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Avaliação In Vitro de Flavonas Sintéticas contra o Trypanosoma cruzi
No full textA doença de Chagas é uma infeção causada pelo protozoário parasita Trypanosoma cruzi e afeta cerca de 8 milhões de pessoas em 21 países da América Latina. O tratamento dessa doença ainda se baseia no uso de benzonidazol ou nifurtimox, que apresentam baixas taxas de cura na fase crônica e frequentemente apresentam muitos efeitos colaterais indesejáveis. Aqui, descrevemos a síntese de flavonas e a avaliação de sua atividade tripanocida. As flavonas foram testadas in vitro contra o T. cruzi e dentre os 13 compostos testados, 6 destes demonstraram alguma atividade tripanocida modesta in vitro. Observaram-se melhorias na atividade anti T. cruzi para flavonas portadoras de substituintes nitro ou metóxi. Notavelmente, foram
mantidas citotoxicidades muito baixas com grupos metoxila, o que sugere que esse grupo funcional favorece compostos tripanocidas mais seletivos. Além disso, a modificação estrutural na posição 3 do anel diidropirona forneceu a flavona mais ativa, o que sugere que a introdução de diferentes funcionalidades nessa posição poderia gerar novos compostos promissores com propriedades tripanocidas.Chagas disease is caused by infection of the parasite protozoan Trypanosoma cruzi and affects about 8 million people in 21 countries in Latin America. Treatment of this disease is still based on the use of benznidazole or nifurtimox, which both present low cure rates in the chronic phase and often have many
undesirable side effects. Herein, we describe the synthesis of flavones and evaluation of their trypanocidal activity. The flavones were tested to in vitro against T. cruzi and amongst the 13 compounds tested, 6 of these demonstrated some modest trypanocidal activity in vitro. Enhancements in anti T. cruzi activity were noted for flavones bearing either nitro or methoxy substituents. Moreover, very low cytotoxicities were maintained for flavones with methoxy groups which suggests that this functional group favors more
selective trypanocidal compounds. Finally, structural modification at position 3 of the dihydropyrone ring provided the most active flavone, which suggests that the introduction of different functionalities at this position could yield promising new compounds with trypanocidal properties
Memory impairment in chronic experimental Chagas disease: Benznidazole therapy reversed cognitive deficit in association with reduction of parasite load and oxidative stress in the nervous tissue
No full textMemory impairment has been associated with chronic Chagas disease (CD), a neglected
tropical disease caused by the protozoan parasite Trypanosoma cruzi. In degenerative diseases,
memory loss has been associated with increased oxidative stress, revealed as
enhanced lipid peroxidation, in the cerebral cortex. Benznidazole (Bz), a trypanocidal drug
efficient to reduce blood parasite load in the acute and chronic phases of infection, showed
controversial effects on heart disease progression, the main clinical manifestation of CD.
Here, we evaluated whether C57BL/6 mice infected with the Colombian type I T. cruzi strain
present memory deficit assessed by (i) the novel object recognition task, (ii) the open field
test and (iii) the aversive shock evoked test, at 120 days post infection (dpi). Next, we tested
the effects of Bz therapy (25mg/Kg/day, for 30 consecutive days) on memory evocation,
and tried to establish a relation between memory loss, parasite load and oxidative stress in
the central nervous system (CNS). At 120 dpi, T. cruzi-infected mice showed memory
impairment, compared with age-matched non-infected controls. Bz therapy (from 120 to
150 dpi) hampered the progression of habituation and aversive memory loss and, moreover,
reversed memory impairment in object recognition. In vehicle-administered infected mice,
neuroinflammation was absent albeit rare perivascular mononuclear cells were found in
meninges and choroid plexus. Bz therapy abrogated the infiltration of the CNS by inflammatory
cells, and reduced parasite load in hippocampus and cerebral cortex. At 120 and 150
dpi, lipid peroxidation was increased in the hippocampus and cortex tissue extracts. Notably,
Bz therapy reduced levels of lipid peroxidation in the cerebral cortex. Therefore, in xperimental chronic T. cruzi infection Bz therapy improved memory loss, in association
with reduction of parasite load and oxidative stress in the CNS, providing a new perspective
to improve the quality of life of Chagas disease patients
Increased oxidative stress in elderly leprosy patients is related to age but not to bacillary load
