76 results on '"Spiller F"'
Search Results
2. Acute-phase protein [alpha]-1-acid glycoprotein mediates neutrophil migration failure in sepsis by a nitric oxide-dependent mechanism
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Mestriner, F.L.A.C., Spiller, F., Laure, H.J., Souto, F.O., Tavares-Murta, B.M., Rosa, J.C., Basile-Filho, A., Ferreira, S.H., Greene, L.J., and Cunha, F.Q.
- Subjects
Neutrophils -- Physiological aspects ,Neutrophils -- Health aspects ,Sepsis -- Causes of ,Sepsis -- Physiological aspects ,Sepsis -- Research ,Science and technology - Abstract
The reduction of circulating neutrophil migration to infection sites is associated with a poor outcome of severe sepsis. [alpha]-1-Acid glycoprotein (AGP) was isolated from the sera of severely septic patients by HPLC and acrylamide gel electrophoresis and identified by mass spectrometry. Both the isolated protein and commercial AGP inhibited carrageenin-induced neutrophil migration into the rat peritoneal cavity when administered i.v. at a dose of 4.0 [micro]g per rat (95 pmol per rat). Analysis by intravital microscopy demonstrated that both proteins inhibited the rolling and adhesion of leukocytes in the mesenteric microcirculation. The inhibitory activity was blocked by 50 mg/kg aminoguanidine, s.c., and was not demonstrable in inducible nitric oxide synthase (iNOS) knockout mice. Incubation of AGP with neutrophils from healthy subjects induced the production of NO and inhibited the neutrophil chemotaxis by an iNOS/NO/cyclic guanosine 3,5-monophosphate-dependent pathway. In addition, AGP induced the L-selectin shedding by neutrophils. The administration of AGP to rats with mild cecal ligation puncture sepsis inhibited neutrophil migration and reduced 7-day survival from [approximately equal to] 80% to 20%. These data demonstrate that AGP, an acute-phase protein, inhibits neutrophil migration by an NO-dependent process and suggest that AGP also participates in human sepsis.
- Published
- 2007
3. Micromechanical Thin-Film Characterization
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Scherge, M., Mollenhauer, O., Spiller, F., and Schaefer, J. A.
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- 1999
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4. Peroxynitrite mediates the failure of neutrophil migration in severe polymicrobial sepsis in mice
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Torres-Dueñas, D, Celes, M R N, Freitas, A, Alves-Filho, J C, Spiller, F, Dal-Secco, D, Dalto, V F, Rossi, M A, Ferreira, S H, and Cunha, F Q
- Published
- 2007
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5. 9 Decreased Alpha-1 Glycoprotein Acid Related to Mortality of Septic Patients in the Emergency Department
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Sousa, R.B., primary, Souto, F.O., additional, Lobo, R.R., additional, Mendonça, P.R., additional, Memoria Junior, R., additional, Spiller, F., additional, Cunha, F.d., additional, and Pazin-Filho, A., additional
- Published
- 2011
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6. 345: Reduction of the Expression of Membrane CXCR2 and BLT1 Receptors on Neutrophils Related to Increased Mortality of Septic Patients In the Emergency Department
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Sousa, R.B., primary, Souto, F.O., additional, Spiller, F., additional, Turato, W.M., additional, Lobo, R.R., additional, Mendonça, P.R., additional, Cunha, F.Q., additional, and Pazin-Filho, A., additional
- Published
- 2010
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7. Heme oxygenase and soluble guanylate cyclase mediate the neutrophil migration failure to the lung in severe sepsis induced by pneumonia
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Czaikoski, PG, primary, Nascimento, DBC, additional, Spiller, F, additional, and Cunha, FQ, additional
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- 2009
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8. CCR2 expression on neutrophils leads to detrimental tissue infiltration during sepsis
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Souto, FO, primary, Alves-Filho, JC, additional, Freitas, A, additional, Spiller, F, additional, Martins, MA, additional, Basile-Filho, A, additional, and Cunha, FQ, additional
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- 2009
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9. Inhibitory role of the acute phase proteins on neutrophil migration in severe sepsis
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Spiller, F, primary, Mestriner, F, additional, Laure, H, additional, Souto, F, additional, Alves-Filho, J, additional, Costa, C, additional, Freitas, A, additional, Rosa, J, additional, Ferreira, S, additional, Altruda, F, additional, Hirsch, E, additional, Tolosano, E, additional, and Cunha, FQ, additional
- Published
- 2009
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10. Mast cell degranulation contributes to neutrophil migration failure and susceptibility of diabetic mice to polymicrobial sepsis
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Carlos, D, primary, Spiller, F, additional, Freitas, A, additional, Sônego, F, additional, and Cunha, FQ, additional
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- 2009
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11. The critical role of heme oxygenase in neutrophil migration impairment in polymicrobial sepsis
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Freitas, A, primary, Alves-Filho, JC, additional, Dal-Secco, D, additional, Spiller, F, additional, and Cunha, FQ, additional
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- 2007
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12. Toll-like receptor 2 induces chemokine receptor CXCR2 downregulation and neutrophil migration impairment in severe sepsis
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Alves-Filho, JC, primary, Freitas, A, additional, Spiller, F, additional, Souto, FO, additional, Paula-Neto, H, additional, Silva, JS, additional, and Cunha, FQ, additional
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- 2007
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13. High-precision positioning and measurement systems for microtribotesting
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Mollenhauer, O., primary, Ahmed, S.I.-U., additional, Spiller, F., additional, and Haefke, H., additional
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- 2006
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14. A new tool for industrial tribology filling the gap between macro‐ and nano‐ tribology
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Achanta, S., primary, Drees, D., additional, Celis, J.‐P., additional, Mollenhauer, O., additional, and Spiller, F., additional
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- 2004
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15. Detection of Micronewton Forces in Tribology
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Scherge, M., primary, Ahmed, S.I., additional, Mollenhauer, O., additional, and Spiller, F., additional
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- 2000
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16. Second Catalogue of Stars measured in the Long-Term Photometry of Variables Project 1986 - 1990
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Sterken, Christiaan, Manfroid, Jean, Anton, K., Barzewski, A., Bibo, E., Bruch, A., Burger, David, Duerbeck, H.~W., Duemmler, R., Heck, Andre, Hensberge, Herman, Hiesgen, M., Inklaar, F., Jorissen, Alain, Juettner, A., Kinkel, U., Liu, Zhenan, Mekkaden, M.~V., Ng, Y.~K., Niarchos, Panagiotis, Puttmann, M., Szeifert, T., Spiller, F., van Dijk, R., Vogt, Nikolaus, Wanders, I., Sterken, Christiaan, Manfroid, Jean, Anton, K., Barzewski, A., Bibo, E., Bruch, A., Burger, David, Duerbeck, H.~W., Duemmler, R., Heck, Andre, Hensberge, Herman, Hiesgen, M., Inklaar, F., Jorissen, Alain, Juettner, A., Kinkel, U., Liu, Zhenan, Mekkaden, M.~V., Ng, Y.~K., Niarchos, Panagiotis, Puttmann, M., Szeifert, T., Spiller, F., van Dijk, R., Vogt, Nikolaus, and Wanders, I.
- Abstract
info:eu-repo/semantics/published
- Published
- 1993
17. Longterm Photometry of Variables at ESO - Part Two - the Second Data Catalogue 1986-1990
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Sterken, Christiaan, Manfroid, Jean, Anton, K., Barzewski, A., Bibo, E., Bruch, A., Burger, David, Duerbeck, H.~W., Duemmler, R., Heck, Andre, Hensberge, Herman, Hiesgen, M., Inklaar, F., Jorissen, Alain, Juettner, A., Kinkel, U., Liu, Zhenan, Mekkaden, M.~V., Ng, Y.~K., Niarchos, Panagiotis, Puttmann, M., Szeifert, T., Spiller, F., van Dijk, R., Vogt, Nikolaus, Wanders, I., Sterken, Christiaan, Manfroid, Jean, Anton, K., Barzewski, A., Bibo, E., Bruch, A., Burger, David, Duerbeck, H.~W., Duemmler, R., Heck, Andre, Hensberge, Herman, Hiesgen, M., Inklaar, F., Jorissen, Alain, Juettner, A., Kinkel, U., Liu, Zhenan, Mekkaden, M.~V., Ng, Y.~K., Niarchos, Panagiotis, Puttmann, M., Szeifert, T., Spiller, F., van Dijk, R., Vogt, Nikolaus, and Wanders, I.
- Abstract
info:eu-repo/semantics/published
- Published
- 1993
18. α1-Acid glycoprotein decreases neutrophil migration and increases susceptibility to sepsis in diabetic mice.
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Spiller F, Carlos D, Souto FO, de Freitas A, Soares FS, Vieira SM, Paula FJ, Alves-Filho JC, Cunha FQ, Spiller, Fernando, Carlos, Daniela, Souto, Fabrício O, de Freitas, Andressa, Soares, Fernanda S, Vieira, Silvio M, Paula, Francisco J A, Alves-Filho, José C, and Cunha, Fernando Q
- Abstract
The mechanisms underlying immune deficiency in diabetes are largely unknown. In the present study, we demonstrate that diabetic mice are highly susceptible to polymicrobial sepsis due to reduction in rolling, adhesion, and migration of leukocytes to the focus of infection. In addition, after sepsis induction, CXCR2 was strongly downregulated in neutrophils from diabetic mice compared with nondiabetic mice. Furthermore, CXCR2 downregulation was associated with increased G-protein-coupled receptor kinase 2 (GRK2) expression in these cells. Different from nondiabetic mice, diabetic animals submitted to mild sepsis displayed a significant augment in α1-acid glycoprotein (AGP) hepatic mRNA expression and serum protein levels. Administration of AGP in nondiabetic mice subjected to mild sepsis inhibited the neutrophil migration to the focus of infection, as well as induced l-selectin shedding and rise in CD11b of blood neutrophils. Insulin treatment of diabetic mice reduced mortality rate, prevented the failure of neutrophil migration, impaired GRK2-mediated CXCR2 downregulation, and decreased the generation of AGP. Finally, administration of AGP abolished the effect of insulin treatment in diabetic mice. Together, these data suggest that AGP may be involved in reduction of neutrophil migration and increased susceptibility to sepsis in diabetic mice. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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19. Inhibition of neutrophil migration by hemopexin leads to increased mortality due to sepsis in mice.
