxylamine by an extract of the autotrophic nitrifying micro-organism Nitrosomonas in the presence of methylene blue as electron acceptor. PMID:14342235

  14. Variation of nitric oxide levels in imported Plasmodium falciparum ...

    African Journals Online (AJOL)

    SERVER

    2008-03-18

    Mar 18, 2008 ... Nitric oxide (NO) has been recognized during the past two decades as one of the most versatile players in the immune system. Even though the molecular mechanisms responsible by the naturally acquired immunity against malaria are still to be clarified, the production of NO seems to play an important role.

  15. Inhibition of Inducible Nitric Oxide Synthase, Cycleooxygenase-2 ...

    African Journals Online (AJOL)

    HP

    Won Chung, Jin Uk Oh, Sehyung Lee and Sung-Jin Kim* ... was determined by Western blot analysis for iNOS and COX-2 expression in LPS-stimulated RAW ..... Nitric oxide-scavenging and antioxidant effects ofUraria crinite root. Food.

  16. Nitric oxide and neopterin in bipolar affective disorder

    NARCIS (Netherlands)

    Hoekstra, R.; Fekkes, D.; Pepplinkhuizen, L.; Loonen, A.J.M.; Tuinier, S.; Verhoeven, W.M.A.

    2006-01-01

    Background: There is an increasing interest in the role of nitric oxide (NO) and pterines in the pathophysiology of neuropsychiatric disorders. The results so far show an inconsistent pattern. Methods: In the present study, neopterin and a measure of NO synthesis in plasma of symptomatic and

  17. Total Glucosides of Paeonia lactiflora Pall Suppress Nitric Oxide ...

    African Journals Online (AJOL)

    iNOS) expression and ... Keywords: Total glucosides, Paeonia lactiflora, Nitric oxide, iNOs, Nuclear factor-κB. Tropical Journal of Pharmaceutical Research ... Nuclear factor (NF)-κB is the key transcriptional factor regulating iNOS gene transcription.

  18. Localization of nitric oxide synthase in human skeletal muscle

    DEFF Research Database (Denmark)

    Frandsen, Ulrik; Lopez-Figueroa, M.; Hellsten, Ylva

    1996-01-01

    The present study investigated the cellular localization of the neuronal type I and endothelial type III nitric oxide synthase in human skeletal muscle. Type I NO synthase immunoreactivity was found in the sarcolemma and the cytoplasm of all muscle fibres. Stronger immunoreactivity was expressed...

  19. Nitric oxide in health and disease of the respiratory system

    NARCIS (Netherlands)

    Ricciardolo, Fabio L. M.; Sterk, Peter J.; Gaston, Benjamin; Folkerts, Gert

    2004-01-01

    During the past decade a plethora of studies have unravelled the multiple roles of nitric oxide (NO) in airway physiology and pathophysiology. In the respiratory tract, NO is produced by a wide variety of cell types and is generated via oxidation of l-arginine that is catalyzed by the enzyme NO

  20. Serum Iron and Nitric Oxide Production in Trypanosoma brucei ...

    African Journals Online (AJOL)

    JTEkanem

    reduction in the serum iron status and a modulation of nitric oxide synthase activity of T. brucei infected rats. ... inflammation and tissue damage15. ... The serum iron level was determined ... concentration or of total nitrate and nitrite ... 15. 16. 17. 18. Days. S e ru m iro n lev e l mg. /ml. Infected treated. Infected untreated. 0.

  1. Cellular inactivation of nitric oxide induces p53-dependent ...

    African Journals Online (AJOL)

    Tropical Journal of Pharmaceutical Research August 2016; 15 (8): 1595-1603 ... Cellular inactivation of nitric oxide induces p53-dependent apoptosis in ... apoptosis induced by a selective iNOS inhibitor, N-[(3-aminomethyl) benzyl] acetamidine (1400W), .... and nitrate. ... Nitrite production was measured in culture media.

  2. Endothelial nitric oxide synthase polymorphism G298T in ...

    Indian Academy of Sciences (India)

    Supplementary data: Endothelial nitric oxide synthase polymorphism G298T in association with oxidative DNA damage in coronary atherosclerosis. Rajesh G. Kumar, Mrudula K. Spurthi, Kishore G. Kumar, Sanjib K. Sahu and Surekha H. Rani. J. Genet. 91, 349–352. Table 1. The demographic and clinical data of the CHD ...

  3. Aluminium dissolution for spray pulverization with nitric acid

    International Nuclear Information System (INIS)

    Rodrigo Otero, A.; Rodrigo Vilaseca, F.; Morales Calvo, G.

    1977-01-01

    A comparative study of the nitric acid dissolution of aluminium, by immersion and spray pulverization has been carried out in laboratory scale. As a result, the optimum operation conditions to control reaction in the plant are fixed. Operation costs are also evaluated. (author) [es

  4. Mechanisms of electrochemical reduction and oxidation of nitric oxide

    NARCIS (Netherlands)

    Vooys, de A.C.A.; Beltramo, G.L.; Riet, van B.; Veen, van J.A.R.; Koper, M.T.M.

    2004-01-01

    A summary is given of recent work on the reactivity of nitric oxide on various metal electrodes. The significant differences between the reactivity of adsorbed NO and NO in solution are pointed out, both for the reduction and the oxidation reaction(s). Whereas adsorbed NO can be reduced only to

  5. Nitric acid flowsheet with late wash PHA testing

    International Nuclear Information System (INIS)

    Zamecnik, J.R.

    1993-01-01

    This Task Technical Plan outlines the activities to be conducted in the Integrated DWPF Melter System (IDMS) in ongoing support of the Defense Waste Processing Facility (DWPF) Chemical Process Cell (CPC) utilizing the Nitric Acid Flowsheet in the Sludge Receipt and Adjustment Tank (SRAT) and Precipitate Hydrolysis Aqueous (PHA) produced by the Late Wash Flowsheet. The IDMS facility is to be operated over a series of runs (2 to 4) using the Nitric Acid Flowsheet. The PHA will be produced with the Late Wash Flowsheet in the Precipitate Hydrolysis Experimental Facility (PHEF). All operating conditions shall simulate the expected DWPF operating conditions as closely as possible. The task objectives are to perform at least two IDMS runs with as many operating conditions as possible at nominal DWPF conditions. The major purposes of these runs are twofold: verify that the combined Late Wash and Nitric Acid flowsheets produce glass of acceptable quality without additional changes to process equipment, and determine the reproducibility of data from run to run. These runs at nominal conditions will be compared to previous runs made with PHA produced from the Late Wash flowsheet and with the Nitric Acid flowsheet in the SRAT (Purex 4 and Purex 5)

  6. Simulated dry deposition of nitric acid near forest edges

    NARCIS (Netherlands)

    DeJong, JJM; Klaassen, W; Jong, J.J.M. de

    1997-01-01

    Dry deposition is simulated to understand and generalize observations of enhanced deposition of air pollution near forest edges. Nitric acid is taken as an example as its deposition velocity is often assumed to be determined by turbulent transport only. The simulations are based on the

  7. Extraction of fission product rhodium from nitric acid solutions. 1

    International Nuclear Information System (INIS)

    Gorski, B.; Beer, M.; Russ, L.

    1988-01-01

    The extraction of noble metals from nitric acid solutions represents one problem of separating valueable substances from nuclear wastes in nuclear fuel reprocessing. Results of distribution experiments demonstrate the possibility of solvent extraction of rhodium using tertiary amines in presence of nitrite. Even short mixing times realize high distribution coefficients allowing quantitative separation from aqueous solutions. (author)

  8. Water vapour and carbon dioxide decrease nitric oxide readings

    NARCIS (Netherlands)

    vanderMark, TW; Kort, E; Meijer, RJ; Postma, DS; Koeter, GH

    Measurement of nitric oxide levels in exhaled ah-is commonly performed using a chemiluminescence detector. However, water vapour and carbon dioxide affect the chemiluminescence process, The influence of these gases at the concentrations present in exhaled air has not vet been studied. For this in

  9. Melatonin inhibits endothelin-1 and induces endothelial nitric oxide ...

    African Journals Online (AJOL)

    Although, I/R augmented the endothelin-1 (ET-1) gene expression and the level of big endothelin-1 (big ET-1) in liver tissue, melatonin attenuated these increases. Conversely, non-significant decrease in endothelial nitric oxide synthase (eNOS) mRNA expression in I/R group was significantly elevated by melatonin in ...

  10. Analysis of genetic variation of inducible nitric oxide synthase and ...

    African Journals Online (AJOL)

    The genetic diversity of 100 Malaysian native chickens was investigated using polymerase chain reaction-restriction fragment polymorphism (PCR-RFLP) for two candidate genes: inducible nitric oxide synthase (INOS) and natural resistance-associated macrophage protein 1 (NRAMP1). The two genes were selected ...

  11. Arginine, citrulline and nitric oxide metabolism in sepsis

    Science.gov (United States)

    Arginine has vasodilatory effects, via its conversion by nitric oxide (NO) synthase into NO, and immunomodulatory actions that play important roles in sepsis. Protein breakdown affects arginine availability, and the release of asymmetric dimethylarginine, an inhibitor of NO synthase, may therefore a...

  12. Mechanism of nitric acid reduction and kinetic modelling

    International Nuclear Information System (INIS)

    Sicsic, David; Balbaud-Celerier, Fanny; Tribollet, Bernard

    2014-01-01

    In France, the recycling of nuclear waste fuels involves the use of hot concentrated nitric acid. The understanding and prediction of the behaviour of the structural materials (mainly austenitic stainless steels) requires the determination and modelling of the nitric acid reduction process. Nitric acid is indirectly reduced by an autocatalytic mechanism depending on the cathodic overpotential and acid concentration. This mechanism has been widely studied. All the authors agree on its autocatalytic nature, characterized by the predominant role of the reduction products. It is also generally admitted that neither nitric acid nor the nitrate ion is the electro-active species. However, the nature of the electro-active species, the place where the catalytic species regenerates and the thermodynamic and kinetic behaviour of the reaction intermediates remain uncertain. The aim of this study was to clarify some of these uncertainties by performing an electrochemical investigation of the reduction of 4 M nitric acid at 40 C at an inert electrode (platinum or gold). An inert electrode was chosen as the working electrode in a first step to avoid its oxidation and focus the research on the reduction mechanism. This experimental work enabled us to suggest a coherent sequence of electrochemical and chemical reactions. Kinetic modelling of this sequence was then carried out for a gold rotating disk electrode. A thermodynamic study at 25 C allowed the composition of the liquid and gaseous phases of nitric acid solutions in the concentration range 0.5-22 M to be evaluated. The kinetics of the reduction of 4 M nitric acid was investigated by cyclic voltammetry and chrono-amperometry at an inert electrode at 40 C. The coupling of chrono-amperometry and FTIR spectroscopy in the gaseous phase led to the identification of the gaseous reduction products as a function of the cathodic overpotential. The results showed that the reduction process is autocatalytic for potentials between 0

  13. The influence of a subanaesthetic dose of ketamine on circulating pro-inflammatory cytokines and serotonin in brain reply

    Czech Academy of Sciences Publication Activity Database

    Horáček, J.; Tejkalová, H.; Novák, T.; Bubeníková-Valešová, V.; Páleníček, T.; Rambousek, L.; Růžičková, Šárka; Vaculín, Š.; Hoeschl, C.

    2011-01-01

    Roč. 41, č. 8 (2011), s. 1787-1789 ISSN 0033-2917 Institutional research plan: CEZ:AV0Z50520701 Keywords : serotonin * proinflammatory * cytokines Subject RIV: AN - Psychology Impact factor: 6.159, year: 2011

  14. Fusobacterium nucleatum-Induced Impairment of Autophagic Flux Enhances the Expression of Proinflammatory Cytokines via ROS in Caco-2 Cells.

    Directory of Open Access Journals (Sweden)

    Bin Tang

    Full Text Available Fusobacterium nucleatum (F. nucleatum plays a critical role in gastrointestinal inflammation. However, the exact mechanism by which F. nucleatum contributes to inflammation is unclear. In the present study, it was revealed that F. nucleatum could induce the production of proinflammatory cytokines (IL-8, IL-1β and TNF-α and reactive oxygen species (ROS in Caco-2 colorectal adenocarcinoma cells. Furthermore, ROS scavengers (NAC or Tiron could decrease the production of proinflammatory cytokines during F. nucleatum infection. In addition, we observed that autophagy is impaired in Caco-2 cells after F. nucleatum infection. The production of proinflammatory cytokines and ROS induced by F. nucleatum was enhanced with either autophagy pharmacologic inhibitors (3-methyladenine, bafilomycin A1 or RNA interference in essential autophagy genes (ATG5 or ATG12 in Caco-2 cells. Taken together, these results indicate that F. nucleatum-induced impairment of autophagic flux enhances the expression of proinflammatory cytokines via ROS in Caco-2 Cells.

  15. Impact of Work Task-Related Acute Occupational Smoke Exposures on Select Proinflammatory Immune Parameters in Wildland Firefighters

    Science.gov (United States)

    Objective: A repeated measures study was used to assess the effect of work tasks on select proinflammatory biomarkers in firefighters working at prescribed burns. Methods: Ten firefighters and two volunteers were monitored for particulate matter and carbon monoxide on workdays, ...

  16. Nitric oxide–mediated regulation of ferroportin-1 controls macrophage iron homeostasis and immune function in Salmonella infection

    Science.gov (United States)

    Nairz, Manfred; Schleicher, Ulrike; Schroll, Andrea; Sonnweber, Thomas; Theurl, Igor; Ludwiczek, Susanne; Talasz, Heribert; Brandacher, Gerald; Moser, Patrizia L.; Muckenthaler, Martina U.; Fang, Ferric C.; Bogdan, Christian

    2013-01-01

    Nitric oxide (NO) generated by inducible NO synthase 2 (NOS2) affects cellular iron homeostasis, but the underlying molecular mechanisms and implications for NOS2-dependent pathogen control are incompletely understood. In this study, we found that NO up-regulated the expression of ferroportin-1 (Fpn1), the major cellular iron exporter, in mouse and human cells. Nos2−/− macrophages displayed increased iron content due to reduced Fpn1 expression and allowed for an enhanced iron acquisition by the intracellular bacterium Salmonella typhimurium. Nos2 gene disruption or inhibition of NOS2 activity led to an accumulation of iron in the spleen and splenic macrophages. Lack of NO formation resulted in impaired nuclear factor erythroid 2-related factor-2 (Nrf2) expression, resulting in reduced Fpn1 transcription and diminished cellular iron egress. After infection of Nos2−/− macrophages or mice with S. typhimurium, the increased iron accumulation was paralleled by a reduced cytokine (TNF, IL-12, and IFN-γ) expression and impaired pathogen control, all of which were restored upon administration of the iron chelator deferasirox or hyperexpression of Fpn1 or Nrf2. Thus, the accumulation of iron in Nos2−/− macrophages counteracts a proinflammatory host immune response, and the protective effect of NO appears to partially result from its ability to prevent iron overload in macrophages PMID:23630227

  17. Non-asthmatic patients show increased exhaled nitric oxide concentrations

    Directory of Open Access Journals (Sweden)

    Beatriz M. Saraiva-Romanholo

    2009-01-01

    Full Text Available OBJECTIVE: Evaluate whether exhaled nitric oxide may serve as a marker of intraoperative bronchospasm. INTRODUCTION: Intraoperative bronchospasm remains a challenging event during anesthesia. Previous studies in asthmatic patients suggest that exhaled nitric oxide may represent a noninvasive measure of airway inflammation. METHODS: A total of 146,358 anesthesia information forms, which were received during the period from 1999 to 2004, were reviewed. Bronchospasm was registered on 863 forms. From those, three groups were identified: 9 non-asthmatic patients (Bronchospasm group, 12 asthmatics (Asthma group and 10 subjects with no previous airway disease or symptoms (Control group. All subjects were submitted to exhaled nitric oxide measurements (parts/billion, spirometry and the induced sputum test. The data was compared by ANOVA followed by the Tukey test and Kruskal-Wallis followed by Dunn's test. RESULTS: The normal lung function test results for the Bronchospasm group were different from those of the asthma group (p <0.05. The median percentage of eosinophils in induced sputum was higher for the Asthma [2.46 (0.45-6.83] compared with either the Bronchospasm [0.55 (0-1.26] or the Control group [0.0 (0] (p <0.05; exhaled nitric oxide followed a similar pattern for the Asthma [81.55 (57.6-86.85], Bronchospasm [46.2 (42.0 -62.6] and Control group [18.7 (16.0-24.7] (p< 0.05. CONCLUSIONS: Non-asthmatic patients with intraoperative bronchospasm detected during anesthesia and endotracheal intubation showed increased expired nitric oxide.

  18. Nitric oxide synthesis and biological functions of nitric oxide released from ruthenium compounds

    Directory of Open Access Journals (Sweden)

    A.C. Pereira

    2011-09-01

    Full Text Available During three decades, an enormous number of studies have demonstrated the critical role of nitric oxide (NO as a second messenger engaged in the activation of many systems including vascular smooth muscle relaxation. The underlying cellular mechanisms involved in vasodilatation are essentially due to soluble guanylyl-cyclase (sGC modulation in the cytoplasm of vascular smooth cells. sGC activation culminates in cyclic GMP (cGMP production, which in turn leads to protein kinase G (PKG activation. NO binds to the sGC heme moiety, thereby activating this enzyme. Activation of the NO-sGC-cGMP-PKG pathway entails Ca2+ signaling reduction and vasodilatation. Endothelium dysfunction leads to decreased production or bioavailability of endogenous NO that could contribute to vascular diseases. Nitrosyl ruthenium complexes have been studied as a new class of NO donors with potential therapeutic use in order to supply the NO deficiency. In this context, this article shall provide a brief review of the effects exerted by the NO that is enzymatically produced via endothelial NO-synthase (eNOS activation and by the NO released from NO donor compounds in the vascular smooth muscle cells on both conduit and resistance arteries, as well as veins. In addition, the involvement of the nitrite molecule as an endogenous NO reservoir engaged in vasodilatation will be described.

  19. Interleukin 1 beta induces diabetes and fever in normal rats by nitric oxide via induction of different nitric oxide synthases

    DEFF Research Database (Denmark)

    Reimers, J I; Bjerre, U; Mandrup-Poulsen, T

    1994-01-01

    Substantial in vitro evidence suggests that nitric oxide may be a major mediator of interleukin 1 (IL-1) induced pancreatic beta-cell inhibition and destruction in the initial events leading to insulin-dependent diabetes mellitus. Using NG-nitro-L-arginine methyl ester, an inhibitor of both...

  20. Surface modification of PLGA nanoparticles to deliver nitric oxide to inhibit Escherichia coli growth

    Energy Technology Data Exchange (ETDEWEB)

    Reger, Nina A. [Department of Chemistry and Biochemistry, Duquesne University, Pittsburgh, PA 15282 (United States); Meng, Wilson S. [Division of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282 (United States); Gawalt, Ellen S., E-mail: gawalte@duq.edu [Department of Chemistry and Biochemistry, Duquesne University, Pittsburgh, PA 15282 (United States); McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219 (United States)

    2017-04-15

    Highlights: • Thin film functionalized PLGA nanoparticles were modified to release nitric oxide from an s-nitrosothiol donor. • The nitric oxide modified nanoparticles were bacteriostatic against Escherichia coli. • The nitric oxide modified nanoparticles increased the effectiveness of tetracycline against Escherichia coli. • The modified nitric oxide nanoparticles did not exhibit cytotoxic effects against fibroblasts. - Abstract: Polymer nanoparticles consisting of poly (DL-lactic-co-glycolic acid) were surface functionalized to deliver nitric oxide. These biodegradable and biocompatible nanoparticles were modified with an S-nitrosothiol molecule, S-nitrosocysteamine, as the nitric oxide delivery molecule. S-nitrosocysteamine was covalently immobilized on the nanoparticle surface using small organic molecule linkers and carbodiimide coupling. Nanoparticle size, zeta potential, and morphology were determined using dynamic light scattering and scanning electron microscopy, respectively. Subsequent attachment of the S-nitrosothiol resulted in a nitric oxide release of 37.1 ± 1.1 nmol per milligram of nanoparticles under physiological conditions. This low concentration of nitric oxide reduced Escherichia coli culture growth by 31.8%, indicating that the nitric oxide donor was effective at releasing nitric oxide even after attachment to the nanoparticle surface. Combining the nitric oxide modified nanoparticles with tetracycline, a commonly prescribed antibiotic for E. coli infections, increased the effectiveness of the antibiotic by 87.8%, which allows for lower doses of antibiotics to be used in order to achieve the same effect. The functionalized nanoparticles were not cytotoxic to mouse fibroblasts.

  1. Surface modification of PLGA nanoparticles to deliver nitric oxide to inhibit Escherichia coli growth

    International Nuclear Information System (INIS)

    Reger, Nina A.; Meng, Wilson S.; Gawalt, Ellen S.

    2017-01-01

    Highlights: • Thin film functionalized PLGA nanoparticles were modified to release nitric oxide from an s-nitrosothiol donor. • The nitric oxide modified nanoparticles were bacteriostatic against Escherichia coli. • The nitric oxide modified nanoparticles increased the effectiveness of tetracycline against Escherichia coli. • The modified nitric oxide nanoparticles did not exhibit cytotoxic effects against fibroblasts. - Abstract: Polymer nanoparticles consisting of poly (DL-lactic-co-glycolic acid) were surface functionalized to deliver nitric oxide. These biodegradable and biocompatible nanoparticles were modified with an S-nitrosothiol molecule, S-nitrosocysteamine, as the nitric oxide delivery molecule. S-nitrosocysteamine was covalently immobilized on the nanoparticle surface using small organic molecule linkers and carbodiimide coupling. Nanoparticle size, zeta potential, and morphology were determined using dynamic light scattering and scanning electron microscopy, respectively. Subsequent attachment of the S-nitrosothiol resulted in a nitric oxide release of 37.1 ± 1.1 nmol per milligram of nanoparticles under physiological conditions. This low concentration of nitric oxide reduced Escherichia coli culture growth by 31.8%, indicating that the nitric oxide donor was effective at releasing nitric oxide even after attachment to the nanoparticle surface. Combining the nitric oxide modified nanoparticles with tetracycline, a commonly prescribed antibiotic for E. coli infections, increased the effectiveness of the antibiotic by 87.8%, which allows for lower doses of antibiotics to be used in order to achieve the same effect. The functionalized nanoparticles were not cytotoxic to mouse fibroblasts.

  2. Galectin-2 induces a proinflammatory, anti-arteriogenic phenotype in monocytes and macrophages.

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    Cansu Yıldırım

    Full Text Available Galectin-2 is a monocyte-expressed carbohydrate-binding lectin, for which increased expression is genetically determined and associated with decreased collateral arteriogenesis in obstructive coronary artery disease patients. The inhibiting effect of galectin-2 on arteriogenesis was confirmed in vivo, but the mechanism is largely unknown. In this study we aimed to explore the effects of galectin-2 on monocyte/macrophage phenotype in vitro and vivo, and to identify the receptor by which galectin-2 exerts these effects. We now show that the binding of galectin-2 to different circulating human monocyte subsets is dependent on monocyte surface expression levels of CD14. The high affinity binding is blocked by an anti-CD14 antibody but not by carbohydrates, indicating a specific protein-protein interaction. Galectin-2 binding to human monocytes modulated their transcriptome by inducing proinflammatory cytokines and inhibiting pro-arteriogenic factors, while attenuating monocyte migration. Using specific knock-out mice, we show that galectin-2 acts through the CD14/toll-like receptor (TLR-4 pathway. Furthermore, galectin-2 skews human macrophages to a M1-like proinflammatory phenotype, characterized by a reduced motility and expression of an anti-arteriogenic cytokine/growth factor repertoire. This is accompanied by a switch in surface protein expression to CD40-high and CD206-low (M1. In a murine model we show that galectin-2 administration, known to attenuate arteriogenesis, leads to increased numbers of CD40-positive (M1 and reduced numbers of CD206-positive (M2 macrophages surrounding actively remodeling collateral arteries. In conclusion galectin-2 is the first endogenous CD14/TLR4 ligand that induces a proinflammatory, non-arteriogenic phenotype in monocytes/macrophages. Interference with CD14-Galectin-2 interaction may provide a new intervention strategy to stimulate growth of collateral arteries in genetically compromised cardiovascular

  3. Atypical antipsychotics induce both proinflammatory and adipogenic gene expression in human adipocytes in vitro.

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    Sárvári, Anitta K; Veréb, Zoltán; Uray, Iván P; Fésüs, László; Balajthy, Zoltán

    2014-08-08

    Schizophrenia requires lifelong treatment, potentially causing systemic changes in metabolic homeostasis. In the clinical setting, antipsychotic treatment may differentially lead to weight gain among individual patients, although the molecular determinants of such adverse effects are currently unknown. In this study, we investigated changes in the expression levels of critical regulatory genes of adipogenesis, lipid metabolism and proinflammatory genes during the differentiation of primary human adipose-derived stem cells (ADSCs). These cells were isolated from patients with body mass indices <25 and treated with the second-generation antipsychotics olanzapine, ziprasidone, clozapine, quetiapine, aripiprazole and risperidone and the first-generation antipsychotic haloperidol. We found that antipsychotics exhibited a marked effect on key genes involved in the regulation of cell cycle, signal transduction, transcription factors, nuclear receptors, differentiation markers and metabolic enzymes. In particular, we observed an induction of the transcription factor NF-KB1 and NF-KB1 target genes in adipocytes in response to these drugs, including the proinflammatory cytokines TNF-α, IL-1β, IL-8 and MCP-1. In addition, enhanced secretion of both IL8 and MCP-1 was observed in the supernatant of these cell cultures. In addition to their remarkable stimulatory effects on proinflammatory gene transcription, three of the most frequently prescribed antipsychotic drugs, clozapine, quetiapine and aripiprazole, also induced the expression of essential adipocyte differentiation genes and the adipocyte hormones leptin and adiponectin, suggesting that both glucose and fat metabolism may be affected by these drugs. These data further suggest that antipsychotic treatments in patients alter the gene expression patterns in adipocytes in a coordinated fashion and priming them for a low-level inflammatory state. Copyright © 2014 Elsevier Inc. All rights reserved.

  4. Host transcription factors in the immediate pro-inflammatory response to the parasitic mite Psoroptes ovis.

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    Stewart T G Burgess

    Full Text Available BACKGROUND: Sheep scab, caused by infestation with the ectoparasitic mite Psoroptes ovis, results in the rapid development of cutaneous inflammation and leads to the crusted skin lesions characteristic of the disease. We described previously the global host transcriptional response to infestation with P. ovis, elucidating elements of the inflammatory processes which lead to the development of a rapid and profound immune response. However, the mechanisms by which this response is instigated remain unclear. To identify novel methods of intervention a better understanding of the early events involved in triggering the immune response is essential. The objective of this study was to gain a clearer understanding of the mechanisms and signaling pathways involved in the instigation of the immediate pro-inflammatory response. RESULTS: Through a combination of transcription factor binding site enrichment and pathway analysis we identified key roles for a number of transcription factors in the instigation of cutaneous inflammation. In particular, defined roles were elucidated for the transcription factors NF-kB and AP-1 in the orchestration of the early pro-inflammatory response, with these factors being implicated in the activation of a suite of inflammatory mediators. CONCLUSIONS: Interrogation of the host temporal response to P. ovis infestation has enabled the further identification of the mechanisms underlying the development of the immediate host pro-inflammatory response. This response involves key regulatory roles for the transcription factors NF-kB and AP-1. Pathway analysis demonstrated that the activation of these transcription factors may be triggered following a host LPS-type response, potentially involving TLR4-signalling and also lead to the intriguing possibility that this could be triggered by a P. ovis allergen.

  5. Induction of intestinal pro-inflammatory immune responses by lipoteichoic acid

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    Zadeh Mojgan

    2012-03-01

    Full Text Available Abstract Background The cellular and molecular mechanisms of inflammatory bowel disease are not fully understood; however, data indicate that uncontrolled chronic inflammation induced by bacterial gene products, including lipoteichoic acid (LTA, may trigger colonic inflammation resulting in disease pathogenesis. LTA is a constituent glycolipid of Gram-positive bacteria that shares many inflammatory properties with lipopolysaccharide and plays a critical role in the pathogenesis of severe inflammatory responses via Toll-like receptor 2. Accordingly, we elucidate the role of LTA in immune stimulation and induced colitis in vivo. Methods To better understand the molecular mechanisms utilized by the intestinal microbiota and their gene products to induce or subvert inflammation, specifically the effect(s of altered surface layer protein expression on the LTA-mediated pro-inflammatory response, the Lactobacillus acidophilus surface layer protein (Slp genes encoding SlpB and SlpX were deleted resulting in a SlpB- and SlpX- mutant that continued to express SlpA (assigned as NCK2031. Results Our data show profound activation of dendritic cells by NCK2031, wild-type L. acidophilus (NCK56, and purified Staphylococcus aureus-LTA. In contrary to the LTA-deficient strain NCK2025, the LTA-expressing strains NCK2031 and NCK56, as well as S. aureus-LTA, induce pro-inflammatory innate and T cell immune responses in vivo. Additionally, neither NCK2031 nor S. aureus-LTA supplemented in drinking water protected mice from DSS-colitis, but instead, induced significant intestinal inflammation resulting in severe colitis and tissue destruction. Conclusions These findings suggest that directed alteration of two of the L. acidophilus NCFM-Slps did not ameliorate LTA-induced pro-inflammatory signals and subsequent colitis.

  6. c-Myc is essential to prevent endothelial pro-inflammatory senescent phenotype.

