Short-Term Adverse Effects of the Fourth Dose of Vaccination against COVID-19 in Adults over 40 Years of Age.

Booster vaccines are a strategy to mitigate the conditions in the health, social, and economic fields that the COVID-19 pandemic has brought. A series of adverse effects have been observed since the first vaccination. The present investigation aims to describe the short-term adverse effects of the fourth dose against COVID-19 in adults older than 40 from a region of Peru. The study population was over 40 years of age at the COVID-19 vaccination center in Trujillo, Peru. A 21-day follow-up was conducted from vaccination with the fourth dose, considering sex, age, body mass index, comorbidities, history of COVID-19 infection, vaccination schedule, and simultaneous vaccination against influenza as variables of interest. Multinomial logistic regression with robust variance was used to estimate the risk ratio (RR). In total, 411 people were recruited, and it was found that 86.9% of the participants presented adverse effects after injection with the fourth dose of the vaccine against COVID-19. Pain at the injection site was the most reported symptom after 3 days. Assessment of adverse effects after 3 days found that age ≥ 60 years was associated with a lower likelihood of adverse effects compared to those younger than 60 years (RRc: 0.32; 95% CI: 0.0.18-0.59), males compared to females were associated with a lower likelihood of adverse effects (RRc: 0.54; 95% CI 0.30-0.98), being overweight (RRc: 2.34; 95% CI: 1.12-4.89), and last vaccine with Pfizer-BioN-Tech (RRc: 0.42; 95% CI: 0.18-0.96). Associated adverse effects are mild to moderate. Injection site pain and general malaise are the most frequent adverse effects.

Benznidazole and amiodarone combined treatment attenuates cytoskeletal damage in Trypanosoma cruzi-infected cardiac cells.

Chagas disease (CD), a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi, is an important public health problem mainly in Latin America, leading to approximately 12,000 annual deaths. Current etiological treatment for CD is limited to two nitro compounds, benznidazole (Bz) and nifurtimox (Nif), both presenting relevant limitations. Different approaches have been employed to establish more effective and safer schemes to treat T. cruzi infection, mostly based on drug repurposing and combination therapies. Amiodarone (AMD), an antiarrhythmic medicament of choice for patients with the chronic cardiac form of CD, is also recognized as a trypanocidal agent. Therefore, our aim is to investigate the combined treatment Bz + AMD on trypomastigote viability, control of T. cruzi intracellular form proliferation, and recovery of the infection-induced cytoskeleton alterations in cardiac cells. The combination of Bz + AMD did not improve the direct trypanocidal effect of AMD on the infective blood trypomastigote and replicative intracellular forms of the parasite. Otherwise, the treatment of T. cruzi-infected cardiac cells with Bz plus AMD attenuated the infection-triggered cytoskeleton damage of host cells and the cytotoxic effects of AMD. Thus, the combined treatment Bz + AMD may favor parasite control and hamper tissue damage.

Update of the acquisition parameters of the Brazilian National School Feeding Program based on the Dietary Guidelines for the Brazilian Population. / Atualização dos parâmetros de aquisição do Programa Nacional de Alimentação Escolar com base no Guia Alimentar para a População Brasileira.

The Dietary Guidelines for the Brazilian Population is acknowledged as a powerful inducer of public food and nutrition policies. In this perspective, this article presents the methodological path and evidence that supported the elaboration of the new parameters of food acquisition of the Brazilian National School Feeding Program (PNAE). This elaboration involved the analyses of: (1) participation of federal resources used to purchase food, grouped according to the NOVA classification, used in Dietary Guidelines for the Brazilian Population, by the set of Brazilian municipalities and according to the classification of the execution (positive or negative); (2) monthly reference menus that were prepared following Dietary Guidelines for the Brazilian Population recommendations; (3) analysis of food acquisition by the sampling of 525 municipalities, involving the relative participation of food groups (according to NOVA) in total expenditures and energy and nutritional quality of purchased foods; and (4) analysis of ultra-processed foods that should not be offered in the school environment. We proposed the adoption of the following parameters for the participation of food groups in relation to the total federal resources used in the purchase of food: ≥ 75% of resources for fresh or minimally processed foods; < 20% for processed or ultra-processed foods and < 5% for processed culinary ingredients, as well as the expansion of the list of foods whose acquisition with federal resources from PNAE is prohibited. This process supported the elaboration of Resolution CD/FNDE n. 6 of May 8, 2020, which provides for the attendance of school feeding to primary education students within the PNAE.

