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1.
Nat Immunol ; 25(7): 1270-1282, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38877178

RESUMO

The relative and synergistic contributions of genetics and environment to interindividual immune response variation remain unclear, despite implications in evolutionary biology and medicine. Here we quantify interactive effects of genotype and environment on immune traits by investigating C57BL/6, 129S1 and PWK/PhJ inbred mice, rewilded in an outdoor enclosure and infected with the parasite Trichuris muris. Whereas cellular composition was shaped by interactions between genotype and environment, cytokine response heterogeneity including IFNγ concentrations was primarily driven by genotype with consequence on worm burden. In addition, we show that other traits, such as expression of CD44, were explained mostly by genetics on T cells, whereas expression of CD44 on B cells was explained more by environment across all strains. Notably, genetic differences under laboratory conditions were decreased following rewilding. These results indicate that nonheritable influences interact with genetic factors to shape immune variation and parasite burden.


Assuntos
Interação Gene-Ambiente , Camundongos Endogâmicos C57BL , Tricuríase , Trichuris , Animais , Trichuris/imunologia , Tricuríase/imunologia , Tricuríase/parasitologia , Camundongos , Receptores de Hialuronatos/genética , Receptores de Hialuronatos/metabolismo , Linfócitos B/imunologia , Genótipo , Interferon gama/metabolismo , Linfócitos T/imunologia , Feminino , Masculino
2.
Res Sq ; 2024 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-38712032

RESUMO

How macrophages in the tissue environment integrate multiple stimuli will depend on the genetic background of the host, but this is poorly understood. Here, we investigated C57BL/6 and BALB/c strain specific in vivo IL-4 activation of tissue-resident macrophages (TRMs) from the peritoneal cavity. C57BL/6 TRMs are more transcriptionally responsive to IL-4 stimulation, with a greater association of induced genes with super enhancers, induced enhancers, and topologically associating domains (TAD) boundaries. IL-4-directed epigenomic remodeling revealed BL/6 specific enrichment of NF-κB, IRF, and STAT motifs. Additionally, IL-4-activated BL/6 TRMs demonstrated an augmented synergistic response upon in vitro lipopolysaccharide (LPS) exposure compared to BALB/c TRMs, despite naïve BALB/c TRMs displaying a more robust transcriptional response to LPS than naïve BL/6 TRMs. Single-cell RNA sequencing (scRNA-seq) analysis of mixed bone marrow chimeric mice indicated that transcriptional differences between BL/6 and BALB/c TRMs, and synergy between IL-4 and LPS, are cell intrinsic within the same tissue environment. Hence, genetic variation alters IL-4-induced cell intrinsic epigenetic reprogramming resulting in strain specific synergistic responses to LPS exposure.

4.
bioRxiv ; 2023 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-36993484

RESUMO

The relative and synergistic contributions of genetics and environment to inter-individual immune response variation remain unclear, despite its implications for understanding both evolutionary biology and medicine. Here, we quantify interactive effects of genotype and environment on immune traits by investigating three inbred mouse strains rewilded in an outdoor enclosure and infected with the parasite, Trichuris muris. Whereas cytokine response heterogeneity was primarily driven by genotype, cellular composition heterogeneity was shaped by interactions between genotype and environment. Notably, genetic differences under laboratory conditions can be decreased following rewilding, and variation in T cell markers are more driven by genetics, whereas B cell markers are driven more by environment. Importantly, variation in worm burden is associated with measures of immune variation, as well as genetics and environment. These results indicate that nonheritable influences interact with genetic factors to shape immune variation, with synergistic impacts on the deployment and evolution of defense mechanisms.

