Importância das resolvinas na infecção por Leishmania amazonensis

Submitted by Ana Maria Fiscina Sampaio ([email protected]) on 2017-07-21T14:24:53Z No. of bitstreams: 1 Hayna Malta Santos Importancia das resolvinas... 2017.pdf: 3216578 bytes, checksum: a4cc298a1ecfd936566bd3c7001b9d1d (MD5)Approved for entry into archive by Ana Maria Fiscina Sampaio ([email protected]) on 2017-07-21T16:05:03Z (GMT) No. of bitstreams: 1 Hayna Malta Santos Importancia das resolvinas... 2017.pdf: 3216578 bytes, checksum: a4cc298a1ecfd936566bd3c7001b9d1d (MD5)Made available in DSpace on 2017-07-21T16:05:03Z (GMT). No. of bitstreams: 1 Hayna Malta Santos Importancia das resolvinas... 2017.pdf: 3216578 bytes, checksum: a4cc298a1ecfd936566bd3c7001b9d1d (MD5) Previous issue date: 2017-03-20CNPqFundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, BrasilINTRODUÇÃO: A Leishmaniose Cutânea Difusa (LCD) é uma manifestação clínica rara causada pela Leishmania amazonensis que é caracterizada por uma resposta celular parasitária ineficiente e macrófagos intensamente parasitados nas lesões cutâneas. Mediadores lipídicos e seus precursores desempenham um papel crucial durante a infecção por Leishmania. Estudos prévios demonstram que pacientes com leishmaniose tegumentar, exibem um distinto balanço de eicosanoides in situ e sistêmico. Recentemente, demonstrou-se que mediadores lipídicos especializados na pró-resolução desempenham um papel crítico na redução de processos inflamatórios patológicos induzindo a restauração da homeostasia em diferentes modelos experimentais. Entre esses mediadores, as resolvinas da série D exibem potente atividade anti-inflamatória e imuno-regulatória que inclui a inibição da quimiotaxia leucocitária e bloqueio na produção de citocinas pró-inflamatórias. No entanto, ainda é desconhecido se as resolvinas desempenham um papel significativo no estabelecimento e persistência da infecção por Leishmania. OBJETIVO: Nesse estudo, avaliamos os níveis circulantes de Resolvina D1 (RvD1) em pacientes com leishmaniose tegumentar apresentando a forma clínica cutânea localizada (LCL) ou difusa. RESULTADOS: Nossos resultados demonstram que pacientes com LCD apresentam maiores níveis plasmáticos de RvD1 quando comparados a LCL ou controles endêmicos. Além disso, os níveis séricos de RvD1 em pacientes com LCD se correlacionam positivamente com a Arginase I e TGF- β, enquanto que inversamente com os níveis sistêmicos de TNF-α. Experimentos adicionais in vitro utilizando macrófagos humanos revelaram que a RvD1 promove a replicação intracelular da L. amazonensis por um mecanismo associado a indução da enzima heme oxigenase-1. CONCLUSÃO: Os resultados sugerem que a via de produção da RvD1 pode servir como uma potencial estratégia terapêutica para os pacientes com LCDINTRODUCTION: Diffuse Cutaneous Leishmaniasis (DCL) is a rare clinical manifestation caused by Leishmania amazonensis that is characterized by an inefficient parasite-specific cellular responses and heavily parasitized macrophages in skin lesions. Lipid mediators and their precursors play a crucial role during Leishmania infection. Previous works have shown that patients with cutaneous leishmaniasis exhibit a distinct in situ and systemic balance of this eicosanoids. Recently, pro-resolution lipid mediators have been shown to play critical role in dampening pathological inflammatory processes to reestablish homeostasis in a diverse range of experimental settings. Among these mediators, resolvins from D series have been described to exhibit potent antiinflammatory and immune-regulatory activities that include inhibition of leukocyte chemotaxis and blockage on the production of proinflammatory cytokines. However, whether resolvins play significant roles in establishment and persistence of Leishmania infection is currently unknown. AIM: We addressed this question by assessing circulating levels of resolvin D1 (RvD1) in tegumentary leishmaniasis patients presenting localized cutaneous leishmaniasis (LCL) or diffuse disease. RESULTS: We found that DCL patients have higher plasma levels of RvD1 when compared with LCL patients or endemic controls. In addition, the levels of this mediator were positively correlated with arginase-I and TGF-β and were negatively correlated with TNF-α levels. Additional in vitro experiments using primary human macrophages revealed that resolvin D1 promotes the intracellular L. amazonensis replication for a mechanism dependent on induction of heme oxygenase-1 enzyme. CONCLUSION: These results indicate that targeting RvD1 could serve as potential strategy for DCL patients