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    Victoria Florea

    Full Text Available The proto-oncogene c-Myc is vital for vascular development and promotes tumor angiogenesis, but the mechanisms by which it controls blood vessel growth remain unclear. In the present work we investigated the effects of c-Myc knockdown in endothelial cell functions essential for angiogenesis to define its role in the vasculature. We provide the first evidence that reduction in c-Myc expression in endothelial cells leads to a pro-inflammatory senescent phenotype, features typically observed during vascular aging and pathologies associated with endothelial dysfunction. c-Myc knockdown in human umbilical vein endothelial cells using lentivirus expressing specific anti-c-Myc shRNA reduced proliferation and tube formation. These functional defects were associated with morphological changes, increase in senescence-associated-β-galactosidase activity, upregulation of cell cycle inhibitors and accumulation of c-Myc-deficient cells in G1-phase, indicating that c-Myc knockdown in endothelial cells induces senescence. Gene expression analysis of c-Myc-deficient endothelial cells showed that senescent phenotype was accompanied by significant upregulation of growth factors, adhesion molecules, extracellular-matrix components and remodeling proteins, and a cluster of pro-inflammatory mediators, which include Angptl4, Cxcl12, Mdk, Tgfb2 and Tnfsf15. At the peak of expression of these cytokines, transcription factors known to be involved in growth control (E2f1, Id1 and Myb were downregulated, while those involved in inflammatory responses (RelB, Stat1, Stat2 and Stat4 were upregulated. Our results demonstrate a novel role for c-Myc in the prevention of vascular pro-inflammatory phenotype, supporting an important physiological function as a central regulator of inflammation and endothelial dysfunction.

  7. Proinflammatory proteins in female and male patients with primary antiphospholipid syndrome: preliminary data.

    Science.gov (United States)

    Bećarević, Mirjana; Ignjatović, Svetlana

    2016-10-01

    The latest classification criteria for the diagnosis of the antiphospholipid syndrome (APS, an autoimmune disease characterized by thromboses, miscarriages and presence of antiphospholipid antibodies (Abs)) emphasized that thrombotic manifestations of APS should be without any signs of an inflammatory process. However, atherosclerosis (a chronic inflammatory response to the accumulation of lipoproteins in the walls of arteries) and APS are characterized by some similar features. We evaluated whether proinflammatory proteins were associated with the features of the primary APS (PAPS). PAPS patients without obstetric complications and with impaired lipid profile were included in the study. Antiphospholipid antibodies, TNF-alpha, and apo(a) were determined by ELISA. Complement components and hsCRP were measured by immunonephelometry. Decreased C3c was observed in female patients with increased titers of IgG anti-β2gpI (χ(2) = 3.939, P = 0.047) and in male patients with increased IgM anticardiolipin Abs (χ(2) = 4.286, P = 0.038). Pulmonary emboli were associated with interleukin (IL)-6 in male (χ(2) = 6.519, P = 0.011) and in female (χ(2) = 10.405, P = 0.001) patients. Cerebrovascular insults were associated with LDL-cholesterol (P = 0.05, 95 % CI: 1.003 - 12.739) in female and with apo(a) (P = 0.016, 95 % CI: 0.000-0.003) in male patients. Older female patients had increased LDL-cholesterol levels and frequency of myocardial infarctions. Proinflammatory proteins were associated with features of primary APS. No real gender differences in regard to proinflammatory protein levels were observed. Premenopausal state of female PAPS patients confers lower cardiovascular risk.

  8. NFAT5-Regulated Macrophage Polarization Supports the Proinflammatory Function of Macrophages and T Lymphocytes.

    Science.gov (United States)

    Tellechea, Mónica; Buxadé, Maria; Tejedor, Sonia; Aramburu, Jose; López-Rodríguez, Cristina

    2018-01-01

    Macrophages are exquisite sensors of tissue homeostasis that can rapidly switch between pro- and anti-inflammatory or regulatory modes to respond to perturbations in their microenvironment. This functional plasticity involves a precise orchestration of gene expression patterns whose transcriptional regulators have not been fully characterized. We had previously identified the transcription factor NFAT5 as an activator of TLR-induced responses, and in this study we explore its contribution to macrophage functions in different polarization settings. We found that both in classically and alternatively polarized macrophages, NFAT5 enhanced functions associated with a proinflammatory profile such as bactericidal capacity and the ability to promote Th1 polarization over Th2 responses. In this regard, NFAT5 upregulated the Th1-stimulatory cytokine IL-12 in classically activated macrophages, whereas in alternatively polarized ones it enhanced the expression of the pro-Th1 mediators Fizz-1 and arginase 1, indicating that it could promote proinflammatory readiness by regulating independent genes in differently polarized macrophages. Finally, adoptive transfer assays in vivo revealed a reduced antitumor capacity in NFAT5-deficient macrophages against syngeneic Lewis lung carcinoma and ID8 ovarian carcinoma cells, a defect that in the ID8 model was associated with a reduced accumulation of effector CD8 T cells at the tumor site. Altogether, detailed analysis of the effect of NFAT5 in pro- and anti-inflammatory macrophages uncovered its ability to regulate distinct genes under both polarization modes and revealed its predominant role in promoting proinflammatory macrophage functions. Copyright © 2017 by The American Association of Immunologists, Inc.

  9. LL-37 directs macrophage differentiation toward macrophages with a proinflammatory signature.

    Science.gov (United States)

    van der Does, Anne M; Beekhuizen, Henry; Ravensbergen, Bep; Vos, Tim; Ottenhoff, Tom H M; van Dissel, Jaap T; Drijfhout, Jan W; Hiemstra, Pieter S; Nibbering, Peter H

    2010-08-01

    The human cathelicidin LL-37 has broad-spectrum antimicrobial activity. It also participates at the interface of innate and adaptive immunity by chemoattracting immune effector cells, modulating the production of a variety of inflammatory mediators by different cell types, and regulating the differentiation of monocytes into dendritic cells. In this study, we investigated the effects of LL-37 on the differentiation of human monocytes into anti-inflammatory macrophages (MPhi-2; driven by M-CSF) versus proinflammatory macrophages (MPhi-1; driven by GM-CSF) as well as on fully differentiated MPhi-1 and MPhi-2. Results revealed that monocytes cultured with M-CSF in the presence of LL-37 resulted in macrophages displaying a proinflammatory signature, namely, low expression of CD163 and little IL-10 and profound IL-12p40 production on LPS stimulation. The effects of LL-37 on M-CSF-driven macrophage differentiation were dose- and time-dependent with maximal effects observed at 10 microg/ml when the peptide was present from the start of the cultures. The peptide enhanced the GM-CSF-driven macrophage differentiation. Exposure of fully differentiated MPhi-2 to LL-37 for 6 d resulted in macrophages that produced less IL-10 and more IL-12p40 on LPS stimulation than control MPhi-2. In contrast, LL-37 had no effect on fully differentiated MPhi-1. Peptide mapping using a set of 16 overlapping 22-mer peptides covering the complete LL-37 sequence revealed that the C-terminal portion of LL-37 is responsible for directing macrophage differentiation. Our results furthermore indicate that the effects of LL-37 on macrophage differentiation required internalization of the peptide. Together, we conclude that LL-37 directs macrophage differentiation toward macrophages with a proinflammatory signature.

  10. Proinflammatory gene polymorphisms are potentially associated with Korean non-Sjogren dry eye patients

    Science.gov (United States)

    Na, Kyung-Sun; Mok, Jee-Won; Kim, Ja Yeon

    2011-01-01

    Purpose To determine whether proinflammatory cytokine genes were potential susceptibility candidate genes for Korean patients with non-Sjogren dry eye, we investigated the association of the interleukin 1 beta (IL1B), interleukin 6 (IL6), and interleukin 6 receptor (IL6R) variations with this disease in Korean patients. Methods Genomic DNA was extracted from blood samples of unrelated non-Sjogren dry eye patients and healthy control individuals who visited the Eye Center and Health Promotion Center of St. Mary’s Hospital in Seoul, Korea. For screening genetic variations in proinflammatory cytokine genes, the 511 (rs16944) and 31 (rs1143627) positions in the promoter region of IL1B, rs1143634 in exon 5 of IL1B, rs1800795 of the IL6 promoter, and Asp358Ala (rs8192284) of IL6R were genotyped using the polymerase chain reaction, restriction fragment length polymorphisms, and direct sequencing. Results Among the polymorphisms, rs1143634 (F105F) in exon 5 of IL1B was significantly different between the patient and control groups. The frequency of the C/T genotype in dry eye patients was decreased relative to that of the control subjects (10.4% versus 3.9%, p=0.043, OR=3.337). For the IL6R gene, the genotypic and allelic distribution of rs8192284 was different between the dry eye patients and the controls: CC genotype (p=0.017, OR=2.12) and C allele (OR=1.26). Conclusions This is the first report of genetic variation screening of proinflammatory cytokine genes in Korean non-Sjogren dry eye patients. It is suggested that rs1143634 of IL1B and rs8192284 of IL6R act as susceptibility variations in Korean non-Sjogren dry eye patients. PMID:22128229

  11. High expression of arachidonate 15-lipoxygenase and proinflammatory markers in human ischemic heart tissue

    International Nuclear Information System (INIS)

    Magnusson, Lisa U.; Lundqvist, Annika; Asp, Julia; Synnergren, Jane; Johansson, Cecilia Thalén; Palmqvist, Lars; Jeppsson, Anders; Hultén, Lillemor Mattsson

    2012-01-01

    Highlights: ► We found a 17-fold upregulation of ALOX15 in the ischemic heart. ► Incubation of human muscle cells in hypoxia showed a 22-fold upregulation of ALOX15. ► We observed increased levels of proinflammatory markers in ischemic heart tissue. ► Suggesting a link between ischemia and inflammation in ischemic heart biopsies. -- Abstract: A common feature of the ischemic heart and atherosclerotic plaques is the presence of hypoxia (insufficient levels of oxygen in the tissue). Hypoxia has pronounced effects on almost every aspect of cell physiology, and the nuclear transcription factor hypoxia inducible factor-1α (HIF-1α) regulates adaptive responses to low concentrations of oxygen in mammalian cells. In our recent work, we observed that hypoxia increases the proinflammatory enzyme arachidonate 15-lipoxygenase (ALOX15B) in human carotid plaques. ALOX15 has recently been shown to be present in the human myocardium, but the effect of ischemia on its expression has not been investigated. Here we test the hypothesis that ischemia of the heart leads to increased expression of ALOX15, and found an almost 2-fold increase in HIF-1α mRNA expression and a 17-fold upregulation of ALOX15 mRNA expression in the ischemic heart biopsies from patients undergoing coronary bypass surgery compared with non ischemic heart tissue. To investigate the effect of low oxygen concentration on ALOX15 we incubated human vascular muscle cells in hypoxia and showed that expression of ALOX15 increased 22-fold compared with cells incubated in normoxic conditions. We also observed increased mRNA levels of proinflammatory markers in ischemic heart tissue compared with non-ischemic controls. In summary, we demonstrate increased ALOX15 in human ischemic heart biopsies. Furthermore we demonstrate that hypoxia increases ALOX15 in human muscle cells. Our results yield important insights into the underlying association between hypoxia and inflammation in the human ischemic heart disease.

  12. Irradiation induces a biphasic expression of pro-inflammatory cytokines in the lung

    International Nuclear Information System (INIS)

    Ruebe, C.E.; Wilfert, F.; Palm, J.; Burdak-Rothkamm, S.; Ruebe, C.; Koenig, J.; Liu Li; Schuck, A.; Willich, N.

    2004-01-01

    Background and purpose: the precise pathophysiological mechanisms of radiation-induced lung injury are poorly understood, but have been shown to correlate with dysregulation of different cytokines. The purpose of this study was to evaluate the time course of the pro-inflammatory cytokines tumor necrosis factor-(TNF-)α, interleukin-(IL)-1α and IL-6 after whole-lung irradiation. Material and methods: the thoraces of C57BL/6J mice were irradiated with 12 Gy. Treated and control mice were sacrificed at 0.5, 1, 3, 6, 12, 24, 48, 72 h, 1, 2, 4, 8, 16, and 24 weeks post irradiation (p.i.). Real-time multiplex RT-PCR (reverse transcriptase polmyerase chain reaction) was established to evaluate the expression of TNF-α, IL-1α and IL-6 in the lung tissue of the mice. For histological analysis, lung tissue sections were stained by hematoxylin and eosin. Results: multiplex RT-PCR analysis revealed a biphasic expression of these pro-inflammatory cytokines in the lung tissue after irradiation. After an initial increase at 1 h p.i. for TNF-α and at 6 h p.i. for IL-1α and IL-6, the mRNA expression of these pro-inflammatory cytokines returned to basal levels (48 h, 72 h, 1 week, 2 weeks p.i.). During the pneumonic phase, TNF-α, IL-1α and IL-6 were significantly elevated and revealed their maximum at 8 weeks p.i. Histopathologic evaluation of the lung sections obtained within 4 weeks p.i. revealed only minor lung damage in 5-30% of the lung tissue. By contrast, at 8, 16, and 24 weeks p.i., 70-90% of the lung tissue revealed histopathologically detectable organizing alveolitis. Conclusion: irradiation induces a biphasic expression of pro-inflammatory cytokines in the lung. The initial transitory cytokine response occurred within the first hours after lung irradiation with no detectable histopathologic alterations. The second, more persistent cytokine elevation coincided with the onset of histologically discernible organizing acute pneumonitis. (orig.)

  13. Phenolic excipients of insulin formulations induce cell death, pro-inflammatory signaling and MCP-1 release

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    Claudia Weber

    2015-01-01

    Insulin solutions displayed cytotoxic and pro-inflammatory potential caused by phenol or m-cresol. We speculate that during insulin pump therapy phenol and m-cresol might induce cell death and inflammatory reactions at the infusion site in vivo. Inflammation is perpetuated by release of MCP-1 by activated monocytic cells leading to enhanced recruitment of inflammatory cells. To minimize acute skin complications caused by phenol/m-cresol accumulation, a frequent change of infusion sets and rotation of the infusion site is recommended.

  14. Cervical cerclage placement decreases local levels of proinflammatory cytokines in patients with cervical insufficiency.

    Science.gov (United States)

    Monsanto, Stephany P; Daher, Silvia; Ono, Erika; Pendeloski, Karen Priscilla Tezotto; Trainá, Évelyn; Mattar, Rosiane; Tayade, Chandrakant

    2017-10-01

    Cervical insufficiency is characterized by premature, progressive dilation and shortening of the cervix during pregnancy. If left unattended, this can lead to the prolapse and rupture of the amniotic membrane, which usually results in midtrimester pregnancy loss or preterm birth. Previous studies have shown that proinflammatory cytokines such as interleukin-1β, interleukin-6, interleukin-8, and tumor necrosis factor alpha are up-regulated in normal parturition but are also associated with preterm birth. Studies evaluating such markers in patients with cervical insufficiency have evaluated only their diagnostic potential. Even fewer studies have studied them within the context of cerclage surgery. The objective of the study was to evaluate the impact of local and systemic inflammatory markers on the pathogenesis of cervical insufficiency and the effect of cerclage surgery on the local immune microenvironment of women with cervical insufficiency. We recruited 28 pregnant women (12-20 weeks' gestation) diagnosed with insufficiency and referred for cerclage surgery and 19 gestational age-matched normal pregnant women as controls. Serum and cervicovaginal fluid samples were collected before and after cerclage surgery and during a routine checkup for normal women and analyzed using a targeted 13-plex proinflammatory cytokine assay. Before surgery, patients with cervical insufficiency had higher levels of interleukin-1β, interleukin-6, interleukin-12, monocyte chemoattractant protein-1 and tumor necrosis factor alpha in cervicovaginal fluid compared to controls, but after surgery, these differences disappeared. No differences were found in serum of insufficiency versus control women. In patients with insufficiency, the levels of interleukin-1β, interleukin-6, interleukin-8, monocyte chemoattractant protein-1, and interferon gamma in cervicovaginal fluid declined significantly after cerclage compared with before intervention, but these changes were not detected in serum

  15. Irradiation induces a biphasic expression of pro-inflammatory cytokines in the lung

    Energy Technology Data Exchange (ETDEWEB)

    Ruebe, C.E.; Wilfert, F.; Palm, J.; Burdak-Rothkamm, S.; Ruebe, C. [Dept. of Radiotherapy - Radiooncology, Saarland Univ., Homburg/Saar (Germany); Koenig, J. [Inst. of Medical Biometrics, Epidemiology and Medical Informatics, Saarland Univ., Homburg/Saar (Germany); Liu Li [Dept. of Radiotherapy - Radiooncology, Saarland Univ., Homburg/Saar (Germany); Cancer Center, Union Hospital Tongji Medical Coll., Huazhong Univ. of Science and Technology, Wuhan (China); Schuck, A.; Willich, N. [Dept. of Radiotherapy - Radiooncology, Univ. of Muenster (Germany)

    2004-07-01

    Background and purpose: the precise pathophysiological mechanisms of radiation-induced lung injury are poorly understood, but have been shown to correlate with dysregulation of different cytokines. The purpose of this study was to evaluate the time course of the pro-inflammatory cytokines tumor necrosis factor-(TNF-){alpha}, interleukin-(IL)-1{alpha} and IL-6 after whole-lung irradiation. Material and methods: the thoraces of C57BL/6J mice were irradiated with 12 Gy. Treated and control mice were sacrificed at 0.5, 1, 3, 6, 12, 24, 48, 72 h, 1, 2, 4, 8, 16, and 24 weeks post irradiation (p.i.). Real-time multiplex RT-PCR (reverse transcriptase polmyerase chain reaction) was established to evaluate the expression of TNF-{alpha}, IL-1{alpha} and IL-6 in the lung tissue of the mice. For histological analysis, lung tissue sections were stained by hematoxylin and eosin. Results: multiplex RT-PCR analysis revealed a biphasic expression of these pro-inflammatory cytokines in the lung tissue after irradiation. After an initial increase at 1 h p.i. for TNF-{alpha} and at 6 h p.i. for IL-1{alpha} and IL-6, the mRNA expression of these pro-inflammatory cytokines returned to basal levels (48 h, 72 h, 1 week, 2 weeks p.i.). During the pneumonic phase, TNF-{alpha}, IL-1{alpha} and IL-6 were significantly elevated and revealed their maximum at 8 weeks p.i. Histopathologic evaluation of the lung sections obtained within 4 weeks p.i. revealed only minor lung damage in 5-30% of the lung tissue. By contrast, at 8, 16, and 24 weeks p.i., 70-90% of the lung tissue revealed histopathologically detectable organizing alveolitis. Conclusion: irradiation induces a biphasic expression of pro-inflammatory cytokines in the lung. The initial transitory cytokine response occurred within the first hours after lung irradiation with no detectable histopathologic alterations. The second, more persistent cytokine elevation coincided with the onset of histologically discernible organizing acute

  16. Impaired production of proinflammatory cytokines in response to lipopolysaccharide (LPS) stimulation in elderly humans

    DEFF Research Database (Denmark)

    Bruunsgaard, H.; Pedersen, Agnes Nadelmann; Schroll, M.

    1999-01-01

    following LPS stimulation, representing an ex vivo model of sepsis. Levels of tumour necrosis factor-alpha (TNF-alpha), IL-1 beta and IL-6 in whole blood supernatants were measured after in vitro LPS stimulation for 24 h in 168 elderly humans aged 81 years from the 1914 cohort in Glostrup, Denmark and in 91...... of proinflammatory cytokines compared with young men, but this difference was blurred by ageing. No relation was found between circulating plasma levels of TNF-alpha and levels after in vitro LPS stimulation. In conclusion, decreased production of TNF-alpha and IL-1 beta after exposure to LPS may reflect impaired...

  17. Decreased proinflammatory cytokine production by peripheral blood mononuclear cells from vitiligo patients following aspirin treatment

    International Nuclear Information System (INIS)

    Zailaie, Mohammad Z.

    2005-01-01

    Limited studies have shown that treatment of cells with aspirin modulates their cytokine production. Consequently, the aim of the present study is to investigate the pattern of important proinflammatory cytokines production by stimulated peripheral blood mononuclear cells (PBMC) from patients with active vitiligo following long-term treatment with low-dose oral aspirin. The study was conducted at the Vitiligo Unit, King Abdul-Aziz University Medical Center, Jeddah, Kingdom of Saudi Arabia between March and October 2003. Thirty-two patients (18 females and 14 males) with non-segmental vitiligo were divided into 2 equal groups, one group received a daily single dose of oral aspirin (300 mg) and the other group received placebo for a period of 12 weeks. The concentrations of interleukin (IL)-1beta, IL-6, IL-8 and tumor necrosis factor-alpha (TNF-alpha) were determined in the supernatant of isolated cultured PMBC after being stimulated with bacterial lipopolysaccharide (LPS), before the start of aspirin treatment and at end of treatment period. Cytokine levels were measured using the quantitative sandwich enzyme-linked immunosorbent assay (ELISA) technique, utilizing commercially available kits. The proinflammatory cytokine production by the PBMC of patients with active vitiligo was significantly increased compared to normal controls. Thus, the relative percentage increase in the production of IL-1beta, IL-6, IL-8 and TNF-alpha was: 39.4%, 110.5% (p<0.05), 91.5% (p<0.01), and 37% (p<0.05). At the end of treatment, proinflammatory cytokine production in the aspirin-treated group of active vitiligo patients was significantly decreased compared to the placebo group. Thus, the relative percentage decrease in the production of IL-1beta IL-6, IL-8 and TNF-alpha was: 42.5%, 45.2% (p<0.05), 30.8% (p<0.01), and 50.6% (p<0.05). The vitiligo activity was arrested in all aspirin-treated patients, while 2 patients demonstrated significant repigmentation.Chronic administration of

  18. Nitric oxide-induced interstrand cross-links in DNA.

    Science.gov (United States)

    Caulfield, Jennifer L; Wishnok, John S; Tannenbaum, Steven R

    2003-05-01

    The DNA damaging effects of nitrous acid have been extensively studied, and the formation of interstrand cross-links have been observed. The potential for this cross-linking to occur through a common nitrosating intermediate derived from nitric oxide is investigated here. Using a HPLC laser-induced fluorescence (LIF) system, the amount of interstrand cross-link formed on nitric oxide treatment of the 5'-fluorescein-labeled oligomer ATATCGATCGATAT was determined. This self-complimentary sequence contains two 5'-CG sequences, which is the preferred site for nitrous acid-induced cross-linking. Nitric oxide was delivered to an 0.5 mM oligomer solution at 15 nmol/mL/min to give a final nitrite concentration of 652 microM. The resulting concentration of the deamination product, xanthine, in this sample was found to be 211 +/- 39 nM, using GC/MS, and the amount of interstrand cross-link was determined to be 13 +/- 2.5 nM. Therefore, upon nitric oxide treatment, the cross-link is found at approximately 6% of the amount of the deamination product. Using this system, detection of the cross-link is also possible for significantly lower doses of nitric oxide, as demonstrated by treatment of the same oligomer with NO at a rate of 18 nmol/mL/min resulting in a final nitrite concentration of 126 microM. The concentration of interstrand cross-link was determined to be 3.6 +/- 0.1 nM in this sample. Therefore, using the same dose rate, when the total nitric oxide concentration delivered drops by a factor of approximately 5, the concentration of cross-link drops by a factor of about 4-indicating a qausi-linear response. It may now be possible to predict the number of cross-links in a small genome based on the number of CpG sequences and the yield of xanthine derived from nitrosative deamination.

  19. Nitric oxide signalling and neuronal nitric oxide synthase in the heart under stress.

    Science.gov (United States)

    Zhang, Yin Hua

    2017-01-01

    Nitric oxide (NO) is an imperative regulator of the cardiovascular system and is a critical mechanism in preventing the pathogenesis and progression of the diseased heart. The scenario of bioavailable NO in the myocardium is complex: 1) NO is derived from both endogenous NO synthases (endothelial, neuronal, and/or inducible NOSs [eNOS, nNOS, and/or iNOS]) and exogenous sources (entero-salivary NO pathway) and the amount of NO from exogenous sources varies significantly; 2) NOSs are located at discrete compartments of cardiac myocytes and are regulated by distinctive mechanisms under stress; 3) NO regulates diverse target proteins through different modes of post-transcriptional modification (soluble guanylate cyclase [sGC]/cyclic guanosine monophosphate [cGMP]/protein kinase G [PKG]-dependent phosphorylation, S -nitrosylation, and transnitrosylation); 4) the downstream effectors of NO are multidimensional and vary from ion channels in the plasma membrane to signalling proteins and enzymes in the mitochondria, cytosol, nucleus, and myofilament; 5) NOS produces several radicals in addition to NO (e.g. superoxide, hydrogen peroxide, peroxynitrite, and different NO-related derivatives) and triggers redox-dependent responses. However, nNOS inhibits cardiac oxidases to reduce the sources of oxidative stress in diseased hearts. Recent consensus indicates the importance of nNOS protein in cardiac protection under pathological stress. In addition, a dietary regime with high nitrate intake from fruit and vegetables together with unsaturated fatty acids is strongly associated with reduced cardiovascular events. Collectively, NO-dependent mechanisms in healthy and diseased hearts are better understood and shed light on the therapeutic prospects for NO and NOSs in clinical applications for fatal human heart diseases.

  20. Smoking and gingivitis: focus on inducible nitric oxide synthase, nitric oxide and basic fibroblast growth factor.

    Science.gov (United States)

    Özdemir, B; Özmeric, N; Elgün, S; Barış, E

    2016-10-01

    Periodontal disease pathogenesis has been associated with smoking. Gingivitis is a mild and reversible form of periodontal disease and it tends to progress to periodontitis only in susceptible individuals. In the present study, we aimed to examine the impact of smoking on host responses in gingivitis and to evaluate and compare the inducible nitric oxide synthase (iNOS) activity in gingival tissue and NO and basic fibroblast growth factor (bFGF) levels in the gingival crevicular fluid of patients with gingivitis and healthy individuals. Forty-one participants were assigned to the gingivitis-smoker (n = 13), gingivitis (n = 13), healthy-smoker (n = 7) and healthy groups (n = 8). Clinical indices were recorded; gingival biopsy and gingival crevicular fluid samples were obtained from papillary regions. iNOS expression was evaluated by immunohistochemical staining. The immunoreactive cells were semiquantitatively assessed. For the quantitative determination of nitrite and nitrate in gingival crevicular fluid, the NO assay kit was used. The amount of bFGF in gingival crevicular fluid was determined by enzyme-linked immunosorbent assay. The gingivitis-smoker group demonstrated a stronger iNOS expression than the non-smoker gingivitis group. iNOS expression intensity was lower in the non-smoker healthy group compared to that in healthy-smokers. No significant gingival crevicular fluid NO and bFGF level changes were observed between groups. Among patients with gingivitis, a positive correlation was detected between gingival crevicular fluid NO and bFGF levels (r = 0.806, p = 0.001). Our data suggest that smoking has significant effects on iNOS expression but not on gingival crevicular fluid NO or bFGF levels in healthy and patients with gingivitis. However, our results suggest that bFGF might be involved in the regulation of NO production via iNOS. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  1. Regulation and control of nitric oxide (NO) in macrophages

    DEFF Research Database (Denmark)

    Kovacevic, Zaklina; Sahni, Sumit; Lok, K.H.

    2017-01-01

    We recently demonstrated that a novel storage and transport mechanism for nitric oxide (NO) mediated by glutathione-S-transferase P1 (GSTP1) and multidrug resistance protein 1 (MRP1/ABCC1), protects M1-macrophage (M1-MØ) models from large quantities of endogenous NO. This system stores and transp......We recently demonstrated that a novel storage and transport mechanism for nitric oxide (NO) mediated by glutathione-S-transferase P1 (GSTP1) and multidrug resistance protein 1 (MRP1/ABCC1), protects M1-macrophage (M1-MØ) models from large quantities of endogenous NO. This system stores...... be responsible for delivering cytotoxic NO as DNICs via MRP1 from M1-MØs, to tumor cell targets....

  2. Arginine affects appetite via nitric oxide in ducks.

    Science.gov (United States)

    Wang, C; Hou, S S; Huang, W; Xu, T S; Rong, G H; Xie, M

    2014-08-01

    The objective of the study was to investigate the mechanism by which arginine regulates feed intake in Pekin ducks. In experiment 1, one hundred forty-four 1-d-old male Pekin ducks were randomly allotted to 3 dietary treatments with 6 replicate pens of 8 birds per pen. Birds in each group were fed a corn-corn gluten meal diet containing 0.65, 0.95, and 1.45% arginine. Ducks fed the diet containing 0.65% arginine had lower feed intake and plasma nitric oxide level (P ducks were allotted to 1 of 2 treatments. After 2 h fasting, birds in the 2 groups were intraperitoneally administrated saline and l-NG-nitro-arginine methyl ester HCl (L-NAME) for 3 d, respectively. Feed intake (P study implied that arginine modifies feeding behavior possibly through controlling endogenous synthesis of nitric oxide in Pekin ducks. © Poultry Science Association Inc.

  3. Reactivity of Resorcinol Formaldehyde Resin with Nitric Acid

    International Nuclear Information System (INIS)

    King, William D.; Fondeur, Fernando F.; Wilmarth, William R.; Pettis, Myra E.

    2005-01-01

    Solid-state infrared spectroscopy, differential scanning calorimetry, and elemental analysis have been used to evaluate the reactivity of resorcinol formaldehyde resin with nitric acid and characterize the solid product. Two distinct reactions were identified within the temperature range 25-55 C. The first reaction is primarily associated with resin nitration, while the second involves bulk oxidation and degradation of the polymer network leading to dissolution and off-gassing. The threshold conditions promoting reaction have been identified. Reaction was confirmed with nitric acid concentrations as low as 3 M at 25 C applied temperature and 0.625 M at 66 C. Although a nitrated resin product can be isolated under appropriate experimental conditions, calorimetry testing indicates no significant hazard associated with handling the dry material

  4. NITRIC OXIDE AND ENDOTHELIN-1 IN CHILDREN WITH DIGESTIVE DISORDERS

    Directory of Open Access Journals (Sweden)

    I. V. Panova

    2012-01-01

    Full Text Available The important part in the group of biological compounds, participating in the regulation of the functions of the gastro-intestinal tract, is assigned to endothelial factors because of their impact on the majority of physiological and pathophysiological processes of the digestive system. The article provides information about physiological role of nitric oxide and endothelin-1 and presents a review of scientific data on the participation of nitric oxide and endothelin-1 in the pathogenesis of many digestive system diseases, emphasizing chronic inflammatory disorders of the upper gastrointestinal tract. The authors accentuate the importance of endothelium endocrine function research in children with esophagogastroduodenal disorders at the beginning of puberty, which is the critical period of ontogenesis.

  5. Fate of aliphatic compounds in nitric acid processing solutions

    International Nuclear Information System (INIS)

    Clark, W.E.; Howerton, W.B.