5.
Inflamm Res ; 71(12): 1535-1546, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36280620

RESUMO

OBJECTIVE AND DESIGN: Our research aimed to investigate the role of CD14 in pulmonary infection by Achromobacter xylosoxidans in an experimental murine model. METHODS: C57Bl/6 or CD14-deficient mice were infected intratracheally with non-lethal inoculum of A. xylosoxidans. At times 1, 3 and 7 days after infection, lungs, bronchoalveolar lavage and blood were collected. CD14 gene expression was determined by RT-PCR. The bacterial load in the lungs was assessed by counting colony forming units (CFU). Cytokines, chemokines, lipocalin-2 and sCD14 were quantified by the ELISA method. Inflammatory infiltrate was observed on histological sections stained with HE, and leukocyte subtypes were assessed by flow cytometry. In another set of experiments, C57Bl/6 or CD14-deficient mice were inoculated with lethal inoculum and the survival rate determined. RESULTS: CD14-deficient mice are protected from A. xylosoxidans-induced death, which is unrelated to bacterial load. The lungs of CD14-deficient mice presented a smaller area of tissue damage, less neutrophil and macrophage infiltration, less pulmonary edema, and a lower concentration of IL-6, TNF-α, CXCL1, CCL2 and CCL3 when compared with lungs of C57Bl/6 mice. We also observed that A. xylosoxidans infection increases the number of leukocytes expressing mCD14 and the levels of sCD14 in BALF and serum of C57Bl/6-infected mice. CONCLUSIONS: In summary, our data show that in A. xylosoxidans infection, the activation of CD14 induces intense pulmonary inflammatory response resulting in mice death.


Assuntos
Achromobacter denitrificans , Infecções por Bactérias Gram-Negativas , Receptores de Lipopolissacarídeos , Pneumonia , Animais , Camundongos , Receptores de Lipopolissacarídeos/genética , Receptores de Lipopolissacarídeos/metabolismo , Pulmão/metabolismo , Camundongos Endogâmicos C57BL , Fator de Necrose Tumoral alfa/metabolismo , Infecções por Bactérias Gram-Negativas/metabolismo
6.
Front Immunol ; 13: 869163, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35572520

RESUMO

Helminth infection currently affect over 2 billion people worldwide, with those with the most pathologies and morbidities, living in regions with unequal and disproportionate access to effective healthcare solutions. Host genetics and environmental factors play critical roles in modulating and regulating immune responses following exposure to various pathogens and insults. However, the interplay of environment and genetic factors in influencing who gets infected and the establishment, persistence, and clearance of helminth parasites remains unclear. Inbred strains of mice have long been used to investigate the role of host genetic factors on pathogenesis and resistance to helminth infection in a laboratory setting. This review will discuss the use of ecological and environmental mouse models to study helminth infections and how this could be used in combination with host genetic variation to explore the relative contribution of these factors in influencing immune response to helminth infections. Improved understanding of interactions between genetics and the environment to helminth immune responses would be important for efforts to identify and develop new prophylactic and therapeutic options for the management of helminth infections and their pathogenesis.


Assuntos
Helmintíase , Helmintos , Parasitos , Animais , Interações Hospedeiro-Parasita/genética , Humanos , Imunidade , Camundongos
7.
Immunobiology ; 227(2): 152191, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35189540

RESUMO

Macrophages play pivotal roles during homeostasis and inflammation. They sense exogenous and endogenous molecular patterns via surface and intracellular receptors, which trigger innate immune responses. CD14 is a co-receptor for lipopolysaccharide (LPS), but also drives macrophage responses to Tityus serrulatus scorpion venom (TsV). Cellular activation is tightly coupled with metabolism that sustain their polarization and generate antimicrobial and signaling molecules. Macrophage's origin and nature of stimulus are critical for their responses, but whether these factors impact macrophage metabolism is unknown. Moreover, the regulation of intracellular metabolism by CD14 has not been assessed. Using an untargeted metabolomics approach, we determined the longitudinal metabolic responses of peritoneal (PMs) and bone marrow derived macrophages (BMDMs) stimulated with LPS and TsV for 12 h. These data revealed alterations on the relative levels of several metabolites and pathways related to amino acids, nucleotides, lipids, and vitamins. Our data suggest activation of selenoamino acid metabolism and increased abundance of selenomethionine in both cell subsets stimulated with LPS. Moreover, the results suggest a differential activity of vitamin B3 metabolism pathway in response to TsV stimulus, with differences on regulation of the relative levels of nicotinamide mononucleotide and deamino-NAD+. CD14 deficiency affects the metabolome of both cell subsets at steady state. Moreover, CD14 was required for arginine consumption in PMs stimulated with LPS, but not TsV or by BMDMs stimulated by both stimuli. Importantly, the data suggest that CD14 mediates the accumulation of lipids in both macrophage subsets stimulated with LPS, providing insights into the potential role of CD14 for the development of metabolic diseases. We conclude that macrophages acquire a spectrum of metabolic profiles that depend on the origin of these cells, the nature of the stimuli and signaling by innate immune receptors.