O Guia Alimentar para a População Brasileira é reconhecido como um potente indutor de políticas públicas de alimentação e nutrição. Nessa perspectiva, este artigo apresenta o percurso metodológico e as evidências que subsidiaram a elaboração dos novos parâmetros de aquisição de alimentos do Programa Nacional de Alimentação Escolar (PNAE). Tal elaboração envolveu as análises de: (1) participação dos recursos federais utilizados para compra de alimentos, agrupados segundo a classificação NOVA, empregada no Guia Alimentar para a População Brasileira, pelo conjunto de municípios brasileiros e segundo classificação da execução (positiva ou negativa); (2) cardápios mensais de referência que foram elaborados seguindo recomendações do Guia Alimentar para a População Brasileira; (3) aquisição de alimentos por amostra de 525 municípios, envolvendo a participação relativa dos grupos de alimentos (segundo a NOVA) no total de gastos e de energia e a qualidade nutricional dos alimentos adquiridos; e (4) alimentos ultraprocessados que não devem ser ofertados no ambiente escolar. Foi proposta a adoção dos seguintes parâmetros para participação dos grupos de alimentos em relação ao total de recursos federais empregados na compra de alimentos: ≥ 75% de recursos para alimentos in natura ou minimamente processados; < 20% para alimentos processados ou ultraprocessados e < 5% para ingredientes culinários processados e a ampliação da lista de alimentos cuja aquisição com recursos federais do PNAE é proibida. Esse processo subsidiou a elaboração da Resolução CD/FNDE nº 6, de 8 de maio de 2020, que dispõe sobre o atendimento da alimentação escolar aos alunos da educação básica no âmbito do PNAE.

La Guía Alimentaria para la Población Brasileña está reconocida como un potente inductor de políticas públicas de alimentación y nutrición. Desde esta perspectiva, este artículo presenta la trayectoria metodológica y evidencias que apoyaron la elaboración de los nuevos parámetros de adquisición de alimentos del Programa Nacional de Alimentación Escolar (PNAE). Tal elaboración implicó los análisis de: (1) participación de los recursos federales utilizados para la compra de alimentos, agrupados según la clasificación NOVA, empleada en el Guía Alimentaria para la Población Brasileña, por el conjunto de municipios brasileños, y según la clasificación de la ejecución (positiva o negativa); (2) menús mensuales de referencia que fueron elaborados siguiendo recomendaciones del Guía Alimentaria para la Población Brasileña; (3) adquisición de alimentos mediante una muestra de 525 municipios, implicando la participación relativa de los grupos de alimentos (según NOVA) en el total de gastos y de energía, así como la calidad nutricional de los alimentos adquiridos; y (4) alimentos ultraprocesados que no deben ser ofrecidos en el entorno escolar. Se propuso la adopción de los siguientes parámetros para la participación de los grupos de alimentos, en relación con el total de recursos federales empleados en la compra de alimentos: ≥ 75% de recursos para alimentos in natura o mínimamente procesados; < 20% para alimentos procesados o ultraprocesados, y < 5% para ingredientes culinarios procesados, así como la ampliación de la lista de alimentos, cuya adquisición con recursos federales del PNAE está prohibida. Este proceso apoyó la elaboración de la Resolución CD/FNDE nº 6, del 8 de mayo de 2020, que organiza la atención de la alimentación escolar a alumnos de educación básica en el ámbito del PNAE.

Synthesis, Antitrypanosomal and Antimycobacterial Activities of Coumarin N-acylhydrazonic Derivatives.

BACKGROUND: Near to 5-7 million people are infected with T. cruzi in the world, and about 10,000 people per year die of problems associated with this disease. METHODS: Herein, the synthesis, antitrypanosomal and antimycobacterial activities of seventeen coumarinic N-acylhydrazonic derivatives have been reported. RESULTS: These compounds were synthesized using methodology with reactions global yields ranging from 46%-70%. T. cruzi in vitro effects were evaluated against trypomastigote and amastigote, forming M. tuberculosis activity towards H37Rv sensitive strain and resistant strains. DISCUSSION: Against T. cruzi, the more active compounds revealed only moderate activity IC50/96h~20 µM for both trypomastigotes and amastigotes intracellular forms. (E)-2-oxo-N'- (3,4,5-trimethoxybenzylidene)-2H-chromene-3-carbohydrazide showed meaningful activity in INH resistant/RIP resistant strain. CONCLUSION: These compound acting as multitarget could be good leads for the development of new trypanocidal and bactericidal agents.

