Belo Horizonte, Brazil
Belo Horizonte, Brazil

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Sousa L.P.,Programa de Pos Graduacao em Biologia Celular | Sousa L.P.,Laboratorio Of Imunofarmacologia | Sousa L.P.,Federal University of Minas Gerais | Vago J.P.,Programa de Pos Graduacao em Biologia Celular | And 11 more authors.
Journal of Leukocyte Biology | Year: 2012

This study aimed at assessing whether AnxA1, a downstream mediator for the anti-inflammatory effects of GCs, could affect the fate of immune cells in tissue exudates, using LPS-induced pleurisy in BALB/c mice. AnxA1 protein expression in exudates was increased during natural resolution, as seen at 48-72 h post-LPS, an effect augmented by treatment with GC and associated with marked presence of apoptotic neutrophils in the pleural exudates. The functional relevance of AnxA1 was determined using a neutralizing antibody or a nonspecific antagonist at FPR/ALXRs: either treatment inhibited both spontaneous and GC-induced resolution of inflammation. Injection of Ac2-26 (100 μg, given 4 h into the LPS response), an AnxA1-active N-terminal peptide, promoted active resolution and augmented the extent of neutrophil apoptosis. Such an effect was prevented by the pan-caspase inhibitor zVAD-fmk. Mechanistically, resolution of neutrophilic inflammation was linked to cell apoptosis with activation of Bax and caspase-3 and inhibition of survival pathways Mcl-1, ERK1/2, and NF-κB. These novel in vivo data, using a dynamic model of acute inflammation, provide evidence that AnxA1 is a mediator of natural and GC-induced resolution of inflammation with profound effects on neutrophil apoptosis. © Society for Leukocyte Biology.


Bozza F.A.,Brazilian National Institute of Technology | Bozza F.A.,DOr Institute for Research and Education IDOR | D'Avila J.C.,Brazilian National Institute of Technology | D'Avila J.C.,Laboratorio Of Imunofarmacologia | And 6 more authors.
Shock | Year: 2013

Sepsis is a major cause of mortality and morbidity in intensive care units. Acute and long-term brain dysfunctions have been demonstrated both in experimental models and septic patients. Sepsis-associated encephalopathy is an early and frequent manifestation but is underdiagnosed, because of the absence of specific biomarkers and of confounding factors such as sedatives used in the intensive care unit. Sepsis-associated encephalopathy may have acute and long-term consequences including development of autonomic dysfunction, delirium, and cognitive impairment. The mechanisms of sepsis-associated encephalopathy involve mitochondrial and vascular dysfunctions, oxidative stress, neurotransmission disturbances, inflammation, and cell death. Here we review specific evidence that links bioenergetics, mitochondrial dysfunction, and oxidative stress in the setting of brain dysfunctions associated to sepsis. Copyright © 2013 by the Shock Society.


PubMed | Laboratorio Interacao Micro organismo Hospedeiro, Federal University of Pernambuco, Laboratorio Of Imunofarmacologia and Federal University of Minas Gerais
Type: | Journal: Pharmacological research | Year: 2016

Irinotecan is a useful chemotherapeutic agent for the treatment of several solid tumors. However, this therapy is associated with side effects, including leukopenia and mucositis. Reactive oxygen species (ROS) activate inflammatory pathways and contribute to Irinotecan-induced mucositis. Fullerol is a nanocomposite with anti-oxidant properties that may reduce tissue damage after inflammatory stimuli. In this paper, the effects of Fullerol and mechanisms of protection were investigated in a model of Irinotecan-induced mucositis. Mucositis was induced by an injection of Irinotecan per 4 days in C57BL/6. Fullerol or a vehicle was injected every 12h. On day 7, the intestines were removed to evaluate histological changes, leukocyte influx, and the production of cytokines and ROS. Irinotecan therapy resulted in weight loss, an increased clinical score and intestinal injury. Treatment with Fullerol attenuated weight loss, decreased clinical score and intestinal damage. Irinotecan also induced increased ROS production in enterocytes, oxidative stress, IL-1 production, neutrophil and eosinophil influx in the ileum. Fullerol treatment decreased production of ROS in the enterocytes, oxidative stress, IL-1 production, neutrophil and eosinophil influx in the ileum. Irinotecan therapy also induced leukopenia in an ROS-dependent manner because leukopenia reverted in WT mice treated with Fullerol or Apocynin or in Gp91phox(-/-) mice. Mice treated with Irinotecan presented less melanoma tumor growth compared to the control group. Fullerol does not interfere in the anti-tumor action of Irinotecan. Fullerol has a great pharmacology potential to decreases the severity of mucositis and of leukopenia during chemotherapy treatment.