    1975-01-01

    The reaction of hyperazeotropic iodic acid-saturated nitric acid with short chain aliphatic iodides, nitrates, and acids was studied in order to determine the conditions for complete removal of organic materials from nitric acid systems. The aliphatic iodides are converted to the nitrates and the nitrates in strong HNO 3 are extensively converted into CO 2 and acids. The aliphatic acids are rather stable; acetic acid was unattacked by boiling in 20M HNO 3 and n-butyric acid was 80 percent unattacked. The dibasic acids oxalic and malonic are extensively attacked, but succinic acid is relatively stable. A wet oxidation method is successful in destroying acetic acid in 5 to 8M HNO 3 . (U.S.)

  6. Buffering effects on electrograining of aluminium in nitric acid

    International Nuclear Information System (INIS)

    Koroleva, E.V.; Thompson, G.E.; Skeldon, P.; Hollrigl, G.; Lockwood, S.; Smith, G.

    2005-01-01

    Electrograining of a binary Al-Si alloy has been undertaken in nitric acid based electrolytes, with the resultant surfaces examined by scanning and transmission electron microscopies. Depending on electrograining conditions, the pit appearance varies from hemispherical to large lateral pits, with the latter favoured in relatively acidic electrolytes. The conditions prevailing in the pit have been explored through use of aluminium ion additions to the nitric acid electrolyte as well as additions of species which influence the precipitation and dissolution of aluminium hydroxide. These confirm that control of the pit solution pH, through hydroxide generation, as a result of the selected electrograining conditions and consequent anodic and cathodic polarisation, enables tailoring of the resultant electrograined surface appearance

  7. Nitric-glycolic flowsheet testing for maximum hydrogen generation rate

    Energy Technology Data Exchange (ETDEWEB)

    Martino, C. J. [Savannah River Site (SRS), Aiken, SC (United States). Savannah River National Lab. (SRNL); Newell, J. D. [Savannah River Site (SRS), Aiken, SC (United States). Savannah River National Lab. (SRNL); Williams, M. S. [Savannah River Site (SRS), Aiken, SC (United States). Savannah River National Lab. (SRNL)

    2016-03-01

    The Defense Waste Processing Facility (DWPF) at the Savannah River Site is developing for implementation a flowsheet with a new reductant to replace formic acid. Glycolic acid has been tested over the past several years and found to effectively replace the function of formic acid in the DWPF chemical process. The nitric-glycolic flowsheet reduces mercury, significantly lowers the chemical generation of hydrogen and ammonia, allows purge reduction in the Sludge Receipt and Adjustment Tank (SRAT), stabilizes the pH and chemistry in the SRAT and the Slurry Mix Evaporator (SME), allows for effective adjustment of the SRAT/SME rheology, and is favorable with respect to melter flammability. The objective of this work was to perform DWPF Chemical Process Cell (CPC) testing at conditions that would bound the catalytic hydrogen production for the nitric-glycolic flowsheet.

  8. Macrophage proinflammatory response to the titanium alloy equipment in dental implantation.

    Science.gov (United States)

    Chen, X; Li, H S; Yin, Y; Feng, Y; Tan, X W

    2015-08-07

    Titanium alloy and stainless steel (SS) had been widely used as dental implant materials because of their affinity with epithelial tissue and connective tissue, and good physical, chemical, biological, mechanical properties and processability. We compared the effects of titanium alloy and SS on macrophage cytokine expression as well as their biocompatibility. Mouse macrophage RAW264.7 cells were cultured on titanium alloy and SS surfaces. Cells were counted by scanning electron microscopy. A nitride oxide kit was used to detect released nitric oxide by macrophages on the different materials. An enzyme linked immunosorbent assay was used to detect monocyte chemoattractant protein-1 levels. Scanning electron microscopy revealed fewer macrophages on the surface of titanium alloy (48.2 ± 6.4 x 10(3) cells/cm(2)) than on SS (135 ± 7.3 x 10(3) cells/cm(2)). The nitric oxide content stimulated by titanium alloy was 22.5 mM, which was lower than that stimulated by SS (26.8 mM), but the difference was not statistically significant (P = 0.07). The level of monocyte chemoattractant protein-1 released was significantly higher in the SS group (OD value = 0.128) than in the titanium alloy group (OD value = 0.081) (P = 0.024). The transforming growth factor-b1 mRNA expression levels in macrophages after stimulation by titanium alloy for 12 and 36 h were significantly higher than that after stimulation by SS (P = 0.31 and 0.25, respectively). Macrophages participate in the inflammatory response by regulating cytokines such as nitric oxide, monocyte chemoattractant protein-1, and transforming growth factor-b1. There were fewer macrophages and lower inflammation on the titanium alloy surface than on the SS surface. Titanium alloy materials exhibited better biological compatibility than did SS.

  9. Cellular Mechanics of Primary Human Cervical Fibroblasts: Influence of Progesterone and a Pro-inflammatory Cytokine.

    Science.gov (United States)

    Shukla, Vasudha; Barnhouse, Victoria; Ackerman, William E; Summerfield, Taryn L; Powell, Heather M; Leight, Jennifer L; Kniss, Douglas A; Ghadiali, Samir N

    2018-01-01

    The leading cause of neonatal mortality, pre-term birth, is often caused by pre-mature ripening/opening of the uterine cervix. Although cervical fibroblasts play an important role in modulating the cervix's extracellular matrix (ECM) and mechanical properties, it is not known how hormones, i.e., progesterone, and pro-inflammatory insults alter fibroblast mechanics, fibroblast-ECM interactions and the resulting changes in tissue mechanics. Here we investigate how progesterone and a pro-inflammatory cytokine, IL-1β, alter the biomechanical properties of human cervical fibroblasts and the fibroblast-ECM interactions that govern tissue-scale mechanics. Primary human fibroblasts were isolated from non-pregnant cervix and treated with estrogen/progesterone, IL-1β or both. The resulting changes in ECM gene expression, matrix remodeling, traction force generation, cell-ECM adhesion and tissue contractility were monitored. Results indicate that IL-1β induces a significant reduction in traction force and ECM adhesion independent of pre-treatment with progesterone. These cell level effects altered tissue-scale mechanics where IL-1β inhibited the contraction of a collagen gel over 6 days. Interestingly, progesterone treatment alone did not modulate traction forces or gel contraction but did result in a dramatic increase in cell-ECM adhesion. Therefore, the protective effect of progesterone may be due to altered adhesion dynamics as opposed to altered ECM remodeling.

  10. Medium-chain fatty acid-sensing receptor, GPR84, is a proinflammatory receptor.

    Science.gov (United States)

    Suzuki, Masakatsu; Takaishi, Sachiko; Nagasaki, Miyuki; Onozawa, Yoshiko; Iino, Ikue; Maeda, Hiroaki; Komai, Tomoaki; Oda, Tomiichiro

    2013-04-12

    G protein-coupled receptor 84 (GPR84) is a putative receptor for medium-chain fatty acids (MCFAs), whose pathophysiological roles have not yet been clarified. Here, we show that GPR84 was activated by MCFAs with the hydroxyl group at the 2- or 3-position more effectively than nonhydroxylated MCFAs. We also identified a surrogate agonist, 6-n-octylaminouracil (6-OAU), for GPR84. These potential ligands and the surrogate agonist, 6-OAU, stimulated [(35)S]GTP binding and accumulated phosphoinositides in a GPR84-dependent manner. The surrogate agonist, 6-OAU, internalized GPR84-EGFP from the cell surface. Both the potential ligands and 6-OAU elicited chemotaxis of human polymorphonuclear leukocytes (PMNs) and macrophages and amplified LPS-stimulated production of the proinflammatory cytokine IL-8 from PMNs and TNFα from macrophages. Furthermore, the intravenous injection of 6-OAU raised the blood CXCL1 level in rats, and the inoculation of 6-OAU into the rat air pouch accumulated PMNs and macrophages in the site. Our results indicate a proinflammatory role of GPR84, suggesting that the receptor may be a novel target to treat chronic low grade inflammation associated-disease.

  11. Edaravone protects endotoxin-induced liver injury by inhibiting apoptosis and reducing proinflammatory cytokines.

    Science.gov (United States)

    Zong, L; Yu, Q H; Du, Y X; Deng, X M

    2014-02-01

    Studies have shown that edaravone may prevent liver injury. This study aimed to investigate the effects of edaravone on the liver injury induced by D-galactosamine (GalN) and lipopolysaccharide (LPS) in female BALB/c mice. Edaravone was injected into mice 30 min before and 4 h after GalN/LPS injection. The survival rate was determined within the first 24 h. Animals were killed 8 h after GalN/LPS injection, and liver injury was biochemically and histologically assessed. Hepatocyte apoptosis was measured by TUNEL staining; proinflammatory cytokines [tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6)] in the liver were assayed by ELISA; expression of caspase-8 and caspase-3 proteins was detected by Western blot assay; and caspase-3 activity was also determined. Results showed that GalN/LPS induced marked elevations in serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Edaravone significantly inhibited elevation of serum AST and ALT, accompanied by an improvement in histological findings. Edaravone lowered the levels of TNF-α and IL-6 and reduced the number of TUNEL-positive cells. In addition, 24 h after edaravone treatment, caspase-3 activity and mortality were reduced. Edaravone may effectively ameliorate GalN/LPS-induced liver injury in mice by reducing proinflammatory cytokines and inhibiting apoptosis.

  12. Edaravone protects endotoxin-induced liver injury by inhibiting apoptosis and reducing proinflammatory cytokines

    Energy Technology Data Exchange (ETDEWEB)

    Zong, L. [Second Military Medical University, Changhai Hospital, Department of Anesthesiology, Shanghai, China, Department of Anesthesiology, Changhai Hospital, Second Military Medical University, Shanghai (China); No. 82 Hospital of People' s Liberation Army, Department of Anesthesiology, Jiangsu, China, Department of Anesthesiology, No. 82 Hospital of People' s Liberation Army, Jiangsu (China); Yu, Q. H. [Second Military Medical University, Changhai Hospital, Department of Gastroenterology, Shanghai, China, Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai (China); Du, Y. X. [No. 82 Hospital of People' s Liberation Army, Department of Anesthesiology, Jiangsu, China, Department of Anesthesiology, No. 82 Hospital of People' s Liberation Army, Jiangsu (China); Deng, X. M. [Second Military Medical University, Changhai Hospital, Department of Anesthesiology, Shanghai, China, Department of Anesthesiology, Changhai Hospital, Second Military Medical University, Shanghai (China)

    2014-03-03

    Studies have shown that edaravone may prevent liver injury. This study aimed to investigate the effects of edaravone on the liver injury induced by D-galactosamine (GalN) and lipopolysaccharide (LPS) in female BALB/c mice. Edaravone was injected into mice 30 min before and 4 h after GalN/LPS injection. The survival rate was determined within the first 24 h. Animals were killed 8 h after GalN/LPS injection, and liver injury was biochemically and histologically assessed. Hepatocyte apoptosis was measured by TUNEL staining; proinflammatory cytokines [tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6)] in the liver were assayed by ELISA; expression of caspase-8 and caspase-3 proteins was detected by Western blot assay; and caspase-3 activity was also determined. Results showed that GalN/LPS induced marked elevations in serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Edaravone significantly inhibited elevation of serum AST and ALT, accompanied by an improvement in histological findings. Edaravone lowered the levels of TNF-α and IL-6 and reduced the number of TUNEL-positive cells. In addition, 24 h after edaravone treatment, caspase-3 activity and mortality were reduced. Edaravone may effectively ameliorate GalN/LPS-induced liver injury in mice by reducing proinflammatory cytokines and inhibiting apoptosis.

  13. Edaravone protects endotoxin-induced liver injury by inhibiting apoptosis and reducing proinflammatory cytokines

    Directory of Open Access Journals (Sweden)

    L. Zong

    2014-03-01

    Full Text Available Studies have shown that edaravone may prevent liver injury. This study aimed to investigate the effects of edaravone on the liver injury induced by D-galactosamine (GalN and lipopolysaccharide (LPS in female BALB/c mice. Edaravone was injected into mice 30 min before and 4 h after GalN/LPS injection. The survival rate was determined within the first 24 h. Animals were killed 8 h after GalN/LPS injection, and liver injury was biochemically and histologically assessed. Hepatocyte apoptosis was measured by TUNEL staining; proinflammatory cytokines [tumor necrosis factor-α (TNF-α and interleukin-6 (IL-6] in the liver were assayed by ELISA; expression of caspase-8 and caspase-3 proteins was detected by Western blot assay; and caspase-3 activity was also determined. Results showed that GalN/LPS induced marked elevations in serum aspartate aminotransferase (AST and alanine aminotransferase (ALT. Edaravone significantly inhibited elevation of serum AST and ALT, accompanied by an improvement in histological findings. Edaravone lowered the levels of TNF-α and IL-6 and reduced the number of TUNEL-positive cells. In addition, 24 h after edaravone treatment, caspase-3 activity and mortality were reduced. Edaravone may effectively ameliorate GalN/LPS-induced liver injury in mice by reducing proinflammatory cytokines and inhibiting apoptosis.

  14. Edaravone protects endotoxin-induced liver injury by inhibiting apoptosis and reducing proinflammatory cytokines

    International Nuclear Information System (INIS)

    Zong, L.; Yu, Q.H.; Du, Y.X.; Deng, X.M.

    2014-01-01

    Studies have shown that edaravone may prevent liver injury. This study aimed to investigate the effects of edaravone on the liver injury induced by D-galactosamine (GalN) and lipopolysaccharide (LPS) in female BALB/c mice. Edaravone was injected into mice 30 min before and 4 h after GalN/LPS injection. The survival rate was determined within the first 24 h. Animals were killed 8 h after GalN/LPS injection, and liver injury was biochemically and histologically assessed. Hepatocyte apoptosis was measured by TUNEL staining; proinflammatory cytokines [tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6)] in the liver were assayed by ELISA; expression of caspase-8 and caspase-3 proteins was detected by Western blot assay; and caspase-3 activity was also determined. Results showed that GalN/LPS induced marked elevations in serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Edaravone significantly inhibited elevation of serum AST and ALT, accompanied by an improvement in histological findings. Edaravone lowered the levels of TNF-α and IL-6 and reduced the number of TUNEL-positive cells. In addition, 24 h after edaravone treatment, caspase-3 activity and mortality were reduced. Edaravone may effectively ameliorate GalN/LPS-induced liver injury in mice by reducing proinflammatory cytokines and inhibiting apoptosis

  15. The pro-inflammatory effects of platelet contamination in plasma and mitigation strategies for avoidance

    Science.gov (United States)

    Bercovitz, R. S.; Kelher, M. R.; Khan, S. Y.; Land, K. J.; Berry, T. H.; Silliman, C. C.

    2013-01-01

    Background and Objectives Plasma and platelet concentrates are disproportionately implicated in transfusion-related acute lung injury (TRALI). Platelet-derived pro-inflammatory mediators, including soluble CD40 ligand (sCD40L), accumulate during storage. We hypothesized that platelet contamination induces sCD40L generation that causes neutrophil [polymorphonuclear leucocyte (PMN)] priming and PMN-mediated cytotoxicity. Materials and Methods Plasma was untreated, centrifuged (12 500 g) or separated from leucoreduced whole blood (WBLR) prior to freezing. Platelet counts and sCD40L concentrations were measured 1–5 days post-thaw. The plasma was assayed for PMN priming activity and was used in a two-event in vitro model of PMN-mediated human pulmonary microvascular endothelial cell (HMVEC) cytotoxicity. Results Untreated plasma contained 42 ± 4.2 × 103/μl platelets, which generated sCD40L accumulation (1.6-eight-fold vs. controls). Priming activity and HMVEC cytotoxicity were directly proportional to sCD40L concentration. WBLR and centrifugation reduced platelet and sCD40L contamination, abrogating the pro-inflammatory potential. Conclusion Platelet contamination causes sCD40L accumulation in stored plasma that may contribute to TRALI. Platelet reduction is potentially the first TRALI mitigation effort in plasma manufacturing. PMID:22092073

  16. Metoprolol Reduces Proinflammatory Cytokines and Atherosclerosis in ApoE−/− Mice

    Directory of Open Access Journals (Sweden)

    Marcus A. Ulleryd

    2014-01-01

    Full Text Available A few studies in animals and humans suggest that metoprolol (β1-selective adrenoceptor antagonist may have a direct antiatherosclerotic effect. However, the mechanism behind this protective effect has not been established. The aim of the present study was to evaluate the effect of metoprolol on development of atherosclerosis in ApoE−/− mice and investigate its effect on the release of proinflammatory cytokines. Male ApoE−/− mice were treated with metoprolol (2.5 mg/kg/h or saline for 11 weeks via osmotic minipumps. Atherosclerosis was assessed in thoracic aorta and aortic root. Total cholesterol levels and Th1/Th2 cytokines were analyzed in serum and macrophage content in lesions by immunohistochemistry. Metoprolol significantly reduced atherosclerotic plaque area in thoracic aorta (P<0.05 versus Control. Further, metoprolol reduced serum TNFα and the chemokine CXCL1 (P<0.01 versus Control for both as well as decreasing the macrophage content in the plaques (P<0.01 versus Control. Total cholesterol levels were not affected. In this study we found that a moderate dose of metoprolol significantly reduced atherosclerotic plaque area in thoracic aorta of ApoE−/− mice. Metoprolol also decreased serum levels of proinflammatory cytokines TNFα and CXCL1 and macrophage content in the plaques, showing that metoprolol has an anti-inflammatory effect.

  17. Proinflammatory Factors Mediate Paclitaxel-Induced Impairment of Learning and Memory

    Directory of Open Access Journals (Sweden)

    Zhao Li

    2018-01-01

    Full Text Available The chemotherapeutic agent paclitaxel is widely used for cancer treatment. Paclitaxel treatment impairs learning and memory function, a side effect that reduces the quality of life of cancer survivors. However, the neural mechanisms underlying paclitaxel-induced impairment of learning and memory remain unclear. Paclitaxel treatment leads to proinflammatory factor release and neuronal apoptosis. Thus, we hypothesized that paclitaxel impairs learning and memory function through proinflammatory factor-induced neuronal apoptosis. Neuronal apoptosis was assessed by TUNEL assay in the hippocampus. Protein expression levels of tumor necrosis factor-α (TNF-α and interleukin-1β (IL-1β in the hippocampus tissue were analyzed by Western blot assay. Spatial learning and memory function were determined by using the Morris water maze (MWM test. Paclitaxel treatment significantly increased the escape latencies and decreased the number of crossing in the MWM test. Furthermore, paclitaxel significantly increased the number of TUNEL-positive neurons in the hippocampus. Also, paclitaxel treatment increased the expression levels of TNF-α and IL-1β in the hippocampus tissue. In addition, the TNF-α synthesis inhibitor thalidomide significantly attenuated the number of paclitaxel-induced TUNEL-positive neurons in the hippocampus and restored the impaired spatial learning and memory function in paclitaxel-treated rats. These data suggest that TNF-α is critically involved in the paclitaxel-induced impairment of learning and memory function.

  18. Controlled Inhibition of the Mesenchymal Stromal Cell Pro-inflammatory Secretome via Microparticle Engineering

    Directory of Open Access Journals (Sweden)

    Sudhir H. Ranganath

    2016-06-01

    Full Text Available Mesenchymal stromal cells (MSCs are promising therapeutic candidates given their potent immunomodulatory and anti-inflammatory secretome. However, controlling the MSC secretome post-transplantation is considered a major challenge that hinders their clinical efficacy. To address this, we used a microparticle-based engineering approach to non-genetically modulate pro-inflammatory pathways in human MSCs (hMSCs under simulated inflammatory conditions. Here we show that microparticles loaded with TPCA-1, a small-molecule NF-κB inhibitor, when delivered to hMSCs can attenuate secretion of pro-inflammatory factors for at least 6 days in vitro. Conditioned medium (CM derived from TPCA-1-loaded hMSCs also showed reduced ability to attract human monocytes and prevented differentiation of human cardiac fibroblasts to myofibroblasts, compared with CM from untreated or TPCA-1-preconditioned hMSCs. Thus, we provide a broadly applicable bioengineering solution to facilitate intracellular sustained release of agents that modulate signaling. We propose that this approach could be harnessed to improve control over MSC secretome post-transplantation, especially to prevent adverse remodeling post-myocardial infarction.

  19. Shigella dysenteriae infection activates proinflammatory response through β-catenin/NF-κB signaling pathway.

    Directory of Open Access Journals (Sweden)

    Ashidha Gopal

    Full Text Available Shigella dysenteriae (S.dysenteriae the causative agent of bacillary dysentery invades the human colonic epithelium resulting in severe intestinal inflammatory response and epithelial destruction. However, the mechanism by which S.dysenteriae infection regulates proinflammatory cytokines during intestinal inflammation is still obscure. In this study, we evaluated whether the interaction of β-catenin and NF-κB regulates proinflammatory cytokines TNF-α and IL-8 by modulating GSK-3β activity during S.dysenteriae infection in rat ileal loop model. Here we demonstrated that S.dysenteriae infection stimulate β-catenin degradation which in turn decreased the association between NF-κB and β-catenin. Also, we showed that S.dysenteriae infection increased GSK-3β kinase activity which in turn phosphorylates β-catenin for its degradation by ubiquitination and upregulates IL-8 through NF-κB activation thereby leading to inflammation. Thus these findings revealed the role of β-catenin/ NF-κB and GSK-3β in modulating the inflammatory response during bacterial infection and also showed that β-catenin acts as a critical regulator of inflammation.

  20. Nitric oxide synthase isoforms in spontaneous and salt hypertension

    Czech Academy of Sciences Publication Activity Database

    Hojná, Silvie; Kuneš, Jaroslav; Zicha, Josef

    2007-01-01

    Roč. 25, Suppl. 2 (2007), S 338-S 338 ISSN 0263-6352. [European Meeting on Hypertension /17./. 15.06.2007-19.06.2007, Milan] R&D Projects: GA MŠk(CZ) 1M0510 Institutional research plan: CEZ:AV0Z50110509 Keywords : nitric oxide synthase isoforms * spontaneous and salt hypertension Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery

  1. Isoxazole derivatives as new nitric oxide elicitors in plants

    Directory of Open Access Journals (Sweden)

    Anca Oancea

    2017-04-01

    Full Text Available Several 3,5-disubstituted isoxazoles were obtained in good yields by regiospecific 1,3-dipolar cycloaddition reactions between aromatic nitrile oxides, generated in situ from the corresponding hydroxyimidoyl chlorides, with non-symmetrical activated alkynes in the presence of catalytic amounts of copper(I iodide. Effects of 3,5-disubstituted isoxazoles on nitric oxide and reactive oxygen species generation in Arabidopsis tissues was studied using specific diaminofluoresceine dyes as fluorescence indicators.

  2. Features of molybdenum disulfide interaction with nitric acid

    International Nuclear Information System (INIS)

    Chursanov, Yu.V.; Potashnikov, Yu.M.; Rumyantsev, V.K.

    1987-01-01

    Experiments on studying composition of products of molybdenite concentrate (MoS 2 ) oxidation by HNO 3 solutions were conducted. Molybdenite oxidation was conducted in a glass temperature controlled vessel in absence of oxygen. It was shown that nitrogen (2) oxide represented the final product of molybdenite interaction with nitric acid. The process was accompanied as well by separation of NO 2 and HNO 2 under dynamic conditions, and nitrogen (4) oxide acted as catalyst of oxidation at that

  3. Enhancement of vascular targeting by inhibitors of nitric oxide synthase

    International Nuclear Information System (INIS)

    Davis, Peter D.; Tozer, Gillian M.; Naylor, Matthew A.; Thomson, Peter; Lewis, Gemma; Hill, Sally A.

    2002-01-01

    Purpose: This study investigates the enhancement of the vascular targeting activity of the tubulin-binding agent combretastatin A4 phosphate (CA4P) by various inhibitors of nitric oxide synthases. Methods and Materials: The syngeneic tumors CaNT and SaS growing in CBA mice were used for this study. Reduction in perfused vascular volume was measured by injection of Hoechst 33342 24 h after drug administration. Necrosis (hematoxylin and eosin stain) was assessed also at 24 h after treatment. Combretastatin A4 phosphate was synthesized by a modification of the published procedure and the nitric oxide synthase inhibitors L-NNA, L-NMMA, L-NIO, L-NIL, S-MTC, S-EIT, AMP, AMT, and L-TC, obtained from commercial sources. Results: A statistically significant augmentation of the reduction in perfused vascular volume by CA4P in the CaNT tumor was observed with L-NNA, AMP, and AMT. An increase in CA4P-induced necrosis in the same tumor achieved significance with L-NNA, L-NMMA, L-NIL, and AMT. CA4P induced little necrosis in the SaS tumor, but combination with the inhibitors L-NNA, L-NMMA, L-NIO, S-EIT, and L-TC was effective. Conclusions: Augmentation of CA4P activity by nitric oxide synthase inhibitors of different structural classes supports a nitric oxide-related mechanism for this effect. L-NNA was the most effective inhibitor studied

  4. Nitric oxide and non-quantal acetylcholine release

    Czech Academy of Sciences Publication Activity Database

    Vyskočil, František

    2003-01-01

    Roč. 7, č. 3 (2003), s. 241-243 ISSN 1211-7579. [Celostátní konference biologické psychiatrie /11./. Luhačovice, 11.06.2003-14.06.2003] R&D Projects: GA ČR GA305/02/1333 Institutional research plan: CEZ:AV0Z5011922; CEZ:MSM 113100003 Keywords : nitric oxide Subject RIV: ED - Physiology

  5. Exercise promotes collateral artery growth mediated by monocytic nitric oxide.

    Science.gov (United States)

    Schirmer, Stephan H; Millenaar, Dominic N; Werner, Christian; Schuh, Lisa; Degen, Achim; Bettink, Stephanie I; Lipp, Peter; van Rooijen, Nico; Meyer, Tim; Böhm, Michael; Laufs, Ulrich

    2015-08-01

    Collateral artery growth (arteriogenesis) is an important adaptive response to hampered arterial perfusion. It is unknown whether preventive physical exercise before limb ischemia can improve arteriogenesis and modulate mononuclear cell function. This study aimed at investigating the effects of endurance exercise before arterial occlusion on MNC function and collateral artery growth. After 3 weeks of voluntary treadmill exercise, ligation of the right femoral artery was performed in mice. Hindlimb perfusion immediately after surgery did not differ from sedentary mice. However, previous exercise improved perfusion restoration ≤7 days after femoral artery ligation, also when exercise was stopped at ligation. This was accompanied by an accumulation of peri-collateral macrophages and increased expression of endothelial nitric oxide synthase and inducible nitric oxide synthase (iNOS) in hindlimb collateral and in MNC of blood and spleen. Systemic monocyte and macrophage depletion by liposomal clodronate but not splenectomy attenuated exercise-induced perfusion restoration, collateral artery growth, peri-collateral macrophage accumulation, and upregulation of iNOS. iNOS-deficient mice did not show exercise-induced perfusion restoration. Transplantation of bone marrow-derived MNC from iNOS-deficient mice into wild-type animals inhibited exercise-induced collateral artery growth. In contrast to sedentary controls, thrice weekly aerobic exercise training for 6 months in humans increased peripheral blood MNC iNOS expression. Circulating mononuclear cell-derived inducible nitric oxide is an important mediator of exercise-induced collateral artery growth. © 2015 American Heart Association, Inc.

  6. Stainless steel welding method with excellent nitric acid corrosion resistance

    International Nuclear Information System (INIS)

    Matsushita, Yukinobu; Inazumi, Toru; Hyakubo, Tamako; Masamura, Katsumi.

    1996-01-01

    The present invention concerns a welding method for a stainless steel used in a circumstance being in contact with a highly oxidizing nitric acid solution such as nuclear fuel reprocessing facilities, upon welding 316 type austenite steel containing Mo while giving excellent nitric acid resistance. A method of TIG welding using a filler metal having a composition of C, Si, Mn, P, S, Ni, Cr, Mo and Cu somewhat different from a stainless steel mother material in which C, Si, Mn, P, S, Ni, Cr and Mo are specified comprises a step of TIG-welding the surface of the mother material and a step of TIG-welding the rear face of the mother material, in which the welding conditions for the rear face of the mother material are such that the distance between the surface of the outermost welding metal layer on the side of the surface of the mother material and the bottom of the groove is not less than 5mm, and an amount of welding heat is made constant. As a result, even if the method is used in a circumstance being in contact with a highly corrosive solution such as nitric acid, corrosion resistance is not degraded. (N.H.)

  7. Uranium carbide dissolution in nitric solution: Sonication vs. silent conditions

    International Nuclear Information System (INIS)

    Virot, Matthieu; Szenknect, Stéphanie; Chave, Tony; Dacheux, Nicolas; Moisy, Philippe; Nikitenko, Sergey I.

    2013-01-01

    The dissolution of uranium carbide (UC) in nitric acid media is considered by means of power ultrasound (sonication) or magnetic stirring. The induction period required to initiate UC dissolution was found to be dramatically shortened when sonicating a 3 M nitric solution (Ar, 20 kHz, 18 W cm −2 , 20 °C). At higher acidity, magnetic stirring offers faster dissolution kinetics compared to sonication. Ultrasound-assisted UC dissolution is found to be passivated after ∼60% dissolution and remains incomplete whatever the acidity which is confirmed by ICP–AES, LECO and SEM–EDX analyses. In general, the kinetics of UC dissolution is linked to the in situ generation of nitrous acid in agreement with the general mechanism of UC dissolution; the nitrous acid formation is reported to be faster under ultrasound at low acidity due to the nitric acid sonolysis. The carbon balance shared between the gaseous, liquid, and solid phases is strongly influenced by the applied dissolution procedure and HNO 3 concentration

  8. Uranium carbide dissolution in nitric solution: Sonication vs. silent conditions

    Science.gov (United States)

    Virot, Matthieu; Szenknect, Stéphanie; Chave, Tony; Dacheux, Nicolas; Moisy, Philippe; Nikitenko, Sergey I.

    2013-10-01

    The dissolution of uranium carbide (UC) in nitric acid media is considered by means of power ultrasound (sonication) or magnetic stirring. The induction period required to initiate UC dissolution was found to be dramatically shortened when sonicating a 3 M nitric solution (Ar, 20 kHz, 18 W cm-2, 20 °C). At higher acidity, magnetic stirring offers faster dissolution kinetics compared to sonication. Ultrasound-assisted UC dissolution is found to be passivated after ∼60% dissolution and remains incomplete whatever the acidity which is confirmed by ICP-AES, LECO and SEM-EDX analyses. In general, the kinetics of UC dissolution is linked to the in situ generation of nitrous acid in agreement with the general mechanism of UC dissolution; the nitrous acid formation is reported to be faster under ultrasound at low acidity due to the nitric acid sonolysis. The carbon balance shared between the gaseous, liquid, and solid phases is strongly influenced by the applied dissolution procedure and HNO3 concentration.

