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Search Results: 1 - 10 of 37458 matches for " Fernando Q Cunha "
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Cytokine inhibitors and pain control
Verri Jr., Waldiceu A.;Cunha, Thiago M.;Poole, Stephen;Ferreira, Sérgio H.;Cunha, Fernando Q.;
Revista Brasileira de Reumatologia , 2007, DOI: 10.1590/S0482-50042007000500009
Abstract: the authors describe the evidences supporting the role of cytokines in experimental pain, discussing possible approaches for pain control using cytokine-targeting therapies.
Interleukin-11 attenuates ifosfamide-induced hemorrhagic cystitis
Mota, Jose M.;Brito, Gerly A.;Loiola, Raphael T.;Cunha, Fernando Q.;Ribeiro, Ronaldo de A.;
International braz j urol , 2007, DOI: 10.1590/S1677-55382007000500013
Abstract: objective: to investigate the possible protective effect of recombinant human interleukin-11 (rhil-11) against ifosfamide (ifs)-induced hemorrhagic cystitis (hc) materials and methods: male swiss mice (20-30g) were pretreated with rhil-11 (25-625 mg, subcutaneously.) 30 min before intraperitoneal injection of ifs (400 mg/kg) or with saline (control group). twelve hours later, hc was evaluated by bladder wet weight (bww) to quantify edema, evans blue extravasation (ebe) to measure vascular permeability, and macroscopic and microscopic analysis. all bladders were assessed by histopathological analysis results: rhil-11 (at 125 and 625 mg) attenuated the ifs- induced increase of bww (37.48% and 45.44%, respectively, p < 0.05) and ebe (62.35% and 56.47%, respectively, p < 0.05). ifs- induced macroscopic edema and hemorrhage and microscopic alterations, were also prevented by rhil-11 at 625 mg. (p < 0.05) conclusion: our results demonstrate a protective effect of rhil-11 on experimental ifs- induced hc, not previously reported.
Failure of neutrophil migration toward infectious focus in severe sepsis: a critical event for the outcome of this syndrome
Alves-Filho, José Carlos;Benjamim, Claudia;Tavares-Murta, Beatriz Martins;Cunha, Fernando Q;
Memórias do Instituto Oswaldo Cruz , 2005, DOI: 10.1590/S0074-02762005000900038
Abstract: sepsis is a systemic inflammatory response commonly caused by bacterial infection. we demonstrated that the outcome of sepsis induced by cecal ligation and puncture (clp) correlates with the severity of the neutrophil migration failure towards infectious focus. failure appears to be due to a decrease in the rolling and adhesion of neutrophil to endothelium cells. it seems that neutrophil migration impairment is mediated by the circulating inflammatory cytokines, such as tnf-a and il-8, which induce the nitric oxide (no) production systemically. it is supported by the fact that intravenous administration of these cytokines reduces the neutrophil migration induced by different inflammatory stimuli, and in severe sepsis the circulating concentrations of the cytokines and chemokines are significantly increased. moreover, the neutrophil migration failure and the reduction in the rolling/adhesion were not observed in inos-/- mice and, aminoguanidine prevented this event. we also demonstrated that the failure of neutrophil migration is a toll-4 receptor (tlr4) dependent mechanism, since it was not observed in tlr4 deficient mice. furthermore, it was also observed that circulating neutrophils obtained from septic patients present failure of neutrophil chemotaxis toward fmlp, il-8, and ltb4 and an increased in sera concentrations of no3 and cytokines. in conclusion, we demonstrated that, in sepsis, failure of neutrophil migration is critical for the outcome and that no is involved in the process.