No full textProdução científica do Laboratório de Hanseníase.Produção científica do Laboratório de Microbiologia Celular.Author summary: Leprosy, which has been reported throughout human history since Biblical times, still presents unclear aspects in regards to its pathogeny, and represents a public health concern, particularly in developing countries, where poor sanitary conditions of socially disfavored groups is a relevant contributing factor in maintaining disease dissemination. Although its signs and symptoms are primarily found in young adults, the increasing number of elderly individuals with leprosy is a recent phenomenon that requires clarification. Considering the specific biochemical profile of the elderly, as well as the influence thereof on their immune response to infection, this work demonstrates that elderly leprosy patients present increased levels of oxidative damage in blood and skin lesions when compared to younger patients. Such findings appear to be correlated with low gene expression of antioxidant enzymes, particularly among multibacillary patients. This work intends to contribute to a better understanding on the progress of leprosy in elderly groups.Background: Leprosy continues to be a public health problem in Brazil. Furthermore, detection rates in elderly people have increased, particularly those of multibacillary (L-Lep) patients, who are responsible for transmitting M. leprae. Part of the decline in physiological function during aging is due to increased oxidative damage and change in T cell subpopulations, which are critical in defense against the disease. It is not still clear how age-related changes like those related to oxidation affect elderly people with leprosy. The aim of this work was to verify whether the elderly leprosy patients have higher ROS production and how it can impact the evolution of leprosy. Methodology/Principal findings: 87 leprosy patients, grouped according to age range and clinical form of leprosy, and 25 healthy volunteers were analyzed. Gene expression analysis of antioxidant and oxidative burst enzymes were performed in whole blood using Biomark’s microfluidic-based qPCR. The same genes were evaluated in skin lesion samples by RT-qPCR. The presence of oxidative damage markers (carbonylated proteins and 4-hydroxynonenal) was analyzed by a DNPH colorimetric assay and immunofluorescence. Carbonylated protein content was significantly higher in elderly compared to young patients. One year after multidrug therapy (MDT) discharge and M. leprae clearance, oxidative damage increased in young L-Lep patients but not in elderly ones. Both elderly T and L-Lep patients present higher 4-HNE in cutaneous lesions than the young, mainly surrounding memory CD8+ T cells. Furthermore, young L-Lep demonstrated greater ability to neutralize ROS compared to elderly L-Lep patients, who presented lower gene expression of antioxidant enzymes, mainly glutathione peroxidase. Conclusions/Significance: We conclude that elderly patients present exacerbated oxidative damage both in blood and in skin lesions and that age-related changes can be an important factor in leprosy immunopathogenesis. Ultimately, elderly patients could benefit from co-supplementation of antioxidants concomitant to MDT, to avoid worsening of the disease
Identification of 1,2,3-triazole-phthalimide derivatives as potential drugs against COVID-19: a virtual screening, docking and molecular dynamic study
No full textFACEPEIn this work we aimed to perform an in silico predictive screening, docking and molecular dynamic study to identify 1,2,3-triazole-phthalimide derivatives as drug candidates against SARS-CoV-2. The in silico prediction of pharmacokinetic and toxicological properties of hundred one 1,2,3-triazole-phtalimide derivatives, obtained from SciFinder® library, were investigated. Compounds that did not show good gastrointestinal absorption, violated the Lipinski's rules, proved to be positive for the AMES test, and showed to be hepatotoxic or immunotoxic in our ADMET analysis, were filtered out of our study. The hit compounds were further subjected to molecular docking on SARS-CoV-2 target proteins. The ADMET analysis revealed that 43 derivatives violated the Lipinski's rules and 51 other compounds showed to be positive for the toxicity test. Seven 1,2,3-triazole-phthalimide derivatives (A7, A8, B05, E35, E38, E39, and E40) were selected for molecular docking and MFCC-ab initio analysis. The results of molecular docking pointed the derivative E40 as a promising compound interacting with multiple target proteins of SARS-CoV-2. The complex E40-Mpro was found to have minimum binding energy of -10.26 kcal/mol and a general energy balance, calculated by the quantum mechanical analysis, of -8.63 eV. MD simulation and MMGBSA calculations confirmed that the derivatives E38 and E40 have high binding energies of -63.47 ± 3 and -63.31 ± 7 kcal/mol against SARS-CoV-2 main protease. In addition, the derivative E40 exhibited excellent interaction values and inhibitory potential against SAR-Cov-2 main protease and viral nucleocapsid proteins, suggesting this derivative as a potent antiviral for the treatment and/or prophylaxis of COVID-19. Communicated by Ramaswamy H. Sarma