  9. Nitric oxide-related drug targets in headache

    DEFF Research Database (Denmark)

    Olesen, Jes

    2010-01-01

    SUMMARY: Nitric oxide (NO) is a very important molecule in the regulation of cerebral and extra cerebral cranial blood flow and arterial diameters. It is also involved in nociceptive processing. Glyceryl trinitrate (GTN), a pro-drug for NO, causes headache in normal volunteers and a so-called del......SUMMARY: Nitric oxide (NO) is a very important molecule in the regulation of cerebral and extra cerebral cranial blood flow and arterial diameters. It is also involved in nociceptive processing. Glyceryl trinitrate (GTN), a pro-drug for NO, causes headache in normal volunteers and a so......-called delayed headache that fulfils criteria for migraine without aura in migraine sufferers. Blockade of nitric oxide synthases (NOS) by L-nitromonomethylarginine effectively treats attacks of migraine without aura. Similar results have been obtained for chronic the tension-type headache and cluster headache....... Inhibition of the breakdown of cyclic guanylate phosphate (cGMP) also provokes migraine in sufferers, indicating that cGMP is the effector of NO-induced migraine. Similar evidence suggests an important role of NO in the tension-type headache and cluster headache. These very strong data from human...

  10. Experimental study on thermal hazard of tributyl phosphate-nitric acid mixtures using micro calorimeter technique

    Energy Technology Data Exchange (ETDEWEB)

    Sun, Qi; Jiang, Lin; Gong, Liang; Sun, Jin-Hua, E-mail: sunjh@ustc.edu.cn

    2016-08-15

    Highlights: • Heat flows after mixing TBP with nitric acid are of different orders of magnitude. • Thermodynamics and kinetics of tributyl phosphate-nitric acid mixtures are derived. • Tributyl phosphate directly reacts with nitric acid and form organic red oil. • Thermal runaway could occur at 79 °C with a high nitric acid concentration. - Abstract: During PUREX spent nuclear fuel reprocessing, mixture of tributyl phosphate (TBP) and hydrocarbon solvent are employed as organic solvent to extract uranium in consideration of radiation contaminated safety and resource recycling, meanwhile nitric acid is utilized to dissolve the spent fuel into small pieces. However, once TBP contacts with nitric acid or nitrates above 130 °C, a heavy “red oil” layer would occur accompanied by thermal runaway reactions, even caused several nuclear safety accident. Considering nitric acid volatility and weak exothermic detection, C80 micro calorimeter technique was used in this study to investigate thermal decomposition of TBP mixed with nitric acid. Results show that the concentration of nitric acid greatly influences thermal hazard of the system by direct reactions. Even with a low heating rate, if the concentration of nitric acid increases due to evaporation of water or improper operations, thermal runaway in the closed system could start at a low temperature.

  11. Pro-inflammatory cytokines play a key role in the development of radiotherapy-induced gastrointestinal mucositis

    Directory of Open Access Journals (Sweden)

    Logan Richard M

    2010-03-01

    Full Text Available Abstract Background Mucositis is a toxic side effect of anti-cancer treatments and is a major focus in cancer research. Pro-inflammatory cytokines have previously been implicated in the pathophysiology of chemotherapy-induced gastrointestinal mucositis. However, whether they play a key role in the development of radiotherapy-induced gastrointestinal mucositis is still unknown. Therefore, the aim of the present study was to characterise the expression of pro-inflammatory cytokines in the gastrointestinal tract using a rat model of fractionated radiotherapy-induced toxicity. Methods Thirty six female Dark Agouti rats were randomly assigned into groups and received 2.5 Gys abdominal radiotherapy three times a week over six weeks. Real time PCR was conducted to determine the relative change in mRNA expression of pro-inflammatory cytokines IL-1β, IL-6 and TNF in the jejunum and colon. Protein expression of IL-1β, IL-6 and TNF in the intestinal epithelium was investigated using qualitative immunohistochemistry. Results Radiotherapy-induced sub-acute damage was associated with significantly upregulated IL-1β, IL-6 and TNF mRNA levels in the jejunum and colon. The majority of pro-inflammatory cytokine protein expression in the jejunum and colon exhibited minimal change following fractionated radiotherapy. Conclusions Pro-inflammatory cytokines play a key role in radiotherapy-induced gastrointestinal mucositis in the sub-acute onset setting.

  12. Adherent Human Alveolar Macrophages Exhibit a Transient Pro-Inflammatory Profile That Confounds Responses to Innate Immune Stimulation

    Science.gov (United States)

    Tomlinson, Gillian S.; Booth, Helen; Petit, Sarah J.; Potton, Elspeth; Towers, Greg J.; Miller, Robert F.; Chain, Benjamin M.; Noursadeghi, Mahdad

    2012-01-01

    Alveolar macrophages (AM) are thought to have a key role in the immunopathogenesis of respiratory diseases. We sought to test the hypothesis that human AM exhibit an anti-inflammatory bias by making genome-wide comparisons with monocyte derived macrophages (MDM). Adherent AM obtained by bronchoalveolar lavage of patients under investigation for haemoptysis, but found to have no respiratory pathology, were compared to MDM from healthy volunteers by whole genome transcriptional profiling before and after innate immune stimulation. We found that freshly isolated AM exhibited a marked pro-inflammatory transcriptional signature. High levels of basal pro-inflammatory gene expression gave the impression of attenuated responses to lipopolysaccharide (LPS) and the RNA analogue, poly IC, but in rested cells pro-inflammatory gene expression declined and transcriptional responsiveness to these stimuli was restored. In comparison to MDM, both freshly isolated and rested AM showed upregulation of MHC class II molecules. In most experimental paradigms ex vivo adherent AM are used immediately after isolation. Therefore, the confounding effects of their pro-inflammatory profile at baseline need careful consideration. Moreover, despite the prevailing view that AM have an anti-inflammatory bias, our data clearly show that they can adopt a striking pro-inflammatory phenotype, and may have greater capacity for presentation of exogenous antigens than MDM. PMID:22768282

  13. Extraction of antimony from nitric acid solutions using tributyl phosphate. II. Tributyl phosphate-antimony(V)-nitric acid system

    International Nuclear Information System (INIS)

    Lakaev, V.S.; Smelov, V.S.

    1989-01-01

    The extraction of pentavalent antimony from nitric acid solutions using tributyl phosphate has been investigated. A possible mechanism for the extraction of antimony(V) has been determined and the (pre)concentration constant for the process has been calculated. The composition of the extracted antimony(V) complex has been deduced. A negative effect of temperature on the distribution coefficient for antimony(V) has also been demonstrated

  14. Flavone inhibits nitric oxide synthase (NOS) activity, nitric oxide production and protein S-nitrosylation in breast cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Zhu, Wenzhen; Yang, Bingwu; Fu, Huiling; Ma, Long; Liu, Tingting; Chai, Rongfei; Zheng, Zhaodi [Shandong Provincial Key Laboratory of Animal Resistant Biology, School of Life Sciences, Shandong Normal University, Jinan 250014 (China); Zhang, Qunye, E-mail: wz.zhangqy@sdu.edu.cn [Key Laboratory of Cardiovascular Remodeling and Function Research Chinese Ministry of Education and Ministry of Public Health, Qilu Hospital, Shandong University, Jinan, Shandong (China); Li, Guorong, E-mail: grli@sdnu.edu.cn [Shandong Provincial Key Laboratory of Animal Resistant Biology, School of Life Sciences, Shandong Normal University, Jinan 250014 (China)

    2015-03-13

    As the core structure of flavonoids, flavone has been proved to possess anticancer effects. Flavone's growth inhibitory functions are related to NO. NO is synthesized by nitric oxide synthase (NOS), and generally increased in a variety of cancer cells. NO regulates multiple cellular responses by S-nitrosylation. In this study, we explored flavone-induced regulations on nitric oxide (NO)-related cellular processes in breast cancer cells. Our results showed that, flavone suppresses breast cancer cell proliferation and induces apoptosis. Flavone restrains NO synthesis by does-dependent inhibiting NOS enzymatic activity. The decrease of NO generation was detected by fluorescence microscopy and flow cytometry. Flavone-induced inhibitory effect on NOS activity is dependent on intact cell structure. For the NO-induced protein modification, flavone treatment significantly down-regulated protein S-nitrosylation, which was detected by “Biotin-switch” method. The present study provides a novel, NO-related mechanism for the anticancer function of flavone. - Highlights: • Flavone inhibits proliferation and induces apoptosis in MCF-7 cells. • Flavone decreases nitric oxide production by inhibiting NOS enzymatic activity in breast cancer cells. • Flavone down-regulates protein S-nitrosylation.

  15. Flavone inhibits nitric oxide synthase (NOS) activity, nitric oxide production and protein S-nitrosylation in breast cancer cells

    International Nuclear Information System (INIS)

    Zhu, Wenzhen; Yang, Bingwu; Fu, Huiling; Ma, Long; Liu, Tingting; Chai, Rongfei; Zheng, Zhaodi; Zhang, Qunye; Li, Guorong

    2015-01-01

    As the core structure of flavonoids, flavone has been proved to possess anticancer effects. Flavone's growth inhibitory functions are related to NO. NO is synthesized by nitric oxide synthase (NOS), and generally increased in a variety of cancer cells. NO regulates multiple cellular responses by S-nitrosylation. In this study, we explored flavone-induced regulations on nitric oxide (NO)-related cellular processes in breast cancer cells. Our results showed that, flavone suppresses breast cancer cell proliferation and induces apoptosis. Flavone restrains NO synthesis by does-dependent inhibiting NOS enzymatic activity. The decrease of NO generation was detected by fluorescence microscopy and flow cytometry. Flavone-induced inhibitory effect on NOS activity is dependent on intact cell structure. For the NO-induced protein modification, flavone treatment significantly down-regulated protein S-nitrosylation, which was detected by “Biotin-switch” method. The present study provides a novel, NO-related mechanism for the anticancer function of flavone. - Highlights: • Flavone inhibits proliferation and induces apoptosis in MCF-7 cells. • Flavone decreases nitric oxide production by inhibiting NOS enzymatic activity in breast cancer cells. • Flavone down-regulates protein S-nitrosylation

  16. Alzheimer's disease: a gas model. The NADPH oxidase-Nitric Oxide system as an antibubble biomachinery.

    Science.gov (United States)

    Denis, Pierre A

    2013-12-01

    Alzheimer's disease (AD) is a neurodegenerative disease of unknown origin. The pathological lesions that define AD would be linked to the insidious accumulation of nitrogen, having invaded the brain interstitial fluid (ISF) from the blood via the physiological cycling pool of vascular glucose transporters (GLUT-1). According to this hypothesis, the nitrogen nanobubbles, being chemically inert and actually indestructible for human beings, can not escape from the ISF anymore. They would exert a huge and deleterious pressure against cellular components, especially in microglia and in astrocytes. They could enhance the existing cell oxygen anisotropy, which might enhance the natural bubble nucleation of O2-2O2 in cells or in mitochondria. Indeed, with the help of a new symbolic representation for gas nuclei in chemical reactions, the NADPH oxidase-NO system is identified for the first time, as an antibubble biomachinery, able to break O2-2O2 bubbles up as it releases superoxide O2-. Superoxide is considered as a quantum bubble, which collapses through the reactivity of the gaseous NO radical. Their combination in soluble peroxinitrite provides the change from one state of matter to another, avoiding any risk of a bubble enlargement, and finally avoiding the risk of enzyme crowding or of a bulk pressure variation. However, a bubble is expected to entrap Nitric Oxide (NO), which leads theoretically to a decrease in its bioavailability, and is expected to trigger a guanylyl-cyclase-mediated inflammatory cascade, that could explain the inflammation in AD. In vitro, any increase in the hydrostatic pressure has already been linked to the microtubule disorganization. The amyloid deposits, also known as senile plaques, would behave as a sponge toward ISF nitrogen; Aβ is considered as a foam-stabilizing agent. By taking the shape of cerebral amyloid angiopathy, the amyloid could confine the nitrogen leak from the blood, and progressively insulate the Blood-Brain Barrier

  17. Holi colours contain PM10 and can induce pro-inflammatory responses.

    Science.gov (United States)

    Bossmann, Katrin; Bach, Sabine; Höflich, Conny; Valtanen, Kerttu; Heinze, Rita; Neumann, Anett; Straff, Wolfgang; Süring, Katrin

    2016-01-01

    At Holi festivals, originally celebrated in India but more recently all over the world, people throw coloured powder (Holi powder, Holi colour, Gulal powder) at each other. Adverse health effects, i.e. skin and ocular irritations as well as respiratory problems may be the consequences. The aim of this study was to uncover some of the underlying mechanisms. We analysed four different Holi colours regarding particle size using an Electric field cell counting system. In addition, we incubated native human cells with different Holi colours and determined their potential to induce a pro-inflammatory response by quantifying the resulting cytokine production by means of ELISA (Enzyme Linked Immunosorbent Assay) and the resulting leukocyte oxidative burst by flow cytometric analysis. Moreover, we performed the XTT (2,3-Bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide) and Propidium iodide cytotoxicity tests and we measured the endotoxin content of the Holi colour samples by means of the Limulus Amebocyte Lysate test (LAL test). We show here that all tested Holi colours consist to more than 40 % of particles with an aerodynamic diameter smaller than 10 μm, so called PM10 particles (PM, particulate matter). Two of the analysed Holi powders contained even more than 75 % of PM10 particles. Furthermore we demonstrate in cell culture experiments that Holi colours can induce the production of the pro-inflammatory cytokines TNF-α (Tumor necrosis factor-α), IL-6 (Interleukine-6) and IL-1β (Interleukine-1β). Three out of the four analysed colours induced a significantly higher cytokine response in human PBMCs (Peripheral Blood Mononuclear Cells) and whole blood than corn starch, which is often used as carrier substance for Holi colours. Moreover we show that corn starch and two Holi colours contain endotoxin and that certain Holi colours display concentration dependent cytotoxic effects in higher concentration. Furthermore we reveal that in principle Holi

  18. A pro-inflammatory role of deubiquitinating enzyme cylindromatosis (CYLD) in vascular smooth muscle cells

    International Nuclear Information System (INIS)

    Liu, Shuai; Lv, Jiaju; Han, Liping; Ichikawa, Tomonaga; Wang, Wenjuan; Li, Siying; Wang, Xing Li; Tang, Dongqi; Cui, Taixing

    2012-01-01

    Highlights: ► Cyld deficiency suppresses pro-inflammatory phenotypic switch of VSMCs. ► Cyld deficiency inhibits MAPK rather than NF-kB activity in inflamed VSMCs. ► CYLD is up-regulated in the coronary artery with neointimal hyperplasia. -- Abstract: CYLD, a deubiquitinating enzyme (DUB), is a critical regulator of diverse cellular processes, ranging from proliferation and differentiation to inflammatory responses, via regulating multiple key signaling cascades such as nuclear factor kappa B (NF-κB) pathway. CYLD has been shown to inhibit vascular lesion formation presumably through suppressing NF-κB activity in vascular cells. However, herein we report a novel role of CYLD in mediating pro-inflammatory responses in vascular smooth muscle cells (VSMCs) via a mechanism independent of NF-κB activity. Adenoviral knockdown of Cyld inhibited basal and the tumor necrosis factor alpha (TNFα)-induced mRNA expression of pro-inflammatory cytokines including monocyte chemotactic protein-1 (Mcp-1), intercellular adhesion molecule (Icam-1) and interleukin-6 (Il-6) in rat adult aortic SMCs (RASMCs). The CYLD deficiency led to increases in the basal NF-κB transcriptional activity in RASMCs; however, did not affect the TNFα-induced NF-κB activity. Intriguingly, the TNFα-induced IκB phosphorylation was enhanced in the CYLD deficient RASMCs. While knocking down of Cyld decreased slightly the basal expression levels of IκBα and IκBβ proteins, it did not alter the kinetics of TNFα-induced IκB protein degradation in RASMCs. These results indicate that CYLD suppresses the basal NF-κB activity and TNFα-induced IκB kinase activation without affecting TNFα-induced NF-κB activity in VSMCs. In addition, knocking down of Cyld suppressed TNFα-induced activation of mitogen activated protein kinases (MAPKs) including extracellular signal-activated kinases (ERK), c-Jun N-terminal kinase (JNK), and p38 in RASMCs. TNFα-induced RASMC migration and monocyte adhesion to

  19. Proinflammatory effect in whole blood by free soluble bacterial components released from planktonic and biofilm cells

    Directory of Open Access Journals (Sweden)

    Thay Bernard

    2008-11-01

    Full Text Available Abstract Background Aggregatibacter actinomycetemcomitans is an oral bacterium associated with aggressive forms of periodontitis. Increasing evidence points to a link between periodontitis and cardiovascular diseases, however, the underlying mechanisms are poorly understood. This study investigated the pathogenic potential of free-soluble surface material, released from live planktonic and biofilm A. actinomycetemcomitans cells. Results By employing an ex vivo insert model (filter pore size 20 nm we demonstrated that the A. actinomycetemcomitans strain D7S and its derivatives, in both planktonic and in biofilm life-form, released free-soluble surface material independent of outer membrane vesicles. This material clearly enhanced the production of several proinflammatory cytokines (IL-1β, TNF-α, IL-6, IL-8, MIP-1β in human whole blood, as evidenced by using a cytokine antibody array and dissociation-enhanced-lanthanide-fluorescent-immunoassay. In agreement with this, quantitative real-time PCR indicated a concomitant increase in transcription of each of these cytokine genes. Experiments in which the LPS activity was blocked with polymyxin B showed that the stimulatory effect was only partly LPS-dependent, suggesting the involvement of additional free-soluble factors. Consistent with this, MALDI-TOF-MS and immunoblotting revealed release of GroEL-like protein in free-soluble form. Conversely, the immunomodulatory toxins, cytolethal distending toxin and leukotoxin, and peptidoglycan-associated lipoprotein, appeared to be less important, as evidenced by studying strain D7S cdt/ltx double, and pal single mutants. In addition to A. actinomycetemcomitans a non-oral species, Escherichia coli strain IHE3034, tested in the same ex vivo model also released free-soluble surface material with proinflammatory activity. Conclusion A. actinomycetemcomitans, grown in biofilm and planktonic form, releases free-soluble surface material independent of outer

  20. Proinflammatory effect in whole blood by free soluble bacterial components released from planktonic and biofilm cells.

    Science.gov (United States)

    Oscarsson, Jan; Karched, Maribasappa; Thay, Bernard; Chen, Casey; Asikainen, Sirkka

    2008-11-27

    Aggregatibacter actinomycetemcomitans is an oral bacterium associated with aggressive forms of periodontitis. Increasing evidence points to a link between periodontitis and cardiovascular diseases, however, the underlying mechanisms are poorly understood. This study investigated the pathogenic potential of free-soluble surface material, released from live planktonic and biofilm A. actinomycetemcomitans cells. By employing an ex vivo insert model (filter pore size 20 nm) we demonstrated that the A. actinomycetemcomitans strain D7S and its derivatives, in both planktonic and in biofilm life-form, released free-soluble surface material independent of outer membrane vesicles. This material clearly enhanced the production of several proinflammatory cytokines (IL-1 beta, TNF-alpha, IL-6, IL-8, MIP-1 beta) in human whole blood, as evidenced by using a cytokine antibody array and dissociation-enhanced-lanthanide-fluorescent-immunoassay. In agreement with this, quantitative real-time PCR indicated a concomitant increase in transcription of each of these cytokine genes. Experiments in which the LPS activity was blocked with polymyxin B showed that the stimulatory effect was only partly LPS-dependent, suggesting the involvement of additional free-soluble factors. Consistent with this, MALDI-TOF-MS and immunoblotting revealed release of GroEL-like protein in free-soluble form. Conversely, the immunomodulatory toxins, cytolethal distending toxin and leukotoxin, and peptidoglycan-associated lipoprotein, appeared to be less important, as evidenced by studying strain D7S cdt/ltx double, and pal single mutants. In addition to A. actinomycetemcomitans a non-oral species, Escherichia coli strain IHE3034, tested in the same ex vivo model also released free-soluble surface material with proinflammatory activity. A. actinomycetemcomitans, grown in biofilm and planktonic form, releases free-soluble surface material independent of outer membrane vesicles, which induces proinflammatory

  1. 11β-Hydroxysteroid dehydrogenase 1 contributes to the pro-inflammatory response of keratinocytes

    Energy Technology Data Exchange (ETDEWEB)

    Itoi, Saori; Terao, Mika, E-mail: mterao@derma.med.osaka-u.ac.jp; Murota, Hiroyuki; Katayama, Ichiro

    2013-10-18

    Highlights: •We investigate the role of 11β-HSD1 in skin inflammation. •Various stimuli increase expression of 11β-HSD1 in keratinocytes. •11β-HSD1 knockdown by siRNA decreases cortisol levels in media. •11β-HSD1 knockdown abrogates the response to pro-inflammatory cytokines. •Low-dose versus high-dose cortisol has opposing effects on keratinocyte inflammation. -- Abstract: The endogenous glucocorticoid, cortisol, is released from the adrenal gland in response to various stress stimuli. Extra-adrenal cortisol production has recently been reported to occur in various tissues. Skin is known to synthesize cortisol through a de novo pathway and through an activating enzyme. The enzyme that catalyzes the intracellular conversion of hormonally-inactive cortisone into active cortisol is 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1). We recently reported that 11β-HSD1 is expressed in normal human epidermal keratinocytes (NHEKs) and negatively regulates proliferation of NHEKs. In this study, we investigated the role of 11β-HSD1 in skin inflammation. Expression of 11β-HSD1 was induced by UV-B irradiation and in response to the pro-inflammatory cytokines, IL-1β and TNFα. Increased cortisol concentrations in culture media also increased in response to these stimuli. To investigate the function of increased 11β-HSD1 in response to pro-inflammatory cytokines, we knocked down 11β-HSD1 by transfecting siRNA. Production of IL-6 and IL-8 in response to IL-1β or TNFα stimulation was attenuated in NHEKs transfected with si11β-HSD1 compared with control cells. In addition, IL-1β-induced IL-6 production was enhanced in cultures containing 1 × 10{sup −13} M cortisol, whereas 1 × 10{sup −5} M cortisol attenuated production of IL-6. Thus, cortisol showed immunostimulatory and immunosuppressive activities depending on its concentration. Our results indicate that 11β-HSD1 expression is increased by various stimuli. Thus, regulation of cytosolic cortisol

  2. 11β-Hydroxysteroid dehydrogenase 1 contributes to the pro-inflammatory response of keratinocytes

    International Nuclear Information System (INIS)

    Itoi, Saori; Terao, Mika; Murota, Hiroyuki; Katayama, Ichiro

    2013-01-01

    Highlights: •We investigate the role of 11β-HSD1 in skin inflammation. •Various stimuli increase expression of 11β-HSD1 in keratinocytes. •11β-HSD1 knockdown by siRNA decreases cortisol levels in media. •11β-HSD1 knockdown abrogates the response to pro-inflammatory cytokines. •Low-dose versus high-dose cortisol has opposing effects on keratinocyte inflammation. -- Abstract: The endogenous glucocorticoid, cortisol, is released from the adrenal gland in response to various stress stimuli. Extra-adrenal cortisol production has recently been reported to occur in various tissues. Skin is known to synthesize cortisol through a de novo pathway and through an activating enzyme. The enzyme that catalyzes the intracellular conversion of hormonally-inactive cortisone into active cortisol is 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1). We recently reported that 11β-HSD1 is expressed in normal human epidermal keratinocytes (NHEKs) and negatively regulates proliferation of NHEKs. In this study, we investigated the role of 11β-HSD1 in skin inflammation. Expression of 11β-HSD1 was induced by UV-B irradiation and in response to the pro-inflammatory cytokines, IL-1β and TNFα. Increased cortisol concentrations in culture media also increased in response to these stimuli. To investigate the function of increased 11β-HSD1 in response to pro-inflammatory cytokines, we knocked down 11β-HSD1 by transfecting siRNA. Production of IL-6 and IL-8 in response to IL-1β or TNFα stimulation was attenuated in NHEKs transfected with si11β-HSD1 compared with control cells. In addition, IL-1β-induced IL-6 production was enhanced in cultures containing 1 × 10 −13 M cortisol, whereas 1 × 10 −5 M cortisol attenuated production of IL-6. Thus, cortisol showed immunostimulatory and immunosuppressive activities depending on its concentration. Our results indicate that 11β-HSD1 expression is increased by various stimuli. Thus, regulation of cytosolic cortisol concentrations

  3. A pro-inflammatory role of deubiquitinating enzyme cylindromatosis (CYLD) in vascular smooth muscle cells

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Shuai [Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan 250012 (China); Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29208 (United States); Lv, Jiaju [Department of Urology, Shandong Provincial Hospital, Shandong University, Jinan 250021 (China); Han, Liping; Ichikawa, Tomonaga; Wang, Wenjuan; Li, Siying [Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29208 (United States); Wang, Xing Li [Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan 250012 (China); Tang, Dongqi, E-mail: tangdq@pathology.ufl.edu [Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL 32610-0275 (United States); Cui, Taixing, E-mail: taixing.cui@uscmed.sc.edu [Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29208 (United States)

    2012-03-30

    Highlights: Black-Right-Pointing-Pointer Cyld deficiency suppresses pro-inflammatory phenotypic switch of VSMCs. Black-Right-Pointing-Pointer Cyld deficiency inhibits MAPK rather than NF-kB activity in inflamed VSMCs. Black-Right-Pointing-Pointer CYLD is up-regulated in the coronary artery with neointimal hyperplasia. -- Abstract: CYLD, a deubiquitinating enzyme (DUB), is a critical regulator of diverse cellular processes, ranging from proliferation and differentiation to inflammatory responses, via regulating multiple key signaling cascades such as nuclear factor kappa B (NF-{kappa}B) pathway. CYLD has been shown to inhibit vascular lesion formation presumably through suppressing NF-{kappa}B activity in vascular cells. However, herein we report a novel role of CYLD in mediating pro-inflammatory responses in vascular smooth muscle cells (VSMCs) via a mechanism independent of NF-{kappa}B activity. Adenoviral knockdown of Cyld inhibited basal and the tumor necrosis factor alpha (TNF{alpha})-induced mRNA expression of pro-inflammatory cytokines including monocyte chemotactic protein-1 (Mcp-1), intercellular adhesion molecule (Icam-1) and interleukin-6 (Il-6) in rat adult aortic SMCs (RASMCs). The CYLD deficiency led to increases in the basal NF-{kappa}B transcriptional activity in RASMCs; however, did not affect the TNF{alpha}-induced NF-{kappa}B activity. Intriguingly, the TNF{alpha}-induced I{kappa}B phosphorylation was enhanced in the CYLD deficient RASMCs. While knocking down of Cyld decreased slightly the basal expression levels of I{kappa}B{alpha} and I{kappa}B{beta} proteins, it did not alter the kinetics of TNF{alpha}-induced I{kappa}B protein degradation in RASMCs. These results indicate that CYLD suppresses the basal NF-{kappa}B activity and TNF{alpha}-induced I{kappa}B kinase activation without affecting TNF{alpha}-induced NF-{kappa}B activity in VSMCs. In addition, knocking down of Cyld suppressed TNF{alpha}-induced activation of mitogen activated protein

  4. Behaviour of Pu-IV with various ion exchangers in solutions containing nitric acid and oxalates

    International Nuclear Information System (INIS)

    Walter, E.; Ali, S.A.

    1982-02-01

    The distribution of Pu-IV on the ion exchangers Dowex 50W-X8, Dowex 1-X8 und Dowex Chelating Resin Al-X8 in the presence of various concentrations of nitric acid and oxalate were investigated. The results indicate that nitric acid and oxalic acid influence each other during complexation of Pu-IV with oxalate ions solutions containing nitric acid it is not possible to neglect the formation of Pu-IV nitrate complexes. The complex Pu(IV) (C 2 O 4 ) 3 2 - only is formed in solutions containing low nitric acid and high oxalic acid concentrations. The separation of Pu-IV in Dowex Chelating Resin from nitric acid solution in the presence of higher oxalate concentrations is possible, provided that the nitric acid concentration is lower than 0.25 molar [fr

  5. Method of improving the decontaminating efficiency of ruthenium in evaporating treatment of nitric acid

    International Nuclear Information System (INIS)

    Kubota, Kanya; Yamana, Hajime; Takeda, Seiichiro.

    1984-01-01

    Purpose: To significantly improve the ruthenium removing efficiency in a nitric acid solution in an acid recovery system for the recovery of nitric acid from nitric acid liquid wastes through evaporating condensation. Method: Upon evaporating treatment of nitric acid solution containing ruthenium by supplying and heating the solution to a nitric acid evaporating device, hydrazine is previously added to the nitric acid solution. Hydrazine and intermediate reaction product of hydrazine such as azide causes a reduction reaction with intermediate reaction product of ruthenium tetraoxide to suppress the oxidation of ruthenium and thereby improve the decontaminating efficiency of ruthenium. The amount of hydrazine to be added is preferably between 20 - 500 mg/l and most suitably between 200 - 2000 mg/l per one liter of the liquid in the evaporating device. (Seki, T.)

  6. Investigation of the proinflammatory activity of bronchoalveolar lavage fluid in lung cancer and inflammatory diseases of respiratory organs

    Directory of Open Access Journals (Sweden)

    O. P. Makarova

    2014-01-01

    Full Text Available The proinflammatory activity of bronchoalveolar lavage fluid (BALF was investigated using the biological test system (donor blood in 71 patients with lung cancer and inflammatory disease of respiratory organs (lung abscess, infiltrative tuberculosis, tuberculoma, fibrocavernous tuberculosis. The supernatant of BALF was purified by filtration through millipores and added to blood, and a nitroblue tetrazolium recovery test (HBT was carried out. Hank’s balanced salt solution was used in the control. The proinflammatory effect of BALF was defined as a diformazan-positive neutrophil count ratio in the experimental and control samples (stimulation index. The inflammatory process developing in lung cancer was active, as suggested by the accumulation of neutrophils in the lung and by the high proinflammatory activity of BALF, which were comparable with the similar indicators in lung abscess and fibrocavernous tuberculosis.