Assuntos
Lipopolissacarídeos , Venenos de Escorpião , Receptores de Lipopolissacarídeos/metabolismo , Lipopolissacarídeos/metabolismo , Macrófagos , Metabolômica , Venenos de Escorpião/metabolismo , Transdução de Sinais
8.
Codas ; 33(6): e20200054, 2021.
Artigo em Português, Inglês | MEDLINE | ID: mdl-34431856

RESUMO

PURPOSE: This study aimed to investigate, using the PINT Brasil, the influence of the interstimulus interval on the performance of children with moderate and severe hearing loss fitted with hearing aids. METHODS: Ten children with normal hearing (CG) and 20 children with hearing loss (SG) participated in the study. Both groups were assessed using the speech perception test called PINT Brasil in PAUSE and NO PAUSE situations. RESULTS: When comparing the PAUSE and NO PAUSE situations, only the SG presented a statistically significant difference, indicating that the NO PAUSE situation had the best performance. In this situation, the noise oscillations were smaller, and the noise reduction algorithm, which may cause the loss of message information, was not repeatedly activated. CONCLUSION: The interstimulus interval in the PINT Brasil influenced the performance of children with moderate and severe hearing loss fitted with hearing aids. The NO PAUSE situation presented the best results.


OBJETIVO: Investigar a influência do intervalo interestímulos no desempenho de crianças com deficiência auditiva de grau moderado e severo, adaptadas com aparelhos de amplificação sonora individuais (AASI), no teste PINT Brasil. MÉTODO: Participaram do estudo 10 crianças com audição normal (GC) e 20 crianças com deficiência auditiva (GE). O teste PINT Brasil foi aplicado nas situações SEM pausa e COM pausa para os dois grupos. RESULTADOS: Na comparação entre as situações SEM pausa e COM pausa, houve diferença significativa apenas para o GE, indicando a SEM pausa com melhor desempenho. Nesta última condição, as oscilações ruidosas foram menores e não houve o acionamento repetido do redutor de ruído, o que possibilita a perda de informações da mensagem. CONCLUSÃO: Conclui-se que o intervalo interestímulos no teste de percepção da fala PINT Brasil influenciou o desempenho das crianças com deficiência auditiva de grau moderado e severo, adaptadas com AASI. O melhor resultado foi encontrado na situação SEM PAUSA.


Assuntos
Auxiliares de Audição , Perda Auditiva , Percepção da Fala , Brasil , Criança , Perda Auditiva/diagnóstico , Humanos , Ruído
9.
Braz J Otorhinolaryngol ; 87(2): 164-170, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-31718997

RESUMO

INTRODUCTION: One of the main implications of hearing impairment is the difficulty in perceiving speech sounds, especially in noisy environments. Thus, the frequency-modulated system is considered an important educational tool for children with hearing impairment because it improves speech perception in acoustically-unfavorable environments, such as in the classroom. The assessment of speech perception in noise is included in the verification protocol of this device. OBJECTIVES: To verify the effectiveness of the phrases in noise test Brazil in children with hearing impairment using an frequency-modulated system. METHODS: This was a cross-sectional cohort study. The sample included 40 children, aged 4 years to 11 years and 11 months old, divided into 4 groups: (1) 10 normal hearing children; (2) 13 children with hearing aids and frequency-modulated system; (3) 12 children using cochlear implant and fitted with the frequency-modulated system; and (4) 5 children diagnosed with auditory neuropathy spectrum disorder, fitted with hearing aids and/or cochlear implant and with the frequency-modulated system. The phrases in noise test Brazil was used to evaluate speech perception in noise under the conditions with and without the frequency-modulated system. For the statistical analysis of the data, a significance level of 5% (p < 0.05) was adopted. RESULTS: There was a significant difference between the groups when they were evaluated with the frequency-modulated system. The test was also validated through concurrent and convergent validation measures. Phrases in noise test Brazil is a viable option for monitoring auditory performance in noise in different groups of children with hearing impairmen. CONCLUSION: Phrases in noise test Brazil was effective in assessing speech perception in noise and may contribute to the improvement of the indication, fitting and follow-up protocols for the frequency-modulated system use.