FMRF-related peptides in Aedes aegypti midgut: neuromuscular connections and enteric nervous system
No full textFMRFamide-related peptides (FaRPs) are a class of neuropeptides that participate in a variety of physiological processes in invertebrates. They occur in nerves of stomatogastric ganglia and enteroendocrine cells of the insect digestive tract, where they may control muscle functions. However, their direct involvement in muscle function has never been shown in situ. We studied the relationship between FaRPs and midgut muscle during larval–pupal transition of the mosquito Aedes aegypti. In late L4, FaRP-positive neuronal extensions attach to the bundles of the external circular muscle layer, and muscle stem cells start to undergo mitosis in the internal circular layer. Thereafter, the external muscle layer degenerates, disappearing during early pupal development, and is completely absent in the adult mosquito. Our results indicate that FaRP-based neural signals are involved in the reorganization of the muscle fibers of the mosquito midgut during the larval–pupal transition. In addition to confirming FaRP involvement in muscle function, we show that the mosquito midgut muscles are largely innervated, and that circular and longitudinal muscle have specific neuron bodies associated with them
Benznidazole: Hero or villain of cellular immune response in chronic Chagas disease patients?
No full textAlthough the treatment of chronic Chagas disease (CCD) patients with Benznidazole (Bz) is still controversial, its
use may prevent or delay the progression of the disease to the most severe forms. One of the main factors that can
influence the effectiveness of the treatment is the possible cooperation between drug effect and the host immune
response. Herein, we evaluated the immune response of peripheral blood mononuclear cells (PBMCs) infected
with Trypanosoma cruzi and submitted to Bz treatment. Blood samples of CCD patients (n = 7) and non-infected
individuals (n = 6) were drawn to obtain PBMCs. After cell culture, the supernatants were harvested and stored,
and the cell analyzed by flow cytometer. The results showed that Bz positively regulated the molecular process of
cell activation (CD80) and antigen presentation (HLA-DR), increased phagocytosis receptor and macrophage
activation (CD64), and did not induce an exacerbated immune response. In conclusion, these results highlight the
relevance of using Bz that, despite not being a true hero, it is also not a villain, as it presents a wide range of
pharmacological/immunological response interactions, important for the immune balance in the clinical pro-
gression of CCD.2030-12-3
Pathological findings and morphologic correlation of the lungs of autopsied patients with SARS-CoV-2 infection in the Brazilian Amazon using transmission electron microscopy
No full textElectron microscopy (EM) is a rapid and effective tool that can be used to create images of a whole spectrum of virus-host interactions and, as such, has long been used in the discovery and description of viral mechanisms. Methods: Electron microscopy was used to evaluate the pulmonary pathologies of postmortem lung sections from three patients who died from infection with SARS-associated coronavirus 2 (SARS-CoV-2), a new member of the Coronaviridae family. Results: Diffuse alveolar damage (DAD) was predominant in all three patients. The early exudative stage was characterized principally by edema and extravasation of red blood cells into the alveolar space with injury to the alveolar epithelial cells; this was followed by detachment, apoptosis, and necrosis of type I and II pneumocytes. The capillaries exhibited congestion, exposure of the basement membrane from denuded endothelial cells, platelet adhesion, fibrin thrombi, and rupture of the capillary walls. The proliferative stage was characterized by pronounced proliferation of type II alveolar pneumocytes and multinucleated giant cells. The cytopathic effect of SARS-CoV-2 was observed both in degenerated type II pneumocytes and freely circulating in the alveoli, with components from virions, macrophages, lymphocytes, and cellular debris. Conclusions: Viral particles consistent with the characteristics of SARS-CoV-2 were observed mainly in degenerated pneumocytes, in the endothelium, or freely circulating in the alveoli. In the final stage of illness, the alveolar spaces were replaced by fibrosis