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Spiller F, Costa C, Souto FO, Vinchi F, Mestriner FL, Laure HJ, Alves-Filho JC, Freitas A, Rosa JC, Ferreira SH, Altruda F, Hirsch E, Greene LJ, Tolosano E, and Cunha FQ
- Abstract
RATIONALE: The reduction of neutrophil migration to the bacterial focus is associated with poor outcome in sepsis. OBJECTIVES: The objective of this study was to identify soluble substances in the blood of septic mice that inhibit neutrophil migration. METHODS: A pool of serum obtained from mice 2 hours after the induction of severe sepsis by cecal ligation and puncture inhibited the neutrophil migration. The proteins with inhibitory activity on neutrophil migration were isolated by Blue-Sepharose chromatography, high-performance liquid chromatography, and electrophoresis, and identified by mass spectrometry. MEASUREMENTS AND MAIN RESULTS: Hemopexin was identified as the serum component responsible for the inhibition of neutrophil migration. In sepsis, the pretreatment of wild-type mice with hemopexin inhibited neutrophil migration to the focus of infection and decreased the survival rate from 87.5 to 50.0%. Hemopexin-null mice subjected to severe sepsis presented normal neutrophil migration, low bacteremia, and an improvement of 40% in survival rate. Moreover, hemopexin inhibited the neutrophil chemotaxis response evoked by C5a or macrophage inflammatory protein-2 and induced a reduction of CXCR2 and L-selectin as well as the up-regulation of CD11b expression in neutrophil membranes. The inhibitory effect of hemopexin on neutrophil chemotaxis was prevented by serine protease inhibitors or ATP. In addition, serum levels of ATP were decreased 2 hours after severe sepsis. CONCLUSIONS: These data demonstrate for the first time the inhibitory role of hemopexin in neutrophil migration during sepsis and suggest that the therapeutic inhibition of hemopexin or its protease activity could improve neutrophil migration to the focus of infection and survival in sepsis. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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20. RENOVATING OLD COTTON LANDS.--No. III.
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SPILLER, F. A.
- Published
- 1867
21. Enterococcus faecalis: implications for host health.
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Boeder AM, Spiller F, Carlstrom M, and Izídio GS
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- Humans, Animals, Gastrointestinal Microbiome, Gram-Positive Bacterial Infections microbiology, Anti-Bacterial Agents pharmacology, Host-Pathogen Interactions, Gastrointestinal Tract microbiology, Host Microbial Interactions, Enterococcus faecalis, Probiotics
- Abstract
The microbiota represents a crucial area of research in maintaining human health due to its potential for uncovering novel biomarkers, therapies, and molecular mechanisms relevant to population identification and experimental model characterization. Among these microorganisms, Enterococcus faecalis, a Gram-positive bacterium found in the gastrointestinal tract of humans and animals, holds particular significance. Strains of this bacterial species have sparked considerable debate in the literature due to their dual nature; they can either be utilized as probiotics in the food industry or demonstrate resistance to antibiotics, potentially leading to severe illness, disability, and death. Given the diverse characteristics of Enterococcus faecalis strains, this review aims to provide a comprehensive understanding of their impact on various systems within the host, including the immunological, cardiovascular, metabolic, and nervous systems. Furthermore, we summarize the bacterium-host interaction characteristics and molecular effects to highlight their targets, features, and overall impact on microbial communities and host health., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)
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- 2024
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22. Cannabinoid CB 2 receptor agonist reduces local and systemic inflammation associated with pneumonia-induced sepsis in mice.
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Souza CF, Borges LB, Oliveira FRMB, Silva PCS, Patricio DO, Rosales TO, Souza NF, Spiller F, Mansur DS, Assreuy J, and Sordi R
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- Female, Mice, Male, Animals, Cannabinoid Receptor Agonists pharmacology, Inflammation drug therapy, Inflammation metabolism, Receptors, Cannabinoid, Receptor, Cannabinoid, CB2, Receptor, Cannabinoid, CB1, Pneumonia drug therapy, Cannabinoids pharmacology, Sepsis complications, Sepsis drug therapy, Sepsis metabolism
- Abstract
Sepsis is a severe condition secondary to dysregulated host response to infection leading to tissue damage and organ dysfunction. Cannabinoid CB
2 receptor has modulatory effects on the immune response. Therefore, this study investigated the effects of a cannabinoid CB2 receptor agonist on the local and systemic inflammatory process associated with pneumonia-induced sepsis. Pneumonia-induced sepsis was induced in mice by intratracheal inoculation of Klebsiella pneumoniae. Tissue and bronchoalveolar lavage (BAL) were collected 6, 24, or 48 h after surgery. Mice were treated with CB2 agonist (AM1241, 0.3 and 3 mg/kg, i.p.) and several parameters of inflammation were evaluated 24 h after sepsis induction. Polymorphonuclear cell migration to the infectious focus peaked 24 h after pneumonia-induced sepsis induction in male and female animals. Septic male mice presented a significant reduction of cannabinoid CB2 receptor density in the lung tissue after 24 h, which was not observed in females. CB2 expression in BAL macrophages was also reduced in septic animals. Treatment of septic mice with AM1241 reduced cell migration, local infection, myeloperoxidase activity, protein extravasation, and NOS-2 expression in the lungs. In addition, the treatment reduced plasma IL-1β, increased IL-10 and reduced the severity and mortality of septic animals. These results suggest that AM1241 promotes an interesting balance in the inflammatory response, maintaining lung function and preventing organ injury. Therefore, cannabinoid CB2 receptors are potential targets to control the excessive inflammatory process that occurs in severe conditions, and agonists of these receptors can be considered promising adjuvants in pneumonia-induced sepsis treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)- Published
- 2023
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23. Neuraminidase is a host-directed approach to regulate neutrophil responses in sepsis and COVID-19.
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de Oliveira Formiga R, Amaral FC, Souza CF, Mendes DAGB, Wanderley CWS, Lorenzini CB, Santos AA, Antônia J, Faria LF, Natale CC, Paula NM, Silva PCS, Fonseca FR, Aires L, Heck N, Starick MR, Queiroz-Junior CM, Santos FRS, de Souza FRO, Costa VV, Barroso SPC, Morrot A, Van Weyenbergh J, Sordi R, Alisson-Silva F, Cunha FQ, Rocha EL, Chollet-Martin S, Hurtado-Nedelec MM, Martin C, Burgel PR, Mansur DS, Maurici R, Macauley MS, Báfica A, Witko-Sarsat V, and Spiller F
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- Humans, Mice, Animals, Oseltamivir adverse effects, Zanamivir adverse effects, Neuraminidase metabolism, Neuraminidase pharmacology, Neutrophils, Matrix Metalloproteinase 9 metabolism, Reactive Oxygen Species, Lipopolysaccharides pharmacology, COVID-19, Sepsis chemically induced
- Abstract
Background and Purpose: Neutrophil overstimulation plays a crucial role in tissue damage during severe infections. Because pathogen-derived neuraminidase (NEU) stimulates neutrophils, we investigated whether host NEU can be targeted to regulate the neutrophil dysregulation observed in severe infections., Experimental Approach: The effects of NEU inhibitors on lipopolysaccharide (LPS)-stimulated neutrophils from healthy donors or COVID-19 patients were determined by evaluating the shedding of surface sialic acids, cell activation, and reactive oxygen species (ROS) production. Re-analysis of single-cell RNA sequencing of respiratory tract samples from COVID-19 patients also was carried out. The effects of oseltamivir on sepsis and betacoronavirus-induced acute lung injury were evaluated in murine models., Key Results: Oseltamivir and zanamivir constrained host NEU activity, surface sialic acid release, cell activation, and ROS production by LPS-activated human neutrophils. Mechanistically, LPS increased the interaction of NEU1 with matrix metalloproteinase 9 (MMP-9). Inhibition of MMP-9 prevented LPS-induced NEU activity and neutrophil response. In vivo, treatment with oseltamivir fine-tuned neutrophil migration and improved infection control as well as host survival in peritonitis and pneumonia sepsis. NEU1 also is highly expressed in neutrophils from COVID-19 patients, and treatment of whole-blood samples from these patients with either oseltamivir or zanamivir reduced neutrophil overactivation. Oseltamivir treatment of intranasally infected mice with the mouse hepatitis coronavirus 3 (MHV-3) decreased lung neutrophil infiltration, viral load, and tissue damage., Conclusion and Implications: These findings suggest that interplay of NEU1-MMP-9 induces neutrophil overactivation. In vivo, NEU may serve as a host-directed target to dampen neutrophil dysfunction during severe infections., (© 2022 British Pharmacological Society.)
- Published
- 2023
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24. Chitosan/genipin modified electrode for voltammetric determination of interleukin-6 as a biomarker of sepsis.
- Author
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de Matos Morawski F, Dias GBM, Sousa KAP, Formiga R, Spiller F, Parize AL, Báfica A, and Jost CL
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- Animals, Mice, Interleukin-6, Electrochemical Techniques methods, Biomarkers, Electrodes, Immunoassay methods, Limit of Detection, Chitosan, Biosensing Techniques methods, Sepsis
- Abstract
Ultrasensitive electroanalytical monitoring of interleukin-6 levels in serum samples has emerged as a valuable tool for the early diagnosis of inflammatory diseases. Despite its advantages, there is a lack of strategies for the label-free voltammetric determination of cytokines. Here, a novel chitosan/genipin modified fluorine tin oxide electrode was developed providing an in-situ hydrogel formation (FTO/CSG). This platform was applied for the detection of interleukin-6, a major pro-inflammatory cytokine. Transmission electron microscopy (TEM), cyclic voltammetry (CV), and electrochemical impedance spectroscopy (EIS) indicated genipin serves as an efficient green cross-linker to build the immunosensing platform (FTO/CSG/anti-IL-6). EIS showed an increase in charge transfer resistance from 326 to 1360 kΩ after the immobilization of anti-IL-6 antibodies. By square wave voltammetry, this method achieved a detection limit of 0.03 pg mL
-1 with a wide linear range of 0.05-1000 pg mL-1 . Additionally, it displayed a high selectivity index when tested in the presence of three inflammatory cytokines as interfering proteins: IL-12, IL-1β, and TNF-α. The sample matrix effect showed a peak current variation lower than 5 %. The novel method was applied for the quantification of IL-6 in serum samples of septic mice. No statistical differences were observed between the standard ELISA and the proposed method using a confidence level of 95 %., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)- Published
- 2023
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25. Neuraminidase inhibitors rewire neutrophil function in vivo in murine sepsis and ex vivo in COVID-19.