Starvation and pH stress conditions induced mitochondrial dysfunction, ROS production and autophagy in Trypanosoma cruzi epimastigotes.

Chagas disease is a neglected illness endemic in Latin America that mainly affects rural populations. The etiological agent of Chagas disease is the protozoan Trypanosoma cruzi, which has three different parasite stages and a dixenous life cycle that includes colonization of the vertebrate and invertebrate hosts. During its life cycle, T. cruzi is subjected to stress conditions, including variations in nutrient availability and pH, which impact parasite survival and differentiation. The plasticity of mitochondrial function in trypanosomatids has been defined as mitochondrial activity related to substrate availability. Thus, mitochondrial remodeling and autophagy, which is a constitutive cellular process of turnover and recycling of cellular components, may constitute a response to the nutritional and pH stress in the host. To assess these processes, epimastigotes were subjected to acidic, alkaline, and nutritional stress conditions, and mitochondrial function and its influence on the autophagic process were evaluated. Our data demonstrated that the three stress conditions affected the mitochondrial structure, inducing organelle swelling and impaired oxidative phosphorylation. Stressed epimastigotes produced increased ROS levels and overexpressed antioxidant enzymes. The stress conditions resulted in an increase in the number of autophagosomes and exacerbated the expression of different autophagy-related genes (Atgs). A correlation between mitochondrial dysfunction and autophagic phenotypes was also observed. After 24 h, acid stress and nutritional deprivation induced metacyclogenesis phenotypes (mitochondrial remodeling and autophagy). On the other hand, alkaline stress was transient due to insect blood feeding and culminated in an increase in autophagic flux as a survival mechanism.

Atualização dos parâmetros de aquisição do Programa Nacional de Alimentação Escolar com base no Guia Alimentar para a População Brasileira / Actualización de los parámetros de adquisición del Programa Nacional de Alimentación Escolar en base a la Guía Alimentaria para la Población Brasileña / Update of the acquisition parameters of the Brazilian National School Feeding Program based on the Dietary Guidelines for the Brazilian Population

O Guia Alimentar para a População Brasileira é reconhecido como um potente indutor de políticas públicas de alimentação e nutrição. Nessa perspectiva, este artigo apresenta o percurso metodológico e as evidências que subsidiaram a elaboração dos novos parâmetros de aquisição de alimentos do Programa Nacional de Alimentação Escolar (PNAE). Tal elaboração envolveu as análises de: (1) participação dos recursos federais utilizados para compra de alimentos, agrupados segundo a classificação NOVA, empregada no Guia Alimentar para a População Brasileira, pelo conjunto de municípios brasileiros e segundo classificação da execução (positiva ou negativa); (2) cardápios mensais de referência que foram elaborados seguindo recomendações do Guia Alimentar para a População Brasileira; (3) aquisição de alimentos por amostra de 525 municípios, envolvendo a participação relativa dos grupos de alimentos (segundo a NOVA) no total de gastos e de energia e a qualidade nutricional dos alimentos adquiridos; e (4) alimentos ultraprocessados que não devem ser ofertados no ambiente escolar. Foi proposta a adoção dos seguintes parâmetros para participação dos grupos de alimentos em relação ao total de recursos federais empregados na compra de alimentos: ≥ 75% de recursos para alimentos in natura ou minimamente processados; < 20% para alimentos processados ou ultraprocessados e < 5% para ingredientes culinários processados e a ampliação da lista de alimentos cuja aquisição com recursos federais do PNAE é proibida. Esse processo subsidiou a elaboração da Resolução CD/FNDE nº 6, de 8 de maio de 2020, que dispõe sobre o atendimento da alimentação escolar aos alunos da educação básica no âmbito do PNAE.

