RESUMO
Cytokines of the interleukin (IL)-1 superfamily including the different IL-36 isoforms, have been reported as mediators of acute and chronic inflammation in human skin diseases, such as psoriasis. Here, we demonstrated for the first time that Sporothrix schenckii and S. brasiliensis, the fungi that cause subcutaneous infection sporotrichosis, can induce the expression of IL-36α, IL-36γ and IL-36Ra in human keratinocytes and primary peripheral blood mononuclear cells (PBMCs). Specifically, IL-36γ was differentially expressed by keratinocytes stimulated with Sporothrix yeasts when compared to the commensal microorganism Staphylococcus epidermidis. The exposure of keratinocytes to 24 h or 7-days culture supernatant of PBMCs stimulated with Sporothrix induced higher IL-36γ production compared to direct stimulation of keratinocytes with the live fungus. We identified that IL-36γ mRNA expression in keratinocytes is increased in the presence of IL-17, TNF, IL-1ß and IL-1α and these cytokines may act synergistically to maintain IL-36γ production. Lastly, using a cohort of 164 healthy individuals, we showed that individuals carrying variants of the IL36G gene (rs11690399 and rs11683399) exhibit increased IL-36γ production as well as increased innate cytokine production after Sporothrix exposure. Importantly, stimulation of PBMCs with recombinant IL-36γ increased the production of IL-1ß and IL-6, while IL-36Ra were able to decrease the concentration of these cytokines. Our findings contribute to the understanding of the pathogenesis of sporotrichosis and suggest that IL-36γ may be involved in maintaining the cytokine loop that leads to tissue destruction by exacerbating the immune response in sporotrichosis. Of high interest, we present the IL-36 signalling pathway as a potential new therapeutic target.
Assuntos
Sporothrix , Esporotricose , Humanos , Citocinas/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucinas/genética , Interleucinas/metabolismo , Queratinócitos , Leucócitos Mononucleares , Sporothrix/genéticaRESUMO
Sporotrichosis is a deep mycosis caused by dimorphic species of the genus Sporothrix, with differences in pathogenicity between S. schenckii and S. brasiliensis species. Recently, it was discovered that the cell wall peptidorhamnomannan (PRM) from S. brasiliensis has additional unknown rhamnose residues. We hypothesize that the structural differences of Sporothrix spp PRMs impact the host's immune response and may explain the severity of sporotrichosis caused by S. brasiliensis. We demonstrate that S. brasiliensis yeasts and its PRM (S.b PRM) induced a strong inflammatory response in human PBMCs, with high production of TNF-α, IL-6 and IL-1ß and induction of T-helper cytokines IFN-γ, IL-17 and IL-22. In contrast, S. schenckii yeasts and its PRM induced higher concentrations of interleukin-1 receptor antagonist (IL-1Ra), which resulted in low production of T-helper cytokines such as IL-17 and IL-22. CR3 and dectin-1 were required for cytokine induction by both PRMs, while TLR2 and TLR4 were required for the response of S.s PRM and S.b PRM, respectively. IL-1ß and IL-1α production induced by S. brasiliensis yeasts and S.b PRM were dependent on inflammasome and caspase-1 activation. S. schenckii and S.s PRM were able to induce IL-1ß independent of ROS. In conclusion, these findings improve our understanding of the pathogenesis of Sporothrix spp. by reporting differences of immunological responses induced by S. schenckii and S. brasiliensis. The study also opens the gateway for novel treatment strategies targeting local inflammation and tissue destruction induced by S. brasiliensis infection through IL-1 inhibition.