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de Oliveira Formiga R, Amaral FC, Souza CF, Mendes DAGB, Wanderley CWS, Lorenzini CB, Santos AA, Antônia J, Faria LF, Natale CC, Paula NM, Silva PCS, Fonseca FR, Aires L, Heck N, Starick MR, Queiroz-Junior CM, Santos FRS, de Souza FRO, Costa VV, Barroso SPC, Morrot A, Van Weyenbergh J, Sordi R, Alisson-Silva F, Cunha FQ, Rocha EL, Chollet-Martin S, Hurtado-Nedelec MM, Martin C, Burgel PR, Mansur DS, Maurici R, Macauley MS, Báfica A, Witko-Sarsat V, and Spiller F
- Abstract
Neutrophil overstimulation plays a crucial role in tissue damage during severe infections. Neuraminidase (NEU)-mediated cleavage of surface sialic acid has been demonstrated to regulate leukocyte responses. Here, we report that antiviral NEU inhibitors constrain host NEU activity, surface sialic acid release, ROS production, and NETs released by microbial-activated human neutrophils. In vivo , treatment with Oseltamivir results in infection control and host survival in peritonitis and pneumonia models of sepsis. Single-cell RNA sequencing re-analysis of publicly data sets of respiratory tract samples from critical COVID-19 patients revealed an overexpression of NEU1 in infiltrated neutrophils. Moreover, Oseltamivir or Zanamivir treatment of whole blood cells from severe COVID-19 patients reduces host NEU-mediated shedding of cell surface sialic acid and neutrophil overactivation. These findings suggest that neuraminidase inhibitors can serve as host-directed interventions to dampen neutrophil dysfunction in severe infections., Competing Interests: Competing Interests statement The authors declare that no conflict of interest exists.
- Published
- 2022
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26. Role of toll-like receptor 4 and sex in 6-hydroxydopamine-induced behavioral impairments and neurodegeneration in mice.
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Somensi N, Lopes SC, Gasparotto J, Mayer Gonçalves R, Tiefensee-Ribeiro C, Oppermann Peixoto D, Ozorio Brum P, Pinho CM, Agnes JP, Santos L, de Oliveira J, Spiller F, Fonseca Moreira JC, Zanotto-Filho A, Prediger RD, and Pens Gelain D
- Subjects
- Animals, Brain pathology, Disease Models, Animal, Female, Hydroxydopamines pharmacology, Mice, Inbred C57BL, Mice, Transgenic, Microglia drug effects, Nerve Degeneration chemically induced, Neurodegenerative Diseases chemically induced, Neurodegenerative Diseases pathology, Parkinson Disease genetics, Toll-Like Receptor 4 drug effects, Toll-Like Receptor 4 genetics, Mice, Brain drug effects, Parkinson Disease drug therapy, Sex Factors, Toll-Like Receptor 4 metabolism
- Abstract
Parkinson's disease (PD) is a neurodegenerative disease characterized by progressive loss of the nigrostriatal dopaminergic neurons that are associated with motor alterations and non-motor manifestations (such as depression). Neuroinflammation is a process with a critical role in the pathogenesis of PD. In this regard, toll-like receptor 4 (TLR4) is a central mediator of immune response in PD. Moreover, there are gender-related differences in the incidence, prevalence, and clinical features of PD. Therefore, we aimed to elucidate the role of TLR4 in the sex-dependent response to dopaminergic denervation induced by 6-hydroxydopamine (6-OHDA) in mice. Female and male adult wildtype (WT) and TLR4 knockout (TLR4
-/- ) mice were administered with unilateral injection of 6-OHDA in the dorsal striatum, and non-motor and motor impairments were evaluated for 30 days, followed by biochemistry analysis in the substantia nigra pars compacta (SNc), dorsal striatum, and dorsoventral cortex. Early non-motor impairments (i.e., depressive-like behavior and spatial learning deficits) induced by 6-OHDA were observed in the male WT mice but not in male TLR4-/- or female mice. Motor alterations were observed after administration of 6-OHDA in both strains, and the lack of TLR4 was also related to motor commitment. Moreover, ablation of TLR4 prevented 6-OHDA-induced dopaminergic denervation and microgliosis in the SNc, selectively in female mice. These results reinforced the existence of sex-biased alterations in PD and indicated TLR4 as a promising therapeutic target for the motor and non-motor symptoms of PD, which will help counteract the neuroinflammatory and neurodegenerative processes., (Copyright © 2021 Elsevier Ltd. All rights reserved.)- Published
- 2021
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27. Antioxidants Improve Oxaliplatin-Induced Peripheral Neuropathy in Tumor-Bearing Mice Model: Role of Spinal Cord Oxidative Stress and Inflammation.
- Author
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Agnes JP, Santos VWD, das Neves RN, Gonçalves RM, Delgobo M, Girardi CS, Lückemeyer DD, Ferreira MA, Macedo-Júnior SJ, Lopes SC, Spiller F, Gelain DP, Moreira JCF, Prediger RD, Ferreira J, and Zanotto-Filho A
- Subjects
- Animals, Disease Models, Animal, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Toll-Like Receptor 4, Antineoplastic Agents adverse effects, Antioxidants pharmacology, Hyperalgesia chemically induced, Hyperalgesia drug therapy, Hyperalgesia prevention & control, Neoplasms drug therapy, Neuroinflammatory Diseases chemically induced, Neuroinflammatory Diseases drug therapy, Neuroinflammatory Diseases immunology, Neuroinflammatory Diseases metabolism, Oxaliplatin adverse effects, Oxidative Stress drug effects, Peripheral Nervous System Diseases chemically induced, Peripheral Nervous System Diseases drug therapy, Peripheral Nervous System Diseases prevention & control, Spinal Cord drug effects, Spinal Cord immunology, Spinal Cord metabolism
- Abstract
Chemotherapy-Induced Peripheral Neuropathy (CIPN) is a common, difficult-to-treat, and dose-limiting side effect associated with Oxaliplatin (OXA) treatment. In this study, we evaluated the effect of three antioxidants - namely N-acetylcysteine, α-lipoic acid and vitamin E - upon nociceptive parameters and antitumor efficacy of OXA in a tumor-bearing Swiss mice model. Oral treatment with antioxidants inhibited both mechanical and cold allodynia when concomitantly administrated with OXA (preventive protocol), as well as in animals with previously established CIPN (therapeutic protocol). OXA increased Reactive Oxygen Species (ROS) production and lipoperoxidation, and augmented the content of pro-inflammatory cytokines (IL-1β and TNF-α) and expression of the astrocytic marker Gfap mRNA in the spinal cord. Antioxidants decreased ROS production and lipoperoxidation, and abolished neuroinflammation in OXA-treated animals. Toll-like receptor 4 (Tlr4) and inflammasome enzyme caspase-1/11 knockout mice treated with OXA showed reduced levels of pro-inflammatory cytokines (but not oxidative stress) in the spinal cord, which were associated with resistance to OXA-induced mechanical allodynia. Lastly, antioxidants affected neither antitumor activity nor hematological toxicity of OXA in vivo. The herein presented results are provocative for further evaluation of antioxidants in clinical management of chemotherapy-induced peripheral neuropathy. PERSPECTIVE: This study reports preventive and therapeutic efficacy of orally administrated antioxidants (N-acetylcysteine, α-lipoic-acid and Vitamin-E) in alleviating oxaliplatin-induced peripheral neuropathy in tumor-bearing mice. Antioxidants' anti-nociceptive effects are associated with inhibition of ROS-dependent neuroinflammation, and occur at no detriment of OXA antitumor activity, therefore indicating a translational potential of these compounds., (Copyright © 2021 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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28. Effect of p-cymene and rosmarinic acid on gastric ulcer healing - Involvement of multiple endogenous curative mechanisms.
- Author
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Formiga RO, Alves Júnior EB, Vasconcelos RC, Araújo AA, de Carvalho TG, de Araújo Junior RF, Guerra GBC, Vieira GC, de Oliveira KM, Diniz MFFM, Sobral MV, Barbosa Filho JM, Spiller F, and Batista LM
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- Animals, Anti-Inflammatory Agents therapeutic use, Antioxidants therapeutic use, Male, Plants, Medicinal, Rats, Rats, Wistar, Rosmarinic Acid, Anti-Ulcer Agents therapeutic use, Cinnamates therapeutic use, Cymenes therapeutic use, Depsides therapeutic use, Stomach Ulcer drug therapy
- Abstract
Background: p-Cymene and rosmarinic acid are secondary metabolites found in several medicinal plants and spices. Previous studies have demonstrated their anti-inflammatory, antioxidant, and cytoprotective effects., Purpose: To evaluate their gastroduodenal antiulcer activity, gastric healing and toxicity in experimental models., Methods: Preventive antiulcer effects were assessed using oral pre-treatment on HCl/ethanol-induced gastric lesions and cysteamine-induced duodenal lesions models. Gastric healing, the underlining mechanisms and toxicity after repeated doses were carried out using the acetic acid-induced gastric ulcer rat model and oral treatment for 14 days., Results: In the HCl/ethanol-induced gastric ulcer and cysteamine-induced duodenal injury, p-cymene and rosmarinic acid (50-200 mg/kg) decreased significantly the ulcer area, and so prevented lesions formation. In the acetic acid-induced ulcer model, both compounds (200 mg/kg) markedly reduced the ulcerative injury. These effects were related to an increase in the levels of reduced glutathione (GSH) and interleukin (IL)-10, and due to a decrease in malondialdehyde (MDA), IL-1β, tumor necrosis factor (TNF)-α, total and mitochondrial reactive oxygen species (ROS) levels. Downregulation of factor nuclear kappa B (NFκB) and enhanced expression of suppressor of cytokine signaling (SOCS)3 were also demonstrated. Furthermore, positive vascular endothelial growth factor (VEGF), metalloproteinase (MMP)-2, and cyclooxygenase (COX-2)-stained cells were increased in treated groups. Treatment also upregulated the platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF), transforming growth factor (TGF)-β and epidermal growth factor receptor (EGFR) in gastric tissues. In isolated gastric epithelial cells this healing effect seems to be linked to a modulation of apoptosis, proliferation, survival and protein phosphorylation, such as the extracellular signal-regulated kinases (ERK)1/2 and p38 mitogen-activated protein kinase (MAPK). Oral toxicity investigation for 14 days revealed no alterations in heart, liver, spleen, and kidneys weight nor the biochemical and hematological assessed parameters. p-Cymene and rosmarinic acid also protected animals from body weight loss maintaining feed and water intake., Conclusions: Data altogether suggest low toxicity, antiulcer and gastric healing activities of p-cymene and rosmarinic acid. Antioxidant and immunomodulatory properties seem to be involved in the curative effect as well as the induction of different factors linked to tissue repair., (Copyright © 2021. Published by Elsevier GmbH.)
