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Phytother Res ; 32(12): 2466-2474, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30277282


Microbiota alterations are observed in pathological conditions, and their regulation is a subject of great interest. Gut microbes are affected by diet, and plant polyphenols may have positive effect on gut microbiota; however, plant-derived extracts may have toxic effects. Guarana (Paullinia cupana Mart.) is a nontraditional medicinal plant applied worldwide. Guarana yields an alkaloid and polyphenol-rich seed with antimicrobial, antioxidant, and anti-inflammatory properties, where caffeine is the major compound. We evaluated the effects of guarana seed powder (GSP) and purified caffeine on gut microbial composition and redox and inflammatory parameters in Wistar rats after 21 days of treatment. Fecal microbiota was analyzed utilizing 16S rDNA sequencing. Antioxidant enzymes activities from liver, kidney, and colon, as well as oxidative damage markers, were evaluated. Total nonenzymatic antioxidant potential was also evaluated. Microbiota was altered by both treatments, GSP and caffeine, without loss of diversity. In the liver, the kidney, and the colon, we observed a decrease in the antioxidant enzymes activities in the GSP group with no increase in the expression of oxidative damage markers, although some enzymes were also regulated by caffeine. Taken together, these results suggested that GSP ameliorates redox parameters but negatively affected gut microbiota, partially via caffeine.

Cafeína/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Teobromina/farmacologia , Teofilina/farmacologia , Animais , Antioxidantes/farmacologia , Cafeína/química , Disbiose/induzido quimicamente , Disbiose/microbiologia , Disbiose/patologia , Masculino , Oxirredução/efeitos dos fármacos , Paullinia/química , Extratos Vegetais/farmacologia , Plantas Medicinais/química , Ratos , Ratos Wistar , Sementes , Teobromina/química , Teofilina/química
Cell Physiol Biochem ; 42(6): 2507-2522, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28848092


BACKGROUND/AIMS: Heat shock protein 70 (HSP70) has been recently described with extracellular actions, where it is actively released in inflammatory conditions. Acting as DAMPs (damage associated molecular pattern), extracellular HSP70 (eHSP70) interacts with membrane receptors and activates inflammatory pathways. At this context, the receptor for advanced glycation endproducts (RAGE) emerges as a possible candidate for interaction with eHSP70. RAGE is a pattern-recognition receptor and its expression is increased in several diseases related to a chronic pro-inflammatory state. One of the main consequences of RAGE ligand-binding is the ERK1/2 (extracellular signal-regulated kinases)-dependent activation of NF-kB (nuclear factor kappa B), which leads to expression of TNF-α (tumor necrosis factor alpha) and other cytokines. The purpose of this work is to elucidate if eHSP70 is able to evoke RAGE-dependent signaling using A549 human lung cancer cells, which constitutively express RAGE. METHODS: Immunoprecipitation and protein proximity assay were utilized to demonstrate the linkage between RAGE and eHSP70. To investigate RAGE relevance on cell response to eHSP70, siRNA was used to knockdown the receptor expression. Signaling pathways activation were evaluated by western blotting, gene reporter luciferase and real time quantitative PCR. RESULTS: Protein eHSP70 shown to be interacting physically with the receptor RAGE in our cell model. Treatment with eHSP70 caused ERK1/2 activation and NF-κB transactivation impaired by RAGE knockdown. Moreover, the stimulation of pro-inflammatory cytokines expression by eHSP70 was inhibited in RAGE-silenced cells. Finally, conditioned medium of eHSP70-treated A549 cells caused differential effects in monocytes cytokine expression when A549 RAGE expression is inhibited. CONCLUSIONS: Our results evidence eHSP70 as a novel RAGE agonist capable of influence the cross-talk between cancer and immune system cells.

Proteínas de Choque Térmico HSP70/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , NF-kappa B/metabolismo , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Células A549 , Citocinas/genética , Citocinas/metabolismo , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico HSP70/farmacologia , Humanos , Immunoblotting , Imunoprecipitação , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , NF-kappa B/genética , Fosforilação , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Receptor para Produtos Finais de Glicação Avançada/antagonistas & inibidores , Receptor para Produtos Finais de Glicação Avançada/genética , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/farmacologia , Transdução de Sinais/efeitos dos fármacos , Ativação Transcricional , Células U937
PLoS One ; 8(12): e82457, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24349289


Neuroblastoma is the most common extracranial tumor and a major cause of infant cancer mortality worldwide. Despite its importance, little is known about its molecular mechanisms. A striking feature of this tumor is its clinical heterogeneity. Possible outcomes range from aggressive invasion to other tissues, causing patient death, to spontaneous disease regression or differentiation into benign ganglioneuromas. Several efforts have been made in order to find tumor progression markers. In this work, we have reconstructed the neuroblastoma regulatory network using an information-theoretic approach in order to find genes involved in tumor progression and that could be used as outcome predictors or as therapeutic targets. We have queried the reconstructed neuroblastoma regulatory network using an aggressive neuroblastoma metastasis gene signature in order to find its master regulators (MRs). MRs expression profiles were then investigated in other neuroblastoma datasets so as to detect possible clinical significance. Our analysis pointed MAX as one of the MRs of neuroblastoma progression. We have found that higher MAX expression correlated with favorable patient outcomes. We have also found that MAX expression and protein levels were increased during neuroblastoma SH-SY5Y cells differentiation. We propose that MAX is involved in neuroblastoma progression, possibly increasing cell differentiation by means of regulating the availability of MYC:MAX heterodimers. This mechanism is consistent with the results found in our SH-SY5Y differentiation protocol, suggesting that MAX has a more central role in these cells differentiation than previously reported. Overexpression of MAX has been identified as anti-tumorigenic in other works, but, to our knowledge, this is the first time that the link between the expression of this gene and malignancy was verified under physiological conditions.