Heightened Plasma Levels of Transforming Growth Factor Beta (TGF-β) and Increased Degree of Systemic Biochemical Perturbation Characterizes Hepatic Steatosis in Overweight Pediatric Patients: A Cross-Sectional Study

Nonalcoholic Fatty Liver Disease (NAFLD) is a common cause of chronic liver disease in childhood and strongly associated with obesity. Routine biochemical non-invasive tests remain with low accuracy for diagnosis of NAFLD. We performed a cross-sectional study to examine potential associations between anthropometric and biochemical parameters, specially TGF-β, a prognosis marker for hepatic steatosis (HS). Between May and October 2019, seventy-two overweight adolescents were enrolled, of which 36 had hepatic steatosis. Hepatic, lipidic and glycemic profiles, and levels of vitamin D, ferritin and TGF-β were analyzed. Hierarchical cluster and a discriminant model using canonical correlations were employed to depict the overall expression profile of biochemical markers and the biochemical degree of perturbation. Median values of alanine aminotransferase (ALT), gamma glutamyl transpeptidase (GGT), and TGF-β were higher in the adolescents with HS. Values of body mass index (BMI)/age and ALT, but not of TGF-β, were gradually increased proportionally to augmentation of steatosis severity. In a multivariate analysis, TGF-β plasma concentrations were associated with occurrence of hepatic steatosis independent of other covariates. Discriminant analysis confirmed that TGF-β concentrations can identify HS cases. Our data reveal that HS patients exhibit a distinct biosignature of biochemical parameters and imply TGF-β as an important biomarker to evaluate risk of steatosis development

Differential expression of the eicosanoid pathway in patients with localized or mucosal cutaneous Leishmaniasis

Unfettered inflammation is thought to play critical role in the development of different clinical forms of tegumentary leishmaniasis. Eicosanoids are potent mediators of inflammation and tightly associated with modulation of immune responses. In this cross-sectional exploratory study, we addressed whether targets from the eicosanoid biosynthetic pathway, assessed by multiplexed expression assays in lesion biopsy and plasma specimens, could highlight a distinct biosignature in patients with mucocutaneous leishmaniasis (MCL) or localized cutaneous leishmaniasis (LCL). Differences in immunopathogenesis between MCL and LCL may result from an imbalance between prostaglandins and leukotrienes, which may serve as targets for future host-directed therapies.status: publishe

Arginase I, Polyamine and Prostaglandin E2 Pathways Suppress the Inflammatory Response and Contribute to Diffuse Cutaneous Leishmaniasis

Diffuse cutaneous leishmaniasis (DCL) is a rare clinical manifestation of tegumentary leishmaniasis. The molecular mechanisms underlying DCL pathogenesis remain unclear, and there is no efficient treatment available. This study investigated the systemic and in situ expression of the inflammatory response that might contribute to suppression in DCL. The plasma levels of arginase, ODC, TGF-β and PGE2 were higher in DCL patients, than those from LCL patients or endemic control. In situ transcriptomic analyses reinforced the association between arginase expression and enzymes involved in prostaglandin and polyamine synthesis. Immunohistochemistry confirmed that arginase I, ODC and cyclooxygenase2 expression was higher in DCL than in LCL lesions. Inhibition of arginase or ODC abrogates L. amazonensis replication in infected human macrophages. Our data implicate arginase I, ODC, PGE2 and TGF-β in the failure to mount an efficient immune response and suggest perspectives in the development of new strategies for therapeutic intervention for DCL patients.status: publishe

Differential Expression of the Eicosanoid Pathway in Patients With Localized or Mucosal Cutaneous Leishmaniasis