- Published
- 2021
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29. p -Cymene and Rosmarinic Acid Ameliorate TNBS-Induced Intestinal Inflammation Upkeeping ZO-1 and MUC-2: Role of Antioxidant System and Immunomodulation.
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Formiga RO, Alves Júnior EB, Vasconcelos RC, Guerra GCB, Antunes de Araújo A, Carvalho TG, Garcia VB, de Araújo Junior RF, Gadelha FAAF, Vieira GC, Sobral MV, Barbosa Filho JM, Spiller F, and Batista LM
- Subjects
- Animals, Antioxidants pharmacology, Antioxidants therapeutic use, Cinnamates pharmacology, Cyclooxygenase 2 genetics, Cyclooxygenase 2 metabolism, Cymenes pharmacology, Depsides pharmacology, Immunologic Factors pharmacology, Immunologic Factors therapeutic use, Interferon-gamma genetics, Interferon-gamma metabolism, Interleukins genetics, Interleukins metabolism, Intestinal Mucosa drug effects, Intestinal Mucosa metabolism, Mucin-2 genetics, NF-kappa B genetics, NF-kappa B metabolism, Nitric Oxide Synthase Type II genetics, Nitric Oxide Synthase Type II metabolism, Rats, Rats, Wistar, T-Lymphocytes metabolism, Tumor Necrosis Factor-alpha genetics, Tumor Necrosis Factor-alpha metabolism, Zonula Occludens-1 Protein genetics, Rosmarinic Acid, Anti-Inflammatory Agents, Non-Steroidal therapeutic use, Cinnamates therapeutic use, Colitis, Ulcerative drug therapy, Cymenes therapeutic use, Depsides therapeutic use, Mucin-2 metabolism, Zonula Occludens-1 Protein metabolism
- Abstract
p -Cymene ( p -C) and rosmarinic acid (RA) are secondary metabolites that are present in medicinal herbs and Mediterranean spices that have promising anti-inflammatory properties. This study aimed to evaluate their intestinal anti-inflammatory activity in the trinitrobenzene sulphonic acid (TNBS)-induced colitis model in rats. p -C and RA (25-200 mg/kg) oral administration reduced the macroscopic lesion score, ulcerative area, intestinal weight/length ratio, and diarrheal index in TNBS-treated animals. Both compounds (200 mg/kg) decreased malondialdehyde (MDA) and myeloperoxidase (MPO), restored glutathione (GSH) levels, and enhanced fluorescence intensity of superoxide dismutase (SOD). They also decreased interleukin (IL)-1β and tumor necrosis factor (TNF)-α, and maintained IL-10 basal levels. Furthermore, they modulated T cell populations (cluster of differentiation (CD)4
+ , CD8+ , or CD3+ CD4+ CD25+ ) analyzed from the spleen, mesenteric lymph nodes, and colon samples, and also decreased cyclooxigenase 2 (COX-2), interferon (IFN)-γ, inducible nitric oxide synthase (iNOS), and nuclear transcription factor kappa B subunit p65 (NFκB-p65) mRNA transcription, but only p -C interfered in the suppressor of cytokine signaling 3 (SOCS3) expression in inflamed colons. An increase in gene expression and positive cells immunostained for mucin type 2 (MUC-2) and zonula occludens 1 (ZO-1) was observed. Altogether, these results indicate intestinal anti-inflammatory activity of p -C and RA involving the cytoprotection of the intestinal barrier, maintaining the mucus layer, and preserving communicating junctions, as well as through modulation of the antioxidant and immunomodulatory systems.- Published
- 2020
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30. Targeting nitric oxide as a key modulator of sepsis, arthritis and pain.
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Spiller F, Oliveira Formiga R, Fernandes da Silva Coimbra J, Alves-Filho JC, Cunha TM, and Cunha FQ
- Subjects
- Animals, Humans, Inflammation physiopathology, Neutrophils physiology, Nitric Oxide Synthase Type II metabolism, Arthritis, Rheumatoid physiopathology, Nitric Oxide metabolism, Pain physiopathology, Sepsis physiopathology
- Abstract
Nitric oxide (NO) is produced by enzymatic activity of neuronal (nNOS), endothelial (eNOS), and inducible nitric oxide synthase (iNOS) and modulates a broad spectrum of physiological and pathophysiological conditions. The iNOS isoform is positively regulated at transcriptional level and produces high levels of NO in response to inflammatory mediators and/or to pattern recognition receptor signaling, such as Toll-like receptors. In this review, we compiled the main contributions of our group for understanding of the role of NO in sepsis and arthritis outcome and the peripheral contributions of NO to inflammatory pain development. Although neutrophil iNOS-derived NO is necessary for bacterial killing, systemic production of high levels of NO impairs neutrophil migration to infections through inhibiting neutrophil adhesion on microcirculation and their locomotion. Moreover, neutrophil-derived NO contributes to multiple organ dysfunction in sepsis. In arthritis, NO is chief for bacterial clearance in staphylococcal-induced arthritis; however, it contributes to articular damage and bone mass degradation. NO produced in inflammatory sites also downmodulates pain. The mechanism involved in analgesic effect and inhibition of neutrophil migration is dependent on the activation of the classical sGC/cGMP/PKG pathway. Despite the increasing number of studies performed after the identification of NO as an endothelium-derived relaxing factor, the underlying mechanisms of NO in inflammatory diseases remain unclear., (Copyright © 2019. Published by Elsevier Inc.)
- Published
- 2019
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31. Murine Red Blood Cells Lack Ligands for B Cell Siglecs, Allowing Strong Activation by Erythrocyte Surface Antigens.
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Spiller F, Nycholat CM, Kikuchi C, Paulson JC, and Macauley MS
- Subjects
- Animals, Apoptosis immunology, B-Lymphocytes metabolism, CHO Cells, Cell Line, Cricetulus, Mice, Mice, Inbred C57BL, Mice, Knockout, Muramidase genetics, Muramidase immunology, Muramidase metabolism, Receptors, Antigen, B-Cell immunology, Sialic Acid Binding Ig-like Lectin 2 genetics, Sialic Acids immunology, Antigens, Surface immunology, B-Lymphocytes immunology, Erythrocytes immunology, Immune Tolerance immunology, Lymphocyte Activation immunology, Sialic Acid Binding Ig-like Lectin 2 immunology, Sialic Acid Binding Immunoglobulin-like Lectins immunology
- Abstract
CD22 and sialic acid-binding Ig-like lectin (Siglec)-G are members of the Siglec family of inhibitory coreceptors expressed on B cells that participate in enforcement of peripheral B cell tolerance. We have shown previously that when a BCR engages its cognate Ag on a cell surface that also expresses Siglec ligands, B cell Siglecs are recruited to the immunological synapse, resulting in suppression of BCR signaling and B cell apoptosis. Because all cells display sialic acids, and CD22 and Siglec-G have distinct, yet overlapping, specificities for sialic acid-containing glycan ligands, any cell could, in principle, invoke this tolerogenic mechanism for cell surface Ags. However, we show in this article that C57BL/6J mouse RBCs are essentially devoid of CD22 and Siglec-G ligands. As a consequence, RBCs that display a cell surface Ag, membrane-bound hen egg lysozyme, strongly activate Ag-specific B cells. We reasoned that de novo introduction of CD22 ligands in RBCs should abolish B cell activation toward its cognate Ag on the surface of RBCs. Accordingly, we used a glyco-engineering approach wherein synthetic CD22 ligands linked to lipids are inserted into the membrane of RBCs. Indeed, insertion of CD22 ligands into the RBC cell surface strongly inhibited B cell activation, cytokine secretion, and proliferation. These results demonstrate that the lack of Siglec ligands on the surface of murine RBCs permits B cell responses to erythrocyte Ags and show that Siglec-mediated B cell tolerance is restricted to cell types that express glycan ligands for the B cell Siglecs., (Copyright © 2018 by The American Association of Immunologists, Inc.)
- Published
- 2018
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32. Antibiotic-Induced Pathobiont Dissemination Accelerates Mortality in Severe Experimental Pancreatitis.