de Sousa P.A.M.,Federal University of Rio de Janeiro | Vaisman M.,Federal University of Rio de Janeiro | Carneiro J.R.I.,Federal University of Rio de Janeiro | Guimaraes L.,Federal University of Rio de Janeiro | And 5 more authors.
Arquivos Brasileiros de Endocrinologia e Metabologia | Year: 2013

Objectives: To evaluate the prevalence of goiter and nodular disease in patients with class III obesity, and to correlate results with serum leptin levels and insulin resistance (IR) parameters. Subjects and methods: A cross-sectional study was performed to assess thyroid ultrasound (US) patterns, HOMA-IR, serum leptin, and TSH levels in obese patients and controls. Results: Thyroid volume was positively correlated with body mass index (BMI) (r = 0.240, p = 0.039) and with HOMA-IR (r = 0.329; p < 0.01). Thyroid US patterns were similar between groups. However, when data from the male group was considered, greater thyroid volume was detected in the obese group compared with controls (10.8 vs. 8.5 cm3; p = 0.04). Also, nodules were more frequently detected (67% vs. 18%), as were nodules requiring FNAB (33.3% vs. 0%, p ≥ 0.05-0.09), in this group. Conclusion: Although IR did not correlate directly with the presence of nodules, the results support the hypothesis of a direct association between insulin resistance and thyroid volume. © ABE&M todos os direitos reservados.


Goncalves De Albuquerque C.F.,Laboratorio Of Imunofarmacologia | Burth P.,Federal University of Fluminense | Younes Ibrahim M.,State University of Rio de Janeiro | Garcia D.G.,Laboratorio Of Imunofarmacologia | And 3 more authors.
Mediators of Inflammation | Year: 2012

Although exerting valuable functions in living organisms, nonesterified fatty acids (NEFAs) can be toxic to cells. Increased blood concentration of oleic acid (OLA) and other fatty acids is detected in many pathological conditions. In sepsis and leptospirosis, high plasma levels of NEFA and low albumin concentrations are correlated to the disease severity. Surprisingly, 24h after intravenous or intragastric administration of OLA, main NEFA levels (OLA inclusive) were dose dependently decreased. However, lung injury was detected in intravenously treated mice, and highest dose killed all mice. When administered by the enteral route, OLA was not toxic in any tested conditions. Results indicate that OLA has important regulatory properties on fatty acid metabolism, possibly lowering circulating fatty acid through activation of peroxisome proliferator-activated receptors. The significant reduction in blood NEFA levels detected after OLA enteral administration can contribute to the already known health benefits brought about by unsaturated-fatty-acid-enriched diets. Copyright © 2012 Cassiano Felippe Gonalves de Albuquerque et al.


Gimenez G.,Parasitologia e Inmunologia | Magalhaes K.G.,Laboratorio Of Imunofarmacologia | Belaunzaran M.L.,Parasitologia e Inmunologia | Poncini C.V.,Parasitologia e Inmunologia | And 4 more authors.
Molecular Immunology | Year: 2010