Assuntos
Sporothrix , Esporotricose , Citocinas , Glicoproteínas , Humanos , Interleucina-17 , Esporotricose/patologiaRESUMO
BACKGROUND: Clown intervention has been shown to enhance emotional and behavioral processes, but few studies have comprehensively examined the effectiveness of this practice using biomarkers. OBJECTIVE: The aim of this study was to evaluate the effect of a clown intervention on the levels of psychological stress and cancer-related fatigue in pediatric patients with cancer undergoing chemotherapy. METHODS: Sixteen patients who met all criteria from a pediatric oncology inpatient unit in a Brazilian comprehensive cancer care hospital participated in this quasi-experimental study. Eight saliva samples were collected, comprising 4 at baseline and 4 after clown intervention (+1, +4, +9, and +13 hours after awakening). Salivary cortisol and α-amylase levels were determined using high-sensitivity enzyme-linked immunosorbent assay kits. Stress and fatigue were measured by the Child Stress Scale-ESI and the PedsQL Multidimensional Fatigue Scale, respectively. Relationships among stress, fatigue, and biomarker levels were investigated using nonparametric statistics. RESULTS: In comparison with baseline measurements, the total psychological stress and fatigue levels improved after the clown intervention at the collection time point +4 hours (P = .003 and P = .04, respectively). Salivary cortisol showed a significant decrease after clown intervention at the collection time points +1, +9, and +13 hours (P < .05); however, α-amylase levels remained unchanged. CONCLUSION: These findings provide preliminary evidence that clown intervention merits further study as a way to reduce stress and fatigue in pediatric cancer inpatients, and that self-report and biomarker measures are feasible to collect in this patient group. IMPLICATIONS FOR PRACTICE: Clown intervention as a nonpharmacological intervention may improve stress and fatigue levels in pediatric inpatients with cancer undergoing chemotherapy.
Assuntos
Fadiga/prevenção & controle , Terapia do Riso , Neoplasias/tratamento farmacológico , Neoplasias/psicologia , Estresse Psicológico/prevenção & controle , Adolescente , Biomarcadores/análise , Brasil , Criança , Feminino , Humanos , Hidrocortisona/análise , Masculino , Saliva/química , Resultado do Tratamento , alfa-Amilases/análiseRESUMO
Behavioral comorbidities (depression, anxiety, fatigue, cognitive disturbances, and neuropathic pain) are prevalent in cancer patients and survivors. These mental and neurological health issues reduce quality-of-life, which is a significant societal concern given the increasing rates of long-term survival after various cancers. Hypothesized causes of behavioral comorbidities with cancer include tumor biology, stress associated with the cancer experience, and cancer treatments. A relatively recent leading mechanism by which these causes contribute to changes in neurobiology that underlie behavior is inflammation. Indeed, both basic and clinical research indicates that peripheral inflammation leads to central inflammation and behavioral changes in other illness contexts. Given the limitations of assessing neuroimmunology in clinical populations, this review primarily synthesizes evidence of neuroimmune and neuroinflammatory changes due to two components of cancer (tumor biology and cancer treatments) that are associated with altered affective-like or cognitive behaviors in rodents. Specifically, alterations in microglia, neuroinflammation, and immune trafficking to the brain are compiled in models of tumors, chemotherapy, and/or radiation. Evidence-based neuronal mechanisms by which these neuroimmune changes may lead to changes in behavior are proposed. Finally, converging evidence in clinical cancer populations is discussed.