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Soares FS, Amaral FC, Silva NLC, Valente MR, Santos LKR, Yamashiro LH, Scheffer MC, Castanheira FVES, Ferreira RG, Gehrke L, Alves-Filho JC, Silva LP, Báfica A, and Spiller F
- Abstract
Although antibiotic-induced dysbiosis has been demonstrated to exacerbate intestinal inflammation, it has been suggested that antibiotic prophylaxis may be beneficial in certain clinical conditions such as acute pancreatitis (AP). However, whether broad-spectrum antibiotics, such as meropenem, influence the dissemination of multidrug-resistant (MDR) bacteria during severe AP has not been addressed. In the currently study, a mouse model of obstructive severe AP was employed to investigate the effects of pretreatment with meropenem on bacteria spreading and disease outcome. As expected, animals subjected to biliopancreatic duct obstruction developed severe AP. Surprisingly, pretreatment with meropenem accelerated the mortality of AP mice (survival median of 2 days) when compared to saline-pretreated AP mice (survival median of 7 days). Early mortality was associated with the translocation of MDR strains, mainly Enterococcus gallinarum into the blood stream. Induction of AP in mice with guts that were enriched with E. gallinarum recapitulated the increased mortality rate observed in the meropenem-pretreated AP mice. Furthermore, naïve mice challenged with a mouse or a clinical strain of E. gallinarum succumbed to infection through a mechanism involving toll-like receptor-2. These results confirm that broad-spectrum antibiotics may lead to indirect detrimental effects during inflammatory disease and reveal an intestinal pathobiont that is associated with the meropenem pretreatment during obstructive AP in mice.
- Published
- 2017
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33. Glucose homeostasis in two degrees of sepsis lethality induced by caecum ligation and puncture in mice.
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Ferreira FBD, Dos Santos C, Bruxel MA, Nunes EA, Spiller F, and Rafacho A
- Subjects
- Animals, Cecum surgery, Disease Models, Animal, Hypoglycemic Agents, Insulin Resistance, Ligation methods, Liver metabolism, Male, Mice, Punctures methods, Blood Glucose biosynthesis, Cecum metabolism, Homeostasis physiology, Sepsis mortality
- Abstract
Sepsis is associated with high mortality. Both critically ill humans and animal models of sepsis exhibit changes in their glucose homeostasis, that is, hypoglycaemia, with the progression of infection. However, the relationship between basal glycaemia, glucose tolerance and insulin sensitivity is not well understood. Thus, we aimed to evaluate this glucose homeostasis triad at the late stage of sepsis (24 h after surgery) in male Swiss mice subjected to lethal and sublethal sepsis by the caecal ligation and puncture (CLP) model. The percentage of survival 24 h after CLP procedure in the Lethal and Sublethal groups was around 66% and 100% respectively. Both Lethal and Sublethal groups became hypoglycaemic in fasting and fed states 24 h after surgery. The pronounced fed hypoglycaemia in the Lethal group was not due to worsening anorexic behaviour or hepatic inability to deliver glucose in relation to the Sublethal group. Reduction in insulin sensitivity in CLP mice occurred in a lethality-dependent manner and was not associated with glucose intolerance. Analysis of oral and intraperitoneal glucose tolerance tests, as well as the gastrointestinal motility data, indicated that CLP mice had reduced intestinal glucose absorption. Altogether, we suggest cessation of appetite and intestinal glucose malabsorption are key contributors to the hypoglycaemic state observed during experimental severe sepsis., (© 2017 The Authors. International Journal of Experimental Pathology © 2017 International Journal of Experimental Pathology.)
- Published
- 2017
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34. Molecular basis for Cdk1-regulated timing of Mis18 complex assembly and CENP-A deposition.
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Spiller F, Medina-Pritchard B, Abad MA, Wear MA, Molina O, Earnshaw WC, and Jeyaprakash AA
- Subjects
- Adaptor Proteins, Signal Transducing genetics, CDC2 Protein Kinase genetics, Cell Cycle genetics, Centromere genetics, Centromere physiology, Chromosomal Proteins, Non-Histone metabolism, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Humans, Nucleosomes, Phosphorylation, Protein Binding, Adaptor Proteins, Signal Transducing metabolism, CDC2 Protein Kinase metabolism, CDC2 Protein Kinase pharmacokinetics, Centromere Protein A metabolism, Gene Expression Regulation
- Abstract
The centromere, a chromosomal locus that acts as a microtubule attachment site, is epigenetically specified by the enrichment of CENP-A nucleosomes. Centromere maintenance during the cell cycle requires HJURP-mediated CENP-A deposition, a process regulated by the Mis18 complex (Mis18α/Mis18β/Mis18BP1). Spatial and temporal regulation of Mis18 complex assembly is crucial for its centromere association and function. Here, we provide the molecular basis for the assembly and regulation of the Mis18 complex. We show that the N-terminal region of Mis18BP1 spanning amino acid residues 20-130 directly interacts with Mis18α/β to form the Mis18 complex. Within Mis18α/β, the Mis18α MeDiY domain can directly interact with Mis18BP1. Mis18α/β forms a hetero-hexamer with 4 Mis18α and 2 Mis18β. However, only two copies of Mis18BP1 interact with Mis18α/β to form a hetero-octameric assembly, highlighting the role of Mis18 oligomerization in limiting the number of Mis18BP1 within the Mis18 complex. Furthermore, we demonstrate the involvement of consensus Cdk1 phosphorylation sites on Mis18 complex assembly and thus provide a rationale for cell cycle-regulated timing of Mis18 assembly and CENP-A deposition., (© 2017 The Authors. Published under the terms of the CC BY 4.0 license.)
- Published
- 2017
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35. Centromere localization and function of Mis18 requires Yippee-like domain-mediated oligomerization.
- Author
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Subramanian L, Medina-Pritchard B, Barton R, Spiller F, Kulasegaran-Shylini R, Radaviciute G, Allshire RC, and Arockia Jeyaprakash A
- Subjects
- Carrier Proteins genetics, Centromere genetics, Chromosomal Proteins, Non-Histone genetics, Chromosomal Proteins, Non-Histone metabolism, Crystallography, X-Ray, DNA-Binding Proteins chemistry, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Epigenesis, Genetic, Molecular Chaperones genetics, Molecular Chaperones metabolism, Protein Domains, Protein Multimerization, Schizosaccharomyces genetics, Schizosaccharomyces metabolism, Schizosaccharomyces pombe Proteins genetics, Carrier Proteins chemistry, Carrier Proteins metabolism, Centromere physiology, Schizosaccharomyces pombe Proteins chemistry, Schizosaccharomyces pombe Proteins metabolism
- Abstract
Mis18 is a key regulator responsible for the centromere localization of the CENP-A chaperone Scm3 in Schizosaccharomyces pombe and HJURP in humans, which establishes CENP-A chromatin that defines centromeres. The molecular and structural determinants of Mis18 centromere targeting remain elusive. Here, by combining structural, biochemical, and yeast genetic studies, we show that the oligomerization of S. pombe Mis18, mediated via its conserved N-terminal Yippee-like domain, is crucial for its centromere localization and function. The crystal structure of the N-terminal Yippee-like domain reveals a fold containing a cradle-shaped pocket that is implicated in protein/nucleic acid binding, which we show is required for Mis18 function. While the N-terminal Yippee-like domain forms a homodimer in vitro and in vivo, full-length Mis18, including the C-terminal α-helical domain, forms a homotetramer in vitro We also show that the Yippee-like domains of human Mis18α/Mis18β interact to form a heterodimer, implying a conserved structural theme for Mis18 regulation., (© 2016 The Authors. Published under the terms of the CC BY 4.0 license.)
- Published
- 2016
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36. MyD88-, but not Nod1- and/or Nod2-deficient mice, show increased susceptibility to polymicrobial sepsis due to impaired local inflammatory response.
- Author
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Sônego F, Castanheira FV, Czaikoski PG, Kanashiro A, Souto FO, França RO, Nascimento DC, Freitas A, Spiller F, Cunha LD, Zamboni DS, Alves-Filho JC, and Cunha FQ
- Subjects
- Animals, Disease Models, Animal, Female, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Myeloid Differentiation Factor 88 genetics, Nod1 Signaling Adaptor Protein genetics, Nod2 Signaling Adaptor Protein genetics, Receptor-Interacting Protein Serine-Threonine Kinase 2, Receptor-Interacting Protein Serine-Threonine Kinases genetics, Receptor-Interacting Protein Serine-Threonine Kinases metabolism, Sepsis genetics, Myeloid Differentiation Factor 88 metabolism, Nod1 Signaling Adaptor Protein metabolism, Nod2 Signaling Adaptor Protein metabolism, Sepsis metabolism
- Abstract
Pathogen recognition and triggering of the inflammatory response following infection in mammals depend mainly on Toll-like and Nod-like receptors. Here, we evaluated the role of Nod1, Nod2 and MyD88-dependent signaling in the chemokine production and neutrophil recruitment to the infectious site during sepsis induced by cecal ligation and puncture (CLP) in C57Bl/6 mice. We demonstrate that Nod1 and Nod2 are not involved in the release of chemokines and recruitment of neutrophils to the infectious site during CLP-induced septic peritonitis because these events were similar in wild-type, Nod1-, Nod2-, Nod1/Nod2- and Rip2-deficient mice. Consequently, the local and systemic bacterial loads were not altered. Accordingly, neither Nod1 nor Nod2 was involved in the production of the circulating cytokines and in the accumulation of leukocytes in the lungs. By contrast, we showed that MyD88-dependent signaling is crucial for the establishment of the local inflammatory response during CLP-induced sepsis. MyD88-deficient mice were susceptible to sepsis because of an impaired local production of chemokines and defective neutrophil recruitment to the infection site. Altogether, these data show that Nod1, Nod2 and Rip2 are not required for local chemokine production and neutrophil recruitment during CLP-induced sepsis, and they reinforce the importance of MyD88-dependent signaling for initiation of a protective host response.
- Published
- 2014
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37. Possible mechanisms of neutrophil activation in Behçet's disease.
- Author
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Neves FS and Spiller F
- Subjects
- Animals, Granulocyte Colony-Stimulating Factor immunology, Granulocyte-Macrophage Colony-Stimulating Factor immunology, Humans, Interferon Type I immunology, Interleukin-8 immunology, Th17 Cells immunology, Toll-Like Receptors immunology, Behcet Syndrome immunology, Neutrophil Activation, Neutrophils immunology
- Abstract
Behçet's disease (BD) is a systemic inflammatory disorder characterized by recurrent episodes of acute inflammation consisting mainly of neutrophil infiltration around blood vessels in affected tissues. BD probably occurs due to neutrophil-based innate immune responses orchestrated by a complex interplay among gamma-delta T lymphocytes, natural killer T cells, monocytes and Th17 lymphocytes in which type-I interferon is possibly a key element for inflammatory downregulation. However, strong evidence is still scarce. This article compiles the literature in an attempt to summarize the possible mechanisms by which neutrophils are activated in BD and suggests directions for future research., (© 2013 Elsevier B.V. All rights reserved.)