Assuntos
Implantes Cocleares , Surdez , Auxiliares de Audição , Perda Auditiva , Percepção da Fala , Brasil , Criança , Pré-Escolar , Estudos Transversais , Perda Auditiva/diagnóstico , Humanos , Lactente , Ruído
10.
Life Sci ; 266: 118868, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33310034

RESUMO

Liver steatosis is one of the main drivers for the development of whole-body insulin resistance. Conversely, aerobic training (AT) has been suggested as non-pharmacological tool to improve liver steatosis, however, the underlying molecular mechanism remains unclear. Therefore, the aim of this study was to analyze the effect of 8-weeks AT in non-alcoholic liver disease (NAFLD) outcomes in obese mice. Male C57BL/6 J wild type (WT) were fed with standard (SD) or high-fat diet (HFD) for 12-weeks. Another group fed with HFD underwent 8-weeks of AT (60% of maximum velocity), initiated at the 5th week of experimental protocol. We measured metabolic, body composition parameters, protein and gene expression inflammatory and metabolic mediators. We found that AT attenuates the weight gain, but not body fat accumulation. AT improved triacylglycerol and non-esterified fatty acid plasma concentrations, and also whole-body insulin resistance. Regarding NAFLD, AT decreased the progression of macrovesicular steatosis and inflammation through the upregulation of AMPK Thr172 phosphorylation and PPAR-α protein expression. Moreover, although no effects of intervention in PPAR-γ protein concentration were observed, we found increased levels of its target genes Cd36 and Scd1 in exercised group, demonstrating augmented transcriptional activity. AT reduced liver cytokines concentrations, such as TNF-α, IL-10, MCP-1 and IL-6, regardless of increased Ser536 NF-κB phosphorylation. In fact, none of the interventions regulated NF-κB target genes Il1b and Cccl2, demonstrating its low transcriptional activity. Therefore, we conclude that AT attenuates the progression of liver macrovesicular steatosis and inflammation through AMPK-PPAR-α signaling and PPAR-γ activation, respectively, improving insulin resistance in obese mice.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Inflamação/prevenção & controle , Resistência à Insulina , Hepatopatia Gordurosa não Alcoólica/terapia , Obesidade/complicações , PPAR alfa/metabolismo , Condicionamento Físico Animal , Proteínas Quinases Ativadas por AMP/genética , Animais , Biomarcadores/análise , Citocinas/metabolismo , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Fígado/imunologia , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , PPAR alfa/genética , Transdução de Sinais
11.
Front Microbiol ; 11: 1973, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32922381

RESUMO

Infection by Schistosoma parasites culminates in a chronic granulomatous disease characterized by intense tissue fibrosis. Along the course of schistosomiasis, diverse leukocytes are recruited for inflammatory foci. Innate immune cell accumulation in Th2-driven granulomas around Schistosoma eggs is associated with increased collagen deposition, while monocytes and macrophages exert critical roles during this process. Monocytes are recruited to damaged tissues from blood, produce TGF-ß and differentiate into monocyte-derived macrophages (MDMs), which become alternatively activated by IL-4/IL-13 signaling via IL-4Rα (AAMs). AAMs are key players of tissue repair and wound healing in response to Schistosoma infection. Alternative activation of macrophages is characterized by the activation of STAT6 that coordinates the transcription of Arg1, Chi3l3, Relma, and Mrc1. In addition to these markers, monocyte-derived AAMs also express Raldh2 and Pdl2. AAMs produce high levels of IL-10 and TGF-ß that minimizes tissue damage caused by Schistosoma egg accumulation in tissues. In this review, we provide support to previous findings about the host response to Schistosoma infection reusing public transcriptome data. Importantly, we discuss the role of monocytes and macrophages with emphasis on the mechanisms of alternative macrophage activation during schistosomiasis.

12.
PLoS Pathog ; 15(8): e1007990, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31425553

RESUMO

The granulomatous lesion resulting from infection with the fungus Paracoccidioides brasiliensis is characterized by a compact aggregate of mature cells, surrounded by a fibroblast- and collagen-rich content. Granuloma formation requires signaling elicited by inflammatory molecules such as members of the interleukin-1 family. Two members of this family have been thoroughly studied, namely IL-1α and IL-1ß. In this study, we addressed the mechanisms underlying IL-1α secretion and its functional role on the host resistance to fungal infection. We found that, the expression of caspase-11 triggered by P. brasiliensis infection of macrophages depends on IFN-ß production, because its inhibition reduced procaspase-11 levels. Curiously, caspase-11 deficiency did not impair IL-1ß production, however caspase-11 was required for a rapid pore-mediated cell lysis. The plasma membrane rupture facilitated the release of IL-1α, which was necessary to induce NO production and restrict fungal replication. Furthermore, P. brasiliensis-infected macrophages required IL-1α to produce optimal levels of IL-6, a major component of Th17 lymphocyte differentiation. Indeed, IL-1α deficiency accounted for a significant reduction of Th17 lymphocytes in lungs of infected mice, correlating with diminished neutrophil infiltration in the lungs. Strikingly, we identified that IL-1α directly reprograms the transcriptional profile of Th17-committed lymphocytes, increasing cellular proliferation, as for boosting IL-17 production by these cells. Beyond neutrophil chemotaxis in vivo, IL-17 also amplified IL-1α production by infected macrophages in vitro, endorsing a critical amplification loop of the inflammatory response. Therefore, our data suggest that the IFN-ß/caspase-11/IL-1α pathway shapes a protective antifungal Th17 immunity, revealing a molecular mechanism underlying the cross-talk between innate and adaptive immunity.