La Guía Alimentaria para la Población Brasileña está reconocida como un potente inductor de políticas públicas de alimentación y nutrición. Desde esta perspectiva, este artículo presenta la trayectoria metodológica y evidencias que apoyaron la elaboración de los nuevos parámetros de adquisición de alimentos del Programa Nacional de Alimentación Escolar (PNAE). Tal elaboración implicó los análisis de: (1) participación de los recursos federales utilizados para la compra de alimentos, agrupados según la clasificación NOVA, empleada en el Guía Alimentaria para la Población Brasileña, por el conjunto de municipios brasileños, y según la clasificación de la ejecución (positiva o negativa); (2) menús mensuales de referencia que fueron elaborados siguiendo recomendaciones del Guía Alimentaria para la Población Brasileña; (3) adquisición de alimentos mediante una muestra de 525 municipios, implicando la participación relativa de los grupos de alimentos (según NOVA) en el total de gastos y de energía, así como la calidad nutricional de los alimentos adquiridos; y (4) alimentos ultraprocesados que no deben ser ofrecidos en el entorno escolar. Se propuso la adopción de los siguientes parámetros para la participación de los grupos de alimentos, en relación con el total de recursos federales empleados en la compra de alimentos: ≥ 75% de recursos para alimentos in natura o mínimamente procesados; < 20% para alimentos procesados o ultraprocesados, y < 5% para ingredientes culinarios procesados, así como la ampliación de la lista de alimentos, cuya adquisición con recursos federales del PNAE está prohibida. Este proceso apoyó la elaboración de la Resolución CD/FNDE nº 6, del 8 de mayo de 2020, que organiza la atención de la alimentación escolar a alumnos de educación básica en el ámbito del PNAE.

The Dietary Guidelines for the Brazilian Population is acknowledged as a powerful inducer of public food and nutrition policies. In this perspective, this article presents the methodological path and evidence that supported the elaboration of the new parameters of food acquisition of the Brazilian National School Feeding Program (PNAE). This elaboration involved the analyses of: (1) participation of federal resources used to purchase food, grouped according to the NOVA classification, used in Dietary Guidelines for the Brazilian Population, by the set of Brazilian municipalities and according to the classification of the execution (positive or negative); (2) monthly reference menus that were prepared following Dietary Guidelines for the Brazilian Population recommendations; (3) analysis of food acquisition by the sampling of 525 municipalities, involving the relative participation of food groups (according to NOVA) in total expenditures and energy and nutritional quality of purchased foods; and (4) analysis of ultra-processed foods that should not be offered in the school environment. We proposed the adoption of the following parameters for the participation of food groups in relation to the total federal resources used in the purchase of food: ≥ 75% of resources for fresh or minimally processed foods; < 20% for processed or ultra-processed foods and < 5% for processed culinary ingredients, as well as the expansion of the list of foods whose acquisition with federal resources from PNAE is prohibited. This process supported the elaboration of Resolution CD/FNDE n. 6 of May 8, 2020, which provides for the attendance of school feeding to primary education students within the PNAE.

Antiparasitic and anti-inflammatory activities of ß-lapachone-derived naphthoimidazoles in experimental acute Trypanosoma cruzi infection.

BACKGROUND: Chagas disease, which is caused by the protozoan Trypanosoma cruzi, is endemic to Latin America and mainly affects low-income populations. Chemotherapy is based on two nitrocompounds, but their reduced efficacy encourages the continuous search for alternative drugs. Our group has characterised the trypanocidal effect of naphthoquinones and their derivatives, with naphthoimidazoles derived from ß-lapachone (N1, N2 and N3) being the most active in vitro. OBJECTIVES: In the present work, the effects of N1, N2 and N3 on acutely infected mice were investigated. METHODS: in vivo activity of the compounds was assessed by parasitological, biochemical, histopathological, immunophenotypical, electrocardiographic (ECG) and behavioral analyses. FINDINGS: Naphthoimidazoles led to a decrease in parasitaemia (8 dpi) by reducing the number of bloodstream trypomastigotes by 25-50% but not by reducing mortality. N1 protected mice from heart injury (15 dpi) by decreasing inflammation. Bradycardia was also partially reversed after treatment with N1 and N2. Furthermore, the three compounds did not reverse hepatic and renal lesions or promote the improvement of other evaluated parameters. MAIN CONCLUSION: N1 showed moderate trypanocidal and promising immunomodulatory activities, and its use in combination with benznidazole and/or anti-arrhythmic drugs as well as the efficacy of its alternative formulations must be investigated in the near future.

Synthesis of quinone imine and sulphur-containing compounds with antitumor and trypanocidal activities: redox and biological implications.

Ortho-Quinones represent a special class of redox active compounds associated with a spectrum of pronounced biological activities, including selective cytotoxicity and antimicrobial actions. The modification of the quinone ring by simple nitrogen and sulphur substitutions leads to several new classes of compounds with their own, distinct redox behaviour and equally distinct activities against cancer cell lines and Trypanosoma cruzi. Some of the compounds investigated show activity against T. cruzi at concentrations of 24.3 and 65.6 µM with a selectivity index of around 1. These results demonstrate that simple chemical modifications on the ortho-quinone ring system, in particular, by heteroatoms such as nitrogen and sulphur, transform these simple redox molecules into powerful cytotoxic agents with considerable "potential", not only in synthesis and electrochemistry, but also, in a broader sense, in health sciences.