- Published
- 2013
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38. WITHDRAWN: Neutrophil activation in Behçet's Disease.
- Author
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Neves FS and Spiller F
- Abstract
The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.intimp.2013.07.017. The duplicate article has therefore been withdrawn., (Copyright © 2013 Elsevier B.V. All rights reserved.)
- Published
- 2013
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39. Histamine h2 receptor signaling in the pathogenesis of sepsis: studies in a murine diabetes model.
- Author
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Carlos D, Spiller F, Souto FO, Trevelin SC, Borges VF, de Freitas A, Alves-Filho JC, Silva JS, Ryffel B, and Cunha FQ
- Subjects
- Alloxan, Animals, Bacteremia drug therapy, Cell Movement, Diabetes Mellitus, Experimental complications, Diabetes Mellitus, Experimental microbiology, Down-Regulation drug effects, Female, Histamine metabolism, Histamine H2 Antagonists, Inflammation drug therapy, Mice, Mice, Inbred BALB C, Mice, Inbred NOD, Receptors, Histamine H2 metabolism, Sepsis complications, Sepsis microbiology, Sepsis mortality, Up-Regulation drug effects, p-Methoxy-N-methylphenethylamine pharmacology, Diabetes Mellitus, Experimental mortality, G-Protein-Coupled Receptor Kinase 2 metabolism, Mast Cells immunology, Neutrophils metabolism, Receptors, Interleukin-8B metabolism
- Abstract
Type 1 diabetes enhances susceptibility to infection and favors the sepsis development. In addition, diabetic mice produced higher levels of histamine in several tissues and in the blood after LPS stimulation than nondiabetic mice. In this study, we aimed to explore the role of mast cells (MCs) and histamine in neutrophil migration and, consequently, infection control in diabetic mice with mild sepsis (MS) induced by cecum ligation and puncture. We used female BALB/c, MC-sufficient (WB/B6), MC-deficient (W/W(v)), and NOD mice. Diabetic mice given MS displayed 100% mortality within 24 h, whereas all nondiabetic mice survived for at least 5 d. The mortality rate of diabetic mice was reduced to 57% after the depletion of MC granules with compound 48/80. Moreover, this pretreatment increased neutrophil migration to the focus of infection, which reduced systemic inflammatory response and bacteremia. The downregulation of CXCR2 and upregulation of G protein-coupled receptor kinase 2 in neutrophils was prevented by pretreatment of diabetic mice given MS with compound 48/80. In addition, blocking the histamine H2 receptor restored neutrophil migration, enhanced CXCR2 expression, decreased bacteremia, and improved sepsis survival in alloxan-induced diabetic and spontaneous NOD mice. Finally, diabetic W/W(v) mice had neutrophil migration to the peritoneal cavity, increased CXCR2 expression, and reduced bacteremia compared with diabetic WB/B6 mice. These results demonstrate that histamine released by MCs reduces diabetic host resistance to septic peritonitis in mice.
- Published
- 2013
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40. Heme oxygenase inhibition enhances neutrophil migration into the bronchoalveolar spaces and improves the outcome of murine pneumonia-induced sepsis.
- Author
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Czaikoski PG, Nascimento DC, Sônego F, de Freitas A, Turato WM, de Carvalho MA, Santos RS, de Oliveira GP, dos Santos Samary C, Tefe-Silva C, Alves-Filho JC, Ferreira SH, Rossi MA, Rocco PR, Spiller F, and Cunha FQ
- Subjects
- Acute Lung Injury prevention & control, Animals, Bacteremia microbiology, Bronchi enzymology, Chemokines metabolism, Creatine Kinase, MB Form metabolism, Cytokines metabolism, Deuteroporphyrins pharmacology, Enzyme Inhibitors pharmacology, Klebsiella Infections microbiology, Klebsiella pneumoniae, Mice, Pneumonia, Bacterial microbiology, Receptors, Interleukin-8B metabolism, Bacteremia enzymology, Heme Oxygenase (Decyclizing) antagonists & inhibitors, Immune System Diseases enzymology, Klebsiella Infections enzymology, Leukocyte Disorders enzymology, Pneumonia, Bacterial enzymology, Pulmonary Alveoli enzymology
- Abstract
A reduction of the neutrophil migration into the site of infection during cecal ligation and puncture-induced sepsis increases host mortality. Inhibition of heme oxygenase (HO) prevents this neutrophil paralysis and improves host survival in the cecal ligation and puncture model. Taking into account that almost 50% of all sepsis cases are a consequence of pneumonia, we designed the present study to determine the role of HO in an experimental model of pneumonia-induced sepsis. The objective of this study was to evaluate whether the inhibition of HO improves the outcome and pathophysiologic changes of sepsis induced by an intratracheal instillation of Klebsiella pneumoniae. The pretreatment of mice subjected to pneumonia-induced sepsis with ZnDPBG (zinc deuteroporphyrin 2,4-bis glycol), a nonspecific HO inhibitor, increased the number of neutrophils in the bronchoalveolar spaces, reduced the bacterial load at the site of infection, and prevented the upregulation of CD11b and the downregulation of CXCR2 on blood neutrophils. Moreover, the pretreatment with ZnDPBG decreased alveolar collapse, attenuating the deleterious changes in pulmonary mechanics and gas exchanges and, as a consequence, improved the survival rate of mice from 0% to ∼20%. These results show that heme oxygenase is involved in the pathophysiology of pneumonia-induced sepsis and suggest that HO inhibitors could be helpful for the management of this disease.
- Published
- 2013
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41. Decreased levels of alpha-1-acid glycoprotein are related to the mortality of septic patients in the emergency department.
- Author
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Barroso-Sousa R, Lobo RR, Mendonça PR, Memória RR, Spiller F, Cunha FQ, and Pazin-Filho A
- Subjects
- APACHE, Age Factors, Aged, Aged, 80 and over, Biomarkers blood, Brazil, Female, Hospital Mortality, Humans, Kaplan-Meier Estimate, Logistic Models, Male, Middle Aged, Predictive Value of Tests, Prospective Studies, Sex Factors, Time Factors, Emergency Service, Hospital statistics & numerical data, Orosomucoid analysis, Sepsis blood, Sepsis mortality
- Abstract
Objective: To determine the validity of alpha-1-acid glycoprotein as a novel biomarker for mortality in patients with severe sepsis., Methods: We prospectively included patients with severe sepsis or septic shock at the emergency department at a single tertiary referral teaching hospital. All of the patients were enrolled within the first 24 hours of emergency department admission, and clinical data and blood samples were obtained. As the primary outcome, we investigated the association of serum levels of alpha-1-acid glycoprotein and 96-hour mortality with logistic regression analysis and generalized estimating equations adjusted for age, sex, shock status and Acute Physiology and Chronic Health Evaluation II score., Results: Patients with septic shock had lower alpha-1-acid glycoprotein levels at the time of emergency department admission compared to patients without shock (respectively, 149.1 ±42.7 vs. 189.8 ±68.6; p = 0.005). Similarly, non-survivors in the first 96 hours were also characterized by lower levels of alpha-1-acid glycoprotein at the time of emergency department admission compared to survivors (respectively, 132.18 ±50.2 vs. 179.8 ±61.4; p = 0.01). In an adjusted analysis, alpha-1-acid glycoprotein levels ≤120 mg/dL were significantly associated with 96-hour mortality (odds ratio = 14.37; 95% confidence interval = 1.58 to 130.21)., Conclusion: Septic shock patients exhibited lower circulating alpha-1-acid glycoprotein levels than patients without shock. Alpha-1-acid glycoprotein levels were independently associated with 96-hour mortality in individuals with severe sepsis.
- Published
- 2013
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42. Sildenafil improves the beneficial hemodynamic effects exerted by atorvastatin during acute pulmonary thromboembolism.
- Author
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Neto-Neves EM, Dias-Junior CA, Uzuelli JA, Pereira RP, Spiller F, Czaikoski PG, and Tanus-Santos JE
- Subjects
- Acute Disease, Animals, Atorvastatin, Bronchoalveolar Lavage, Drug Synergism, Enzyme Activation drug effects, Heart Ventricles pathology, Lipid Peroxidation drug effects, Lung drug effects, Lung metabolism, Male, Matrix Metalloproteinases blood, Matrix Metalloproteinases metabolism, Myocytes, Cardiac drug effects, Myocytes, Cardiac metabolism, Neutrophils cytology, Neutrophils drug effects, Oxidative Stress drug effects, Pulmonary Embolism blood, Pulmonary Embolism immunology, Pulmonary Embolism metabolism, Purines pharmacology, Sildenafil Citrate, Hemodynamics drug effects, Heptanoic Acids pharmacology, Piperazines pharmacology, Pulmonary Embolism physiopathology, Pyrroles pharmacology, Sulfones pharmacology
- Abstract
We investigated whether atorvastatin has beneficial hemodynamic effects during acute pulmonary thromboembolism (APT) and whether sildenafil improves these effects. We studied the involvement of oxidative stress, matrix metalloproteinases (MMPs), and neutrophil activation. APT was induced with autologous blood clots (500 mg/kg) in anesthetized male lambs pretreated with atorvastatin (10 mg/kg/day, subcutaneously; 1 week) or vehicle (dimethyl sulfoxide 10% subcutaneously). Sildenafil (0.7 mg/kg intravenously) or saline infusions were performed 60 min after APT induction. Non-embolized control animals received saline. APT significantly increased pulmonary vascular resistance index (PVRI) and mean pulmonary artery pressure (MPAP) by approximately 310% and 258% respectively. While atorvastatin pretreatment attenuated these increases (~150% and 153%, respectively; P < 0.05), its combination with sildenafil was associated with lower increases in PVRI and MPAP (~32% and 36%, respectively). Gelatin zymography showed increased MMP-9 and MMP-2 levels in the bronchoalveolar lavage, and increased MMP-9 levels in plasma from embolized animals. Atorvastatin pretreatment attenuated bronchoalveolar lavage MMP-2 increases. The combination of drugs blunted the MMPs increases in bronchoalveolar lavage and plasma (P < 0.05). Neutrophils accumulated in bronchoalveolar lavage after APT, and atorvastatin pretreatment combined with sildenafil (but not atorvastatin alone) attenuated this effect (P < 0.05). APT increased lung lipid peroxidation and total protein concentrations in bronchoalveolar lavage, thus indicating oxidative stress and alveolar-capillary barrier damage, respectively. Both increases were attenuated by atorvastatin pretreatment alone or combined with sildenafil (P < 0.05). We conclude that pretreatment with atorvastatin protects against the pulmonary hypertension associated with APT and that sildenafil improves this response. These findings may reflect antioxidant effects and inhibited neutrophils/MMPs activation., (Copyright © 2011 Elsevier B.V. All rights reserved.)