Submitted by Ana Maria Fiscina Sampaio ([email protected]) on 2016-04-01T14:29:26Z No. of bitstreams: 1 França-Costa, Jaqueline. Differential expression.....pdf: 412972 bytes, checksum: 13017361cb68f1f405739d3aadd3661a (MD5)Approved for entry into archive by Ana Maria Fiscina Sampaio ([email protected]) on 2016-04-01T16:07:57Z (GMT) No. of bitstreams: 1 França-Costa, Jaqueline. Differential expression.....pdf: 412972 bytes, checksum: 13017361cb68f1f405739d3aadd3661a (MD5)Made available in DSpace on 2016-04-01T16:07:57Z (GMT). No. of bitstreams: 1 França-Costa, Jaqueline. Differential expression.....pdf: 412972 bytes, checksum: 13017361cb68f1f405739d3aadd3661a (MD5) Previous issue date: 2016Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil.Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil / Fundação José Silveira. Multinational Organization Network Sponsoring Translational and Epidemiological Research Initiative. Salvador, BA, Brasil.Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil.Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil / University of Leuven. Rega Institute for Medical Research. Department of Microbiology and Immunology. Belgium.Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil / Universidade Federal da Bahia. Salvador, BA, Brasil.Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil.Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil / Universidade Federal da Bahia. Salvador, BA, Brasil / Instituto Nacional de Ciência e Tecnologia de Investigação em Imunologia. São Paulo, SP, Brasil.Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil.Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil / Universidade Federal da Bahia. Salvador, BA, Brasil / Instituto Nacional de Ciência e Tecnologia de Investigação em Imunologia. São Paulo, SP, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil / Universidade Federal da Bahia. Salvador, BA, Brasil.Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil / Universidade Federal da Bahia. Salvador, BA, Brasil.Unfettered inflammation is thought to play critical role in the development of different clinical forms of tegumentary leishmaniasis. Eicosanoids are potent mediators of inflammation and tightly associated with modulation of immune responses. In this cross-sectional exploratory study, we addressed whether targets from the eicosanoid biosynthetic pathway, assessed by multiplexed expression assays in lesion biopsy and plasma specimens, could highlight a distinct biosignature in patients with mucocutaneous leishmaniasis (MCL) or localized cutaneous leishmaniasis (LCL). Differences in immunopathogenesis between MCL and LCL may result from an imbalance between prostaglandins and leukotrienes, which may serve as targets for future host-directed therapies

Tamoxifen and meglumine antimoniate combined therapy in cutaneous leishmaniasis patients: a randomised trial