Novel nitroimidazole derivatives evaluated for their trypanocidal, cytotoxic, and genotoxic activities.

The current treatment of Chagas disease is based on the use of two drugs, nifurtimox (Nfx) and benznidazole (Bnz), both of which present limited efficacy in the chronic stage of the disease and toxic side effects. Thus, the discovery of novel compounds is urgently required. Herein, we report the successful synthesis of 4-nitroimidazole analogs of Bnz via nucleophilic aromatic substitution or cycloaddition reactions. The analogs were biologically evaluated, and compound 4 (4-cyclopropyl-1-(1-methyl-4-nitro-1H-imidazole-5-yl)-1H-1,2,3-triazole) was identified as the most potent against both the trypomastigote (IC50 = 5.4 µM) and amastigote (IC50 = 12.0 µM) forms of T. cruzi, showing activity in the same range as Bnz (IC50 = 8.8 and 8.7 µM, respectively). The cytotoxic and genotoxic activities of compounds 5, 4 and 11 were assessed. These three compounds were cytotoxic and genotoxic to RAW and HepG2 cells and mutagenic to Salmonella enterica strains. However, 4 exhibited toxic effects only at concentrations higher than those needed for trypanocidal activity. Molecular docking of 4 showed the importance of the size and π-π interactions between the nitroimidazole and the cofactor (flavin mononucleotide) of T.cruzi-nitroreductase (TcNTR). Moreover, the residues His503 and Tyr545 are relevant for binding to TcNTR. Our design strategy was capable of generating novel and active Bnz analogs.

Synthesis and Antitrypanosomal Profile of Novel Hydrazonoyl Derivatives.

BACKGROUND: Approximately, 5-7 million people are infected with T. cruzi in the world, and approximately 10,000 people per year die of complications linked to this disease. METHODS: This work describes the construction of a new family of hidrazonoyl substituted derivatives, structurally designed exploring the molecular hybridization between megazol and nitrofurazone. RESULTS AND DISCUSSION: The compounds were evaluated for their in vitro activity against bloodstream trypomastigotes of Trypanosoma cruzi, etiological agent of Chagas disease, and for their potential toxicity to mammalian cells. CONCLUSION: Among these hydrazonoyl derivatives, we identified the derivative (4) that showed trypanocidal activity (IC50/24 h = 15.0 µM) similar to Bz, the standard drug, and low toxicity to mammalian cells, reaching an SI value of 18.7.

Identification of Novel Functionalized Carbohydrazonamides Designed as Chagas Disease Drug Candidates.

BACKGROUND: Although several research efforts have been made worldwide to discover novel drug candidates for the treatment of Chagas disease, the nitroimidazole drug benznidazol remains the only therapeutic alternative in the control of this disease. However, this drug presents reduced efficacy in the chronic form of the disease and limited safety after long periods of administration, making it necessary to search for new, more potent and safe prototypes. OBJECTIVE: We described herein the synthesis and the trypanocidalaction of new functionalized carbohydrazonamides (2-10) against trypomastigote forms of Trypanosoma cruzi. METHODS: These compounds were designed through the application of molecular hybridization concept between two potent anti-T. cruzi prototypes, the nitroimidazole derivative megazol (1) and the cinnamyl N-acylhydrazone derivative (14) which have been shown to be twice as potent in vitro as benznidazole. RESULTS: The most active compounds were the (Z)-N'-((E)-3-(4-nitrophenyl)-acryloyl)-1-methyl-5- nitro-1H-imidazol-2-carbohydrazonamide (6) (IC50=9.50 µM) and the (Z)-N'-((E)-3-(4- hydroxyphe-nyl)-acryloyl)-1-methyl-5-nitro-1H-imidazol-2-carbohydrazonamide (8) (IC50=12.85 µM), which were almost equipotent to benznidazole (IC50=10.26 µM) used as standard drug. The removal of the amine group attached to the imine subunit in the corresponding N-acylhydrazone derivatives (11-13) resulted in less potent or inactive compounds. The para-hydroxyphenyl derivative (8) presented also a good selectivity index (SI = 32.94) when tested against mammalian cells from Swiss mice. CONCLUSION: The promising trypanocidal profile of new carbohydrazonamide derivatives (6) and (8) was characterized. These compounds have proved to be a good starting point for the design of more effective trypanocidal drug candidates.