- Published
- 2011
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43. Divergent role of heme oxygenase inhibition in the pathogenesis of sepsis.
- Author
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Freitas A, Alves-Filho JC, Trevelin SC, Spiller F, Suavinha MM, Nascimento DC, Pestana CR, Dal-Secco D, Sônego F, Czaikoski PG, Curti C, Barja-Fidalgo C, and Cunha FQ
- Subjects
- Animals, Bilirubin blood, Cecum pathology, Heme metabolism, Hemin pharmacology, Inflammation physiopathology, Male, Mice, Mice, Inbred BALB C, Mitochondria physiology, Neutrophils drug effects, Neutrophils metabolism, Receptors, Interleukin-8B biosynthesis, Sepsis etiology, Sepsis pathology, Heme Oxygenase (Decyclizing) antagonists & inhibitors, Neutrophil Infiltration drug effects, Protoporphyrins pharmacology, Sepsis mortality
- Abstract
The reduction of neutrophil migration to an infectious focus is associated with a high mortality in severe sepsis. Previously, we showed that heme oxygenase (HO) products downregulate neutrophil recruitment in a noninfectious inflammatory model. The present study was designed to determine the role of HO in sepsis induced by cecal ligation and puncture (CLP) model. We demonstrated that pretreatment, but not the combination of pretreatment plus posttreatment with zinc protoporphyrin IX (ZnPP IX), an HO inhibitor, prevented the reduction of CXCR2 on circulating neutrophils and the failure of intraperitoneal neutrophil migration to the site of infection. Consequently, bacterial dissemination, systemic inflammatory response, and organ injury were prevented. In addition, pretreatment with the HO inhibitor avoided hypotension and consequently increased survival. Moreover, in mice subjected to severe CLP, the pretreatment, but not the combination of pretreatment plus posttreatment with ZnPP IX, prevented the increase of plasmatic free heme observed in nontreated severe CLP. The administration of exogenous hemin to mice subjected to moderate sepsis consistently increased the mortality rate. Furthermore, hemin resulted in a reduction of neutrophil migration both in vivo and in vitro. Altogether, our results demonstrated that pretreatment with the HO inhibitor prevents the pathological findings in severe CLP. However, the combination of pretreatment plus posttreatment with ZnPP IX enhances sepsis severity because of an increase in circulating levels of heme, which is deleterious to the host tissues and also inhibits neutrophil migration.
- Published
- 2011
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44. Inhibition of guanylyl cyclase restores neutrophil migration and maintains bactericidal activity increasing survival in sepsis.
- Author
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Paula-Neto HA, Alves-Filho JC, Souto FO, Spiller F, Amêndola RS, Freitas A, Cunha FQ, and Barja-Fidalgo C
- Subjects
- Amidines pharmacology, Animals, Apoptosis drug effects, Benzylamines pharmacology, Blotting, Western, Cells, Cultured, Chemotaxis, Leukocyte drug effects, Female, Flow Cytometry, Fluorescent Antibody Technique, G-Protein-Coupled Receptor Kinase 2 metabolism, Humans, Lipopolysaccharides pharmacology, Male, Mice, Mice, Inbred C57BL, Neutrophils cytology, Neutrophils drug effects, Nitric Oxide Synthase antagonists & inhibitors, Peroxidase metabolism, Sepsis metabolism, Signal Transduction drug effects, Guanylate Cyclase metabolism, Neutrophils metabolism, Sepsis enzymology
- Abstract
Sepsis results from an overwhelming response to infection and is a major contributor to death in intensive care units worldwide. In recent years, we and others have shown that neutrophil functionality is impaired in sepsis. This correlates with sepsis severity and contributes to aggravation of sepsis by precluding bacterial clearance. Nitric oxide (NO) is a major contributor to the impairment of neutrophil function in sepsis. However, attempts to inhibit NO synthesis in sepsis resulted in increased death despite restoring neutrophil migration. This could be in part attributed to a reduction of the NO-dependent microbicidal activity of neutrophils. In sepsis, the beneficial effects resulting from the inhibition of soluble guanylyl cyclase (sGC), a downstream target of NO, have long been appreciated but poorly understood. However, the effects of sGC inhibition on neutrophil function in sepsis have never been addressed. In the present study, we show that TLR activation in human neutrophils leads to decreased chemotaxis, which correlated with chemotactic receptor internalization and increased G protein-coupled receptor kinase 2 expression, in a process involving the NO-sGC-protein kinase G axis. We also demonstrate that inhibition of sGC activity increased survival in a murine model of sepsis, which was paralleled by restored neutrophil migratory function and increased bacterial clearance. Finally, the beneficial effect of sGC inhibition could also be demonstrated in mice treated after the onset of sepsis. Our results suggest that the beneficial effects of sGC inhibition in sepsis could be at least in part attributed to a recovery of neutrophil functionality.
- Published
- 2011
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45. Chronic treatment with quercetin does not inhibit angiotensin-converting enzyme in vivo or in vitro.
- Author
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Neto-Neves EM, Montenegro MF, Dias-Junior CA, Spiller F, Kanashiro A, and Tanus-Santos JE
- Subjects
- Angiotensin I pharmacology, Angiotensin II pharmacology, Angiotensin-Converting Enzyme Inhibitors administration & dosage, Angiotensin-Converting Enzyme Inhibitors pharmacology, Animals, Antihypertensive Agents administration & dosage, Bradykinin pharmacology, Captopril administration & dosage, Captopril pharmacology, Chromatography, High Pressure Liquid, In Vitro Techniques, Injections, Intraperitoneal, Male, Quercetin administration & dosage, Quercetin blood, Rats, Rats, Wistar, Antihypertensive Agents pharmacology, Blood Pressure drug effects, Peptidyl-Dipeptidase A blood, Quercetin pharmacology
- Abstract
The precise mechanisms explaining the anti-hypertensive effects produced by quercetin are not fully known. Here, we tested the hypothesis that chronic quercetin treatment inhibits the angiotensin-converting enzyme (ACE). We examined whether quercetin treatment for 14 days reduces in vivo responses to angiotensin I or enhances the responses to bradykinin in anaesthetised rats. We measured the changes in systemic arterial pressure induced by angiotensin I in doses of 0.03-10 μg/kg, by angiotensin II in doses of 0.01-3 μg/kg, and to bradykinin in doses of 0.03-10 μg/kg in anaesthetised rats pre-treated with vehicle (controls), or daily quercetin 10 mg/kg intraperitoneally for 14 days, or a single i.v. dose of captopril 2 mg/kg. Plasma ACE activity was determined by a fluorometric method. Plasma quercetin concentrations were assessed by high performance liquid chromatography. Quercetin treatment induced no significant changes in the hypertensive responses to angiotensin I and angiotensin II, as well in the hypotensive responses to bradykinin (all p>0.05). Conversely, as expected, a single dose of captopril inhibited the hypertensive responses to angiotensin I and potentiated the bradykinin responses (all p<0.01), while no change was found in the vascular responses to angiotensin II (all p>0.05). In addition, although we found significant amounts of quercetin in plasma samples (mean=206 ng/mL), no significant differences were found in plasma ACE activity in rats treated with quercetin compared with those found in the control group (50±6 his-leu nmol/min/mL and 40±7 his-leu nmol/min/mL, respectively; p>0.05). These findings provide strong evidence indicating that quercetin does not inhibit ACE in vivo or in vitro and indicate that other mechanisms are probably involved in the antihypertensive and protective cardiovascular effects associated with quercetin., (© 2010 The Authors. © 2010 Nordic Pharmacological Society.)
- Published
- 2010
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46. Neutrophil paralysis in sepsis.
- Author
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Alves-Filho JC, Spiller F, and Cunha FQ
- Subjects
- Animals, Cytokines physiology, Humans, Infections immunology, Infections physiopathology, Inflammation Mediators physiology, Multiple Organ Failure etiology, Multiple Organ Failure physiopathology, Nitric Oxide Synthase Type II physiology, Organ Specificity, PPAR gamma physiology, Sepsis complications, Sepsis immunology, Sepsis therapy, Systemic Inflammatory Response Syndrome etiology, Systemic Inflammatory Response Syndrome physiopathology, Toll-Like Receptors physiology, Chemotaxis, Leukocyte physiology, Neutrophils physiology, Sepsis physiopathology
- Abstract
Sepsis develops when the initial host response is unable to contain the primary infection, resulting in widespread inflammation and multiple organ dysfunction. The impairment of neutrophil migration into the infection site, also termed neutrophil paralysis, is a critical hallmark of sepsis, which is directly related to the severity of the disease. Although the precise mechanism of this phenomenon is not fully understood, there has been much advancement in the understanding of this field. In this review, we highlight the recent insights into the molecular mechanisms of neutrophil paralysis during sepsis.
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- 2010
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47. Hydrogen sulfide improves neutrophil migration and survival in sepsis via K+ATP channel activation.