Participation of interleukin-5, interleukin-8 and leukotriene B4 in eosinophil accumulation in two different experimental models
Oliveira, Sandra HP;Faccioli, Lúcia H;Ferreira, Sérgio H;Cunha, Fernando Q;
Memórias do Instituto Oswaldo Cruz , 1997, DOI: 10.1590/S0074-02761997000800028
Abstract: there are several experimental models describing in vivo eosinophil (eo) migration, including ip injection of a large volume of saline (sal) or sephadex beads (sep). the aim of this study was to investigate the mechanisms involved in the eo migration in these two models. two consecutive injections of sal given 48 hr apart, induced a selective recruitment of eo into peritoneal cavity of rats, which peaked 48 hr after the last injection. sep, when injected ip, promoted eo accumulation in rats. the phenomenom was dose-related and peaked 48 hr after sep injection. to investigate the mediators involved in this process we showed that bw a4c, mk 886 and dexamethasone (dxa) inhibited the eo migration induced by sal and sep. to investigate the source of the eo chemotactic factor we showed that mast cells, macrophages (mo), but not lymphocytes, incubated in vitro in presence of sal released a factor which induced eo migration. with sep, only mast cells release a factor that induced eo migration, which was inhibited by bw a4c, mk 886 and dxa. furthermore, the chemotactic activity of sal-stimulated mast cells was inhibited by antisera against il-5 and il-8 (interleukin). sal-stimulated mo were only inhibited by anti-il-8 antibodies as well sep-stimulated mast cells. these results suggest that the eo migration induced by sal may be dependent on resident mast cells and mo and mediated by ltb4, il-5 and il-8. sep-induced eo migration was dependent on mast cells and may be mediated by ltb4 and il-8. furthermore, il-5 and il-8 induced eo migration, which was also dependent on resident cells and mediated by ltb4 . in conclusion, eo migration induced by sal is dependent on mast cells and mo, whereas that induced by sep is dependent on mast cells alone. stimulated mast cells release ltb4, il-5 and il-8 while mo release ltb4 and il-8. the il-5 and il-8 release by the sal or sep-stimulated resident cells may act in an autocrine fashion, thus potentiating ltb4 release.
Participation of interleukin-5, interleukin-8 and leukotriene B4 in eosinophil accumulation in two different experimental models
Oliveira Sandra HP,Faccioli Lúcia H,Ferreira Sérgio H,Cunha Fernando Q
Memórias do Instituto Oswaldo Cruz , 1997,
Abstract: There are several experimental models describing in vivo eosinophil (EO) migration, including ip injection of a large volume of saline (SAL) or Sephadex beads (SEP). The aim of this study was to investigate the mechanisms involved in the EO migration in these two models. Two consecutive injections of SAL given 48 hr apart, induced a selective recruitment of EO into peritoneal cavity of rats, which peaked 48 hr after the last injection. SEP, when injected ip, promoted EO accumulation in rats. The phenomenom was dose-related and peaked 48 hr after SEP injection. To investigate the mediators involved in this process we showed that BW A4C, MK 886 and dexamethasone (DXA) inhibited the EO migration induced by SAL and SEP. To investigate the source of the EO chemotactic factor we showed that mast cells, macrophages (MO), but not lymphocytes, incubated in vitro in presence of SAL released a factor which induced EO migration. With SEP, only mast cells release a factor that induced EO migration, which was inhibited by BW A4C, MK 886 and DXA. Furthermore, the chemotactic activity of SAL-stimulated mast cells was inhibited by antisera against IL-5 and IL-8 (interleukin). SAL-stimulated MO were only inhibited by anti-IL-8 antibodies as well SEP-stimulated mast cells. These results suggest that the EO migration induced by SAL may be dependent on resident mast cells and MO and mediated by LTB4, IL-5 and IL-8. SEP-induced EO migration was dependent on mast cells and may be mediated by LTB4 and IL-8. Furthermore, IL-5 and IL-8 induced EO migration, which was also dependent on resident cells and mediated by LTB4 . In conclusion, EO migration induced by SAL is dependent on mast cells and MO, whereas that induced by SEP is dependent on mast cells alone. Stimulated mast cells release LTB4, IL-5 and IL-8 while MO release LTB4 and IL-8. The IL-5 and IL-8 release by the SAL or SEP-stimulated resident cells may act in an autocrine fashion, thus potentiating LTB4 release.
Nitric oxide mediates the microbicidal activity of eosinophils
Oliveira, Sandra HP;Fonseca, Simone G;Rom?o, Pedro RT;Ferreira, Sérgio H;Cunha, Fernando Q;
Memórias do Instituto Oswaldo Cruz , 1997, DOI: 10.1590/S0074-02761997000800034
Abstract: there are several experimental evidences that nitric oxide (no) is involved in the microbicidal activity of macrophages against a number of intracellular pathogens including leishmania major, trypanozoma cruzi, toxoplasma gondii. it is also well known that eosinophils (eo) have microbicidal activity against many parasites such as schistosoma mansoni, trichinella spiralis, t. cruzi and l. amazonensis. the purpose of this study was to investigate if no is involved in the microbicidal activity of eo against l. major. eosinophils harvested from peritoneal cavity of rats released spontaneously after 24 and 48 hr a small amount of nitrite. this release was enhanced by the treatment of cells with ifn-g (200 iu/ml). this release was blocked by addition of the no synthase inhibitor, l-nio (100 m m) into the culture. to determinate the leishmanicidal activity of eosinophils the parasites were incubated with activated eosinophils with ifn-g and the ability of surviving parasites to incorporate [3h]thymidine was evaluated. ifn-g-activated eosinophils were able to kill l. major and to release high levels of nitrite. the ability to destroy l. major and the release of no were completely blocked by l-nio. these results indicate that activated eosinophils release no which is involved in the microbicidal activity of these cells against l. major.