Babesia bovis is an intraerythrocytic apicomplexan protozoa of cattle that causes an acute infection with parasite persistence. Babesiosis limitation depends on macrophages, essential effector cells of the host innate defense, which generate inflammatory cytokines and nitric oxide. Herein, we report quantitative differences in the lipid composition of merozoites from two B. bovis strains with polar behaviour: attenuated R1A and virulent S2P. Accordingly, we observed a distinct inflammatory response induced by the total lipids of R1A (LA) and S2P (LV) in murine peritoneal macrophages. LA and particularly its fractions phosphatidic acid and phosphatidylserine + phosphatidylinositol (PS + PI), produced a strong activation of these cells with lipid body formation, cyclooxygenase-2 expression and pro-inflammatory TNFα, IL-6 and KC secretion. Although LV did not activate these cells, the corresponding PS + PI fraction induced TNFα, IL-6 and KC release. Therefore, these facts might be suggesting the presence of an inhibitor in LV. Furthermore, the employment of wild type and toll like receptor 2 knockout (TLR2KO) mice allowed us to demonstrate that macrophage activation by the stimulating lipid fractions was mediated through TLR2. Interestingly, only LA activated the extracellular signal-regulated kinases 1 and 2 (ERK1/2). Inhibitory studies employing UO126, indicated that the ERK pathway was required for TNFα, IL-6 and KC release. In conclusion, the absence of inflammatory response observed with the lipids of S2P virulent strain could constitute an evasion mechanism of the innate immune response enabling parasite establishment in the host. © 2010 Elsevier Ltd. All rights reserved.


Japiassu A.M.,Oswaldo Cruz Foundation | Japiassu A.M.,Intensive Care Unit | Japiassu A.M.,Federal University of Rio de Janeiro | Santiago A.P.S.A.,Federal University of Rio de Janeiro | And 7 more authors.
Critical Care Medicine | Year: 2011

OBJECTIVE: Increasing evidence points to the role of mitochondrial dysfunction in the pathogenesis of sepsis. Previous data indicate that mitochondrial function is affected in monocytes from septic patients, but the underlying mechanisms and the impact of these changes on the patients' outcome are unknown. We aimed to determine the mechanisms involved in mitochondrial dysfunction in peripheral blood mononuclear cells from patients with septic shock. DESIGN: A cohort of patients with septic shock to study peripheral blood mononuclear cell mitochondrial respiration by high-resolution respirometry analyses and to compare with cells from control subjects. SETTING: Three intensive care units and an academic research laboratory. SUBJECTS: Twenty patients with septic shock and a control group composed of 18 postoperative patients without sepsis or shock. INTERVENTIONS: Ex vivo measurements of mitochondrial oxygen consumption were carried out in digitonin-permeabilized peripheral blood mononuclear cells from 20 patients with septic shock taken during the first 48 hrs after intensive care unit admission as well as in peripheral blood mononuclear cells from control subjects. Clinical parameters such as hospital outcome and sepsis severity were also analyzed and the relationship between these parameters and the oxygen consumption pattern was investigated. MEASUREMENTS AND MAIN RESULTS: We observed a significant reduction in the respiration specifically associated with adenosine-5′-triphosphate synthesis (state 3) compared with the control group (5.60 vs. 9.89 nmol O2/min/10 cells, respectively, p <.01). Reduction of state 3 respiration in patients with septic shock was seen with increased prevalence of organ failure (r =-0.46, p =.005). Nonsurviving patients with septic shock presented significantly lower adenosine diphosphate-stimulated respiration when compared with the control group (4.56 vs. 10.27 nmol O2/min/10 cells, respectively; p =.004). Finally, the presence of the functional F1Fo adenosine-5'-triphosphate synthase complex (0.51 vs. 1.00 ng oligo/mL/10 cells, p =.02), but not the adenine nucleotide translocator, was significantly lower in patients with septic shock compared with control cells. CONCLUSION: Mitochondrial dysfunction is present in immune cells from patients with septic shock and is characterized as a reduced respiration associated to adenosine-5′-triphosphate synthesis. The molecular basis of this phenotype involve a reduction of F1Fo adenosine-5′-triphosphate synthase activity, which may contribute to the energetic failure found in sepsis. Copyright © 2011 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins.