Assuntos
Caspases/fisiologia , Imunidade Inata/imunologia , Interleucina-1alfa/metabolismo , Macrófagos/imunologia , Paracoccidioides/imunologia , Paracoccidioidomicose/imunologia , Células Th17/imunologia , Animais , Caspases Iniciadoras , Inflamassomos , Macrófagos/metabolismo , Macrófagos/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Paracoccidioidomicose/metabolismo , Paracoccidioidomicose/microbiologia , Células Th17/metabolismo , Células Th17/microbiologia
13.
J Cell Physiol ; 234(4): 5241-5251, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30238979

RESUMO

BACKGROUND: Exercise is a powerful tool for prevention and treatment of many conditions related to the cardiovascular system and also chronic low-grade inflammation. Peroxisome proliferator-activated receptors γ (PPARγ) exerts an import role on the regulation of metabolic profile and subsequent inflammatory response, especially in macrophages. PURPOSE: To investigate the effects of 8-week moderate-exercise training on metabolic and inflammatory parameters in mice with PPARγ deficiency in myeloid cells. METHODS: Twelve-week old mice bearing PPARγ deletion exclusively in myeloid cells (PPARγlox/lox Lys Cre -/+ , knockout [KO]) and littermate controls (PPARγlox/lox Lys Cre -/- , wild type [WT]) were submitted to 8-week exercise training (treadmill running at moderate intensity, 5 days/week). Animals were evaluated for food intake, glucose homeostasis, serum metabolites, adipose tissue and peritoneal macrophage inflammation, and basal and stimulated cytokine secretion. RESULTS: Exercise protocol did not improve glucose metabolism or adiponectin concentrations in serum of KO mice. Moreover, the absence of PPARγ in macrophages exacerbated the proinflammatory profile in sedentary mice. Peritoneal cultured cells had higher tumor necrosis factor-α (TNF-α) secretion in nonstimulated and lipopolysaccharide (LPS)-stimulated conditions and higher Toll-4 receptor (TLR4) gene expression under LPS stimulus. Trained mice showed reduced TNF-α content in adipose tissue independently of the genotype. M2 polarization ability was impaired in KO peritoneal macrophages after exercise training, while adipose tissue-associated macrophages did not present any effect by PPARγ ablation. CONCLUSION: Overall, PPARγ seems necessary to maintain macrophages appropriate response to inflammatory stimulus and macrophage polarization, affecting also whole body lipid metabolism and adiponectin profile. Exercise training showed as an efficient mechanism to restore the immune response impaired by PPARγ deletion in macrophages.


Assuntos
Plasticidade Celular , Metabolismo Energético , Mediadores da Inflamação/metabolismo , Macrófagos Peritoneais/metabolismo , PPAR gama/deficiência , Condicionamento Físico Animal/métodos , Adiponectina/sangue , Tecido Adiposo/metabolismo , Animais , Células Cultivadas , Deleção de Genes , Lipídeos/sangue , Macrófagos Peritoneais/imunologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , PPAR gama/genética , Fenótipo , Resistência Física , Fatores de Tempo
14.
Mol Nutr Food Res ; 62(20): e1800322, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30102465