Stimulation of peripheral Kappa opioid receptors inhibits inflammatory hyperalgesia via activation of the PI3Kγ/AKT/nNOS/NO signaling pathway
Thiago M Cunha, Guilherme R Souza, Andressa C Domingues, Eleonora U Carreira, Celina M Lotufo, Mani I Funez, Waldiceu A Verri, Fernando Q Cunha, Sergio H Ferreira
Molecular Pain , 2012, DOI: 10.1186/1744-8069-8-10
Abstract: Local (paw) administration of U50488 (a selective KOR agonist) directly blocked, PGE2-induced mechanical hyperalgesia in both rats and mice. This effect was reversed by treating animals with L-NMMA or N-propyl-L-arginine (a selective inhibitor of neuronal nitric oxide synthase, nNOS), suggesting involvement of the nNOS/NO pathway. U50488 peripheral effect was also dependent on stimulation of PI3Kγ/AKT because inhibitors of these kinases also reduced peripheral antinociception induced by U50488. Furthermore, U50488 lost its peripheral analgesic effect in PI3Kγ null mice. Observations made in vivo were confirmed after incubation of dorsal root ganglion cultured neurons with U50488 produced an increase in the activation of AKT as evaluated by western blot analyses of its phosphorylated form. Finally, immunofluorescence of DRG neurons revealed that KOR-expressing neurons also express PI3Kγ (? 43%).The present study indicates that activation of peripheral KORs directly blocks inflammatory hyperalgesia through stimulation of the nNOS/NO signaling pathway which is probably stimulated by PI3Kγ/AKT signaling. This study extends a previously study of our group suggesting that PI3Kγ/AKT/nNOS/NO is an important analgesic pathway in primary nociceptive neurons.Inflammatory pain is primarily due to the sensitization of specific classes of nociceptive neurons by the direct action of inflammatory mediators (e.g., prostaglandins). In this context, pharmacologic control of inflammatory pain in the periphery is mainly based on two principal strategies. First, the use of non-steroidal anti-inflammatory drugs (aspirin and aspirin-like drugs) inhibits cyclooxygenase-derived prostaglandin production and, consequently, reduces nociceptor sensitization [1]. This effect ultimately prevents the development of hyperalgesia (decrease in nociceptive threshold) in humans and animals. On the other hand, the second strategy is exemplified by some analgesic drugs, like opioids and dipyrone, which ar
Lipopolysaccharide Induces Inflammatory Hyperalgesia Triggering a TLR4/MyD88-Dependent Cytokine Cascade in the Mice Paw
Igor L. Calil, Ana C. Zarpelon, Ana T. G. Guerrero, Jose C. Alves-Filho, Sergio H. Ferreira, Fernando Q. Cunha, Thiago M. Cunha, Waldiceu A. Verri
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0090013
Abstract: Inflammatory pain can be triggered by different stimuli, such as trauma, radiation, antigen and infection. In a model of inflammatory pain caused by infection, injection in the mice paw of lipopolysaccharide (LPS), a Toll-like receptor 4 (TLR4) agonist, produces mechanical hyperalgesia. We identify here the TLR4 linked signaling pathways that elicit this response. Firstly, LPS paw injection in wild type (WT) mice produced mechanical hyperalgesia that was not altered in TRIF-/- mice. On the other hand, this response was absent in TLR4 mutant and MyD88 null mice and reduced in TNFR1 null mice. Either an IL-1 receptor antagonist, anti-KC/CXCL1 antibody, indomethacin or guanethidine injection also lessened this response. Moreover, LPS-induced time dependent increases in TNF-α, KC/CXCL1 and IL-1β expression in the mice paw, which were absent in TLR4 mutant and MyD88 null mice. Furthermore, in TNFR1 deficient mice, the LPS-induced rises in KC/CXCL1 and IL-1β release were less than in their wild type counterpart. LPS also induced increase of myeloperoxidase activity in the paw skin, which was inhibited in TLR4 mutant and MyD88 null mice, and not altered in TRIF-/- mice. These results suggest that LPS-induced inflammatory pain in mice is solely dependent on the TLR4/MyD88 rather than the TLR4/TRIF signaling pathway. This pathway triggers pronociceptive cytokine TNF-α release that in turn mediates rises in KC/CXCL1 and IL-1β expression. Finally, these cytokines might be involved in stimulating production of directly-acting hyperalgesic mediators such as prostaglandins and sympathomimetic amine.