[Convergence of public policies on education to promote a healthy and appropriate dietConvergencia de las políticas públicas educativas en el fomento de la alimentación adecuada y saludable]. / Convergência de políticas públicas educacionais na promoção da alimentação adequada e saudável.

The present report describes the process of convergence between the Brazilian National School Feeding Program (PNAE) and the Brazilian National Textbook Program (PNLD), highlighting a project that introduced diet and nutrition topics on the covers of textbooks distributed at no cost to all public schools in Brazil. This intersectoral initiative speaks directly to the recommendations of the Dietary Guidelines for the Brazilian Population, the principles of the Nutrition Education Framework for Public Policies, and the proposals laid out in the United Nations Decade of Action on Nutrition. The report shows that the construction of a dialogic and intersectoral space is a possible path to promote a healthy and appropriate diet among students. However, further studies are necessary to evaluate the effectiveness of introducing diet and nutrition topics in textbooks, and also studies investigating the perception of teachers and students regarding the use of books to promote education on diet and nutrition.

El objetivo del presente informe es describir la trayectoria de convergencia del Programa Nacional de Alimentación Escolar (PNAE) con el Programa Nacional de Libros y Materiales Didácticos (PNLD) en Brasil, con hincapié en el proyecto de inclusión de los temas de alimentación y nutrición en las portadas de los libros didácticos distribuidos de manera general y gratuita a todas las escuelas públicas brasileñas. Esa iniciativa intersectorial guarda una relación directa con las recomendaciones de la guía alimentaria para la población brasileña, los principios del marco de educación alimentaria y nutricional para las políticas públicas y las propuestas del Decenio de las Naciones Unidas de Acción sobre la Nutrición. Se comprobó que la construcción de un espacio dialógico e intersectorial es una posible vía para fomentar el consumo de una alimentación adecuada y saludable en los estudiantes. Sin embargo, se recomienda realizar estudios para evaluar la efectividad de la inclusión de los temas de alimentación y nutrición en los libros didácticos e investigar la forma en que el cuerpo docente y discente percibe el empleo de los libros para promover la educación alimentaria y nutricional.

Convergência de políticas públicas educacionais na promoção da alimentação adequada e saudável

[RESUMO]. O presente relato tem como objetivo descrever a trajetória de convergência do Programa Nacional de Alimentação Escolar (PNAE) com o Programa Nacional do Livro e do Material Didático (PNLD) no Brasil, com destaque para o projeto de inclusão dos temas de alimentação e nutrição nas capas de livros didáticos distribuídos de forma universal e gratuita a todas as escolas públicas brasileiras. Essa iniciativa intersetorial dialoga diretamente com as recomendações do Guia Alimentar para a População Brasileira, com os princípios do Marco de Educação Alimentar e Nutricional para as Políticas Públicas e com as propostas da Década da Ação em Nutrição das Nações Unidas. Verificou-se que a construção de um espaço dialógico e intersetorial é um caminho possível para a promoção da alimentação adequada e saudável aos estudantes. Entretanto, sugere-se a realização de estudos que avaliem a efetividade da inserção dos temas de alimentação e nutrição nos livros didáticos e que investiguem a percepção dos docentes e discentes quanto ao uso dos livros para promover a educação alimentar e nutricional.

[ABSTRACT]. The present report describes the process of convergence between the Brazilian National School Feeding Program (PNAE) and the Brazilian National Textbook Program (PNLD), highlighting a project that introduced diet and nutrition topics on the covers of textbooks distributed at no cost to all public schools in Brazil. This intersectoral initiative speaks directly to the recommendations of the Dietary Guidelines for the Brazilian Population, the principles of the Nutrition Education Framework for Public Policies, and the proposals laid out in the United Nations Decade of Action on Nutrition. The report shows that the construction of a dialogic and intersectoral space is a possible path to promote a healthy and appropriate diet among students. However, further studies are necessary to evaluate the effectiveness of introducing diet and nutrition topics in textbooks, and also studies investigating the perception of teachers and students regarding the use of books to promote education on diet and nutrition.