Assuntos
Ansiedade/epidemiologia , Comportamento/fisiologia , Depressão/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Neoplasias/epidemiologia , Neuroimunomodulação , Comportamento Problema/psicologia , Animais , Ansiedade/etiologia , Depressão/etiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/psicologia , Humanos , Inflamação , Neoplasias/psicologia , Neoplasias/terapiaRESUMO
BACKGROUND: Pediatric cancer patients experience different psychological processes during hospitalization that may regulate the immune response and affect recovery and response to cancer treatment. In this study, we aimed to examine the feasibility of longitudinal testing of psychophysiological parameters of stress and fatigue in pediatric osteosarcoma patients hospitalized for chemotherapy submitted to clown intervention; and to investigate whether changes in the levels of biomarkers are associated with psychological stress and fatigue levels in these patients after the clown intervention. METHODS: A pretest-posttest quasi-experimental pilot study was conducted at the pediatric oncology inpatient unit in a comprehensive cancer care center in Brazil including children and adolescents with osteosarcoma hospitalized for chemotherapy. Eight saliva samples were collected, comprising 4 at baseline (pre-intervention) and 4 after the clown intervention (+1, +4, +9, and +13 hours post-awakening). Salivary cortisol, α-amylase (sAA), cytokines, and matrix metalloproteinase-9 (MMP-9) levels were determined using high-sensitivity enzyme-linked immunosorbent assay (ELISA) kits. Stress and fatigue were measured by Child Stress Scale-ESI and PedsQL Multidimensional Fatigue Scale respectively. Bivariate association analysis between stress and fatigue scores and biomarker levels were investigated using nonparametric statistics. Effect sizes were calculated for each outcome variable. RESULTS: Six pediatric osteosarcoma patients were enrolled with no missing data. No significant effects sizes were observed for psychophysiological outcomes. Effect sizes ranged from 0.54 (cortisol) to 0 (interleukin-1ß [IL-1ß]). Decreasing overall trends were observed for cortisol levels for all 6 pediatric osteosarcoma patients over time. In addition, a similar pattern of tumor necrosis factor-α (TNF-α) levels over time was found for all 6 patients. Patients with metastatic osteosarcoma showed a linear trend for a decrease in MMP-9 levels between 1 and 9 hours after the clown intervention and restoration to basal levels after 13 hours. CONCLUSIONS: The results of this pilot study suggest that it is feasible longitudinally measure psychophysiological outcomes in the pediatric osteosarcoma inpatients for chemotherapy. Clown intervention merits further study as a way to reduce stress as well as fatigue, since that the stress and cytokines measurements are feasible based on our work.
Assuntos
Biomarcadores , Neoplasias Ósseas , Fadiga/diagnóstico , Felicidade , Osteossarcoma , Terapia Recreacional/métodos , Estresse Psicológico/diagnóstico , Adolescente , Afeto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores/análise , Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/psicologia , Neoplasias Ósseas/terapia , Criança , Fadiga/etiologia , Fadiga/psicologia , Fadiga/terapia , Feminino , Humanos , Masculino , Osteossarcoma/diagnóstico , Osteossarcoma/psicologia , Osteossarcoma/terapia , Projetos Piloto , Autorrelato , Estresse Psicológico/etiologia , Estresse Psicológico/prevenção & controle , Estresse Psicológico/psicologiaRESUMO
Interleukin 32 (IL-32) is an intracellular cytokine produced by immune and non immune cells after different stimuli. It contributes to inflammation and control of intracellular pathogens mainly by inducing proinflammatory cytokines and microbicidal molecules. Evidence is rising showing that IL-32 can be considered an endogenous danger signal after tissue injury, amplifying the inflammatory process and acquired immune responses. It seems to be a master regulator of intracellular infectious diseases. In this review, first the general properties of IL-32 are described followed by its role in the immunopathogenesis of inflammatory and infectious diseases. Roles of IL-32 in the control of infectious diseases caused by intracellular pathogens are reported, and later a focus on IL-32 in leishmaniases, diseases caused by an intracellular protozoan, is presented.
Assuntos
Mediadores da Inflamação/imunologia , Interleucinas/imunologia , Espaço Intracelular/imunologia , Leishmania/imunologia , Leishmaniose/imunologia , Transdução de Sinais/imunologia , Animais , Citocinas/imunologia , Citocinas/metabolismo , Interações Hospedeiro-Parasita/imunologia , Humanos , Mediadores da Inflamação/metabolismo , Interleucinas/metabolismo , Espaço Intracelular/parasitologia , Leishmania/fisiologia , Leishmaniose/metabolismo , Leishmaniose/parasitologiaRESUMO
Cryptococcal species vary in capsule and cell size, thermotolerance, geographic distribution, and affected populations. Cryptococcus gattii sensu stricto and C. deuterogattii affect mainly immunocompetent hosts; however, C. bacillisporus, C. decagattii, and C. tetragattii cause infections mainly in immunocompromised hosts. This study aimed to compare the capacities of different species of the C. gattii species complex to induce cytokines and antimicrobial molecules in human peripheral blood mononuclear cells (PBMCs). Cryptococcus bacillisporus and C. deuterogattii induced the lowest levels of tumor necrosis factor alpha (TNF-α), interleukin-1ß (IL-1ß), and IL-6 among the five species of the C. gattii complex. Cryptococcus deuterogattii induced higher levels of IL-22 than those induced by C. tetragattii and the environmental species C. flavescens In addition, C. bacillisporus and C. gattii sensu stricto proliferated inside human monocyte-derived macrophages after 24 h of infection. All Cryptococcus species were able to generate reactive oxygen species (ROS) in human PBMCs, with C. bacillisporus and C. deuterogattii being more efficient than the other species. In conclusion, C. bacillisporus and C. deuterogattii induce lower levels of the proinflammatory cytokines TNF-α, IL-1ß, and IL-6 and higher ROS levels than those induced by the other species. Species of the Cryptococcus gattii complex have different abilities to induce cytokine and ROS production by human PBMCs.