Submitted by Ana Maria Fiscina Sampaio ([email protected]) on 2018-08-15T14:30:21Z No. of bitstreams: 1 Machado PRLTamoxifen and meglumine antimoniate....pdf: 120712 bytes, checksum: 5db0d648aa70b8a43463d2aab5a87f37 (MD5)Approved for entry into archive by Ana Maria Fiscina Sampaio ([email protected]) on 2018-08-15T16:34:59Z (GMT) No. of bitstreams: 1 Machado PRLTamoxifen and meglumine antimoniate....pdf: 120712 bytes, checksum: 5db0d648aa70b8a43463d2aab5a87f37 (MD5)Made available in DSpace on 2018-08-15T16:34:59Z (GMT). No. of bitstreams: 1 Machado PRLTamoxifen and meglumine antimoniate....pdf: 120712 bytes, checksum: 5db0d648aa70b8a43463d2aab5a87f37 (MD5) Previous issue date: 2018Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP 2015/09080-2). SRBU is the recipient of a sênior researcher scholarship from CNPqUniversidade Federal da Bahia. Hospital Universitário Prof. Edgard Santos. Serviço de Imunologia. Salvador, BA, BrasilUniversidade Federal da Bahia. Hospital Universitário Prof. Edgard Santos. Serviço de Imunologia. Salvador, BA, BrasilUniversidade Federal da Bahia. Hospital Universitário Prof. Edgard Santos. Serviço de Imunologia. Salvador, BA, Brasil / Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, BrasilUniversidade Federal da Bahia. Hospital Universitário Prof. Edgard Santos. Serviço de Imunologia. Salvador, BA, BrasilUniversidade de São Paulo. Departamento de Parasitologia. São Paulo, SP, BrasilUniversidade de São Paulo. Departamento de Parasitologia. São Paulo, SP, BrasilUniversidade Federal da Bahia. Hospital Universitário Prof. Edgard Santos. Serviço de Imunologia. Salvador, BA, Brasil / Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, BrasilUniversidade Federal da Bahia. Hospital Universitário Prof. Edgard Santos. Serviço de Imunologia. Salvador, BA, Brasil / Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, BrasilUniversidade Federal da Bahia. Hospital Universitário Prof. Edgard Santos. Serviço de Imunologia. Salvador, BA, Brasil / Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, BrasilUniversidade de São Paulo. Departamento de Parasitologia. São Paulo, SP, BrasilThere is a clear need for new strategies of leishmaniasis treatment. This work was conducted to evaluate the efficacy of the co-administration of tamoxifen and meglumine antimoniate (SbV ) in a phase II pilot clinical trial in localised cutaneous leishmaniasis patients. methods A randomised controlled pilot clinical trial was conducted to evaluate the efficacy and safety of oral (40 mg/day for 20 days) or topical tamoxifen (0.1% tamoxifen citrate for 20 days) combined with meglumine antimoniate (20 mg SbV/kg/day for 20 days) vs. a standard SbV protocol (20 mg/kg/day for 20 days) for the treatment of cutaneous leishmaniasis. Primary outcome was complete epithelisation of the lesion 6 months after the end of treatment. Secondary outcomes were lesion healing 2 months after the end of treatment and frequency and severity of adverse events. results A total of 38 subjects were included in the trial, 15 were treated with standard SbV and 23 with the combination of tamoxifen and SbV. Of the patients treated with the co-administration scheme, 12 received tamoxifen orally and 11 were treated with topical tamoxifen. Tamoxifen administered by the oral or topical routes was well tolerated. Cure rates 6 months after the end of treatment per intention to treat were 40% in the group treated with the standard SbV scheme, and 36.4% and 58%, respectively, for groups treated with SbV plus topical or oral tamoxifen. conclusions In the doses and schemes used in this study, co-administration of oral tamoxifen and SbV resulted in higher cure rates in comparison with the standard scheme of treatment, although not to statistically significant levels

Arginase I, polyamine, and prostaglandin E2 pathways suppress the inflammatory response and contribute to diffuse cutaneous leishmaniasis

Submitted by Ana Maria Fiscina Sampaio ([email protected]) on 2016-05-03T17:37:15Z No. of bitstreams: 1 Costa JF Arginase I....pdf: 830131 bytes, checksum: afec4bdb4a62b112b752d5320ef67b84 (MD5)Approved for entry into archive by Ana Maria Fiscina Sampaio ([email protected]) on 2016-05-03T18:21:36Z (GMT) No. of bitstreams: 1 Costa JF Arginase I....pdf: 830131 bytes, checksum: afec4bdb4a62b112b752d5320ef67b84 (MD5)Made available in DSpace on 2016-05-03T18:21:36Z (GMT). No. of bitstreams: 1 Costa JF Arginase I....pdf: 830131 bytes, checksum: afec4bdb4a62b112b752d5320ef67b84 (MD5) Previous issue date: 2015Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil / Universidade Federal da Bahia. Faculdade de Medicina. Salvador, BA, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil / Universidade Federal da Bahia. Faculdade de Medicina. Salvador, BA, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil / Universidade Federal da Bahia. Faculdade de Medicina. Salvador, BA, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil / Universidade Federal da Bahia. Faculdade de Medicina. Salvador, BA, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil / Universidade Federal da Bahia. Faculdade de Medicina. Salvador, BA, BrasilUniversidade Federal do Maranhão. São Luís, MA, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, BrasilFundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil / Universidade Federal da Bahia. Faculdade de Medicina. Salvador, BA, Brasil / Instituto Nacional de Ciência e Tecnologia de Investigação em Imunologia. São Paulo, SP, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil / Universidade Federal da Bahia. Faculdade de Medicina. Salvador, BA, Brasil / Instituto Nacional de Ciência e Tecnologia de Investigação em Imunologia. São Paulo, SP, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil / Universidade Federal da Bahia. Faculdade de Medicina. Salvador, BA, Brasil / Instituto Nacional de Ciência e Tecnologia de Investigação em Imunologia. São Paulo, SP, BrasilDiffuse cutaneous leishmaniasis (DCL) is a rare clinical manifestation of tegumentary leishmaniasis. The molecular mechanisms underlying DCL pathogenesis remain unclear, and there is no efficient treatment available. This study investigated the systemic and in situ expression of the inflammatory response that might contribute to suppression in DCL. The plasma levels of arginase I, ornithine decarboxylase (ODC), transforming growth factor β (TGF-β), and prostaglandin E2 (PGE2) were higher in patients with DCL, compared with patients with localized cutaneous leishmaniasis (LCL) or with controls from an area of endemicity. In situ transcriptomic analyses reinforced the association between arginase I expression and enzymes involved in prostaglandin and polyamine synthesis. Immunohistochemistry confirmed that arginase I, ODC, and cyclooxygenase2 expression was higher in lesion biopsy specimens from patients with DCL than in those from patients with LCL. Inhibition of arginase I or ODC abrogates L. amazonensis replication in infected human macrophages. Our data implicate arginase I, ODC, PGE2, and TGF-β in the failure to mount an efficient immune response and suggest perspectives in the development of new strategies for therapeutic intervention for patients with DCL