Gonalves-De-Albuquerque C.F.,Laboratorio Of Imunofarmacologia | Burth P.,Federal University of Fluminense | Silva A.R.,Laboratorio Of Imunofarmacologia | Younes-Ibrahim M.,State University of Rio de Janeiro | And 2 more authors.
Mediators of Inflammation | Year: 2012

Leptospirosis is an important zoonosis and has a worldwide impact on public health. This paper will discuss both the role of immunogenic and pathogenic molecules during leptospirosis infection and possible new targets for immunotherapy against leptospira components. Leptospira, possess a wide variety of mechanisms that allow them to evade the host immune system and cause infection. Many molecules contribute to the ability of Leptospira to adhere, invade, and colonize. The recent sequencing of the Leptospira genome has increased our knowledge about this pathogen. Although the virulence factors, molecular targets, mechanisms of inflammation, and signaling pathways triggered by leptospiral antigens have been studied, some questions are still unanswered. Toll-like receptors (TLRs) are the primary sensors of invading pathogens. TLRs recognize conserved microbial pattern molecules and activate signaling pathways that are pivotal to innate and adaptive immune responses. Recently, a new molecular target has emergedthe Na/K-ATPasewhich may contribute to inflammatory and metabolic alteration in this syndrome. Na/K-ATPase is a target for specific fatty acids of host origin and for bacterial components such as the glycolipoprotein fraction (GLP) that may lead to inflammasome activation. We propose that in addition to TLRs, Na/K-ATPase may play a role in the innate response to leptospirosis infection. © 2012 C. F. Gonalves-de-Albuquerque et al.


Magalhaes K.G.,Laboratorio Of Imunofarmacologia | Magalhaes K.G.,Instituto Oswaldo Cruz | Almeida P.E.,Laboratorio Of Imunofarmacologia | Atella G.C.,Federal University of Rio de Janeiro | And 6 more authors.
Journal of Infectious Diseases | Year: 2010

Parasite-derived lipids may play important roles in host-pathogen interactions and escape mechanisms. Herein, we evaluated the role of schistosomal-derived lipids in Toll-like receptor (TLR)-2 and eosinophil activation in Schistosoma mansoni infection. Mice lacking TLR2 exhibited reduced liver eosinophilic granuloma, compared with that of wild-type animals, following S. mansoni infection. Decreased eosinophil accumulation and eosinophil lipid body (lipid droplet) formation, at least partially due to reduced production of eotaxin, interleukin (IL)-5, and IL-13 in S. mansoni-infected TLR2-/- mice, compared with the corresponding production in wild-type mice, was noted. Although no differences were observed in survival rates during the acute schistosomal infection (up to 50 days), increased survival of TLR2-/- mice, compared with survival of wild-type mice, was observed during the chronic phase of infection. Schistosomal lipid extract- and schistosomal-derived lysophosphatidylcholine (lyso-PC)-stimulated macrophages in vitro induced TLR2-dependent NF-kB activation and cytokine production. Furthermore, in vivo schistosomal lyso-PC administration induced eosinophil recruitment and cytokine production, in a mechanism largely dependent on TLR2. Taken together, our results suggest that schistosomal-derived lyso-PC may participate in cytokine production and eosinophil activation through a TLR2-dependent pathway in S. mansoni infection. Moreover, our results suggest that TLR2-dependent inflammatory reaction, cytokine production, and eosinophil recruitment and activation may contribute to the pathogenesis and lethality in the chronic phase of infection. © 2010 by the Infectious Diseases Society of America. All rights reserved.


PubMed | CONICET, Laboratorio Of Imunofarmacologia and University of Brasilia
Type: | Journal: Veterinary parasitology | Year: 2016

Toll like receptors (TLRs) are involved in the modulation of diverse host genes expression through a complex network of signalling events that allow for an appropriate response to a microbial pathogen. In the present work we used TLR6KO mice in order to study the role of TLR6 in the immune discrimination of lipids from two Babesia bovis strains, attenuated R1A (LA) and virulent S2P (LV), and the consequent macrophage activation. We demonstrated that TLR6 is required for lipid body induction in murine peritoneal macrophages by both LA and LV. Interestingly, as regards IL-10 and COX-2/PGE2 pathway induction by LA and LV, we observed differences in the biological effects produced by these lipid extracts. Our results indicate a role of TLR6 in the down-modulation of these immunoregulators only in the case of LA, whereas this receptor was not implicated in pro-inflammatory TNF, IL-6 and KC release induced by LA. Remarkably, LV did not exert the down-modulatory effect observed for LA, supporting the notion that LA and LV possess different lipid composition that could correlate with the polar pathogenic effect of both B. bovis strains.

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