  7. Influence of nitric acid on the kinetic of complexation of uranyl nitrate extracted by TBP

    International Nuclear Information System (INIS)

    Pushlenkov, M.F.; Zimenkov, V.V.

    1982-02-01

    The effect of nitric acid on the solvatation rate of uranyl nitrate with tributyl phosphate is studied. In the process of mass transfer, it is shown that nitric acid enables the extraction of uranyl nitrate, therefore its concentration in the organic phase exceeds that in equilibrium solution. Subsequently uranyl nitrate ''displaces'' nitric acid. The presence of the acid in aqueous and organic phases affects in a complicated manner the rate of solvatation of uranyl nitrate with tributyl phosphate [fr

  8. Upregulation of proinflammatory genes in skin lesions may be the cause of keloid formation (Review)

    Science.gov (United States)

    DONG, XIANGLIN; MAO, SHAOLIN; WEN, HAO

    2013-01-01

    It was previously demonstrated that the main cause behind keloid formation may be keloid fibroblast abnormalities, which are closely associated with the microenvironment of the keloid lesion. The post-traumatic and chronic inflammation of the keloid lesion area suggest that inflammatory mediators play an important role in the keloid microenvironment and are crucial for keloid fibroblast abnormalities. In this study, we hypothesized that the mechanism underlying keloid formation may involve the continuous upregulation of proinflammatory gene expression in keloid lesions. This hypothesis may explain the inflammatory response, invasive growth and recurrence following resection of keloids, as well as the selective localization of keloids in specific parts of a patient’s body and the differences in localization among different patients. PMID:24649037

  9. The bronchiolar epithelium as a prominent source of pro-inflammatory cytokines after lung irradiation

    International Nuclear Information System (INIS)

    Ruebe, Claudia E.; Uthe, Daniela; Wilfert, Falk; Ludwig, Daniela; Yang Kunyu; Koenig, Jochem; Palm, Jan; Schuck, Andreas; Willich, Normann; Remberger, Klaus; Ruebe, Christian

    2005-01-01

    Purpose: To study in detail the temporal and spatial release of the pro-inflammatory cytokines tumor necrosis factor α, interleukin (IL)-1α, and IL-6 in the lung tissue of C57BL/6 mice after thoracic irradiation with 12 Gy. Methods and Materials: C57BL/6J mice were exposed to either sham irradiation or a single fraction of 12 Gy delivered to the thorax. Treated and sham-irradiated control mice were killed at 0.5 h, 1 h, 3 h, 6 h, 12 h, 24 h, 48 h, 72 h, 1 week, 2 weeks, 4 weeks, 8 weeks, 16 weeks, and 24 weeks post-irradiation (p.i.). Real-time multiplex reverse transcriptase polymerase chain reaction was established to evaluate the relative messenger RNA (mRNA) expression of TNF-α, IL-1α, and IL-6 in the lung tissue of the mice (compared with nonirradiated lung tissue). Immunohistochemical detection methods (alkaline phosphatase anti-alkaline phosphatase, avidin-biotin-complex [ABC]) and automated image analysis were used to quantify the protein expression of TNF-α, IL-1α, and IL-6 in the lung tissue (percentage of the positively stained area). Results: Radiation-induced release of the pro-inflammatory cytokines TNF-α, IL-1α, and IL-6 in the lung tissue was detectable within the first hours after thoracic irradiation. We observed statistically significant up-regulations for TNF-α at 1 h p.i. on mRNA (4.99 ± 1.60) and at 6 h p.i. on protein level (7.23% ± 1.67%), for IL-1α at 6 h p.i. on mRNA (11.03 ± 0.77) and at 12 h p.i. on protein level (27.58% ± 11.06%), for IL-6 at 6 h p.i. on mRNA (6.0 ± 3.76) and at 12 h p.i. on protein level (7.12% ± 1.93%). With immunohistochemistry, we could clearly demonstrate that the bronchiolar epithelium is the most prominent source of these inflammatory cytokines in the first hours after lung irradiation. During the stage of acute pneumonitis, the bronchiolar epithelium, as well as inflammatory cells in the lung interstitium, produced high amounts of TNF-α (with the maximal value at 4 weeks p.i.: 9.47% ± 1

  10. Necroptotic cells release find-me signal and are engulfed without proinflammatory cytokine production.

    Science.gov (United States)

    Wang, Qiang; Ju, Xiaoli; Zhou, Yang; Chen, Keping

    2015-11-01

    Necroptosis is a form of caspase-independent programmed cell death which is mediated by the RIP1-RIP3 complex. Although phagocytosis of apoptotic cells has been extensively investigated, how necroptotic cells are engulfed has remained elusive. Here, we investigated how necroptotic cells attracted and were engulfed by macrophages. We found that necroptotic cells induced the migration of THP-1 cells in a transwell migration assay. Further analysis showed that ATP released from necroptotic cells acted as a find-me signal that induced the migration of THP-1 cells. We also found that Annexin V blocked phagocytosis of necroptotic cells by macrophages. Furthermore, necroptotic cells were shown to be silently cleared by macrophages without any proinflammatory cytokine production. These data uncover an evolutionarily conserved mechanism of the find-me signal in different types of cell death and immunological consequences between apoptotic and necroptotic cells during phagocytosis.

  11. Different activities of Schinus areira L.: anti-inflammatory or pro-inflammatory effect.

    Science.gov (United States)

    Davicino, R; Mattar, A; Casali, Y; Anesini, C; Micalizzi, B

    2010-12-01

    The anti-inflammatory drugs possess many serious side effects at doses commonly prescribed. It is really important to discover novel regulators of inflammation from natural sources with minimal adverse effects. Schinus areira L. is a plant native from South America and is used in folk medicine as an anti-inflammatory herb. For this study, the activity of aqueous extracts on inflammation and the effect on superoxide anion production in mice macrophages were assayed. Aqueous extracts were prepared by soaking herbs in cold water (cold extract), boiling water (infusion), and simmering water (decoction). Cold extract possess an anti-inflammatory activity. Decoction and infusion showed pro-inflammatory activity. Cold extract increased the production of superoxide anion. It has been proposed to use diverse methods to obtain extracts of S. areira L. with different effects. Cold extract, decoction, and infusion could be utilized as extracts or as pharmacological preparations for topical application.

  12. Human Langerhans Cells with Pro-inflammatory Features Relocate within Psoriasis Lesions

    Science.gov (United States)

    Eidsmo, Liv; Martini, Elisa

    2018-01-01

    Psoriasis is a common skin disease that presents with well-demarcated patches of inflammation. Recurrent disease in fixed areas of the skin indicates a localized disease memory that is preserved in resolved lesions. In line with such concept, the involvement of tissue-resident immune cells in psoriasis pathology is increasingly appreciated. Langerhans cells (LCs) are perfectly placed to steer resident T cells and local tissue responses in psoriasis. Here, we present an overview of the current knowledge of LCs in human psoriasis, including findings that highlight pro-inflammatory features of LCs in psoriasis lesions. We also review the literature on conflicting data regarding LC localization and functionality in psoriasis. Our review highlights that further studies are needed to elucidate the molecular mechanisms that drive LCs functionality in inflammatory diseases. PMID:29520279

  13. 4.3. Decomposition of danburite concentrate of Ak-Arkar Deposit by nitric acid

    International Nuclear Information System (INIS)

    Mirsaidov, U.M.; Kurbonov, A.S.; Mamatov, E.D.

    2015-01-01

    Present article is devoted to decomposition of danburite concentrate of Ak-Arkar Deposit by nitric acid. The influence of temperature on reaction process was studied. The dependence of extraction rate of oxides (B 2 O 3 , Al 2 O 3 , Fe 2 O 3 and Ca O) at nitric acid processing on temperature ranges from 25 to 95 deg C was defined. The dependence of extraction rate of oxides (B 2 O 3 , Al 2 O 3 , Fe 2 O 3 and Ca O) at nitric acid processing on process duration (5-60 minutes) was defined as well. The optimal conditions of decomposition of danburite concentrate by nitric acid were proposed.

  14. Optimization of conditions to produce nitrous gases by electrochemical reduction of nitric acid

    International Nuclear Information System (INIS)

    Lemaire, M.; CEA Centre d'Etudes de la Vallee du Rhone, 30 -Marcoule

    1996-01-01

    Gaseous nitrogen oxides (NO and NO 2 ) involved as oxidizing agents in nuclear fuel reprocessing can be an produced by electrochemical reduction of nitric acid. This could be an interesting alternative to the usual process because no wastes are generated. Voltammetric studies on a platinum electrode show that two reduction potential regions are observed in concentrated nitric acid solutions, between 0.05 V S HE and 0.3 V S HE and O.5 V S HE and 1 V S HE. The highest potential region reduction mechanism was studies by: classical micro-electrolysis methods; macro-electrolysis methods; infra-red spectroscopy couplet to electrochemistry. It was determined that the origin of nitric acid reduction is the electrochemical reduction of nitrous acid in nitric oxide which chemically reduces nitric acid. This reaction produces nitrous acid back which indicate an auto-catalytic behaviour of nitric acid reduction mechanism. Nitrogen dioxide evolution during nitric acid reduction can also be explained by an other chemical reaction. In the potential value of platinum electrode is above 0.8 V S HE, products of the indirect nitric acid reduction are nitrous acid, nitrogen oxide and nitrogen dioxide. Below this value nitric oxide can be reduced in nitrous oxide. Thus the potential value is the most important parameter for the nitrogen oxides production selectivity. However, owing to the auto-catalytic character of the reduction mechanism, potential value can be controlled during intentiostatic industrial electrolysis. (author)

  15. Optimization of the nitrous vapors experimental conditions production by nitric acid electrochemical reduction

    International Nuclear Information System (INIS)

    Lemaire, M.

    1996-01-01

    Gaseous nitrogen oxides (NO and NO 2 ) involved as oxidizing agents in nuclear fuel reprocessing can be produced by electrochemical reduction of nitric acid. This is an interesting alternative to the existing process because no wastes are generated. voltammetric studies on a platinum electrode show that two reduction potential regions are observed in concentrated nitric acid solutions, between 0,05 V SHE and between 0,5 V SHE and 1 V SHE . The highest potential region reduction mechanism was studied by: classical micro-electrolysis methods, macro-electrolysis methods, infrared spectroscopy coupled to electrochemistry. It was determined that the origin of nitric acid reduction is the electrochemical reduction of nitrous acid in nitric oxide which chemically reduces nitric acid. This reaction produces nitrous acid back which indicate an auto-catalytic behaviour of nitric acid reduction mechanism. Nitrogen dioxide evolution during nitric reduction can also explained by an other chemical reaction. If the potential value of platinum electrode is above 0,8 V SHE , products of the indirect nitric acid reduction are nitrous acid, nitrogen oxide and nitrogen dioxide. Below this value nitric oxide can be reduced in nitrous oxide. Thus the potential value is the most important parameter for the nitrogen oxides production selectivity. However, owing to the auto-catalytic character of the reduction mechanism, potential value can be controlled during intentiostatic industrial electrolysis. (author)

  16. Effect of SOCS1 overexpression on RPE cell activation by proinflammatory cytokines.

    Science.gov (United States)

    Bazewicz, Magdalena; Draganova, Dafina; Makhoul, Maya; Chtarto, Abdel; Elmaleh, Valerie; Tenenbaum, Liliane; Caspers, Laure; Bruyns, Catherine; Willermain, François

    2016-09-06

    The purpose of this study was to investigate the in vitro effect of Suppressor Of Cytokine Signaling 1 (SOCS1) overexpression in retinal pigment epithelium (RPE) cells on their activation by pro-inflammatory cytokines IFNγ, TNFα and IL-17. Retinal pigment epithelium cells (ARPE-19) were stably transfected with the control plasmid pIRES2-AcGFP1 or the plasmid pSOCS1-IRES2-AcGFP1. They were stimulated by IFNγ (150ng/ml), TNFα (30ng/ml) or IL-17 (100ng/ml). The levels of SOCS1 mRNA were measured by real-time PCR. Signal Transducer and Activator of Transcription 1 (STAT1) phosphorylation and IκBα expression were analysed by western Blot (WB). IL-8 secretion was analysed by ELISA and expression of MHCII molecules and ICAM-1/CD54 by flow cytometry. Our data show that SOCS1 mRNA overexpression in RPE cells prevents IFNγ-induced SOCS1 mRNA increase and IFNγ-mediated STAT1 phosphorylation. Moreover, SOCS1 overexpression in RPE cells inhibits IFNγ-induced decrease of IL-8 secretion and prevents IFNγ-induced MHC II and ICAM1/CD54 upregulation. However, SOCS1 overexpression does not affect TNFα-induced IκBα degradation nor block TNFα-induced or IL-17-induced IL-8 secretion. On the contrary, IL-17-induced secretion is increased by SOCS1 overexpression. In conclusion, SOCS1 overexpression in RPE cells inhibits some IFNγ-mediated responses that lead to uveitis development. This notion raises the possibility that SOCS1 overexpression could be a novel target for treating non-infectious uveitis. However, some proinflammatory effects of TNFα and IL-17 stimulation on RPE are not blocked by SOCS1 overexpression. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  17. The adaptor CRADD/RAIDD controls activation of endothelial cells by proinflammatory stimuli.

    Science.gov (United States)

    Qiao, Huan; Liu, Yan; Veach, Ruth A; Wylezinski, Lukasz; Hawiger, Jacek

    2014-08-08

    A hallmark of inflammation, increased vascular permeability, is induced in endothelial cells by multiple agonists through stimulus-coupled assembly of the CARMA3 signalosome, which contains the adaptor protein BCL10. Previously, we reported that BCL10 in immune cells is targeted by the "death" adaptor CRADD/RAIDD (CRADD), which negatively regulates nuclear factor κB (NFκB)-dependent cytokine and chemokine expression in T cells (Lin, Q., Liu, Y., Moore, D. J., Elizer, S. K., Veach, R. A., Hawiger, J., and Ruley, H. E. (2012) J. Immunol. 188, 2493-2497). This novel anti-inflammatory CRADD-BCL10 axis prompted us to analyze CRADD expression and its potential anti-inflammatory action in non-immune cells. We focused our study on microvascular endothelial cells because they play a key role in inflammation. We found that CRADD-deficient murine endothelial cells display heightened BCL10-mediated expression of the pleotropic proinflammatory cytokine IL-6 and chemokine monocyte chemoattractant protein-1 (MCP-1/CCL2) in response to LPS and thrombin. Moreover, these agonists also induce significantly increased permeability in cradd(-/-), as compared with cradd(+/+), primary murine endothelial cells. CRADD-deficient cells displayed more F-actin polymerization with concomitant disruption of adherens junctions. In turn, increasing intracellular CRADD by delivery of a novel recombinant cell-penetrating CRADD protein (CP-CRADD) restored endothelial barrier function and suppressed the induction of IL-6 and MCP-1 evoked by LPS and thrombin. Likewise, CP-CRADD enhanced barrier function in CRADD-sufficient endothelial cells. These results indicate that depletion of endogenous CRADD compromises endothelial barrier function in response to inflammatory signals. Thus, we define a novel function for CRADD in endothelial cells as an inducible suppressor of BCL10, a key mediator of responses to proinflammatory agonists. © 2014 by The American Society for Biochemistry and Molecular Biology

  18. Lifetime Exposure to Intimate Partner Violence and Proinflammatory Cytokine Levels Across the Perinatal Period.

    Science.gov (United States)

    Robertson Blackmore, Emma; Mittal, Mona; Cai, Xueya; Moynihan, Jan A; Matthieu, Monica M; O'Connor, Thomas G

    2016-10-01

    Intimate partner violence (IPV) is a public health concern, affecting one-third of US women. Prior research suggests an association between exposure to IPV and poor maternal perinatal health, but the underlying biological correlates are not well understood. This study examined the relationship between exposure to IPV and proinflammatory cytokine levels, a candidate mechanism accounting for poor psychiatric and obstetric outcomes, across the perinatal period. Data were obtained from a prospective, longitudinal cohort study of 171 women receiving obstetrical care from a hospital-based practice serving a predominantly low-income minority population. Participants completed questionnaires on IPV exposure, psychiatric symptoms, and psychosocial and obstetric factors and provided blood samples at 18 and 32 weeks of gestation and 6 weeks and 6 months postpartum. Serum levels of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) were assayed via enzyme-linked immunosorbent assay. Thirty-five (20.5%) women reported lifetime exposure to IPV and 7 (4.1%) reported being physically hurt in the preceding 12 months (4 while pregnant). Lifetime exposure to IPV was associated with increased likelihood of experiencing perinatal depression and smoking during pregnancy. Women with a history of IPV had significantly higher levels of TNF-α at 18 weeks (z = -2.29, p < 0.05), but significantly smaller changes in levels of IL-6 (β = -0.36, p = 0.04) across time. Lifetime exposure to IPV was associated with a range of adverse mental health outcomes and may affect proinflammatory cytokine levels in pregnancy.

  19. β-Catenin promotes colitis and colon cancer through imprinting of proinflammatory properties in T cells.

    Science.gov (United States)

    Keerthivasan, Shilpa; Aghajani, Katayoun; Dose, Marei; Molinero, Luciana; Khan, Mohammad W; Venkateswaran, Vysak; Weber, Christopher; Emmanuel, Akinola Olumide; Sun, Tianjao; Bentrem, David J; Mulcahy, Mary; Keshavarzian, Ali; Ramos, Elena M; Blatner, Nichole; Khazaie, Khashayarsha; Gounari, Fotini

    2014-02-26

    The density and type of lymphocytes that infiltrate colon tumors are predictive of the clinical outcome of colon cancer. High densities of T helper 17 (T(H)17) cells and inflammation predict poor outcome, whereas infiltration by T regulatory cells (Tregs) that naturally suppress inflammation is associated with longer patient survival. However, the role of Tregs in cancer remains controversial. We recently reported that Tregs in colon cancer patients can become proinflammatory and tumor-promoting. These properties were directly linked with their expression of RORγt (retinoic acid-related orphan receptor-γt), the signature transcription factor of T(H)17 cells. We report that Wnt/β-catenin signaling in T cells promotes expression of RORγt. Expression of β-catenin was elevated in T cells, including Tregs, of patients with colon cancer. Genetically engineered activation of β-catenin in mouse T cells resulted in enhanced chromatin accessibility in the proximity of T cell factor-1 (Tcf-1) binding sites genome-wide, induced expression of T(H)17 signature genes including RORγt, and promoted T(H)17-mediated inflammation. Strikingly, the mice had inflammation of small intestine and colon and developed lesions indistinguishable from colitis-induced cancer. Activation of β-catenin only in Tregs was sufficient to produce inflammation and initiate cancer. On the basis of these findings, we conclude that activation of Wnt/β-catenin signaling in effector T cells and/or Tregs is causatively linked with the imprinting of proinflammatory properties and the promotion of colon cancer.

  20. Reduced tissue osmolarity increases TRPV4 expression and pro-inflammatory cytokines in intervertebral disc cells

    Directory of Open Access Journals (Sweden)

    BA Walter

    2016-07-01

    Full Text Available The mechanical behaviour and cellular metabolism of intervertebral discs (IVDs and articular cartilage are strongly influenced by their proteoglycan content and associated osmotic properties. This osmotic environment is a biophysical signal that changes with disease and may contribute to the elevated matrix breakdown and altered biologic response to loading observed in IVD degeneration and osteoarthritis. This study tested the hypothesis that changes in osmo-sensation by the transient receptor potential vallinoid-4 (TRPV4 ion channel occur with disease and contribute to the inflammatory environment found during degeneration. Immunohistochemistry on bovine IVDs from an inflammatory organ culture model were used to investigate if TRPV4 is expressed in the IVD and how expression changes with degeneration. Western blot, live-cell calcium imaging, and qRT-PCR were used to investigate whether osmolarity changes or tumour necrosis factor α (TNFα regulate TRPV4 expression, and how altered TRPV4 expression influences calcium signalling and pro-inflammatory cytokine expression. TRPV4 expression correlated with TNFα expression, and was increased when cultured in reduced medium osmolarity and unaltered with TNFα-stimulation. Increased TRPV4 expression increased the calcium flux following TRPV4 activation and increased interleukin-1β (IL-1β and IL-6 gene expression in IVD cells. TRPV4 expression was qualitatively elevated in regions of aggrecan depletion in degenerated human IVDs. Collectively, results suggest that reduced tissue osmolarity, likely following proteoglycan degradation, can increase TRPV4 signalling and enhance pro-inflammatory cytokine production, suggesting changes in TRPV4 mediated osmo-sensation may contribute to the progressive matrix breakdown in disease.

  1. Regional Brain Shrinkage over Two Years: Individual Differences and Effects of Pro-Inflammatory Genetic Polymorphisms

    Science.gov (United States)

    Persson, N.; Ghisletta, P.; Dahle, C.L.; Bender, A.R.; Yang, Y.; Yuan, P.; Daugherty, A.M.; Raz, N.

    2014-01-01

    We examined regional changes in brain volume in healthy adults (N = 167, age 19-79 years at baseline; N = 90 at follow-up) over approximately two years. With latent change score models, we evaluated mean change and individual differences in rates of change in 10 anatomically-defined and manually-traced regions of interest (ROIs): lateral prefrontal cortex (LPFC), orbital frontal cortex (OF), prefrontal white matter (PFw), hippocampus (HC), parahippocampal gyrus (PhG), caudate nucleus (Cd), putamen (Pt), insula (In), cerebellar hemispheres (CbH), and primary visual cortex (VC). Significant mean shrinkage was observed in the HC, CbH, In, OF, and the PhG, and individual differences in change were noted in all regions, except the OF. Pro-inflammatory genetic variants mediated shrinkage in PhG and CbH. Carriers of two T alleles of interleukin-1β (IL-1βC-511T, rs16944) and a T allele of methylenetetrahydrofolate reductase (MTHFRC677T, rs1801133) polymorphisms showed increased PhG shrinkage. No effects of a pro-inflammatory polymorphism for C-reactive protein (CRP-286C>A>T, rs3091244) or apolipoprotein (APOE) ε4 allele were noted. These results replicate the pattern of brain shrinkage observed in previous studies, with a notable exception of the LPFC thus casting doubt on the unique importance of prefrontal cortex in aging. Larger baseline volumes of CbH and In were associated with increased shrinkage, in conflict with the brain reserve hypothesis. Contrary to previous reports, we observed no significant linear effects of age and hypertension on regional brain shrinkage. Our findings warrant further investigation of the effects of neuroinflammation on structural brain change throughout the lifespan. PMID:25264227

  2. Suppression of pro-inflammatory T-cell responses by human mesothelial cells.

    Science.gov (United States)

    Lin, Chan-Yu; Kift-Morgan, Ann; Moser, Bernhard; Topley, Nicholas; Eberl, Matthias

    2013-07-01

    Human γδ T cells reactive to the microbial metabolite (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP) contribute to acute inflammatory responses. We have previously shown that peritoneal dialysis (PD)-associated infections with HMB-PP producing bacteria are characterized by locally elevated γδ T-cell frequencies and poorer clinical outcome compared with HMB-PP negative infections, implying that γδ T cells may be of diagnostic, prognostic and therapeutic value in acute disease. The regulation by local tissue cells of these potentially detrimental γδ T-cell responses remains to be investigated. Freshly isolated γδ or αβ T cells were cultured with primary mesothelial cells derived from omental tissue, or with mesothelial cell-conditioned medium. Stimulation of cytokine production and proliferation by peripheral T cells in response to HMB-PP or CD3/CD28 beads was assessed by flow cytometry. Resting mesothelial cells were potent suppressors of pro-inflammatory γδ T cells as well as CD4+ and CD8+ αβ T cells. The suppression of γδ T-cell responses was mediated through soluble factors released by primary mesothelial cells and could be counteracted by SB-431542, a selective inhibitor of TGF-β and activin signalling. Recombinant TGF-β1 but not activin-A mimicked the mesothelial cell-mediated suppression of γδ T-cell responses to HMB-PP. The present findings indicate an important regulatory function of mesothelial cells in the peritoneal cavity by dampening pro-inflammatory T-cell responses, which may help preserve the tissue integrity of the peritoneal membrane in the steady state and possibly during the resolution of acute inflammation.

  3. Antimicrobial peptides and pro-inflammatory cytokines are differentially regulated across epidermal layers following bacterial stimuli.

    Science.gov (United States)

    Percoco, Giuseppe; Merle, Chloé; Jaouen, Thomas; Ramdani, Yasmina; Bénard, Magalie; Hillion, Mélanie; Mijouin, Lily; Lati, Elian; Feuilloley, Marc; Lefeuvre, Luc; Driouich, Azeddine; Follet-Gueye, Marie-Laure

    2013-12-01

    The skin is a natural barrier between the body and the environment and is colonised by a large number of microorganisms. Here, we report a complete analysis of the response of human skin explants to microbial stimuli. Using this ex vivo model, we analysed at both the gene and protein level the response of epidermal cells to Staphylococcus epidermidis (S. epidermidis) and Pseudomonas fluorescens (P. fluorescens), which are present in the cutaneous microbiota. We showed that both bacterial species affect the structure of skin explants without penetrating the living epidermis. We showed by real-time quantitative polymerase chain reaction (qPCR) that S. epidermidis and P. fluorescens increased the levels of transcripts that encode antimicrobial peptides (AMPs), including human β defensin (hBD)2 and hBD3, and the pro-inflammatory cytokines interleukin (IL)-1α and (IL)-1-β, as well as IL-6. In addition, we analysed the effects of bacterial stimuli on the expression profiles of genes related to innate immunity and the inflammatory response across the epidermal layers, using laser capture microdissection (LCM) coupled to qPCR. We showed that AMP transcripts were principally upregulated in suprabasal keratinocytes. Conversely, the expression of pro-inflammatory cytokines was upregulated in the lower epidermis. These findings were confirmed by protein localisation using specific antibodies coupled to optical or electron microscopy. This work underscores the potential value of further studies that use LCM on human skin explants model to study the roles and effects of the epidermal microbiota on human skin physiology. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  4. Polycystic Ovary Syndrome as a Proinflammatory State: The Role of Adipokines.

    Science.gov (United States)

    Dimitriadis, Georgios K; Kyrou, Ioannis; Randeva, Harpal S

    2016-01-01

    Polycystic Ovary Syndrome (PCOS) is a complex heterogeneous disorder and the most common endocrinopathy amongst women of reproductive age. It is characterized by androgen excess, chronic anovulation and an altered cardiometabolic profile. PCOS is linked to impaired adipose tissue (AT) physiology and women with this disorder present with greater risk for insulin resistance (IR), hyperinsulinemia, central adiposity, nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) than matched for age and body mass index (BMI) women without PCOS. Hyperandrogenaemia appears to be driving adipocyte hypertrophy observed in PCOS under the influence of a hyperinsulinaemic state. Changes in the function of adipocytes have an impact on the secretion of adipokines, adipose tissue-derived proinflammatory factors promoting susceptibility to low grade inflammation. In this article, we review the existing knowledge on the interplay between hyperandrogenaemia, insulin resistance, impaired adipocyte biology, adipokines and chronic low-grade inflammation in PCOS. In PCOS, more than one mechanisms have been suggested in the development of a chronic low-grade inflammation state with the most prevalent being that of a direct effect of the immune system on adipose tissue functions as previously reported in obese women without PCOS. Despite the lack of conclusive evidence regarding a direct mechanism linking hyperandrogenaemia to pro-inflammation in PCOS, there have been recent findings indicating that hyperandrogenaemia might be involved in chronic inflammation by exerting an effect on adipocytes morphology and attributes. Increasing evidence suggests that there is an important connection and interaction between proinflammatory pathways, hyperinsulinemia, androgen excess and adipose tissue hypertrophy and, dysfunction in PCOS. While lifestyle changes and individualized prescription of insulin-sensitizing drugs are common in managing PCOS, further studies are warranted to

  5. Parenteral nutrition in short bowel syndrome patients, regardless of its duration, increases serum proinflammatory cytokines.

    Science.gov (United States)

    Bizari, Letícia; da Silva Santos, Andressa Feijó; Foss, Norma Tiraboschi; Marchini, Júlio Sérgio; Suen, Vivian Marques Miguel

    2016-07-01

    Short bowel syndrome is a severe malabsorption disorder, and prolonged parenteral nutrition is essential for survival in some cases. Among the undesirable effects of long-term parenteral nutrition is an increase in proinflammatory cytokines. The aim of the present study was to measure the serum levels of interleukin-6, interleukin-10, tumor necrosis factor alpha, and transforming growth factor beta, in patients with short bowel syndrome on cyclic parenteral nutrition and patients who had previously received but no longer require parenteral nutrition. The study was cross-sectional and observational. Three groups were studied as follows: Parenteral nutrition group, 9 patients with short bowel syndrome that receive cyclic parenteral nutrition; Oral nutrition group, 10 patients with the same syndrome who had been weaned off parenteral nutrition for at least 1 year prior to the study; Control group, 13 healthy adults, matched for age and sex to parenteral and oral groups. The following data were collected: age, tobacco use, drug therapies, dietary intake, body weight, height, blood collection. All interleukins were significantly higher in the parenteral group compared with the control group as follows: interleukin-6: 22 ± 19 vs 1.5 ± 1.4 pg/mL, P= .0002; transforming growth factor β: 854 ± 204 vs 607 ± 280 pg/mL, P= .04; interleukin-10: 8 ± 37 vs 0.6 ± 4, P= .03; tumor necrosis factor α: 20 ± 8 vs 8 ± 4 pg/mL, Pparenteral nutrition in short bowel syndrome patients, regardless of its duration, increases serum proinflammatory cytokines. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Sulfocerebrosides upregulate liposome uptake in human astrocytes without inducing a proinflammatory response.