RESUMO

SCOPE: Fatty acids (FAs) may affect endothelial cell (EC) function, influencing atherogenesis and inflammatory processes. Palmitoleic acid (POA) has been described as an anti-inflammatory FA. However, its effects on ECs are underexplored. This study compares the effects of POA with those of palmitic acid (PA) and oleic acid (OA) on EC inflammatory responses. METHODS AND RESULTS: EAHy926 cells (EC lineage) are exposed to PA, OA, or POA, and stimulated with tumor necrosis factor (TNF)-α. Associated with the FA's own incorporation, PA induces a twofold increase in arachidonic acid, while POA increases the amount of cis-vaccenic acid. PA, but not OA, enhances the production of IL-6 and IL-8 in response to TNF-α. In contrast, POA decreases production of monocyte chemotactic protein (MCP)-1, IL-6, and IL-8 compared to PA. TNF-α increases surface intercellular adhesion molecule-1 expression previously decreased by POA. TNF-α stimulation increases the expression of NFκB, cyclooxygenase (COX)-2, MCP-1, and IL-6 genes and reduces the expression of peroxisome proliferator-activated receptor (PPAR)-α gene. PA enhances the expression of MCP-1, IL-6, and COX-2 genes, while POA downregulates these genes, decreases expression of NFκB, and upregulates PPAR-α gene expression. CONCLUSION: POA has anti-inflammatory effects on ECs stimulated with TNF-α and may counter endothelial dysfunction.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Células Endoteliais/efeitos dos fármacos , Ácidos Graxos Monoinsaturados/farmacologia , Ácido Oleico/farmacologia , Ácidos Palmíticos/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Quimiocina CCL5/genética , Quimiocina CCL5/metabolismo , Ácidos Graxos Monoinsaturados/farmacocinética , Regulação da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana , Humanos , Inflamação/tratamento farmacológico , Inflamação/genética , Inflamação/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Ácido Oleico/farmacocinética , Ácidos Palmíticos/farmacocinética , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
15.
Front Immunol ; 8: 949, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28871251

RESUMO

Paracoccidioidomycosis (PCM), a chronic granulomatous disease caused by the thermally dimorphic fungus Paracoccidioides brasiliensis and Paracoccidioides lutzii, has the highest mortality rate among systemic mycosis. The T helper 1-mediated immunity is primarily responsible for acquired resistance during P. brasiliensis infection, while susceptibility is associated with Th2 occurrence. Th17 is a population of T CD4+ cells that, among several chemokines and cytokines, produces IL-17A and requires the presence of IL-1, IL-6, and TGF-ß for differentiation in mice and IL-23 for its maintenance. Th17 has been described as an arm of the immune system that enhances host protection against several bacterial and fungal infections, as Pneumocystis carinii and Candida albicans. In this study, we aimed to evaluate the Th17 immune response and the role of Th17-associated cytokines (IL-6, IL-23, and IL-17A) during experimental PCM. First, we observed that P. brasiliensis infection [virulent yeast strain 18 of P. brasiliensis (Pb18)] increased the IL-17A production in vitro and all the evaluated Th17-associated cytokines in the lung tissue from C57BL/6 wild-type mice. In addition, the deficiency of IL-6, IL-23, or IL-17 receptor A (IL-17RA) impaired the compact granuloma formation and conferred susceptibility during infection, associated with reduced tumor necrosis factor-α, IFN-γ, and inducible nitric oxide synthase enzyme expression. Our data suggest that IL-6 production by bone marrow-derived macrophages (BMDMs) is important to promote the Th17 differentiation during Pb18 infection. In accordance, the adoptive transfer of BMDMs from C57BL/6 to infected IL-6-/- or IL-17RA-/- mice reduced the fungal burden in the lungs compared to nontransferred mice and reestablished the pulmonary granuloma formation. Taken together, these results suggest that Th17-associated cytokines are involved in the modulation of immune response and granuloma formation during experimental PCM.

16.
Sci Rep ; 7(1): 1070, 2017 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-28432311

RESUMO

Ingested fluoride (F) is absorbed mainly in the small intestine, which is controlled by the Enteric Nervous System (ENS). Although important intestinal symptomatology has been described after excessive F exposure, there have been no studies reporting the effects of F on the ENS. In this study, the effects of chronic F exposure were evaluated on the duodenums of rats through proteomic and morphological analyses. Concentrations of 0, 10, or 50 ppm of F were applied to the drinking water for 30 days. Immunofluorescence techniques were performed in the myenteric plexus of the duodenum to detect HuC/D, neuronal nitric oxide (nNOS), vasoactive intestinal peptide (VIP), calcitonin gene related peptide (CGRP), and substance P (SP). The 50 ppm F group presented a significant decrease in the density of nNOS-IR neurons. Significant morphological alterations were also observed in HUC/D-IR and nNOS-IR neurons; VIP-IR, CGRP-IR, and SP-IR varicosities for both groups (10 and 50 ppm F). Proteomic analysis of the duodenum demonstrated alterations in the expression of several proteins, especially those related to important biological processes, such as protein polymerization, which helps to explain the downregulation of many proteins upon exposure to 50 ppm of F.