Caspase-1 is involved in the genesis of inflammatory hypernociception by contributing to peripheral IL-1β maturation
Thiago M Cunha, Jhimmy Talbot, Larissa G Pinto, Silvio M Vieira, Guilherme R Souza, Ana T Guerrero, Fabiane Sonego, Waldiceu A Verri, Dario S Zamboni, Sergio H Ferreira, Fernando Q Cunha
Molecular Pain , 2010, DOI: 10.1186/1744-8069-6-63
Abstract: Mechanical inflammatory hypernociception was evaluated using an electronic version of the von Frey test. The production of cytokines, PGE2 and neutrophil migration were evaluated by ELISA, radioimmunoassay and myeloperoxidase activity, respectively. The interleukin (IL)-1β and cyclooxygenase (COX)-2 protein expression were evaluated by western blotting. The mechanical hypernociception induced by intraplantar injection of carrageenin, tumour necrosis factor (TNF)α and CXCL1/KC was reduced in casp1-/- mice compared with WT mice. However, the hypernociception induced by IL-1β and PGE2 did not differ in WT and casp1-/- mice. Carrageenin-induced TNF-α and CXCL1/KC production and neutrophil recruitment in the paws of WT mice were not different from casp1-/- mice, while the maturation of IL-1β was reduced in casp1-/- mice. Furthermore, carrageenin induced an increase in the expression of COX-2 and PGE2 production in the paw of WT mice, but was reduced in casp1-/- mice.These results suggest that caspase-1 plays a critical role in the cascade of events involved in the genesis of inflammatory hypernociception by promoting IL-1β maturation. Because caspase-1 is involved in the induction of COX-2 expression and PGE2 production, our data support the assertion that caspase-1 is a key target to control inflammatory pain.Inflammatory hypernociception results mainly from the sensitisation of primary afferent neurons and is detected as a decrease of the nociceptive threshold in animal models [1]. It is induced by inflammatory mediators, such as prostaglandins and sympathetic amines, that directly sensitise peripheral nociceptive neurons [2-4]. The release of these direct-acting hyperalgesic mediators is generally preceded by a cascade of cytokines [5]. Recently, we demonstrated that inflammatory hypernociception in mice is mediated by a concomitant release of tumour necrosis factor alpha (TNFα) and keratinocyte-derived chemokine (CXCL1/KC). Both mediators stimulate the subsequent rel
T Cell Post-Transcriptional miRNA-mRNA Interaction Networks Identify Targets Associated with Susceptibility/Resistance to Collagen-induced Arthritis
Paula B. Donate, Thais A. Fornari, Claudia Macedo, Thiago M. Cunha, Daniele C. B. Nascimento, Elza T. Sakamoto-Hojo, Eduardo A. Donadi, Fernando Q. Cunha, Geraldo A. Passos
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0054803
Abstract: Background Due to recent studies indicating that the deregulation of microRNAs (miRNAs) in T cells contributes to increased severity of rheumatoid arthritis, we hypothesized that deregulated miRNAs may interact with key mRNA targets controlling the function or differentiation of these cells in this disease. Methodology/Principal Findings To test our hypothesis, we used microarrays to survey, for the first time, the expression of all known mouse miRNAs in parallel with genome-wide mRNAs in thymocytes and na?ve and activated peripheral CD3+ T cells from two mouse strains the DBA-1/J strain (MHC-H2q), which is susceptible to collagen induced arthritis (CIA), and the DBA-2/J strain (MHC-H2d), which is resistant. Hierarchical clustering of data showed the several T cell miRNAs and mRNAs differentially expressed between the mouse strains in different stages of immunization with collagen. Bayesian statistics using the GenMir++ algorithm allowed reconstruction of post-transcriptional miRNA-mRNA interaction networks for target prediction. We revealed the participation of miR-500, miR-202-3p and miR-30b*, which established interactions with at least one of the following mRNAs: Rorc, Fas, Fasl, Il-10 and Foxo3. Among the interactions that were validated by calculating the minimal free-energy of base pairing between the miRNA and the 3′UTR of the mRNA target and luciferase assay, we highlight the interaction of miR-30b*-Rorc mRNA because the mRNA encodes a protein implicated in pro-inflammatory Th17 cell differentiation (Rorγt). FACS analysis revealed that Rorγt protein levels and Th17 cell counts were comparatively reduced in the DBA-2/J strain. Conclusions/Significance This result showed that the miRNAs and mRNAs identified in this study represent new candidates regulating T cell function and controlling susceptibility and resistance to CIA.
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