[RESUMEN]. El objetivo del presente informe es describir la trayectoria de convergencia del Programa Nacional de Alimentación Escolar (PNAE) con el Programa Nacional de Libros y Materiales Didácticos (PNLD) en Brasil, con hincapié en el proyecto de inclusión de los temas de alimentación y nutrición en las portadas de los libros didácticos distribuidos de manera general y gratuita a todas las escuelas públicas brasileñas. Esa iniciativa intersectorial guarda una relación directa con las recomendaciones de la guía alimentaria para la población brasileña, los principios del marco de educación alimentaria y nutricional para las políticas públicas y las propuestas del Decenio de las Naciones Unidas de Acción sobre la Nutrición. Se comprobó que la construcción de un espacio dialógico e intersectorial es una posible vía para fomentar el consumo de una alimentación adecuada y saludable en los estudiantes. Sin embargo, se recomienda realizar estudios para evaluar la efectividad de la inclusión de los temas de alimentación y nutrición en los libros didácticos e investigar la forma en que el cuerpo docente y discente percibe el empleo de los libros para promover la educación alimentaria y nutricional.

Synthesis of quinones with highlighted biological applications: A critical update on the strategies towards bioactive compounds with emphasis on lapachones.

Naphthoquinones are of key importance in organic synthesis and medicinal chemistry. In the last few years, various synthetic routes have been developed to prepare bioactive compounds derived or based on lapachones. In this sense, this review is mainly focused on the synthetic aspects and strategies used for the design of these compounds on the basis of their biological activities for the development of drugs against the neglected diseases leishmaniases and Chagas disease and also cancer. Three strategies used to develop bioactive quinones are discussed and categorized: (i) C-ring modification, (ii) redox centre modification and (iii) A-ring modification. Framed within these strategies for the development of naphthoquinoidal compounds against T. cruzi. Leishmania and cancer, reactions including copper-catalyzed azide-alkyne cycloaddition (click chemistry), palladium-catalysed cross couplings, C-H activation reactions, Ullmann couplings and heterocyclisations reported up to July 2019 will be discussed. The aim of derivatisation is the generation of novel molecules that can potentially inhibit cellular organelles/processes, generate reactive oxygen species and increase lipophilicity to enhance penetration through the plasma membrane. Modified lapachones have emerged as promising prototypes for the development of drugs against leishmaniases, Chagas disease and cancer.

In vitro genotoxicity of nitroimidazoles as a tool in the search of new trypanocidal agents.

BACKGROUND: Only benznidazole (Bnz) (1) and nifurtimox (Nfx) (2) are licensed for the treatment of Chagas disease although their safety and efficacy profile are far from ideal. Farmanguinhos from Fiocruz has developed seven nitroimidazole compounds (4-10) analogs of megazol (3). OBJECTIVES: To evaluate whether the genotoxic effect of 3 was abolished in the seven nitroimidazoles (4-10) analogs using the in vitro alkaline comet assay (CA) and the in vitro cytokinesis-block micronucleus assay (CBMN) in whole human blood cells (WHBC) and correlate this effect with their trypanocidal activity using bloodstream trypomastigote forms of Trypanosoma cruzi. METHODS: The toxicity of 3-10 to WHBC in the in vitro CA was determined using the fluorescein diacetate/ethidium bromide assay. DNA damage in the in vitro CA was evaluated according to tail size in four classes (0-3) and methyl methane-sulfonate (MMS) was used as a positive control. The cytotoxicity of 3-10 to WHBC in the CBMN was measured using the cytokinesis-block proliferation index and the replication index. The number of the micronucleate cells in 2,000 binucleate cells by experimental group was determined. Mitomycin C and N-deacetyl-N-methylcolchicine were used as positive controls. FINDINGS: Compound 3 showed a significant DNA strand break effect through the in vitro CA and highly significant clastogenic and/or aneugenic effect in the CBMN. Compounds 5, 6, 8, 9 and 10 showed negative results in the CBMN and positive results in the in vitro CA, while the inverse effect was observed for 4 and 7. MAIN CONCLUSIONS: Compound 10 was the most promising to proceed with the development as a drug candidate in the treatment of Chagas disease showing absence of chromosomal cytogenetic damage and high activity against T. cruzi, about two times higher than 3 and the clinical drug 1.