Assuntos
Cariostáticos/administração & dosagem , Duodeno/efeitos dos fármacos , Fluoretos/administração & dosagem , Sistema Nervoso/efeitos dos fármacos , Proteoma/análise , Administração Oral , Animais , Cariostáticos/toxicidade , Duodeno/patologia , Imunofluorescência , Fluoretos/toxicidade , Sistema Nervoso/patologia , Proteômica , Ratos
17.
PLoS One ; 11(3): e0151548, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27015538

RESUMO

White adipose tissue (WAT) plays a fundamental role in maintaining energy balance and important endocrine functions. The loss of WAT modifies adipokine secretion and disrupts homeostasis, potentially leading to severe metabolic effects and a reduced quality of life. Doxorubicin is a chemotherapeutic agent used clinically because of its good effectiveness against various types of cancer. However, doxorubicin has deleterious effects in many healthy tissues, including WAT, liver, and skeletal and cardiac muscles. Our objective was to investigate the effects of doxorubicin on white adipocytes through in vivo and in vitro experiments. Doxorubicin reduced the uptake of glucose by retroperitoneal adipocytes and 3T3-L1 cells via the inhibition of AMP-activated protein kinase Thr172 phosphorylation and glucose transporter 4 content. Doxorubicin also reduced the serum level of adiponectin and, to a greater extent, the expression of genes encoding lipogenic (Fas and Acc) and adipogenic factors (Pparg, C/ebpa, and Srebp1c) in retroperitoneal adipose tissue. In addition, doxorubicin inhibited both lipogenesis and lipolysis and reduced the hormone-sensitive lipase and adipose tissue triacylglycerol lipase protein levels. Therefore, our results demonstrate the impact of doxorubicin on WAT. These results are important to understand some side effects observed in patients receiving chemotherapy and should encourage new adjuvant treatments that aim to inhibit these side effects.


Assuntos
Adipocinas/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Doxorrubicina/administração & dosagem , Metabolismo Energético/efeitos dos fármacos , Células 3T3-L1 , Proteínas Quinases Ativadas por AMP/biossíntese , Proteínas Quinases Ativadas por AMP/genética , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Adiponectina/biossíntese , Adiponectina/genética , Tecido Adiposo Branco/metabolismo , Animais , Doxorrubicina/efeitos adversos , Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Humanos , Insulina/genética , Insulina/metabolismo , Lipogênese/genética , Camundongos
18.
Biomed Rep ; 3(6): 827-830, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26623024

RESUMO

Studies have shown that topiramate (TPM)-induced weight loss can be dependent on the central nervous system (CNS). However, the direct action of TPM on adipose tissue has not been tested previously. Thus, the present study aimed to examine whether TPM modulates lipolysis in 3T3-L1. The 3T3-L1 cells were incubated in 50 µM TPM for 30 min. The ß-adrenergic stimulator, isoproterenol, was used as a positive control. The release of lactate dehydrogenase, non-esterified fatty acid, glycerol and incorporation of 14C-palmitate to lipid were analyzed. The phosphorylation of protein kinase A (PKA), hormone-sensitive lipase (HSL), adipocyte triglyceride lipase (ATGL) and perilipin A, as well as the protein levels of comparative genetic identification 58 (CGI-58) were assessed. The levels of glycerol and non-esterified fatty acid increased markedly when the cells were treated with TPM. The TPM effects were similar to the isoproterenol positive control. Additionally, TPM reduced lipogenesis. These results were observed without any change in cell viability. Finally, the phosphorylation of PKA, HSL, ATGL and perilipin A, as well as the protein levels of CGI-58 were increased compared to the control cells. These results were similar to those observed in the cells treated with isoproterenol. The present results show that TPM increased the phosphorylation of pivotal lipolytic enzymes, which induced lipolysis in 3T3-L1 adipocytes, suggesting that this drug may act directly in the adipose tissue independent from its effect on the CNS.