Assuntos
Criptococose/metabolismo , Criptococose/microbiologia , Cryptococcus gattii/fisiologia , Citocinas/metabolismo , Proliferação de Células , Humanos , Mediadores da Inflamação/metabolismo , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/microbiologia , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/microbiologia , Modelos Biológicos , Espécies Reativas de Oxigênio/metabolismoRESUMO
BACKGROUND: Thyroid cancer is a common malignant disease of the endocrine system with increasing incidence rates over the last few decades. In this study, we sought to analyze the possible association of 45 single nucleotide polymorphisms (SNPs) with thyroid cancer in a population from Rio Grande do Norte, Brazil. METHODS: Based on histological analysis by a pathologist, 80 normal thyroid specimens of tissue adjacent to thyroid tumors were obtained from the biobank at the Laboratory of Pathology of Liga Norte Riograndense Contra o Câncer, Natal, RN. Patient samples were then genotyped using the MassARRAY platform (Sequenon, Inc) followed by statistical analysis employing the SNPassoc package in R program. The genotypic frequencies of all 45 SNPs obtained from the International HapMap Project database and based on data from the ancestral populations of European and African origin were used to compose the control study group. RESULTS: In our study, the following 9 SNPs showed significant differences in their frequency when comparing the study and control groups: rs3744962, rs258107, rs1461855, rs4075022, rs9943744, rs4075570, rs2356508, rs17485896, and rs2651339. Furthermore, the SNPs rs374492 C/T and rs258107 C/T were associated with a relative risk for thyroid carcinoma of 3.78 (p = 6.27 × 10e-5) and 2.91 (p = 8.27 × 10e-5), respectively, after Bonferroni's correction for multiple comparisons. CONCLUSIONS: These nine polymorphisms could be potential biomarkers of predisposition to thyroid carcinoma in the population from Rio Grande do Norte. However, complementary studies including a control group with samples obtained from healthy subjects in Rio Grande do Norte state, should be conducted to confirm these results.
Assuntos
Estudos de Associação Genética/métodos , Polimorfismo de Nucleotídeo Único , Neoplasias da Glândula Tireoide/genética , Adulto , Brasil , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Projetos Piloto , Estudos RetrospectivosRESUMO
Mucosal leishmaniasis (ML) caused by Leishmania (Vianna) braziliensis usually appears after the healing of the primary lesion when amastigotes disseminate from the infection site to the mucosal area. Here, we investigated murine infection with amastigotes obtained from patients with ML or localized cutaneous leishmaniasis (LCL). Amastigotes were used to infect wild type, IFN-γ KO and inducible nitric oxide synthase (iNOS) KO mice. Amastigotes from patients with LCL induced lesions that appeared earlier in IFN-γ KO than parasites from ML. The lesion after infection with ML appeared early in iNOS KO than in IFN-γ KO mice and in iNOS KO mice parasites from ML and LCL cause similar lesions at the initial phase of infection, while parasites from ML induced greater lesions than the ones from LCL at the late phase. A greater number of parasites were observed in spleen of IFN-γ KO and iNOS KO mice infected with amastigotes from patients with ML than those with LCL. Parasites from ML infect a lower percentage of macrophages and are killed independent on IFN-γ and dependent on NO. The data suggest that amastigotes responsible for mucosal lesion in humans develop slowly on the initial phase of infection due to high susceptibility to NO and they have an increased ability to disseminate.