    Science.gov (United States)

    Suesca, Elizabeth; Alejo, Jose Luis; Bolaños, Natalia I; Ocampo, Jackson; Leidy, Chad; González, John M

    2013-07-01

    Astrocytes are involved in the pathogenesis of demyelinating diseases, where they actively regulate the secretion of proinflammatory factors, and trigger the recruitment of immune cells in the central nervous system (CNS). Antigen presentation of myelin-derived proteins has been shown to trigger astrocyte response, suggesting that astrocytes can directly sense demyelination. However, the direct response of astrocytes to lipid-debris generated during demyelination has not been investigated. The lipid composition of the myelin sheath is distinct, presenting significant amounts of cerebrosides, sulfocerebrosides (SCB), and ceramides. Studies have shown that microglia are activated in the presence of myelin-derived lipids, pointing to the possibility of lipid-induced astrocyte activation. In this study, a human astrocyte cell line was exposed to liposomes enriched in each myelin lipid component. Although liposome uptake was observed for all compositions, astrocytes had augmented uptake for liposomes containing sulfocerebroside (SCB). This enhanced uptake did not modify their expression of human leukocyte antigen (HLA) molecules or secretion of chemokines. This was in contrast to changes observed in astrocyte cells stimulated with IFNγ. Contrary to human monocytes, astrocytes did not internalize beads in the size-range of liposomes, indicating that liposome uptake is lipid specific. Epifluorescence microscopy corroborated that liposome uptake takes place through endocytosis. Soluble SCB were found to partially block uptake of liposomes containing this same lipid. Endocytosis was not decreased when cells were treated with cytochalasin D, but it was decreased by cold temperature incubation. The specific uptake of SCB in the absence of a proinflammatory response indicates that astrocytes may participate in the trafficking and regulation of sulfocerebroside metabolism and homeostasis in the CNS. Copyright © 2013 International Society for Advancement of Cytometry.

  7. Dysfunctional nitric oxide signalling increases risk of myocardial infarction.

    Science.gov (United States)

    Erdmann, Jeanette; Stark, Klaus; Esslinger, Ulrike B; Rumpf, Philipp Moritz; Koesling, Doris; de Wit, Cor; Kaiser, Frank J; Braunholz, Diana; Medack, Anja; Fischer, Marcus; Zimmermann, Martina E; Tennstedt, Stephanie; Graf, Elisabeth; Eck, Sebastian; Aherrahrou, Zouhair; Nahrstaedt, Janja; Willenborg, Christina; Bruse, Petra; Brænne, Ingrid; Nöthen, Markus M; Hofmann, Per; Braund, Peter S; Mergia, Evanthia; Reinhard, Wibke; Burgdorf, Christof; Schreiber, Stefan; Balmforth, Anthony J; Hall, Alistair S; Bertram, Lars; Steinhagen-Thiessen, Elisabeth; Li, Shu-Chen; März, Winfried; Reilly, Muredach; Kathiresan, Sekar; McPherson, Ruth; Walter, Ulrich; Ott, Jurg; Samani, Nilesh J; Strom, Tim M; Meitinger, Thomas; Hengstenberg, Christian; Schunkert, Heribert

    2013-12-19

    Myocardial infarction, a leading cause of death in the Western world, usually occurs when the fibrous cap overlying an atherosclerotic plaque in a coronary artery ruptures. The resulting exposure of blood to the atherosclerotic material then triggers thrombus formation, which occludes the artery. The importance of genetic predisposition to coronary artery disease and myocardial infarction is best documented by the predictive value of a positive family history. Next-generation sequencing in families with several affected individuals has revolutionized mutation identification. Here we report the segregation of two private, heterozygous mutations in two functionally related genes, GUCY1A3 (p.Leu163Phefs*24) and CCT7 (p.Ser525Leu), in an extended myocardial infarction family. GUCY1A3 encodes the α1 subunit of soluble guanylyl cyclase (α1-sGC), and CCT7 encodes CCTη, a member of the tailless complex polypeptide 1 ring complex, which, among other functions, stabilizes soluble guanylyl cyclase. After stimulation with nitric oxide, soluble guanylyl cyclase generates cGMP, which induces vasodilation and inhibits platelet activation. We demonstrate in vitro that mutations in both GUCY1A3 and CCT7 severely reduce α1-sGC as well as β1-sGC protein content, and impair soluble guanylyl cyclase activity. Moreover, platelets from digenic mutation carriers contained less soluble guanylyl cyclase protein and consequently displayed reduced nitric-oxide-induced cGMP formation. Mice deficient in α1-sGC protein displayed accelerated thrombus formation in the microcirculation after local trauma. Starting with a severely affected family, we have identified a link between impaired soluble-guanylyl-cyclase-dependent nitric oxide signalling and myocardial infarction risk, possibly through accelerated thrombus formation. Reversing this defect may provide a new therapeutic target for reducing the risk of myocardial infarction.

  8. THE ESTROGENS / CHROMIUM INTERACTION IN THE NITRIC OXIDE GENERATION.

    Science.gov (United States)

    Sawicka, Ewa; Piwowar, Agnieszka; Musiala, Tomasz; Dlugosz, Anna

    2017-05-01

    The interaction of estrogens with environmental toxins in free radicals generation: reactive oxygen species (ROS) or reactive nitrogen species (RNS) which participates in cancerogenesis is not yet recognized. Chromium(VI) is widely present in environment. One of its toxicity pathway is free radicals generation. Estrogens have the ability to scavenge free radicals, but may also act as prooxidants. Both chromium(VI) and estrogens are classified by International Agency for Research on Cancer (IARC) as carcinogens, so synergistic effect seems very dangerous. The interaction of chromium and estrogens in ROS generation are partly described but there are no reports on estrogen/chromium interaction on nitric oxide (NO) generation. The aim of the study was to examine the interaction of chromium(VI) and 17-p-estradiol (E2) on NO level in human blood as well as the role of E2 metabolites: 4-hydroxyestradiol (4-OHE2) and 16a-hydroxyestrone (16α-OHE1) in these processes. The NO level was estimated with the diagnostic kit (Nitric Oxide Colorimetric Detection Kit from Arbor Assays) in human blood in vitm. The results showed that Cr(VI) in used concentration (0.5; 1.0 and 5.0 gg/mL) decreases significantly NO level in blood, acting antagonistically to E2 and 4-OHE2. Estrogens (E2, 4-OHE2 and 16α-OHEI) do not protect against inhibiting effect of Cr(VI) on nitric oxide generation in blood because after combined exposure the decreased production of NO in blood was noted. In conclusion, presented results provide the information about the character of estrogen/Cr(VI) interaction in NO level in human blood. It is important knowledge for cardio protected effect e.g., hormone replacement therapy in environmental or occupational exposure to Cr(VI), chromium supplementation, also important for cancer risk evaluation.

  9. Arginase expression modulates nitric oxide production in Leishmania (Leishmania) amazonensis.

    Science.gov (United States)

    Acuña, Stephanie Maia; Aoki, Juliana Ide; Laranjeira-Silva, Maria Fernanda; Zampieri, Ricardo Andrade; Fernandes, Juliane Cristina Ribeiro; Muxel, Sandra Marcia; Floeter-Winter, Lucile Maria

    2017-01-01

    Arginase is an enzyme that converts L-arginine to urea and L-ornithine, an essential substrate for the polyamine pathway supporting Leishmania (Leishmania) amazonensis replication and its survival in the mammalian host. L-arginine is also the substrate of macrophage nitric oxide synthase 2 (NOS2) to produce nitric oxide (NO) that kills the parasite. This competition can define the fate of Leishmania infection. The transcriptomic profiling identified a family of oxidoreductases in L. (L.) amazonensis wild-type (La-WT) and L. (L.) amazonensis arginase knockout (La-arg-) promastigotes and axenic amastigotes. We highlighted the identification of an oxidoreductase that could act as nitric oxide synthase-like (NOS-like), due to the following evidences: conserved domain composition, the participation of NO production during the time course of promastigotes growth and during the axenic amastigotes differentiation, regulation dependence on arginase activity, as well as reduction of NO amount through the NOS activity inhibition. NO quantification was measured by DAF-FM labeling analysis in a flow cytometry. We described an arginase-dependent NOS-like activity in L. (L.) amazonensis and its role in the parasite growth. The increased detection of NO production in the mid-stationary and late-stationary growth phases of La-WT promastigotes could suggest that this production is an important factor to metacyclogenesis triggering. On the other hand, La-arg- showed an earlier increase in NO production compared to La-WT, suggesting that NO production can be arginase-dependent. Interestingly, La-WT and La-arg- axenic amastigotes produced higher levels of NO than those observed in promastigotes. As a conclusion, our work suggested that NOS-like is expressed in Leishmania in the stationary growth phase promastigotes and amastigotes, and could be correlated to metacyclogenesis and amastigotes growth in a dependent way to the internal pool of L-arginine and arginase activity.

  10. Daily life negative mood and exhaled nitric oxide in asthma.

    Science.gov (United States)

    Ritz, Thomas; Kullowatz, Antje; Bill, Michelle N; Rosenfield, David

    2016-07-01

    Psychosocial stress and negative affect have been linked to asthma exacerbations, but longitudinal studies demonstrating a daily life association between negative affect and airway nitric oxide are missing. The longitudinal association between negative mood fluctuations, exhaled nitric oxide, and lung function in asthma was examined. Self-assessments of the fraction of exhaled nitric oxide (FeNO), spirometry (forced expiratory volume in the first second, FEV1), negative mood, and daily activities were obtained from 20 patients with asthma for 2 months, resulting in 1108 assessments for the analyses (approximately 55 per patient). Concurrent and prospective associations between FeNO, FEV1, and negative mood were analyzed using mixed effects regression models for longitudinal data. Negative mood was positively associated with changes in FeNO during the same day, and to a stronger extent when prior day negative mood was included in the prediction. FeNO and negative mood were positively associated with same-day FEV1, with the latter relation being partially mediated by changes in FeNO. Associations between FeNO and FEV1 were stronger in younger patients, with earlier onset of asthma, or with lower asthma control. Findings were not changed when controlling for physical activity, medication, cold symptoms, air pollution, and hours spent outside. Daily life changes of negative mood in asthma are positively associated with FeNO changes and FeNO increases are associated with a mild bronchodilation. These findings indicate that psychological influences need to be considered when using FeNO as indicator of airway inflammation and guide for treatment decisions. Copyright © 2016 Elsevier B.V. All rights reserved.

  11. Reduction Rates for Higher Americium Oxidation States in Nitric Acid

    Energy Technology Data Exchange (ETDEWEB)

    Grimes, Travis Shane [Idaho National Lab. (INL), Idaho Falls, ID (United States); Mincher, Bruce Jay [Idaho National Lab. (INL), Idaho Falls, ID (United States); Schmitt, Nicholas C [Idaho National Lab. (INL), Idaho Falls, ID (United States)

    2015-09-30

    The stability of hexavalent americium was measured using multiple americium concentrations and nitric acid concentrations after contact with the strong oxidant sodium bismuthate. Contrary to our hypotheses Am(VI) was not reduced faster at higher americium concentrations, and the reduction was only zero-order at short time scales. Attempts to model the reduction kinetics using zero order kinetic models showed Am(VI) reduction in nitric acid is more complex than the autoreduction processes reported by others in perchloric acid. The classical zero-order reduction of Am(VI) was found here only for short times on the order of a few hours. We did show that the rate of Am(V) production was less than the rate of Am(VI) reduction, indicating that some Am(VI) undergoes two electron-reduction to Am(IV). We also monitored the Am(VI) reduction in contact with the organic diluent dodecane. A direct comparison of these results with those in the absence of the organic diluent showed the reduction rates for Am(VI) were not statistically different for both systems. Additional americium oxidations conducted in the presence of Ce(IV)/Ce(III) ions showed that Am(VI) is reduced without the typical growth of Am(V) observed in the systems sans Ce ion. This was an interesting result which suggests a potential new reduction/oxidation pathway for Am in the presence of Ce; however, these results were very preliminary, and will require additional experiments to understand the mechanism by which this occurs. Overall, these studies have shown that hexavalent americium is fundamentally stable enough in nitric acid to run a separations process. However, the complicated nature of the reduction pathways based on the system components is far from being rigorously understood.

  12. The role of nitrite in nitric oxide homeostasis

    DEFF Research Database (Denmark)

    Jensen, Frank Bo

    2009-01-01

    Nitrite is endogenously produced as an oxidative metabolite of nitric oxide, but it also functions as a NO donor that can be activated by a number of cellular proteins under hypoxic conditions. This article discusses the physiological role of nitrite and nitrite-derived NO in blood flow regulation...... mechanisms. Nitrite reduction to NO provides cytoprotection in tissues during ischemia-reperfusion events by inhibiting mitochondrial respiration and limiting reactive oxygen species. It is argued that the study of hypoxia-tolerant lower vertebrates and diving mammals may help evaluate mechanisms and a full...

  13. Hypoxia tolerance, nitric oxide, and nitrite: Lessons from extreme animals

    DEFF Research Database (Denmark)

    Fago, Angela; B. Jensen, Frank

    2015-01-01

    survival resides in concerted physiological responses, including strong metabolic depression, protection against oxidative damage and – in air breathing animals - redistribution of blood flow. Each of these responses is known to be tightly regulated by nitric oxide (NO) and during hypoxia by its metabolite...... nitrite. The aim of this review is to highlight recent work illustrating the widespread roles of NO and nitrite in the tolerance to extreme oxygen deprivation, in particular in the red-eared slider turtle and crucian carp, but also in diving marine mammals. The emerging picture underscores the importance...... of NO and nitrite signaling in the adaptive response to hypoxia in vertebrate animals....

  14. Nitric Oxide Manipulation: A Therapeutic Target for Peripheral Arterial Disease?

    Directory of Open Access Journals (Sweden)

    Gareth Williams

    2012-01-01

    Full Text Available Peripheral Arterial Disease (PAD is a cause of significant morbidity and mortality in the Western world. Risk factor modification and endovascular and surgical revascularisation are the main treatment options at present. However, a significant number of patients still require major amputation. There is evidence that nitric oxide (NO and its endogenous inhibitor asymmetric dimethylarginine (ADMA play significant roles in the pathophysiology of PAD. This paper reviews experimental work implicating the ADMA-DDAH-NO pathway in PAD, focussing on both the vascular dysfunction and effects within the ischaemic muscle, and examines the potential of manipulating this pathway as a novel adjunct therapy in PAD.

  15. Nitric Oxide-Sensitive Pulmonary Hypertension in Congenital Rubella Syndrome

    Directory of Open Access Journals (Sweden)

    Francesco Raimondi

    2015-01-01

    Full Text Available Persistent pulmonary hypertension is a very rare presentation of congenital virus infection. We discuss the case of complete congenital rubella syndrome presenting at echocardiography with pulmonary hypertension that worsened after ductus ligation. Cardiac catheterization showed a normal pulmonary valve and vascular tree but a PAP=40 mmHg. The infant promptly responded to inhaled nitric oxide while on mechanical ventilation and was later shifted to oral sildenafil. It is not clear whether our observation may be due to direct viral damage to the endothelium or to the rubella virus increasing the vascular tone via a metabolic derangement.

  16. Reactive oxygen species and nitric oxide signaling in bystander cells.

    Science.gov (United States)

    Jella, Kishore Kumar; Moriarty, Roisin; McClean, Brendan; Byrne, Hugh J; Lyng, Fiona M

    2018-01-01

    It is now well accepted that radiation induced bystander effects can occur in cells exposed to media from irradiated cells. The aim of this study was to follow the bystander cells in real time following addition of media from irradiated cells and to determine the effect of inhibiting these signals. A human keratinocyte cell line, HaCaT cells, was irradiated (0.005, 0.05 and 0.5 Gy) with γ irradiation, conditioned medium was harvested after one hour and added to recipient bystander cells. Reactive oxygen species, nitric oxide, Glutathione levels, caspase activation, cytotoxicity and cell viability was measured after the addition of irradiated cell conditioned media to bystander cells. Reactive oxygen species and nitric oxide levels in bystander cells treated with 0.5Gy ICCM were analysed in real time using time lapse fluorescence microscopy. The levels of reactive oxygen species were also measured in real time after the addition of extracellular signal-regulated kinase and c-Jun amino-terminal kinase pathway inhibitors. ROS and glutathione levels were observed to increase after the addition of irradiated cell conditioned media (0.005, 0.05 and 0.5 Gy ICCM). Caspase activation was found to increase 4 hours after irradiated cell conditioned media treatment (0.005, 0.05 and 0.5 Gy ICCM) and this increase was observed up to 8 hours and there after a reduction in caspase activation was observed. A decrease in cell viability was observed but no major change in cytotoxicity was found in HaCaT cells after treatment with irradiated cell conditioned media (0.005, 0.05 and 0.5 Gy ICCM). This study involved the identification of key signaling molecules such as reactive oxygen species, nitric oxide, glutathione and caspases generated in bystander cells. These results suggest a clear connection between reactive oxygen species and cell survival pathways with persistent production of reactive oxygen species and nitric oxide in bystander cells following exposure to irradiated cell

  17. Redox chemistry of americium in nitric acid media

    Energy Technology Data Exchange (ETDEWEB)

    Picart, S.; Jobelin, I.; Armengol, G.; Adnet, JM

    2004-07-01

    The redox properties of the actinides are very important parameters for speciation studies and spent nuclear fuel reprocessing based on liquid-liquid extraction of actinides at different oxidation states (as in the Purex or Sesame process). They are also very useful for developing analytical tools including coulometry and redox titration. This study addressed the americium(IV)/americium(III) and americium(VI)/americium(V) redox couples, focusing on exhaustive acquisition of the thermodynamic and kinetic parameters of americium oxidation at an electrode in a complexing nitric acid medium. (authors)

  18. Redox chemistry of americium in nitric acid media

    International Nuclear Information System (INIS)

    Picart, S.; Jobelin, I.; Armengol, G.; Adnet, JM.

    2004-01-01

    The redox properties of the actinides are very important parameters for speciation studies and spent nuclear fuel reprocessing based on liquid-liquid extraction of actinides at different oxidation states (as in the Purex or Sesame process). They are also very useful for developing analytical tools including coulometry and redox titration. This study addressed the americium(IV)/americium(III) and americium(VI)/americium(V) redox couples, focusing on exhaustive acquisition of the thermodynamic and kinetic parameters of americium oxidation at an electrode in a complexing nitric acid medium. (authors)

  19. The reaction of hydrazine nitrate with nitric acid

    International Nuclear Information System (INIS)

    Kida, Takashi; Sugikawa, Susumu

    2004-03-01

    It is known that hydrazine nitrate used in nuclear fuel reprocessing plants is an unstable substance thermochemically like hydroxylamine nitrate. In order to take the basic data regarding the reaction of hydrazine nitrate with nitric acid, initiation temperatures and heats of this reaction, effect of impurity on initiation temperature and self-accelerating reaction when it holds at constant temperature for a long time were measured by the pressure vessel type reaction calorimeter etc. In this paper, the experimental data and evaluation of the safe handling of hydrazine nitrate in nuclear fuel reprocessing plants are described. (author)

  20. Nitric oxide synthase expression and enzymatic activity in multiple sclerosis

    DEFF Research Database (Denmark)

    Broholm, H; Andersen, B; Wanscher, B

    2004-01-01

    We used post-mortem magnetic resonance imaging (MRI) guidance to obtain paired biopsies from the brains of four patients with clinical definite multiple sclerosis (MS). Samples were analyzed for the immunoreactivity (IR) of the three nitric oxide (NO) synthase isoforms [inducible, neuronal......NOS expressing cells in active lesions. NOS IR expressing cells were widely distributed in plaques, in white and gray matter that appeared normal macroscopically, and on MR. Endothelial NOS (eNOS) was highly expressed in intraparenchymal vascular endothelial cells of MS patients. A control group matched for age...

  1. Nitric Oxide Generating Polymeric Coatings for Subcutaneous Glucose Sensors

    Science.gov (United States)

    2007-10-01

    primary polymer which was then aminated (2) for attachment of (Boc)3-cyclen-N-acetic acid (1). After the conjugation via EDC coupling chemistry, the Boc...dipping procedure is repeated 5 times. This is the needle-type NO sensor currently used (e.g., Figure 4 device but w/o the SePEI and alginic acid ...Cha, M. E. Meyerhoff, " Polymethacrylates with Covalently Linked Cu(II)-Cyclen Complex for the In-Situ Generation of Nitric Oxide from Nitrosothiols in

  2. Direct Reaction of Amides with Nitric Oxide To Form Diazeniumdiolates

    Science.gov (United States)

    2015-01-01

    We report the apparently unprecedented direct reaction of nitric oxide (NO) with amides to generate ions of structure R(C=O)NH–N(O)=NO–, with examples including R = Me (1a) or 3-pyridyl (1b). The sodium salts of both released NO in pH 7.4 buffer, with 37 °C half-lives of 1–3 min. As NO-releasing drug candidates, diazeniumdiolated amides would have the advantage of generating only 1 equiv of base on hydrolyzing exhaustively to NO, in contrast to their amine counterparts, which generate 2 equiv of base. PMID:25210948

  3. Role of Nitric Oxide in the Regulation of Renin and Vasopressin Secretion

    Science.gov (United States)

    Reid, Ian A.

    1994-01-01

    Research during recent years has established nitric oxide as a unique signaling molecule that plays important roles in the regulation of the cardiovascular, nervous, immune, and other systems. Nitric oxide has also been implicated in the control of the secretion of hormones by the pancreas, hypothalamus, and anterior pituitary gland, and evidence is accumulating that it contributes to the regulation of the secretion of renin and vasopressin, hormones that play key roles in the control of sodium and water balance. Several lines of evidence have implicated nitric oxide in the control of renin secretion. The enzyme nitric oxide synthase is present in vascular and tubular elements of the kidney, particularly in cells of the macula densa, a structure that plays an important role in the control of renin secretion. Guanylyl cyclase, a major target for nitric oxide, is also present in the kidney. Drugs that inhibit nitric oxide synthesis generally suppress renin release in vivo and in vitro, suggesting a stimulatory role for the L-arginine/nitric oxide pathway in the control of renin secretion. Under some conditions, however, blockade of nitric oxide synthesis increases renin secretion. Recent studies indicate that nitric oxide not only contributes to the regulation of basal renin secretion, but also participates in the renin secretory responses to activation of the renal baroreceptor, macula densa, and beta adrenoceptor mechanisms that regulate renin secretion. Histochemical and immunocytochemical studies have revealed the presence of nitric oxide synthase in the supraoptic and paraventricular nuclei of the hypothalamus and in the posterior pituitary gland. Colocalization of nitric oxide synthase and vasopressin has been demonstrated in some hypothalamic neurons. Nitric oxide synthase activity in the hypothalamus and pituitary is increased by maneuvers known to stimulate vasopressin secretion, including salt loading and dehydration, Administration of L-arginine and nitric

  4. Differential intracellular calcium influx, nitric oxide production, ICAM-1 and IL8 expression in primary bovine endothelial cells exposed to nonesterified fatty acids.

    Science.gov (United States)

    Loaiza, Anitsi; Carretta, María D; Taubert, Anja; Hermosilla, Carlos; Hidalgo, María A; Burgos, Rafael A

    2016-02-25

    Nonesterified fatty acids (NEFAs) are involved in proinflammatory processes in cattle, including in the increased expression of adhesion molecules in endothelial cells. However, the mechanisms underlying these effects are still unknown. The aim of this study was to assess the effects of NEFAs on the intracellular calcium (Ca(2+) i) influx, nitric oxide production, and ICAM-1 and IL-8 expression in primary bovine umbilical vein endothelial cells (BUVECs). Myristic (MA), palmitic (PA), stearic (SA), oleic (OA) and linoleic acid (LA) rapidly increased Ca(2+) i. The calcium response to all tested NEFAs showed an extracellular calcium dependence and only the LA response was significantly inhibited until the intracellular calcium was chelated. The EC50 values for MA and LA were 125 μM and 37 μM, respectively, and the MA and LA effects were dependent on calcium release from the endoplasmic reticulum stores and on the L-type calcium channels. Only the calcium response to MA was significantly reduced by GW1100, a selective G-protein-coupled free fatty acid receptor (GPR40) antagonist. We also detected a functional FFAR1/GPR40 protein in BUVECs by using western blotting and the FFAR1/GPR40 agonist TAK-875. Only LA increased the cellular nitric oxide levels in a calcium-dependent manner. LA stimulation but not MA stimulation increased ICAM-1 and IL-8-expression in BUVECs. This effect was inhibited by GW1100, an antagonist of FFAR1/GPR40, but not by U-73122, a phospholipase C inhibitor. These findings strongly suggest that each individual NEFA stimulates endothelial cells in a different way, with clearly different effects on intracellular calcium mobilization, NO production, and IL-8 and ICAM-1 expression in primary BUVECs. These findings not only extend our understanding of NEFA-mediated diseases in ruminants, but also provide new insight into the different molecular mechanisms involved during endothelial cell activation by NEFAs.

  5. Ex vivo immunomodulatory effect of ethanolic extract of propolis during Celiac Disease: involvement of nitric oxide pathway.

    Science.gov (United States)

    Medjeber, Oussama; Touri, Kahina; Rafa, Hayet; Djeraba, Zineb; Belkhelfa, Mourad; Boutaleb, Amira Fatima; Arroul-Lammali, Amina; Belguendouz, Houda; Touil-Boukoffa, Chafia

    2018-03-07

    Celiac Disease (CeD) is a chronic immune-mediated enteropathy, in which dietary gluten induces an inflammatory reaction, predominantly in the duodenum. Propolis is a resinous hive product, collected by honeybees from various plant sources. Propolis is well-known for its anti-inflammatory, anti-oxidant and immunomodulatory effects, due to its major compounds, polyphenols and flavonoids. The aim of our study was to assess the ex vivo effect of ethanolic extract of propolis (EEP) upon the activity and expression of iNOS, along with IFN-γ and IL-10 production in Algerian Celiac patients. In this context, PBMCs isolated from peripheral blood of Celiac patients and healthy controls were cultured with different concentrations of EEP. NO production was measured using the Griess method, whereas quantitation of IFN-γ and IL-10 levels was performed by ELISA. Inducible nitric oxide synthase (iNOS) expression, NFκB and pSTAT-3 activity were analyzed by immunofluorescence assay. Our results showed that PBMCs from Celiac patients produced high levels of NO and IFN-γ compared with healthy controls (HC). Interestingly, EEP reduced significantly, NO and IFN-γ levels and significantly increased IL-10 levels at a concentration of 50 µg/mL. Importantly, EEP downmodulated the iNOS expression as well as the activity of NFκB and pSTAT-3 transcription factors. Altogether, our results highlight the immunomodulatory effect of propolis on NO pathway and on pro-inflammatory cytokines. Therefore, we suggest that propolis may constitute a potential candidate to modulate inflammation during Celiac Disease and has a potential therapeutic value.

  6. Dietary rose hip exerts antiatherosclerotic effects and increases nitric oxide-mediated dilation in ApoE-null mice.

    Science.gov (United States)

    Cavalera, Michele; Axling, Ulrika; Rippe, Catarina; Swärd, Karl; Holm, Cecilia

    2017-06-01

    Atherosclerosis is a disease in which atheromatous plaques develop inside arteries, leading to reduced or obstructed blood flow that in turn may cause stroke and heart attack. Rose hip is the fruit of plants of the genus Rosa, belonging to the Rosaceae family, and it is rich in antioxidants with high amounts of ascorbic acid and phenolic compounds. Several studies have shown that fruits, seeds and roots of these plants exert antidiabetic, antiobesity and cholesterol-lowering effects in rodents as well as humans. The aim of this study was to elucidate the mechanisms by which rose hip lowers plasma cholesterol and to evaluate its effects on atherosclerotic plaque formation. ApoE-null mice were fed either an HFD (CTR) or HFD with rose hip supplementation (RH) for 24 weeks. At the end of the study, we found that blood pressure and atherosclerotic plaques, together with oxidized LDL, total cholesterol and fibrinogen levels were markedly reduced in the RH group. Fecal cholesterol content, liver expression of Ldlr and selected reverse cholesterol transport (RCT) genes such as Abca1, Abcg1 and Scarb1 were significantly increased upon RH feeding. In the aorta, the scavenger receptor Cd36 and the proinflammatory Il1β genes were markedly down-regulated compared to the CTR mice. Finally, we found that RH increased nitric oxide-mediated dilation of the caudal artery. Taken together, these results suggest that rose hip is a suitable dietary supplement for preventing atherosclerotic plaques formation by modulating systemic blood pressure and the expression of RCT and inflammatory genes. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  7. Is nitric oxide decrease observed with naphthoquinones in LPS stimulated RAW 264.7 macrophages a beneficial property?

    Directory of Open Access Journals (Sweden)

    Brígida R Pinho

    Full Text Available The search of new anti-inflammatory drugs has been a current preoccupation, due to the need of effective drugs, with less adverse reactions than those used nowadays. Several naphthoquinones (plumbagin, naphthazarin, juglone, menadione, diosquinone and 1,4-naphthoquinone, plus p-hydroquinone and p-benzoquinone were evaluated for their ability to cause a reduction of nitric oxide (NO production, when RAW 264.7 macrophages were stimulated with lipopolysaccharide (LPS. Dexamethasone was used as positive control. Among the tested compounds, diosquinone was the only one that caused a NO reduction with statistical importance and without cytotoxicity: an IC(25 of 1.09±0.24 µM was found, with 38.25±6.50% (p<0.001 NO reduction at 1.5 µM. In order to elucidate if this NO decrease resulted from the interference of diosquinone with cellular defence mechanisms against LPS or to its conversion into peroxynitrite, by reaction with superoxide radical formed by naphthoquinones redox cycling, 3-nitrotyrosine and superoxide determination was also performed. None of these parameters showed significant changes relative to control. Furthermore, diosquinone caused a decrease in the pro-inflammatory cytokines: tumour necrosis factor-alpha (TNF-α and interleukin 6 (IL-6. Therefore, according to the results obtained, diosquinone, studied for its anti-inflammatory potential for the first time herein, has beneficial effects in inflammation control. This study enlightens the mechanisms of action of naphthoquinones in inflammatory models, by checking for the first time the contribution of oxidative stress generated by naphthoquinones to NO reduction.