Fatores de Transcrição de Zíper de Leucina Básica/genética , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Neuroblastoma/genética , Neuroblastoma/patologia , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Linhagem Celular Tumoral , Análise por Conglomerados , Progressão da Doença , Perfilação da Expressão Gênica , Humanos , Modelos Biológicos , Neuroblastoma/metabolismo , Neuroblastoma/mortalidade , Transdução de Sinais , Células Tumorais Cultivadas
J Surg Res ; 141(2): 252-6, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17490683


BACKGROUND: Reactive oxygen species are involved in several intracellular pathways that ultimately lead to the activation of the innate immune system. In addition, oxidized proteins and lipids could stimulate cytokine release from macrophages through the activation of membrane receptors. Thus we here describe the effects of antioxidant administration to septic rats on peritoneal macrophage parameters of oxidative stress and cytokine release. MATERIALS AND METHODS: Peritoneal macrophages from Wistar rats subjected to cecal ligation and puncture (CLP). The animals were divided into four groups: sham operated, CLP, basic support (saline plus antibiotics), basic support plus N-acetylcysteine, and deferoxamine. Several times after CLP macrophages were cultured to the determination of thiobarbituric acid reactive species (TBARS), protein carbonyls, mitochondrial superoxide production, catalase, superoxide dismutase activities, and released cytokines. RESULTS: Sepsis increased TBARS, protein carbonyls, and mitochondrial superoxide production in macrophages and this was associated with an increase release of pro-inflammatory cytokines. Basic support reversed TBARS and protein carbonyls content, but not mitochondrial superoxide production. The addition of antioxidants prevented all oxidative parameters in macrophages, and this was associated with lower cytokine release. Catalase and superoxide dismutase were modulated in the basic support group, but not in the antioxidant treated animals. CONCLUSIONS: Mitochondrial superoxide production seemed to be the differential oxidative parameter associated with antioxidant-induced modulation of cytokine release.

Antioxidantes/uso terapêutico , Citocinas/metabolismo , Macrófagos Peritoneais/imunologia , Mitocôndrias/metabolismo , Sepse/tratamento farmacológico , Superóxidos/metabolismo , Acetilcisteína/uso terapêutico , Animais , Desferroxamina/uso terapêutico , Masculino , Ratos , Ratos Wistar , Sepse/imunologia , Sepse/metabolismo , Transdução de Sinais , Substâncias Reativas com Ácido Tiobarbitúrico/análise
Am J Respir Crit Care Med ; 173(1): 84-90, 2006 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-16192447


RATIONALE: Several new therapeutic strategies have been described for the treatment of sepsis, but to date none are related to alterations in the bombesin/gastrin-releasing peptide (GRP) receptor pathways. OBJECTIVES: To determine the effects of a selective GRP receptor antagonist, RC-3095, on cytokine release from macrophages and its in vivo effects in the cecal ligation and puncture (CLP) model of sepsis and in acute lung injury induced by intratracheal instillation of LPS. METHODS: We determined the effects of RC-3095 in the CLP model of sepsis and in acute lung injury induced by intratracheal instillation of LPS. In addition, we determined the effects of RC-3095 on tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, IL-10, and nitric oxide release from activated macrophages. MEASUREMENTS AND MAIN RESULTS: The GRP antagonist attenuated LPS- or CLP-induced TNF-alpha, IL-1beta, and nitric oxide release in cultured macrophages and decreased the mRNA levels of inducible nitric oxide synthase. The administration of RC-3095 (0.3 mg/kg) 6 h after sepsis induction improved survival in the CLP model, and diminished lung damage after intratracheal instillation of LPS. These effects were associated with attenuation on the circulating TNF-alpha and IL-1beta levels and decreased myeloperoxidase activity in several organs. CONCLUSIONS: We report that a selective GRP receptor antagonist attenuates the release of proinflammatory cytokines in vitro and in vivo and improves survival in "established" sepsis. These are consistent with the involvement of a new inflammatory pathway relevant to the development of sepsis.

Anti-Inflamatórios/farmacologia , Bombesina/análogos & derivados , Fragmentos de Peptídeos/farmacologia , Receptores da Bombesina/antagonistas & inibidores , Síndrome do Desconforto Respiratório do Adulto/imunologia , Sepse/imunologia , Animais , Bombesina/farmacologia , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/biossíntese , Modelos Animais de Doenças , Íleo/efeitos dos fármacos , Íleo/imunologia , Rim/efeitos dos fármacos , Rim/imunologia , Fígado/efeitos dos fármacos , Fígado/imunologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Ativação de Macrófagos/efeitos dos fármacos , Ativação de Macrófagos/imunologia , Masculino , Ratos , Ratos Wistar , Receptores da Bombesina/imunologia