COVID-19 vaccines and the fight against disinformation in the coverage of Folha de S. Paulo
No full textDesde que a COVID-19 foi confirmada como uma pandemia de proporções globais, em março de 2020, o mundo passou a acompanhar com grande expectativa o desenvolvimento de uma vacina que colocasse fim a uma crise sanitária que alterou drasticamente o cotidiano das pessoas. Na esteira dos resultados dos testes com imunizantes fabricados por empresas farmacêuticas de diversos países, começaram a circular com mais intensidade as notícias falsas e enganosas sobre a vacina, exigindo da imprensa um trabalho de checagem e refutação desse conteúdo. Neste artigo, analisamos 41 textos publicados pelo jornal Folha de S. Paulo em 2020 que tiveram como foco o enfrentamento à desinformação sobre a vacina contra a COVID-19, a partir dos enquadramentos, das características dos textos jornalísticos, da presença das agências de fact-checking e classificações utilizadas, das principais fontes acionadas e das mídias sociais mencionadas. O frame Bioético e Jurídico foi predominante, destacando a dicotomia entre verdadeiro e falso, certo e errado, científico e não científico. O outro frame identificado foi Política Pública e Estratégia Política, evidenciando as disputas de poder de atores políticos e os embates ideológicos em torno da vacina. A análise revela a importância da interlocução entre jornalismo e ciência em uma emergência de saúde pública e de uma prática profissional que tenha como base a evidência científica, a pluralidade de fontes e a importância da vacinação para a saúde coletiva.Since COVID-19 was confirmed as a pandemic of global proportions, in March 2020, the world has been watching with great anticipation the development of a vaccine that can put an end to a health crisis that has drastically altered people’s daily lives. In the wake of the results of tests with immunizers manufactured by pharmaceutical companies in several countries, false and misleading news about the vaccine began to circulate more intensely, requiring the media to check and refute this content. In this article, we analyzed 41 texts published by Folha de S. Paulo in 2020 with a focus on tackling disinformation about the COVID-19 vaccine, based on frames, characteristics of the journalistic texts, presence of fact-checking agencies and their classifications, main sources, and the most addressed social media. The Bioethical and Legal frame was predominant, highlighting the dichotomy between true and false, right and wrong, scientific and non-scientific. The other frame identified was the Public Policy and Political Strategy, underlining the disputes of power of political actors and the ideological clashes surrounding the vaccine. The analysis reveals the importance of the dialogue between journalism and science in a public health emergency and a professional practice based on scientific evidence, the plurality of sources, and the importance of vaccination for public health
The protective effect of solidagenone from Solidago chilensis Meyen in a mouse model of airway inflammation
No full textConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). Fundação de Amparo à Pesquisa do Estado da Bahia (FAPESB). Fundação Oswaldo Cruz (FIOCRUZ).Solidagenone is the main active constituent present in Solidago chilensis Meyen which is used in folk medicine to treat pain and inflammatory diseases. This study aimed to evaluate the anti-inflammatory activity of solidagenone in vitro and in a model of allergic airway inflammation. In vitro studies were performed in activated macrophages and lymphocytes. BALB/c mice were sensitized and challenged with ovalbumin and treated with solidagenone orally (30 or 90 mg/kg body weight) or dexamethasone, as a positive control in our in vivo analysis. Supernatant concentrations of nitrite, TNF and IL-1β, as well as gene expression of pro-inflammatory mediators in macrophages cultures, were reduced after solidagenone treatment, without affecting macrophages viability. Besides, solidagenone significantly decreased T cell proliferation and secretion of IFNγ and IL-2. Th2 cytokine concentrations and inflammatory cell counts, especially eosinophils, in bronchoalveolar lavage fluid were reduced in mice treated with solidagenone. Histopathological evaluation of lung tissue was performed, and morphometrical analyses demonstrated reduction of cellular infiltration and mucus hypersecretion. Altogether, solidagenone presented anti-inflammatory activity in vitro and in vivo in the OVA-induced airway inflammation model, suggesting its promising pharmacological use as an anti-inflammatory agent for allergic hypersensitivity