  8. Reactive oxygen species mediate nitric oxide production through ERK/JNK MAPK signaling in HAPI microglia after PFOS exposure

    International Nuclear Information System (INIS)

    Wang, Cheng; Nie, Xiaoke; Zhang, Yan; Li, Ting; Mao, Jiamin; Liu, Xinhang; Gu, Yiyang; Shi, Jiyun; Xiao, Jing; Wan, Chunhua; Wu, Qiyun

    2015-01-01

    Perfluorooctane sulfonate (PFOS), an emerging persistent contaminant that is commonly encountered during daily life, has been shown to exert toxic effects on the central nervous system (CNS). However, the molecular mechanisms underlying the neurotoxicity of PFOS remain largely unknown. It has been widely acknowledged that the inflammatory mediators released by hyper-activated microglia play vital roles in the pathogenesis of various neurological diseases. In the present study, we examined the impact of PFOS exposure on microglial activation and the release of proinflammatory mediators, including nitric oxide (NO) and reactive oxidative species (ROS). We found that PFOS exposure led to concentration-dependent NO and ROS production by rat HAPI microglia. We also discovered that there was rapid activation of the ERK/JNK MAPK signaling pathway in the HAPI microglia following PFOS treatment. Moreover, the PFOS-induced iNOS expression and NO production were attenuated after the inhibition of ERK or JNK MAPK by their corresponding inhibitors, PD98059 and SP600125. Interestingly, NAC, a ROS inhibitor, blocked iNOS expression, NO production, and activation of ERK and JNK MAPKs, which suggested that PFOS-mediated microglial NO production occurs via a ROS/ERK/JNK MAPK signaling pathway. Finally, by exposing SH-SY5Y cells to PFOS-treated microglia-conditioned medium, we demonstrated that NO was responsible for PFOS-mediated neuronal apoptosis. - Highlights: • PFOS exposure induced expression of iNOS and production of NO in HAPI microglia. • PFOS induced the production of ROS in HAPI microglia. • ERK/JNK MAPK pathways were activated following PFOS exposure in HAPI microglia. • NO released by HAPI microglia participated in the apoptosis of SH-SY5Y cells.

  9. Reactive oxygen species mediate nitric oxide production through ERK/JNK MAPK signaling in HAPI microglia after PFOS exposure

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Cheng; Nie, Xiaoke; Zhang, Yan [Department of Nutrition and Food Hygiene, School of Public Health, Nantong University, Nantong, Jiangsu 226001 (China); Li, Ting; Mao, Jiamin [Department of Labor and Environmental Hygiene, School of Public Health, Nantong University, Nantong, Jiangsu 226001 (China); Liu, Xinhang [Department of Occupational Medicine and Environmental Toxicology, School of Public Health, Nantong University, Nantong, Jiangsu 226001 (China); Gu, Yiyang; Shi, Jiyun [Department of Labor and Environmental Hygiene, School of Public Health, Nantong University, Nantong, Jiangsu 226001 (China); Xiao, Jing [Department of Occupational Medicine and Environmental Toxicology, School of Public Health, Nantong University, Nantong, Jiangsu 226001 (China); Wan, Chunhua [Department of Nutrition and Food Hygiene, School of Public Health, Nantong University, Nantong, Jiangsu 226001 (China); Wu, Qiyun, E-mail: wqy@ntu.edu.cn [Department of Nutrition and Food Hygiene, School of Public Health, Nantong University, Nantong, Jiangsu 226001 (China)

    2015-10-15

    Perfluorooctane sulfonate (PFOS), an emerging persistent contaminant that is commonly encountered during daily life, has been shown to exert toxic effects on the central nervous system (CNS). However, the molecular mechanisms underlying the neurotoxicity of PFOS remain largely unknown. It has been widely acknowledged that the inflammatory mediators released by hyper-activated microglia play vital roles in the pathogenesis of various neurological diseases. In the present study, we examined the impact of PFOS exposure on microglial activation and the release of proinflammatory mediators, including nitric oxide (NO) and reactive oxidative species (ROS). We found that PFOS exposure led to concentration-dependent NO and ROS production by rat HAPI microglia. We also discovered that there was rapid activation of the ERK/JNK MAPK signaling pathway in the HAPI microglia following PFOS treatment. Moreover, the PFOS-induced iNOS expression and NO production were attenuated after the inhibition of ERK or JNK MAPK by their corresponding inhibitors, PD98059 and SP600125. Interestingly, NAC, a ROS inhibitor, blocked iNOS expression, NO production, and activation of ERK and JNK MAPKs, which suggested that PFOS-mediated microglial NO production occurs via a ROS/ERK/JNK MAPK signaling pathway. Finally, by exposing SH-SY5Y cells to PFOS-treated microglia-conditioned medium, we demonstrated that NO was responsible for PFOS-mediated neuronal apoptosis. - Highlights: • PFOS exposure induced expression of iNOS and production of NO in HAPI microglia. • PFOS induced the production of ROS in HAPI microglia. • ERK/JNK MAPK pathways were activated following PFOS exposure in HAPI microglia. • NO released by HAPI microglia participated in the apoptosis of SH-SY5Y cells.

  10. A pro-inflammatory diet is associated with increased risk of developing hypertension among middle-aged women

    NARCIS (Netherlands)

    Vissers, L E T; Waller, M; van der Schouw, Y T; Hébert, J R; Shivappa, N; Schoenaker, D A J M; Mishra, G D

    BACKGROUND AND AIMS: A pro-inflammatory diet is thought to lead to hypertension through oxidative stress and vessel wall inflammation. We therefore investigated the association between the dietary inflammatory index (DII) and developing hypertension in a population-based cohort of middle-aged women.

  11. The SaeR/S gene regulatory system induces a pro-inflammatory cytokine response during Staphylococcus aureus infection.

    Directory of Open Access Journals (Sweden)

    Robert L Watkins

    Full Text Available Community-associated methicillin-resistant Staphylococcus aureus accounts for a large portion of the increased staphylococcal disease incidence and can cause illness ranging from mild skin infections to rapidly fatal sepsis syndromes. Currently, we have limited understanding of S. aureus-derived mechanisms contributing to bacterial pathogenesis and host inflammation during staphylococcal disease. Herein, we characterize an influential role for the saeR/S two-component gene regulatory system in mediating cytokine induction using mouse models of S. aureus pathogenesis. Invasive S. aureus infection induced the production of localized and systemic pro-inflammatory cytokines, including tumor necrosis factor alpha (TNF-α, interferon gamma (IFN-γ, interleukin (IL-6 and IL-2. In contrast, mice infected with an isogenic saeR/S deletion mutant demonstrated significantly reduced pro-inflammatory cytokine levels. Additionally, secreted factors influenced by saeR/S elicited pro-inflammatory cytokines in human blood ex vivo. Our study further demonstrated robust saeR/S-mediated IFN-γ production during both invasive and subcutaneous skin infections. Results also indicated a critical role for saeR/S in promoting bacterial survival and enhancing host mortality during S. aureus peritonitis. Taken together, this study provides insight into specific mechanisms used by S. aureus during staphylococcal disease and characterizes a relationship between a bacterial global regulator of virulence and the production of pro-inflammatory mediators.

  12. Effect of prolonged exposure to diesel engine exhaust on proinflammatory markers in different regions of the rat brain

    OpenAIRE

    Wang Kate; Schins Roel PF; Cassee Flemming R; van Berlo Damien; Gerlofs-Nijland Miriam E; Campbell Arezoo

    2010-01-01

    Abstract Background The etiology and progression of neurodegenerative disorders depends on the interactions between a variety of factors including: aging, environmental exposures, and genetic susceptibility factors. Enhancement of proinflammatory events appears to be a common link in different neurological impairments, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. Studies have shown a link between exposure to particulate matter (PM)...

  13. Role of inducible nitric oxide synthase-derived nitric oxide in lipopolysaccharide plus interferon-γ-induced pulmonary inflammation

    International Nuclear Information System (INIS)

    Zeidler, Patti C.; Millecchia, Lyndell M.; Castranova, Vincent

    2004-01-01

    Exposure of mice to lipopolysaccharide (LPS) plus interferon-γ (IFN-γ) increases nitric oxide (NO) production, which is proposed to play a role in the resulting pulmonary damage and inflammation. To determine the role of inducible nitric oxide synthase (iNOS)-induced NO in this lung reaction, the responses of inducible nitric oxide synthase knockout (iNOS KO) versus C57BL/6J wild-type (WT) mice to aspirated LPS + IFN-γ were compared. Male mice (8-10 weeks) were exposed to LPS (1.2 mg/kg) + IFN-γ (5000 U/mouse) or saline. At 24 or 72 h postexposure, lungs were lavaged with saline and the acellular fluid from the first bronchoalveolar lavage (BAL) was analyzed for total antioxidant capacity (TAC), lactate dehydrogenase (LDH) activity, albumin, tumor necrosis factor-α (TNF-α), and macrophage inflammatory protein-2 (MIP-2). The cellular fraction of the total BAL was used to determine alveolar macrophage (AM) and polymorphonuclear leukocyte (PMN) counts, and AM zymosan-stimulated chemiluminescence (AM-CL). Pulmonary responses 24 h postexposure to LPS + IFN-γ were characterized by significantly decreased TAC, increased BAL AMs and PMNs, LDH, albumin, TNF-α, and MIP-2, and enhanced AM-CL to the same extent in both WT and iNOS KO mice. Responses 72 h postexposure were similar; however, significant differences were found between WT and iNOS KO mice. iNOS KO mice demonstrated a greater decline in total antioxidant capacity, greater BAL PMNs, LDH, albumin, TNF-α, and MIP-2, and an enhanced AM-CL compared to the WT. These data suggest that the role of iNOS-derived NO in the pulmonary response to LPS + IFN-γ is anti-inflammatory, and this becomes evident over time

  14. Liquid-Phase Heat-Release Rates of the Systems Hydrazine-Nitric Acid and Unsymmetrical Dimethylhydrazine-Nitric Acid

    Science.gov (United States)

    Somogyi, Dezso; Feiler, Charles E.

    1960-01-01

    The initial rates of heat release produced by the reactions of hydrazine and unsymmetrical dimethylhydrazine with nitric acid were determined in a bomb calorimeter under conditions of forced mixing. Fuel-oxidant weight ratio and injection velocity were varied. The rate of heat release apparently depended on the interfacial area between the propellants. Above a narrow range of injection velocities representing a critical amount of interfacial area, the rates reached a maximum and were almost constant with injection velocity. The maximum rate for hydrazine was about 70 percent greater than that for unsymmetrical dimethylhydrazine. The total heat released did not vary with mixture ratio over the range studied.

  15. NOx generation method from recovered nitric acid by electrolysis

    International Nuclear Information System (INIS)

    Suzuki, Y.; Shimizu, H.; Inoue, M.; Fujiso, M.; Shibuya, M.; Iwamoto, F.; Outou, Y.; Ochi, E.; Tsuyuki, T.

    1998-01-01

    An R and D has been conducted on an electrolytic NO x generation process utilizing recovered nitric acid from a PUREX reprocessing plant. The purpose of the study is to drastically reduce the amount of low-level-liquid waste(LLW). The research program phase-1, constituting mainly of electrochemical reaction mechanism study, material balance evaluation and process design study, finished in 1995. The results were presented in the previous papers). The research program phase-2 has started in 1995. The schedule is as follows: FY 1991-1994: Research program phase-1 Basic study using electrolysis equipment with 100-700 cm 2 electrodes FY 1995-1999: Research program phase-2 Process performance test by larger scale electrolysis equipment with 3.6 m 2 electrodes - pilot plant design (FY 1995) - pilot plant construction (FY 1996) - engineering data acquisition (FY 1997-1999). The process consists of many unit operations such as electrolysis, oxidation, nitric acid concentration, NO x compression and storage, NO x recovery, off-gas treatment and acid supplier. This paper outlines the pilot test plant. (author)

  16. Nitric oxide heme interactions in nitrophorin from Cimex lectularius

    Energy Technology Data Exchange (ETDEWEB)

    Christmann, R.; Auerbach, H., E-mail: auerbach@physik.uni-kl.de [University of Kaiserslautern, Department of Physics (Germany); Berry, R. E.; Walker, F. A. [The University of Arizona, Department of Chemistry and Biochemistry (United States); Schünemann, V. [University of Kaiserslautern, Department of Physics (Germany)

    2016-12-15

    The nitrophorin from the bedbug Cimex lectularius (cNP) is a nitric oxide (NO) carrying protein. Like the nitrophorins (rNPs) from the kissing bug Rhodnius prolixus, cNP forms a stable heme Fe(III)-NO complex, where the NO can be stored reversibly for a long period of time. In both cases, the NPs are found in the salivary glands of blood-sucking bugs. The insects use the nitrophorins to transport the NO to the victim’s tissues, resulting in vasodilation and reduced blood coagulation. However, the structure of cNP is significantly different to those of the rNPs from Rhodnius prolixus. Furthermore, the cNP can bind a second NO molecule to the proximal heme cysteine when present at higher concentrations. High field Mössbauer spectroscopy on {sup 57}Fe enriched cNP complexed with NO shows reduction of the heme iron and formation of a ferrous nitric oxide (Fe(II)-NO) complex. Density functional theory calculations reproduce the experimental Mössbauer parameters and confirm this observation.

  17. Alternative to Nitric Acid for Passivation of Stainless Steel Alloys

    Science.gov (United States)

    Lewis, Pattie L.; Kolody, Mark; Curran, Jerry

    2013-01-01

    Corrosion is an extensive problem that affects the Department of Defense (DoD) and National Aeronautics and Space Administration (NASA). The deleterious effects of corrosion result in steep costs, asset downtime affecting mission readiness, and safety risks to personnel. Consequently, it is vital to reduce corrosion costs and risks in a sustainable manner. The DoD and NASA have numerous structures and equipment that are fabricated from stainless steel. The standard practice for protection of stainless steel is a process called passivation. Typical passivation procedures call for the use of nitric acid; however, there are a number of environmental, worker safety, and operational issues associated with its use. Citric acid offers a variety of benefits including increased safety for personnel, reduced environmental impact, and reduced operational cost. DoD and NASA agreed to collaborate to validate citric acid as an acceptable passivating agent for stainless steel. This paper details our investigation of prior work developing the citric acid passivation process, development of the test plan, optimization of the process for specific stainless steel alloys, ongoing and planned testing to elucidate the process' resistance to corrosion in comparison to nitric acid, and preliminary results.

  18. Exhaled nitric oxide in diagnosis and management of respiratory diseases

    Directory of Open Access Journals (Sweden)

    Abba Abdullah

    2009-01-01

    Full Text Available The analysis of biomarkers in exhaled breath constituents has recently become of great interest in the diagnosis, treatment and monitoring of many respiratory conditions. Of particular interest is the measurement of fractional exhaled nitric oxide (FENO in breath. Its measurement is noninvasive, easy and reproducible. The technique has recently been standardized by both American Thoracic Society and European Respiratory Society. The availability of cheap, portable and reliable equipment has made the assay possible in clinics by general physicians and, in the near future, at home by patients. The concentration of exhaled nitric oxide is markedly elevated in bronchial asthma and is positively related to the degree of esinophilic inflammation. Its measurement can be used in the diagnosis of bronchial asthma and titration of dose of steroids as well as to identify steroid responsive patients in chronic obstructive pulmonary disease. In primary ciliary dyskinesia, nasal NO is diagnostically low and of considerable value in diagnosis. Among lung transplant recipients, FENO can be of great value in the early detection of infection, bronchioloitis obliterans syndrome and rejection. This review discusses the biology, factors affecting measurement, and clinical application of FENO in the diagnosis and management of respiratory diseases.

  19. Hyperbaric oxygen upregulates cochlear constitutive nitric oxide synthase

    Directory of Open Access Journals (Sweden)

    Kao Ming-Ching

    2011-02-01

    Full Text Available Abstract Background Hyperbaric oxygen therapy (HBOT is a known adjuvant for treating ischemia-related inner ear diseases. Controversies still exist in the role of HBOT in cochlear diseases. Few studies to date have investigated the cellular changes that occur in inner ears after HBOT. Nitric oxide, which is synthesized by nitric oxide synthase (NOS, is an important signaling molecule in cochlear physiology and pathology. Here we investigated the effects of hyperbaric oxygen on eardrum morphology, cochlear function and expression of NOS isoforms in cochlear substructures after repetitive HBOT in guinea pigs. Results Minor changes in the eardrum were observed after repetitive HBOT, which did not result in a significant hearing threshold shift by tone burst auditory brainstem responses. A differential effect of HBOT on the expression of NOS isoforms was identified. Upregulation of constitutive NOS (nNOS and eNOS was found in the substructures of the cochlea after HBOT, but inducible NOS was not found in normal or HBOT animals, as shown by immunohistochemistry. There was no obvious DNA fragmentation present in this HBOT animal model. Conclusions The present evidence indicates that the customary HBOT protocol may increase constitutive NOS expression but such upregulation did not cause cell death in the treated cochlea. The cochlear morphology and auditory function are consequently not changed through the protocol.

  20. Implications of glial nitric oxyde in neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Jose Enrique eYuste

    2015-08-01

    Full Text Available Nitric oxide (NO is a pleiotropic janus-faced molecule synthesized by nitric oxide synthases (NOS which plays a critical role in a number of physiological and pathological processes in humans. The physiological roles of NO depend on its local concentrations, as well as its availability and the nature of downstream target molecules. Its double-edged sword action has been linked to neurodegenerative disorders. Excessive NO production, as the evoked by inflammatory signals, has been identified as one of the major causative reasons for the pathogenesis of several neurodegenerative diseases. Moreover, excessive NO synthesis under neuroinflammation leads to the formation of reactive nitrogen species and neuronal cell death. There is an intimate relation between microglial activation, NO and neuroinflammation in the human brain. The role of NO in neuroinflammation has been defined in animal models where this neurotransmitter can modulate the inflammatory process acting on key regulatory pathways, such as those associated with excitotoxicity processes induced by glutamate accumulation and microglial activation. Activated glia express inducible NOS and produce NO that triggers calcium mobilization from the endoplasmic reticulum, activating the release of vesicular glutamate from astroglial cells resulting in neuronal death. This change in microglia potentially contributes to the increased age-associated susceptibility and neurodegeneration. In the current review, information is provided about the role of NO, glial activation and age-related processes in the central nervous system (CNS that may be helpful in the isolation of new therapeutic targets for aging and neurodegenerative diseases.

  1. Nitric Oxide-Mediated Posttranslational Modifications: Impacts at the Synapse

    Directory of Open Access Journals (Sweden)

    Sophie A. Bradley

    2016-01-01

    Full Text Available Nitric oxide (NO is an important gasotransmitter molecule that is involved in numerous physiological processes throughout the nervous system. In addition to its involvement in physiological plasticity processes (long-term potentiation, LTP; long-term depression, LTD which can include NMDAR-mediated calcium-dependent activation of neuronal nitric oxide synthase (nNOS, new insights into physiological and pathological consequences of nitrergic signalling have recently emerged. In addition to the canonical cGMP-mediated signalling, NO is also implicated in numerous pathways involving posttranslational modifications. In this review we discuss the multiple effects of S-nitrosylation and 3-nitrotyrosination on proteins with potential modulation of function but limit the analyses to signalling involved in synaptic transmission and vesicular release. Here, crucial proteins which mediate synaptic transmission can undergo posttranslational modifications with either pre- or postsynaptic origin. During normal brain function, both pathways serve as important cellular signalling cascades that modulate a diverse array of physiological processes, including synaptic plasticity, transcriptional activity, and neuronal survival. In contrast, evidence suggests that aging and disease can induce nitrosative stress via excessive NO production. Consequently, uncontrolled S-nitrosylation/3-nitrotyrosination can occur and represent pathological features that contribute to the onset and progression of various neurodegenerative diseases, including Parkinson’s, Alzheimer’s, and Huntington’s.

  2. Use of extractive distillation to produce concentrated nitric acid

    International Nuclear Information System (INIS)

    Campbell, P.C.; Griffin, T.P.; Irwin, C.F.

    1981-04-01

    Concentrated nitric acid (> 95 wt %) is needed for the treatment of off-gases from a fuels-reprocessing plant. The production of concentrated nitric acid by means of extractive distillation in the two-pot apparatus was studied to determine the steady-state behavior of the system. Four parameters, EDP volume (V/sub EDP/) and temperature (T/sub EDP/), acid feed rate, and solvent recycle, were independently varied. The major response factors were percent recovery (CPRR) and product purity (CCP). Stage efficiencies also provided information about the system response. Correlations developed for the response parameters are: CPRR = 0.02(V/sub EDP/ - 800 cc) + 53.5; CCP = -0.87 (T/sub EDP/ - 140 0 C) + 81; eta/sub V,EDP/ = 9.1(F/sub feed/ - 11.5 cc/min) - 0.047(V/sub EDP/ - 800 cc) - 2.8(F/sub Mg(NO 3 ) 2 / - 50 cc/min) + 390; and eta/sub L,EDP/ = 1.9(T/sub EDP/ - 140 0 C) + 79. A computer simulation of the process capable of predicting steady-state conditions was developed, but it requires further work

  3. Nitric-phosphoric acid oxidation of organic waste materials

    International Nuclear Information System (INIS)

    Pierce, R.A.; Smith, J.R.

    1995-01-01

    A wet chemical oxidation technology has been developed to address issues facing defense-related facilities, private industry, and small-volume generators such as university and medical laboratories. Initially tested to destroy and decontaminate a heterogenous mixture of radioactive-contaminated solid waste, the technology can also remediate other hazardous waste forms. The process, unique to Savannah River, offers a valuable alternative to incineration and other high-temperature or high-pressure oxidation processes. The process uses nitric acid in phosphoric acid; phosphoric acid allows nitric acid to be retained in solution well above its normal boiling point. The reaction converts organics to carbon dioxide and water, and generates NO x vapors which can be recycled using air and water. Oxidation is complete in one to three hours. In previous studies, many organic compounds were completely oxidized, within experimental error, at atmospheric pressure below 180 degrees C; more stable compounds were decomposed at 200 degrees C and 170 kPa. Recent studies have evaluated processing parameters and potential throughputs for three primary compounds: EDTA, polyethylene, and cellulose. The study of polyvinylchloride oxidation is incomplete at this time

  4. How to protect liver graft with nitric oxide

    Institute of Scientific and Technical Information of China (English)

    Hassen Ben Abdennebi; Mohamed Amine Zaoualí; Izabel Alfany-Fernandez; Donia Tabka; Joan Roselló-Catafau

    2011-01-01

    Organ preservation and ischemia reperfusion injury associated with liver transplantation play an important role in the induction of graft injury. One of the earliest events associated with the reperfusion injury is endothelial cell dysfunction. It is generally accepted that endothelial nitric oxide synthase (e-NOS) is cell-protective by mediating vasodilatation, whereas inducible nitric oxide synthase mediates liver graft injury after transplantation. We conducted a critical review of the literature evaluating the potential applications of regulating and promoting e-NOS activity in liver preservation and transplantation, showing the most current evidence to support the concept that enhanced bioavailability of NO derived from e-NOS is detrimental to ameliorate graft liver preservation, as well as preventing subsequent graft reperfusion injury. This review deals mainly with the beneficial effects of promoting "endogenous" pathways for NO generation, via e-NOS inducer drugs in cold preservation solution, surgical strategies such as ischemic preconditioning, and alternative "exogenous" pathways that focus on the enrichment of cold storage liquid with NO donors. Finally, we also provide a basic bench-to-bed side summary of the liver physiology and cell signalling mechanisms that account for explaining the e-NOS protective effects in liver preservation and transplantation.

  5. Speciation of platinum(IV) in nitric acid solutions.

    Science.gov (United States)

    Vasilchenko, Danila; Tkachev, Sergey; Baidina, Iraida; Korenev, Sergey

    2013-09-16

    The speciation of platinum(IV) ions in nitric acid (6-15.8 M) solutions of H2[Pt(OH)6] has been studied by (195)Pt NMR and Raman spectroscopy. Series of aqua-hydroxo-nitrato complexes [Pt(L)(x)(NO3)(6-x)] (L = H2O or OH(-); x = 0, ..., 6) were found to exist in such solutions. The pair additivity model of chemical shifts and statistical theory were used to assign signals in NMR spectra to particular [Pt(L)(x)(NO3)(6-x)] species. Mononuclear hexanitratoplatinates(IV) have been isolated in solid state in substantial yield as pyridinium salt (PyH)2[Pt(NO3)6] and characterized by single-crystal X-ray diffraction. Aging of the platinum nitric acid solutions for more than 5-6 h results in oligomerization of [Pt(L)(x)(NO3)(6-x)] species and the formation of oligonuclear aqua-hydroxo-nitrato complexes with OH(-) and NO3(-) bridging ligands. Oligomeric platinum(IV) complexes with two and four nuclei were unambiguously detected by NMR on (195)Pt -enriched samples. Oligomers with even higher nuclearity were also detected. Dimeric anions [Pt2(μ-OH)2(NO3)8](2-) have been isolated as single crystals of tetramethylammonium salt and characterized by X-ray diffraction.

  6. Exhaled nitric oxide in stable chronic obstructive pulmonary disease

    International Nuclear Information System (INIS)

    Beg Mohammed F S; Alzoghaibi, Mohammad A; Habib, Syed S; Abba, Abdullah A

    2009-01-01

    The objective of the study was to test the hypothesis that fraction of exhaled nitric oxide (FENO) is elevated in nonsmoking subjects with stable chronic obstructive pulmonary disease (COPD) and compare it with the results in patients with asthma and a control population. Pulmonology Clinic at a University Hospital. Twenty five control subjects, 25 steroid naive asthmatics and 14 COPD patients were studied. All the patients were nonsmokers and stable at the time of the study. All subjects completed a questionnaire and underwent spirometry. Exhaled nitric oxide was measured online by chemiluminescence, using single-breath technique. All the study subjects were males. Subjects with stable COPD had significantly higher values of FENO than controls (56.54+ - 28.01 vs 22.00 + -6.69; P =0.0001) but lower than the subjects with asthma (56.54+ - 28.01 vs 84.78+ - 39.32 P 0.0285). The FENO values in COPD subjects were inversely related to the FEV 1 /FVC ratio. There was a significant overlap between the FENO values in COPD and the control subjects. There is a significant elevation in FENO in patients with stable COPD, but the elevation is less than in asthmatic subjects. Its value in clinical practice may be limited by the significant overlap with control subjects. (author)

  7. Requirement of argininosuccinate lyase for systemic nitric oxide production.

    Science.gov (United States)

    Erez, Ayelet; Nagamani, Sandesh C S; Shchelochkov, Oleg A; Premkumar, Muralidhar H; Campeau, Philippe M; Chen, Yuqing; Garg, Harsha K; Li, Li; Mian, Asad; Bertin, Terry K; Black, Jennifer O; Zeng, Heng; Tang, Yaoping; Reddy, Anilkumar K; Summar, Marshall; O'Brien, William E; Harrison, David G; Mitch, William E; Marini, Juan C; Aschner, Judy L; Bryan, Nathan S; Lee, Brendan

    2011-11-13

    Nitric oxide (NO) is crucial in diverse physiological and pathological processes. We show that a hypomorphic mouse model of argininosuccinate lyase (encoded by Asl) deficiency has a distinct phenotype of multiorgan dysfunction and NO deficiency. Loss of Asl in both humans and mice leads to reduced NO synthesis, owing to both decreased endogenous arginine synthesis and an impaired ability to use extracellular arginine for NO production. Administration of nitrite, which can be converted into NO in vivo, rescued the manifestations of NO deficiency in hypomorphic Asl mice, and a nitric oxide synthase (NOS)-independent NO donor restored NO-dependent vascular reactivity in humans with ASL deficiency. Mechanistic studies showed that ASL has a structural function in addition to its catalytic activity, by which it contributes to the formation of a multiprotein complex required for NO production. Our data demonstrate a previously unappreciated role for ASL in NOS function and NO homeostasis. Hence, ASL may serve as a target for manipulating NO production in experimental models, as well as for the treatment of NO-related diseases.

  8. The effect of pro-inflammatory cytokines on immunophenotype, differentiation capacity and immunomodulatory functions of human mesenchymal stem cells.

    Science.gov (United States)

    Pourgholaminejad, Arash; Aghdami, Nasser; Baharvand, Hossein; Moazzeni, Seyed Mohammad

    2016-09-01

    Mesenchymal stem cells (MSCs), as cells with potential clinical utilities, have demonstrated preferential incorporation into inflammation sites. Immunophenotype and immunomodulatory functions of MSCs could alter by inflamed-microenvironments due to the local pro-inflammatory cytokine milieu. A major cellular mediator with specific function in promoting inflammation and pathogenicity of autoimmunity are IL-17-producing T helper 17 (Th17) cells that polarize in inflamed sites in the presence of pro-inflammatory cytokines such as Interleukin-1β (IL-1β), IL-6 and IL-23. Since MSCs are promising candidate for cell-based therapeutic strategies in inflammatory and autoimmune diseases, Th17 cell polarizing factors may alter MSCs phenotype and function. In this study, human bone-marrow-derived MSCs (BM-MSC) and adipose tissue-derived MSCs (AD-MSC) were cultured with or without IL-1β, IL-6 and IL-23 as pro-inflammatory cytokines. The surface markers and their differentiation capacity were measured in cytokine-untreated and cytokine-treated MSCs. MSCs-mediated immunomodulation was analyzed by their regulatory effects on mixed lymphocyte reaction (MLR) and the level of IL-10, TGF-β, IL-4, IFN-γ and TNF-α production as immunomodulatory cytokines. Pro-inflammatory cytokines showed no effect on MSCs morphology, immunophenotype and co-stimulatory molecules except up-regulation of CD45. Adipogenic and osteogenic differentiation capacity increased in CD45+ MSCs. Moreover, cytokine-treated MSCs preserved the suppressive ability of allogeneic T cell proliferation and produced higher level of TGF-β and lower level of IL-4. We concluded pro-inflammatory cytokines up-regulate the efficacy of MSCs in cell-based therapy of degenerative, inflammatory and autoimmune disorders. Copyright © 2016. Published by Elsevier Ltd.

  9. Lack of endothelial nitric oxide synthase aggravates murine accelerated anti-glomerular basement membrane glomerulonephritis

    NARCIS (Netherlands)

    Heeringa, P; van Goor, H; Itoh-Lindstrom, Y; Maeda, N; Falk, RJ; Assmann, KJM; Kallenberg, CGM; Jennette, JC

    Nitric oxide (NO) radicals generated by endothelial nitric oxide synthase (eNOS) are involved in the regulation of vascular tone. In addition, NO radicals derived from eNOS inhibit platelet aggregation and leukocyte adhesion to the endothelium and, thus, may have anti-inflammatory effects. To study

  10. Nitric-oxide supplementation for treatment of long-term complications in argininosuccinic aciduria

    Science.gov (United States)

    Argininosuccinate lyase (ASL) is required for the synthesis and channeling of L-arginine to nitric oxide synthase (NOS) for nitric oxide (NO) production. Congenital ASL deficiency causes argininosuccinic aciduria (ASA), the second most common urea cycle disorder, and leads to deficiency of both urea...