Effects of Standardized Brazilian Green Propolis Extract (EPP-AF®) on Inflammation in Haemodialysis Patients: A Clinical Trial

Background. Patients on haemodialysis (HD) present a significant inflammatory status, which has a pronounced negative impact on their outcomes. Propolis is a natural resin with anti-inflammatory and immunomodulatory properties. We assessed the safety and impact of a standardized Brazilian green propolis extract (EPP-AF®) on the inflammatory status in patients under conventional HD. Methods. Patients were assigned to receive 200 mg/day of EPP-AF® for 4 weeks followed by 4 weeks without the drug, and changes in plasma levels of interleukins (ILs), interferon gamma (IFN-γ), tumour necrosis factor-alpha (TNF-α), and high-sensitivityc-reactive protein (HsCRP) were measured. A heatmap was used to illustrate trends in data variation. Results. In total, 37 patients were included in the final analysis. Patients presented an exacerbated inflammatory state at baseline. During EPP-AF® use, there was a significant reduction in IFN-γ (p=0.005), IL-13 (p=0.04 2), IL-17 (p=0.039), IL-1ra (p=0.008), IL-8 (p=0.009), and TNF-α (p < 0.001) levels compared to baseline, and significant changes were found in Hs-CRP levels. The heatmap demonstrated a pattern of pronounced proinflammatory status at baseline, especially in patients with primary glomerulopathies, and a clear reduction in this pattern during the use of EPP-AF®. There was a tendency to maintain this reduction after suspension of EPP-AF®. No significant side effects were observed. Conclusion. Patients under haemodialysis presented a pronounced inflammatory status, and EPP-AF® was demonstrated to be safe and associated with a significant and maintained reduction in proinflammatory cytokines in this population. This trial is registered with Clinicaltrials.gov NCT04072341

Anemia and anti-tuberculosis treatment outcome in persons with pulmonary tuberculosis: A multi-center prospective cohort study

Background: Tuberculosis (TB) remains a major plague of humanity. People with TB (PWTB) are commonly anemic. Here, we assessed whether the severity of anemia in PWTB prior to anti-TB treatment (ATT) was a risk factor for an unfavorable outcome. Methods: Patients ≥ 18 years old with culture-confirmed drug-susceptible pulmonary TB enrolled between 2015 and 2019 in a multi-center Brazilian cohort were followed for up to 24 months and classified according to anemia severity (mild, moderate, and severe), based on hemoglobin levels. A multinomial logistic regression model was employed to assess whether anemia was associated with unfavorable outcome (death, failure, loss to follow-up, regimen modification or relapse), compared to treatment success (cure or treatment completion). Results: Among 786 participants who met inclusion criteria, 441 (56 %) were anemic at baseline. Patients with moderate/severe anemia were more HIV-seropositive, as well as more symptomatic and had higher frequencies of unfavorable outcomes compared to the other groups. Moderate/severe anemia (adjusted OR [aOR]: 7.80, 95 %CI:1.34–45.4, p = 0.022) was associated with death independent of sex, age, BMI, HIV and glycemic status. Conclusion: Moderate/severe anemia prior to ATT was a significant risk factor for death. Such patients should be closely monitored given the high risk of unfavorable ATT outcomes