- Author
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Spiller F, Orrico MI, Nascimento DC, Czaikoski PG, Souto FO, Alves-Filho JC, Freitas A, Carlos D, Montenegro MF, Neto AF, Ferreira SH, Rossi MA, Hothersall JS, Assreuy J, and Cunha FQ
- Subjects
- Animals, CD11b Antigen physiology, Down-Regulation drug effects, Endothelium, Vascular, Intercellular Adhesion Molecule-1 drug effects, L-Selectin physiology, Male, Mesentery blood supply, Mice, Neutrophils physiology, Receptors, Interleukin-8B physiology, Up-Regulation drug effects, Cell Movement drug effects, Hydrogen Sulfide pharmacology, KATP Channels physiology, Neutrophils drug effects, Sepsis mortality, Sepsis pathology
- Abstract
Rationale: Recovering the neutrophil migration to the infectious focus improves survival in severe sepsis. Recently, we demonstrated that the cystathionine gamma-lyase (CSE)/hydrogen sulfide (H(2)S) pathway increased neutrophil recruitment to inflammatory focus during sterile inflammation., Objectives: To evaluate if H(2)S administration increases neutrophil migration to infectious focus and survival of mice., Methods: Sepsis was induced by cecal ligation and puncture (CLP)., Measurements and Main Results: The pretreatments of mice with H(2)S donors (NaHS or Lawesson's reagent) improved leukocyte rolling/adhesion in the mesenteric microcirculation as well as neutrophil migration. Consequently, bacteremia levels were reduced, hypotension and lung lesions were prevented, and the survival rate increased from approximately 13% to approximately 80%. Even when treatment was delayed (6 h after CLP), a highly significant reduction in mortality compared with untreated mice was observed. Moreover, H(2)S pretreatment prevented the down-regulation of CXCR2 and l-selectin and the up-regulation of CD11b and G protein-coupled receptor kinase 2 in neutrophils during sepsis. H(2)S also prevented the reduction of intercellular adhesion molecule-1 expression in the endothelium of the mesenteric microcirculation in severe sepsis. Confirming the critical role of H(2)S on sepsis outcome, pretreatment with dl-propargylglycine (a CSE inhibitor) inhibited neutrophil migration to the infectious focus, enhanced lung lesions, and induced high mortality in mice subjected to nonsevere sepsis (from 0 to approximately 80%). The beneficial effects of H(2)S were blocked by glibenclamide (a ATP-dependent K(+) channel blocker)., Conclusions: These results showed that H(2)S restores neutrophil migration to the infectious focus and improves survival outcome in severe sepsis by an ATP-dependent K(+) channel-dependent mechanism.
- Published
- 2010
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48. Regulation of chemokine receptor by Toll-like receptor 2 is critical to neutrophil migration and resistance to polymicrobial sepsis.
- Author
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Alves-Filho JC, Freitas A, Souto FO, Spiller F, Paula-Neto H, Silva JS, Gazzinelli RT, Teixeira MM, Ferreira SH, and Cunha FQ
- Subjects
- Animals, Chemotaxis drug effects, Down-Regulation drug effects, G-Protein-Coupled Receptor Kinase 2 metabolism, Gene Expression Regulation drug effects, Immunity, Innate drug effects, Lipopolysaccharides administration & dosage, Lipopolysaccharides pharmacology, Mice, Neutrophils drug effects, Neutrophils enzymology, Peritonitis complications, Receptors, Interleukin-8B genetics, Sepsis complications, Signal Transduction drug effects, Survival Analysis, Teichoic Acids administration & dosage, Teichoic Acids pharmacology, Toll-Like Receptor 2 agonists, Toll-Like Receptor 2 deficiency, Cell Movement drug effects, Neutrophils cytology, Receptors, Interleukin-8B metabolism, Sepsis immunology, Sepsis microbiology, Toll-Like Receptor 2 metabolism
- Abstract
Patients with sepsis have a marked defect in neutrophil migration. Here we identify a key role of Toll-like receptor 2 (TLR2) in the regulation of neutrophil migration and resistance during polymicrobial sepsis. We found that the expression of the chemokine receptor CXCR2 was dramatically down-regulated in circulating neutrophils from WT mice with severe sepsis, which correlates with reduced chemotaxis to CXCL2 in vitro and impaired migration into an infectious focus in vivo. TLR2 deficiency prevented the down-regulation of CXCR2 and failure of neutrophil migration. Moreover, TLR2(-/-) mice exhibited higher bacterial clearance, lower serum inflammatory cytokines, and improved survival rate during severe sepsis compared with WT mice. In vitro, the TLR2 agonist lipoteichoic acid (LTA) down-regulated CXCR2 expression and markedly inhibited the neutrophil chemotaxis and actin polymerization induced by CXCL2. Moreover, neutrophils activated ex vivo by LTA and adoptively transferred into naïve WT recipient mice displayed a significantly reduced competence to migrate toward thioglycolate-induced peritonitis. Finally, LTA enhanced the expression of G protein-coupled receptor kinases 2 (GRK2) in neutrophils; increased expression of GRK2 was seen in blood neutrophils from WT mice, but not TLR2(-/-) mice, with severe sepsis. Our findings identify an unexpected detrimental role of TLR2 in polymicrobial sepsis and suggest that inhibition of TLR2 signaling may improve survival from sepsis.
- Published
- 2009
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49. The role of neutrophils in severe sepsis.
- Author
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Alves-Filho JC, de Freitas A, Spiller F, Souto FO, and Cunha FQ
- Subjects
- Animals, Cell Movement, Chemokines metabolism, Chemotaxis, Cytokines metabolism, Endothelium metabolism, Humans, Immune System, Neutrophil Activation immunology, Neutrophil Infiltration immunology, Neutrophils metabolism, Nitric Oxide metabolism, Peroxynitrous Acid metabolism, Sepsis microbiology, Toll-Like Receptors metabolism, Neutrophils cytology, Neutrophils physiology, Sepsis blood, Sepsis immunology
- Abstract
Neutrophils are key effectors of the innate immune response. Reduction of neutrophil migration to infection sites is associated with a poor outcome in sepsis. We have demonstrated a failure of neutrophil migration in lethal sepsis. Together with this failure, we observed more bacteria in both peritoneal exudates and blood, followed by a reduction in survival rate. Furthermore, neutrophils obtained from severe septic patients displayed a marked reduction in chemotactic response compared with neutrophils from healthy subjects. The mechanisms of neutrophil migration failure are not completely understood. However, it is known that they involve systemic Toll-like receptor activation by bacteria and/or their products and result in excessive levels of circulating cytokines/chemokines. These mediators acting together with LPS stimulate expression of iNOS that produces high amounts of NO, which in turn mediates the failure of neutrophil migration. NO reduced expression of CXCR2 on neutrophils and the levels of adhesion molecules on both endothelial cells and neutrophils. These events culminate in decreased endothelium-leukocyte interactions, diminished neutrophil chemotactic response, and neutrophil migration failure. Additionally, the NO effect, at least in part, is mediated by peroxynitrite. In this review, we summarize what is known regarding the mechanisms of neutrophil migration impairment in severe sepsis.
- Published
- 2008
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50. Anti-inflammatory effects of red pepper (Capsicum baccatum) on carrageenan- and antigen-induced inflammation.
- Author
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Spiller F, Alves MK, Vieira SM, Carvalho TA, Leite CE, Lunardelli A, Poloni JA, Cunha FQ, and de Oliveira JR
- Subjects
- Animals, Anti-Inflammatory Agents, Non-Steroidal chemistry, Anti-Inflammatory Agents, Non-Steroidal isolation & purification, Capillary Permeability, Capsaicin chemistry, Capsaicin isolation & purification, Carrageenan, Cell Movement drug effects, Edema chemically induced, Edema drug therapy, Exudates and Transudates drug effects, Inflammation drug therapy, Inflammation immunology, Interleukin-1beta analysis, L-Lactate Dehydrogenase analysis, Leukocytes drug effects, Leukocytes physiology, Male, Mice, Mice, Inbred C57BL, Peritonitis chemically induced, Peritonitis drug therapy, Phytotherapy, Plant Preparations chemistry, Plant Preparations isolation & purification, Pleurisy chemically induced, Pleurisy drug therapy, Rats, Rats, Wistar, Serum Albumin, Bovine immunology, Tumor Necrosis Factor-alpha analysis, Anti-Inflammatory Agents, Non-Steroidal therapeutic use, Capsaicin therapeutic use, Capsicum chemistry, Plant Preparations therapeutic use
- Abstract
Inflammation is a pivotal component of a variety of diseases, such as atherosclerosis and tumour progression. Various naturally occurring phytochemicals exhibit anti-inflammatory activity and are considered to be potential drug candidates against inflammation-related pathological processes. Capsicum baccatum L. var. pendulum (Willd.) Eshbaugh (Solanaceae) is the most consumed species in Brazil, and its compounds, such as capsaicinoids, have been found to inhibit the inflammatory process. However, the anti-inflammatory effects of C. baccatum have not been characterized. Thus, this study was designed to evaluate the effects of C. baccatum juice in animal models of acute inflammation induced by carrageenan and immune inflammation induced by methylated bovine serum albumin. Pretreatment (30 min) of rats with pepper juice (0.25-2.0 g kg(-1)) significantly decreased leucocyte and neutrophil migration, exudate volume and protein and LDH concentration in pleural exudates of a pleurisy model. This juice also inhibited neutrophil migration and reduced the vascular permeability on carrageenan-induced peritonitis in mice. C. baccatum juice also reduced neutrophil recruitment and exudate levels of pro-inflammatory cytokines TNF-alpha and IL-1beta in mouse inflammatory immune peritonitis. Furthermore, we demonstrated that the main constituent of C. baccatum juice, as extracted with chloroform, is capsaicin. In agreement with this, capsaicin was able to inhibit the neutrophil migration towards the inflammatory focus. To our knowledge, this is the first demonstration of the anti-inflammatory effect of C. baccatum juice and our data suggest that this effect may be induced by capsaicin. Moreover, the anti-inflammatory effect induced by red pepper may be by inhibition of pro-inflammatory cytokine production at the inflammatory site.
- Published
- 2008
- Full Text
- View/download PDF
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