  11. Mercury-free dissolution of aluminum-clad fuel in nitric acid

    Science.gov (United States)

    Christian, Jerry D.; Anderson, Philip A.

    1994-01-01

    A mercury-free dissolution process for aluminum involves placing the aluminum in a dissolver vessel in contact with nitric acid-fluoboric acid mixture at an elevated temperature. By maintaining a continuous flow of the acid mixture through the dissolver vessel, an effluent containing aluminum nitrate, nitric acid, fluoboric acid and other dissolved components are removed.

  12. Transportation impact analysis for the shipment of low specific activity nitric acid. Revisison 1

    Energy Technology Data Exchange (ETDEWEB)

    Green, J.R.

    1995-05-16

    This is in support of the Plutonium-Uranium Extraction (PUREX) Facility Low Specific Activity (LSA) Nitric Acid Shipment Environmental Assessment. It analyzes potential toxicological and radiological risks associated with transportation of PUREX Facility LSA Nitric Acid from the Hanford Site to Portsmouth VA, Baltimore MD, and Port Elizabeth NJ.

  13. SOIL NITROUS OXIDE, NITRIC OXIDE, AND AMMONIA EMISSIONS FROM A RECOVERING RIPARIAN ECOSYSTEM IN SOUTHERN APPALACHIA

    Science.gov (United States)

    The paper presents two years of seasonal nitric oxide, ammonia, and nitrous oxide trace gas fluxes measured in a recovering riparian zone with cattle excluded and in an adjacent riparian zone grazed by cattle. In the recovering riparian zone, average nitric oxide, ammonia, and ni...

  14. Nitric oxide mediates the stress response induced by diatom aldehydes in the sea urchin Paracentrotus lividus.

    Directory of Open Access Journals (Sweden)

    Giovanna Romano

    Full Text Available Diatoms are ubiquitous and abundant primary producers that have been traditionally considered as a beneficial food source for grazers and for the transfer of carbon through marine food webs. However, many diatom species produce polyunsaturated aldehydes that disrupt development in the offspring of grazers that feed on these unicellular algae. Here we provide evidence that production of the physiological messenger nitric oxide increases after treatment with the polyunsaturated aldehyde decadienal in embryos of the sea urchin Paracentrotus lividus. At high decadienal concentrations, nitric oxide mediates initial apoptotic events leading to loss of mitochondrial functionality through the generation of peroxynitrite. At low decadienal concentrations, nitric oxide contributes to the activation of hsp70 gene expression thereby protecting embryos against the toxic effects of this aldehyde. When nitric oxide levels were lowered by inhibiting nitric oxide synthase activity, the expression of hsp70 in swimming blastula decreased and the proportion of abnormal plutei increased. However, in later pluteus stages nitric oxide was no longer able to exert this protective function: hsp70 and nitric oxide synthase expression decreased with a consequent increase in the expression of caspase-8. Our findings that nitric oxide production increases rapidly in response to a toxic exogenous stimulus opens new perspectives on the possible role of this gas as an important messenger to environmental stress in sea urchins and for understanding the cellular mechanisms underlying toxicity during diatom blooms.

  15. Analysis of Steam Heating of a Two-Layer TBP/N-Paraffin/Nitric Acid Mixtures

    International Nuclear Information System (INIS)

    Laurinat, J.E.; Hassan, N.M.; Rudisill, T.S.; Askew, N.M.

    1998-01-01

    This report presents an analysis of steam heating of a two-layer tri-n-butyl phosphate (TBP)/n-paraffin-nitric acid mixture.The purpose of this study is to determine if the degree of mixing provided by the steam jet or by bubbles generated by the TBP/nitric acid reaction is sufficient to prevent a runaway reaction

  16. Transportation impact analysis for the shipment of low specific activity nitric acid. Revisison 1

    International Nuclear Information System (INIS)

    Green, J.R.

    1995-01-01

    This is in support of the Plutonium-Uranium Extraction (PUREX) Facility Low Specific Activity (LSA) Nitric Acid Shipment Environmental Assessment. It analyzes potential toxicological and radiological risks associated with transportation of PUREX Facility LSA Nitric Acid from the Hanford Site to Portsmouth VA, Baltimore MD, and Port Elizabeth NJ

  17. Transportation impact analysis for the shipment of Low Specific Activity Nitric Acid

    International Nuclear Information System (INIS)

    Green, J.R.

    1994-01-01

    This document was written in support of the Plutonium-Uranium Extraction (PUREX) Facility Low Specific Activity (LSA) Nitric Acid Shipment Environmental Assessment. It analyzes the potential toxicological and radiological risks associated with the transportation of PUREX Facility LSA Nitric Acid from the Hanford Site in Washington State to three Eastern ports

  18. Increase of hepatic nitric oxide levels in a nutritional model of fatty ...

    African Journals Online (AJOL)

    GREGORY

    2010-08-30

    Aug 30, 2010 ... (MDA) and protein carbonyl (PC), and also nitric oxide (NO) in over fed broiler breeder hens, 198 hens. (30 weeks old) .... The total protein in the liver tissue was determined by a method ... Table 1. Egg production and LHS in broiler breeder hens .... trations of nitric oxide metabolites (nitrates-nitrites) in rat.

  19. Role of nitric oxide in glucose-, fructose and galactose-induced ...

    African Journals Online (AJOL)

    Previous studies have shown that the infusion of glucose, fructose and galactose resulted in significant increases in intestinal glucose uptake (IGU) and the role of nitric oxide in these responses was not known. The present study was designed to investigate the role of nitric oxide in the observed increases in IGU.

  20. Hyperbaric oxygen therapy may overcome nitric oxide blockage during cyanide intoxication

    DEFF Research Database (Denmark)

    Polzik, Peter; Hansen, Marco Bo; Olsen, Niels Vidiendal

    2017-01-01

    PURPOSE: To determine the effects of a blockade of nitric oxide (NO) synthesis on hyperbaric oxygen (HBO₂) therapy during cyanide (CN) intoxication. METHODS: 39 anesthetized female Sprague-Dawley rats were exposed to CN intoxication (5.4 mg/kg intra-arterially) with or without previous nitric oxide...

  1. Modulation of cholinergic airway reactivity and nitric oxide production by endogenous arginase activity

    NARCIS (Netherlands)

    Meurs, Herman; Hamer, M.A M; Pethe, S; Vadon-Le Goff, S; Boucher, J.-L; Zaagsma, Hans

    1 Cholinergic airway constriction is functionally antagonized by agonist-induced constitutive nitric oxide synthase (cNOS)-derived nitric oxide (NO). Since cNOS and arginase, which hydrolyzes L-arginine to L-ornithine and urea, use L-arginine as a common substrate, competition between both enzymes

  2. Sludge batch 9 follow-on actual-waste testing for the nitric-glycolic flowsheet

    Energy Technology Data Exchange (ETDEWEB)

    Martino, C. J. [Savannah River Site (SRS), Aiken, SC (United States). Savannah River National Lab. (SRNL); Newell, J. D. [Savannah River Site (SRS), Aiken, SC (United States). Savannah River National Lab. (SRNL); Crawford, C. L. [Savannah River Site (SRS), Aiken, SC (United States). Savannah River National Lab. (SRNL); Pareizs, J. M. [Savannah River Site (SRS), Aiken, SC (United States). Savannah River National Lab. (SRNL); Williams, M. S. [Savannah River Site (SRS), Aiken, SC (United States). Savannah River National Lab. (SRNL)

    2017-03-23

    An actual-waste Sludge Batch 9 qualification run with the nitric-glycolic flowsheet (SC-18) was performed in FY16. In order to supplement the knowledge base for the nitric-glycolic flowsheet, additional testing was performed on the product slurries, condensates, and intermediate samples from run SC-18.

  3. A study on electrochemical redox behavior of nitric acid by using a glassy carbon fiber column electrode system

    International Nuclear Information System (INIS)

    Kim, K. W.; Song, K. C.; Lee, I. H.; Choi, I. K.; You, J. H.

    1999-01-01

    Electrochemical redox behaviors of nitric acid were studied by using a glassy carbon fiber column electrode system, and its reaction mechanism was analyzed in several ways. The electrochemical reaction in less than 2.0 M nitric acid was not observed, but in more than 2.0 M nitric acid, the reduction rate of nitric acid to produce nitrous acid was slow so that the nitric acid solution had to be contacted with electrode enough in order for a apparent reduction current of nitric acid to nitrous acid be to observed. The nitrous acid generated in more than 2.0 M nitric acid was rapidly and easily reduced to NOx through an autocatalytic reaction. Sulfamic acid was confirmed to be effective to destroy the nitrous acid. The sulfamic acid of at least 0.05M was necessary to remove the nitrous acid generated in 3.5 M nitric acid

  4. Infection and upregulation of proinflammatory cytokines in human brain vascular pericytes by human cytomegalovirus

    Directory of Open Access Journals (Sweden)

    Alcendor Donald J

    2012-05-01

    Full Text Available Abstract Background Congenital human cytomegalovirus (HCMV infections can result in CNS abnormalities in newborn babies including vision loss, mental retardation, motor deficits, seizures, and hearing loss. Brain pericytes play an essential role in the development and function of the blood–brain barrier yet their unique role in HCMV dissemination and neuropathlogy has not been reported. Methods Primary human brain vascular pericytes were exposed to a primary clinical isolate of HCMV designated ‘SBCMV’. Infectivity was analyzed by microscopy, immunofluorescence, Western blot, and qRT-PCR. Microarrays were performed to identify proinflammatory cytokines upregulated after SBCMV exposure, and the results validated by real-time quantitative polymerase chain reaction (qPCR methodology. In situ cytokine expression of pericytes after exposure to HCMV was examined by ELISA and in vivo evidence of HCMV infection of brain pericytes was shown by dual-labeled immunohistochemistry. Results HCMV-infected human brain vascular pericytes as evidenced by several markers. Using a clinical isolate of HCMV (SBCMV, microscopy of infected pericytes showed virion production and typical cytomegalic cytopathology. This finding was confirmed by the expression of major immediate early and late virion proteins and by the presence of HCMV mRNA. Brain pericytes were fully permissive for CMV lytic replication after 72 to 96 hours in culture compared to human astrocytes or human brain microvascular endothelial cells (BMVEC. However, temporal transcriptional expression of pp65 virion protein after SBCMV infection was lower than that seen with the HCMV Towne laboratory strain. Using RT-PCR and dual-labeled immunofluorescence, proinflammatory cytokines CXCL8/IL-8, CXCL11/ITAC, and CCL5/Rantes were upregulated in SBCMV-infected cells, as were tumor necrosis factor-alpha (TNF-alpha, interleukin-1 beta (IL-1beta, and interleukin-6 (IL-6. Pericytes exposed to SBCMV elicited

  5. Pro-inflammatory cytokines and leukocyte oxidative burst in chronic kidney disease: culprits or innocent bystanders?

    Science.gov (United States)

    Neirynck, Nathalie; Glorieux, Griet; Schepers, Eva; Dhondt, Annemieke; Verbeke, Francis; Vanholder, Raymond

    2015-06-01

    Pro-inflammatory cytokines are elevated in chronic kidney disease (CKD), a condition characterized by microinflammation with oxidative stress as key feature. However, their role in the inflammatory response at uraemic concentrations has not yet been defined. In this study, the contribution of cytokines on induction of leukocyte oxidative stress was investigated. Whole blood from healthy donors was incubated with 20-1400 pg/mL TNFα, 5-102.8 pg/mL IL-6, 20-400 pg/mL IL-1β and 75-1200 pg/mL IL-18 separately or in combination. Oxidative burst was measured, at baseline and after stimulation with fMLP (Phagoburst™). The effect of the TNFα blocker, adalimumab (Ada), was evaluated on TNFα-induced ROS production. Finally, the association between TNFα and the composite end point all-cause mortality or first cardiovascular event was analysed in a CKD population stage 4-5 (n = 121). While interleukin (IL)-6, IL-1β and IL-18 alone induced no ROS activation of normal leukocytes, irrespective of concentrations, TNFα induced ROS activation at baseline (P < 0.01) and after fMLP stimulation (P < 0.05), but only at uraemic concentrations in the high range (400 and 1400 pg/mL). A similar pattern was observed with all cytokines in combination, but already at intermediate uraemic concentrations (all P < 0.05, except for monocytes after fMLP stimulation: n.s.), suggesting synergism between cytokines. ROS production induced by TNFα (400 pg/mL) and the cytokine combination was blocked with Ada. Uraemia-related oxidative stress in leukocytes of haemodialysis patients was however not blocked by Ada. In patients, TNFα was not associated to adverse events (HR: 1.52, 95% CI 0.81-2.85, P = 0.13). Among several pro-inflammatory cytokines, TNFα alone was pro-oxidative but only at high-range uraemic concentrations. Adding a TNFα blocker, Ada, blocked this ROS production, but not the oxidative stress in blood samples from haemodialysis patients, suggesting that other uraemic toxins than

  6. Embelin and its derivatives unravel the signaling, proinflammatory and antiatherogenic properties of GPR84 receptor.

    Science.gov (United States)

    Gaidarov, Ibragim; Anthony, Todd; Gatlin, Joel; Chen, Xiaohua; Mills, David; Solomon, Michelle; Han, Sangdon; Semple, Graeme; Unett, David J

    2018-05-01

    GPR84 is an orphan G-protein coupled receptor, expressed on monocytes, macrophages and neutrophils and is significantly upregulated by inflammatory stimuli. The physiological role of GPR84 remains largely unknown. Medium chain fatty acids (MCFA) activate the receptor and have been proposed to be its endogenous ligands, although the high concentrations of MCFAs required for receptor activation generally exceed normal physiological levels. We identified the natural product embelin as a highly potent and selective surrogate GPR84 agonist (originally disclosed in patent application WO2007027661A2, 2007) and synthesized close structural analogs with widely varying receptor activities. These tools were used to perform a comprehensive study of GPR84 signaling and function in recombinant cells and in primary human macrophages and neutrophils. Activation of recombinant GPR84 by embelin in HEK293 cells results in G i/o as well as G12/13-Rho signaling. In human macrophages, GPR84 initiates PTX sensitive Erk1/2 and Akt phosphorylation, PI-3 kinase activation, calcium flux, and release of prostaglandin E2. In addition, GPR84 signaling in macrophages elicits G i Gβγ-mediated augmentation of intracellular cAMP, rather than the decrease expected from G iα engagement. GPR84 activation drives human neutrophil chemotaxis and primes them for amplification of oxidative burst induced by FMLP and C5A. Loss of GPR84 is associated with attenuated LPS-induced release of proinflammatory mediators IL-6, KC-GROα, VEGF, MIP-2 and NGAL from peritoneal exudates. While initiating numerous proinflammatory activities in macrophages and neutrophils, GPR84 also possesses GPR109A-like antiatherosclerotic properties in macrophages. Macrophage receptor activation leads to upregulation of cholesterol transporters ABCA1 and ABCG1 and stimulates reverse cholesterol transport. These data suggest that GPR84 may be a target of therapeutic value and that distinct modes of receptor modulation (inhibition vs

  7. Surface modifications of silica nanoparticles are crucial for their inert versus proinflammatory and immunomodulatory properties

    Directory of Open Access Journals (Sweden)

    Marzaioli V

    2014-06-01

    Full Text Available Viviana Marzaioli,1 Juan Antonio Aguilar-Pimente,1,2 Ingrid Weichenmeier,1 Georg Luxenhofer,3 Martin Wiemann,4 Robert Landsiedel,5 Wendel Wohlleben,5 Stefanie Eiden,6 Martin Mempel,7 Heidrun Behrendt,1 Carsten Schmidt-Weber,1 Jan Gutermuth,1,8 Francesca Alessandrini1 1Center of Allergy and Environment (ZAUM, Technische Universität and Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL, Munich, Germany; 2Department of Dermatology and Allergy Biederstein, Technische Universität München (TUM and German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany, 3Institute of Developmental Genetics, Helmholtz Zentrum München, Neuherberg, Germany; 4IBE R&D gGmbH, Münster, Germany; 5BASF, Ludwigshafen, Germany; 6Bayer Technology Services, Leverkusen, Germany; 7Department of Dermatology, Venereology and Allergology, Universitätsmedizin Göttingen (UMG, Göttingen, Germany; 8Department of Dermatology, Vrije Universiteit Brussel, Brussels, Belgium Background: Silica (SiO2 nanoparticles (NPs are widely used in diverse industrial and biomedical applications. Their applicability depends on surface modifications, which can limit potential health problems. Objective: To assess the potential impact of SiO2 NP exposure and NPs chemical modifications in allergic airway inflammation. Methods: Mice were sensitized by five repetitive intraperitoneal injections of ovalbumin/aluminum hydroxide (1 µg over 42 days, then intratracheally instilled with plain or modified SiO2 NPs (50 µg/mouse, and subsequently aerosol challenged for 20 minutes with ovalbumin. One or 5 days later, allergic inflammation was evaluated by cell differentiation of bronchoalveolar lavage fluid, lung function and gene expression and histopathology, as well as electron and confocal microscopy of pulmonary tissue. Results: Plain SiO2 NPs induced proinflammatory and immunomodulatory effects in vivo

  8. Total body fat, pro-inflammatory cytokines and insulin resistance in Indian subjects

    Energy Technology Data Exchange (ETDEWEB)

    Yajnik, C S [Diabetes Unit, KEM Hospital Research Centre, Pune (India); Yudkin, J S [Whittington Hospital, University College of London, London (United Kingdom); Shetty, P S [London School of Hygiene and Tropical Medicine, London (United Kingdom); Kurpad, A [St. John' s Medical College, Bangalore (India)

    1999-07-01

    There is a growing epidemic of insulin resistance syndrome (IRS) in Indians. We postulate that increased susceptibility of the urban Indians to insulin resistance is a result of a tendency to increased fat deposition from the time of intrauterine life (thrifty phenotype), exaggerated in the urban environment by a positive energy balance. The pro-inflammatory cytokines secreted by the inflammatory cells as well by the adipose tissue could aggravate insulin resistance and endothelial damage and therefore, increase the susceptibility to type 2 diabetes and coronary heart disease (CHD) independent of the previously proposed glucose fatty acid cycle mechanism. In a preliminary study, we propose to make detailed measurements of the proposed mechanisms in a selected population from 3 geographical locations in and near the city of Pune, India and also validate simple 'epidemiologic' measurements of body composition with 'reference' measurements. One hundred men (30 to 50y) each from the three geographical locations (rural, urban slum-dwellers and urban middle class in Pune) will be studied for: (i) Body composition: Anthropometric and bioimpedance measurement of total body fat (to be calibrated against deuterated water in 30 subjects from each location), and muscle mass by anthropometry and urinary creatinine excretion; (ii) Body fat distribution by subscapular- triceps ratio, waist-hip ratio; (iii) Metabolic: Glucose tolerance and insulin resistance variables (insulin, lipids, NEFA) and leptin; (iv) Endothelial markers: e-Selectin and von Willebrand Factor (vWF); (v) Inflammatory markers and pro-inflammatory cytokines: C-reactive protein (CRP), Interleukin-6 (IL-6) and tumour necrosis factor (TNF- {alpha}); (vi) Energy Balance: Assessment of nutritional intake (calories, carbohydrates, proteins and fats, n3 and n6 fatty acids) and physical activity by a questionnaire. Insulin resistance variables, endothelial markers, cytokines and obesity parameters will be compared in

  9. Pro-Inflammatory Cytokine Levels in HIV Infected and Uninfected Pregnant Women with and without Preeclampsia.

    Science.gov (United States)

    Maharaj, Niren Ray; Phulukdaree, Alisa; Nagiah, Savania; Ramkaran, Prithiksha; Tiloke, Charlette; Chuturgoon, Anil Amichund

    2017-01-01

    Preeclampsia and HIV/AIDS are inflammatory conditions that contribute significantly to adverse maternal and foetal outcomes. The immune reconstitution effects of HAART on inflammatory mediators has not been adequately studied in pregnancy and may impact on the inflammatory cytokine network in women with co-morbid preeclampsia. Our study evaluated changes in pro-inflammatory cytokines IL-2, TNF-α, IFN-γ and IL-6 in HIV infected preeclamptic women on HAART. A prospective experimental study was conducted at Prince Mshiyeni Memorial Hospital between July 2013 and September 2014. One hundred and ninety three pregnant women were recruited into 4 groups: uninfected normotensive (50; 26%), infected normotensive (45; 23%), uninfected preeclamptic (53; 28%) and infected preeclamptic women (45; 23%). Serum levels of cytokines TNF-α, IFN- γ, IL-2 and IL-6 were determined using commercially available kits and a Cytometric Bead Array (CBA). Comparative data was recorded and analysed descriptively. In the control groups (normotensive), significantly lower values were found in IL-2 (p = 0.010), TNF-α (p = 0.045), and IL-6 (p = 0.005); and a non-significant decrease was observed in IFN-γ (p = 0.345) in HIV infected women on HAART compared to uninfected controls. In the experimental group (preeclamptic) women, significantly reduced levels were observed in IL-2 and TNF-α (p = 0.001; p = 0.000) and non-significant decreases were observed in IFN-γ and IL-6 (p = 0.023; p = 0.086) in HIV infected women on HAART compared with uninfected preeclamptic women. Non-significant differences were observed between uninfected preeclamptic and normotensive women. In uncomplicated/normotensive pregnancies, HIV/HAART is associated with significant decreases in IL-2, TNF-α and IL-6, and in preeclamptic women significant decreases in IL-2 and TNF-α were observed. These findings suggest that HIV/HAART impacts on pro-inflammatory cytokines in women with co-morbid preeclampsia. This provides a

  10. Total body fat, pro-inflammatory cytokines and insulin resistance in Indian subjects

    International Nuclear Information System (INIS)

    Yajnik, C.S.; Yudkin, J.S.; Shetty, P.S.; Kurpad, A.

    1999-01-01

    There is a growing epidemic of insulin resistance syndrome (IRS) in Indians. We postulate that increased susceptibility of the urban Indians to insulin resistance is a result of a tendency to increased fat deposition from the time of intrauterine life (thrifty phenotype), exaggerated in the urban environment by a positive energy balance. The pro-inflammatory cytokines secreted by the inflammatory cells as well by the adipose tissue could aggravate insulin resistance and endothelial damage and therefore, increase the susceptibility to type 2 diabetes and coronary heart disease (CHD) independent of the previously proposed glucose fatty acid cycle mechanism. In a preliminary study, we propose to make detailed measurements of the proposed mechanisms in a selected population from 3 geographical locations in and near the city of Pune, India and also validate simple 'epidemiologic' measurements of body composition with 'reference' measurements. One hundred men (30 to 50y) each from the three geographical locations (rural, urban slum-dwellers and urban middle class in Pune) will be studied for: (i) Body composition: Anthropometric and bioimpedance measurement of total body fat (to be calibrated against deuterated water in 30 subjects from each location), and muscle mass by anthropometry and urinary creatinine excretion; (ii) Body fat distribution by subscapular- triceps ratio, waist-hip ratio; (iii) Metabolic: Glucose tolerance and insulin resistance variables (insulin, lipids, NEFA) and leptin; (iv) Endothelial markers: e-Selectin and von Willebrand Factor (vWF); (v) Inflammatory markers and pro-inflammatory cytokines: C-reactive protein (CRP), Interleukin-6 (IL-6) and tumour necrosis factor (TNF- α); (vi) Energy Balance: Assessment of nutritional intake (calories, carbohydrates, proteins and fats, n3 and n6 fatty acids) and physical activity by a questionnaire. Insulin resistance variables, endothelial markers, cytokines and obesity parameters will be compared in the 3

  11. Adiponectin and pro-inflammatory cytokines are modulated in Vietnamese patients with type 2 diabetes mellitus.

    Science.gov (United States)

    Tong, Hoang Van; Luu, Nguyen Kim; Son, Ho Anh; Hoan, Nguyen Van; Hung, Trinh Thanh; Velavan, Thirumalaisamy P; Toan, Nguyen Linh

    2017-05-01

    Adipose tissue-derived hormones are associated with metabolic disorders including type 2 diabetes mellitus. The present study investigated the levels of adiponectin and pro-inflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin-1 beta (IL-1β) and IL-10 in Vietnamese patients with type 2 diabetes mellitus, and their correlations with clinical parameters of overweight and type 2 diabetes mellitus. Based on body mass index, 73 patients with type 2 diabetes mellitus were categorized either as overweight or non-overweight. As healthy controls, 57 overweight and non-overweight individuals without type 2 diabetes mellitus were included. The adiponectin, TNF-α, IL-1β and IL-10 levels were measured in the sera samples in all study participants by enzyme-linked immunosorbent assay and were correlated with clinical parameters. The adiponectin levels were lower in patients with type 2 diabetes mellitus (2.5 ± 1.5 μg/mL) compared with controls (16 ± 18.6 μg/mL; P < 0.0001), and were decreased in overweight individuals compared with those who were not overweight. The TNF-α and IL-1β levels were increased, whereas the IL-10 levels were decreased in patients with type 2 diabetes mellitus and in overweight controls compared with non-overweight controls (P < 0.0001). The adiponectin levels were correlated with the TNF-α, IL-1β, IL-10 levels, and the clinical parameters of overweight and type 2 diabetes mellitus. The quantitative insulin sensitivity check index and homeostasis model assessment insulin resistance indexes were correlated with the relative ratios of adiponectin/TNF-α, adiponectin/IL-1β, adiponectin/IL-10, TNF-α/IL-10 and IL-1β/IL-10. Adiponectin and pro-inflammatory cytokines are associated with type 2 diabetes mellitus, and might serve as a prognostic marker and a therapeutic intervention for overweight-related type 2 diabetes mellitus. © 2016 The Authors. Journal of Diabetes Investigation published by Asian Association for the

  12. Pro-Inflammatory Cytokine Levels in HIV Infected and Uninfected Pregnant Women with and without Preeclampsia.

    Directory of Open Access Journals (Sweden)

    Niren Ray Maharaj

    Full Text Available Preeclampsia and HIV/AIDS are inflammatory conditions that contribute significantly to adverse maternal and foetal outcomes. The immune reconstitution effects of HAART on inflammatory mediators has not been adequately studied in pregnancy and may impact on the inflammatory cytokine network in women with co-morbid preeclampsia. Our study evaluated changes in pro-inflammatory cytokines IL-2, TNF-α, IFN-γ and IL-6 in HIV infected preeclamptic women on HAART.A prospective experimental study was conducted at Prince Mshiyeni Memorial Hospital between July 2013 and September 2014. One hundred and ninety three pregnant women were recruited into 4 groups: uninfected normotensive (50; 26%, infected normotensive (45; 23%, uninfected preeclamptic (53; 28% and infected preeclamptic women (45; 23%. Serum levels of cytokines TNF-α, IFN- γ, IL-2 and IL-6 were determined using commercially available kits and a Cytometric Bead Array (CBA. Comparative data was recorded and analysed descriptively.In the control groups (normotensive, significantly lower values were found in IL-2 (p = 0.010, TNF-α (p = 0.045, and IL-6 (p = 0.005; and a non-significant decrease was observed in IFN-γ (p = 0.345 in HIV infected women on HAART compared to uninfected controls. In the experimental group (preeclamptic women, significantly reduced levels were observed in IL-2 and TNF-α (p = 0.001; p = 0.000 and non-significant decreases were observed in IFN-γ and IL-6 (p = 0.023; p = 0.086 in HIV infected women on HAART compared with uninfected preeclamptic women. Non-significant differences were observed between uninfected preeclamptic and normotensive women.In uncomplicated/normotensive pregnancies, HIV/HAART is associated with significant decreases in IL-2, TNF-α and IL-6, and in preeclamptic women significant decreases in IL-2 and TNF-α were observed. These findings suggest that HIV/HAART impacts on pro-inflammatory cytokines in women with co-morbid preeclampsia. This provides

  13. Recovery of Tin and Nitric Acid from Spent Solder Stripping Solutions

    International Nuclear Information System (INIS)

    Ahn, Jae-Woo; Ryu, Seong-Hyung; Kim, Tae-young

    2015-01-01

    Spent solder-stripping solutions containing tin, copper, iron, and lead in nitric acid solution, are by-products of the manufacture of printed-circuit boards. The recovery of these metals and the nitric acid, for re-use has economic and environmental benefits. In the spent solder-stripping solution, a systematic method to determine a suitable process for recovery of valuable metals and nitric acid was developed. Initially, more than 90% of the tin was successfully recovered as high-purity SnO 2 by thermal precipitation at 80 ℃ for 3 hours. About 94% of the nitric acid was regenerated effectively from the spent solutions by diffusion dialysis, after which there remained copper, iron, and lead in solution. Leakage of tin through the anion-exchange membrane was the lowest (0.026%), whereas Pb-leakage was highest (4.26%). The concentration of the regenerated nitric acid was about 5.1 N.

  14. Interfacial tension in systems involving TBP in dodecane, nitric acid, uranyl nitrate and water

    International Nuclear Information System (INIS)

    Kolarik, Z.; Pipkin, N.

    1982-08-01

    The interfacial tension was measured at 25 0 C in the systems TBP - n-dodecane/nitric acid - water and TBP - n-dodecane/nitric acid - uranyl nitrate - water. Empirical equations describing the interfacial tension as a function of the concentration of TBP in the starting organic phase and of uranium-(VI) and nitric acid in the equilibrium aqueous phase were suggested. In the absence of uranium (VI), the interfacial tension can also be correlated with the concentration of water in the equilibrium organic phase. Free TBP, hydrated or nonhydrated, and hydrated TBP solvates of nitric acid are interfacially active. Anhydrous TBP solvates of nitric acid and the TBP solvate of uranyl nitrate, which neither is hydrated, do not exhibit any visible interfacial activity. (orig.) [de

  15. Role of nitric oxide in methamphetamine neurotoxicity: protection by 7-nitroindazole, an inhibitor of neuronal nitric oxide synthase.

    Science.gov (United States)

    Di Monte, D A; Royland, J E; Jakowec, M W; Langston, J W

    1996-12-01

    The role of nitric oxide (NO.) in the neurotoxic effects of me