19.
Cell Physiol Biochem ; 36(4): 1659-69, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26160389

RESUMO

BACKGROUND/AIMS: The main purpose of this study was to investigate the effects of celecoxib and ibuprofen, both non-steroidal anti-inflammatory drugs (NSAIDs), on the decreased gluconeogenesis observed in liver of Walker-256 tumor-bearing rats. METHODS: Celecoxib and ibuprofen (both at 25 mg/Kg) were orally administered for 12 days, beginning on the same day when the rats were inoculated with Walker-256 tumor cells. RESULTS: Celecoxib and ibuprofen treatment reversed the reduced production of glucose, pyruvate, lactate and urea from alanine as well as the reduced production of glucose from pyruvate and lactate in perfused liver from tumor-bearing rats. Besides, celecoxib and ibuprofen treatment restored the decreased ATP content, increased triacylglycerol levels and reduced mRNA expression of carnitine palmitoyl transferase 1 (CPT1), while ibuprofen treatment restored the reduced mRNA expression of peroxisome proliferator-activated receptor alpha (PPARα) in the liver of tumor-bearing rats. Both treatments tended to decrease TNFα, IL6 and IL10 in the liver of tumor-bearing rats. Finally, the treatment with celecoxib, but not with ibuprofen, reduced the growth of Walker-256 tumor. CONCLUSION: Celecoxib and ibuprofen restored the decreased gluconeogenesis in the liver of Walker-256 tumor-bearing rats. These effects did not involve changes in tumor growth and probably occurred by anti-inflammatory properties of these NSAIDs, which increased expression of genes associated with fatty acid oxidation (PPARα and CPT1) and consequently the ATP production, normalizing the energy status in the liver of tumor-bearing rats.


Assuntos
Trifosfato de Adenosina/metabolismo , Anti-Inflamatórios não Esteroides/uso terapêutico , Celecoxib/uso terapêutico , Gluconeogênese/efeitos dos fármacos , Ibuprofeno/uso terapêutico , Fígado/efeitos dos fármacos , Neoplasias/metabolismo , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Celecoxib/farmacologia , Ibuprofeno/farmacologia , Fígado/metabolismo , Masculino , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Ratos , Ratos Wistar
20.
Mol Cell Biochem ; 399(1-2): 237-46, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25359170

RESUMO

The contribution of anti-inflammatory property of celecoxib in the improvement of metabolic disorders in cancer is unknown. The purpose of this study was to compare the effects of celecoxib and ibuprofen, non-steroidal anti-inflammatory drugs (NSAIDs), on several metabolic changes observed in Walker-256 tumor-bearing rats. The effects of these NSAIDs on the tumor growth were also assessed. Celecoxib or ibuprofen (both at 25 mg/Kg) was administered orally for 12 days, beginning on the day the rats were inoculated with Walker-256 tumor cells. Celecoxib treatment prevented the losses in body mass and mass of retroperitoneal adipose tissue, gastrocnemius, and extensor digitorum longus muscles in tumor-bearing rats. Celecoxib also prevented the rise in blood levels of triacylglycerol, urea, and lactate, the inhibition of peripheral response to insulin and hepatic glycolysis, and tended to attenuate the decrease in the food intake, but had no effect on the reduction of glycemia induced by the tumor. In addition, celecoxib treatment increased the number of Walker-256 cells with signs of apoptosis and the tumor necrosis area and prevented the tumor growth. In contrast, ibuprofen treatment had no effect on metabolic parameters affected by the Walker-256 tumor or tumor growth. It can be concluded that celecoxib, unlike ibuprofen, ameliorated several metabolic changes in rats with Walker-256 tumor due to its anti-tumor effect and not its anti-inflammatory property.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Caquexia/tratamento farmacológico , Carcinoma 256 de Walker/metabolismo , Ibuprofeno/farmacologia , Pirazóis/farmacologia , Sulfonamidas/farmacologia , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Área Sob a Curva , Caquexia/etiologia , Carcinoma 256 de Walker/complicações , Carcinoma 256 de Walker/tratamento farmacológico , Celecoxib , Linhagem Celular Tumoral , Ingestão de Alimentos/efeitos dos fármacos , Ibuprofeno/uso terapêutico , Gordura Intra-Abdominal/efeitos dos fármacos , Gordura Intra-Abdominal/patologia , Masculino , Transplante de Neoplasias , Tamanho do Órgão/efeitos dos fármacos , Pirazóis/uso terapêutico , Ratos Wistar , Sulfonamidas/uso terapêutico , Redução de Peso/efeitos dos fármacos
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