Assuntos
Leishmania braziliensis , Leishmaniose Cutânea/metabolismo , Leishmaniose Cutânea/microbiologia , Óxido Nítrico/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Humanos , Interferon gama/deficiência , Leishmaniose Cutânea/genética , Leishmaniose Cutânea/patologia , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/parasitologia , Masculino , Camundongos , Camundongos Knockout , Óxido Nítrico Sintase Tipo II/deficiência , Carga Parasitária , FagocitoseRESUMO
Objectives: Warfarin treatment is influenced by environmental and genetic factors. The influence of polymorphisms in genesencoding metalloproteinase 9 (MMP9), lymphotoxin-alpha (LTA) andTNFSF14 (LIGHT), related to the inflammatory process ofcoronary artery disease, on warfarin dose and time to reach target was investigated in this study.Methods: Outpatients on warfarin treatment (n=227), 20 to 92 years, were enrolled at the Institute Dante Pazzanese of Cardiology(IDPC). Genomic DNA was obtained from peripheral whole blood to evaluate MMP9 rs17576 (Gln279Arg, A>G), LTA rs1041981(Thr60Asn, C>A) and rs909253 (c.252T>C) and TNFSF14rs2291668 (c.147C>T) and rs344560 (Lys214Glu, G>A) polymorphismsby pyrosequencing in Q24PyroMark.Results: The patients carrying MMP9 rs17576GG genotype were more likely to require a lower warfarin weekly dose (OR:2.73, 95% CI: 1.01-7.41, p=0.048). Also, LTA rs909253 variant was associated with a longer time to reach the target internationalnormalized ratio (INR) (OR: 1.98, 95% CI: 1.02-3.86, p=0.043). Age was inversely correlated with the target INR (r=-0.387, p<0.001),and dose was directly correlated with time to reach target INR (r=0.244, p<0.001).Conclusion: MMP9 rs17576 variant may have an important influence on warfarin weekly dose, and that LTA rs909253polymorphism may also influence the time to reach the target INR.
Assuntos
Polimorfismo Genético , VarfarinaRESUMO
BACKGROUND: There are few studies relating the practice of water exercises and blood pressure responses. AIM: The objective of this study was to evaluate the subacute blood pressure behaviour in elderly hypertensive women after a water exercise session. METHODS: This was a controlled clinical trial, carried out with 16 hypertensive elderly women with the following characteristics (mean ± SD): age 66 ± 2.94 years, body weight 68.43 ± 12.08 kg, height 158 ± 5.34 cm and body mass index 27.32 ± 4.30 kg/m(2). The study occurred on 2 days, 48 hours apart, with an experimental protocol and a control protocol. The experimental protocol underwent a moderately intense and predominantly aerobic 40-minute session with water exercises for the upper and lower limbs. The control protocol did not enter the pool and did not exercise, but all other procedures were similar to those of the experimental protocol. The blood pressure measurements were performed at times before and every 10 minutes for 30 minutes after the protocols. Student's t-test was used to determine if the averages of the two samples were significantly different. RESULTS: Blood pressure increased significantly but not greatly after the water exercise session, but this did not happen with the control protocol. Systolic blood pressure in the experimental protocol decreased significantly only 30 minutes after the exercise session, which did not occur in the control protocol. Diastolic blood pressure, on the other hand, decreased significantly at minutes 10, 20 and 30. This also did not occur with the control protocol, but an intergroup analysis showed that diastolic blood pressure was similar for the two protocols. CONCLUSIONS: The results of this study show that a prescription of water exercises can be carried out in relative safety with this group of patients, and that systolic blood pressure tended to decrease, as shown by the measurement at minute 30.