In vitro genotoxicity of nitroimidazoles as a tool in the search of new trypanocidal agents

BACKGROUND Only benznidazole (Bnz) (1) and nifurtimox (Nfx) (2) are licensed for the treatment of Chagas disease although their safety and efficacy profile are far from ideal. Farmanguinhos from Fiocruz has developed seven nitroimidazole compounds (4-10) analogs of megazol (3). OBJECTIVES To evaluate whether the genotoxic effect of 3 was abolished in the seven nitroimidazoles (4-10) analogs using the in vitro alkaline comet assay (CA) and the in vitro cytokinesis-block micronucleus assay (CBMN) in whole human blood cells (WHBC) and correlate this effect with their trypanocidal activity using bloodstream trypomastigote forms of Trypanosoma cruzi. METHODS The toxicity of 3-10 to WHBC in the in vitro CA was determined using the fluorescein diacetate/ethidium bromide assay. DNA damage in the in vitro CA was evaluated according to tail size in four classes (0-3) and methyl methane-sulfonate (MMS) was used as a positive control. The cytotoxicity of 3-10 to WHBC in the CBMN was measured using the cytokinesis-block proliferation index and the replication index. The number of the micronucleate cells in 2,000 binucleate cells by experimental group was determined. Mitomycin C and N-deacetyl-N-methylcolchicine were used as positive controls. FINDINGS Compound 3 showed a significant DNA strand break effect through the in vitro CA and highly significant clastogenic and/or aneugenic effect in the CBMN. Compounds 5, 6, 8, 9 and 10 showed negative results in the CBMN and positive results in the in vitro CA, while the inverse effect was observed for 4 and 7. MAIN CONCLUSIONS Compound 10 was the most promising to proceed with the development as a drug candidate in the treatment of Chagas disease showing absence of chromosomal cytogenetic damage and high activity against T. cruzi, about two times higher than 3 and the clinical drug 1.

Rhodium-catalyzed C-H bond activation for the synthesis of quinonoid compounds: Significant Anti-Trypanosoma cruzi activities and electrochemical studies of functionalized quinones.

Thirty four halogen and selenium-containing quinones, synthesized by rhodium-catalyzed C-H bond activation and palladium-catalyzed cross-coupling reactions, were evaluated against bloodstream trypomastigotes of T. cruzi. We have identified fifteen compounds with IC50/24 h values of less than 2 µM. Electrochemical studies on A-ring functionalized naphthoquinones were also performed aiming to correlate redox properties with trypanocidal activity. For instance, (E)-5-styryl-1,4-naphthoquinone 59 and 5,8-diiodo-1,4-naphthoquinone 3, which are around fifty fold more active than the standard drug benznidazole, are potential derivatives for further investigation. These compounds represent powerful new agents useful in Chagas disease therapy.

Clear Shot at Primary Aim: Susceptibility of Trypanosoma cruzi Organelles, Structures and Molecular Targets to Drug Treatment.

Chagas disease, caused by Trypanosoma cruzi, stands out due to its socio-economic effects on low-income tropical populations. This disease affects millions of people worldwide. The current chemotherapy for it is based on benznidazole (Bz) and nifurtimox (Nif) and is unsatisfactory. In this review, we will focus on the search for potential target organelles and molecules for the chemotherapy of Chagas disease. We consider as potential target organelles those that are absent or significantly different in host cells and present in the clinically relevant forms of the parasite (trypomastigotes and amastigotes), which are the mitochondrion, cytoskeletal-related structures, the acidocalcisomes/ contractile vacuole complex and glycosomes. Most molecular targets are key enzymes involved in processes that are essential to parasite survival, such as sterol biosynthesis, antioxidant defences and bioenergetic pathways. Among the molecular targets, enzymes of the sterol pathway, particularly C14α-sterol demethylase, are still the most promising target, even if clinical trials with posaconazole and E1224 have failed to sustain efficacy. We believe that in the near future, the Chagas community will have a "clear shot" at new drug candidates for Chagas disease based on the accumulated knowledge about trypanosomatid biochemistry, preclinical studies, advances in screening technologies, the efforts of medicinal chemists in the synthesis of both azolic and non-azolic inhibitors, and the interest of pharmaceutical companies in the development of new antifungal agents, which form a critical mass of information.

Synthesis and biological evaluation of N-alkyl naphthoimidazoles derived from ß-lapachone against Trypanosoma cruzi bloodstream trypomastigotes.

The QSAR study of 34 2-aryl-naphthoimidazoles screened so far revealed that σi is the most important factor for their lytic activity on the bloodstream trypomastigote forms of T. cruzi, the etiologic agent of Chagas disease. Based on this result, 16 new N-alkyl-naphthoimidazoles derived from 6,6-dimethyl-3,4,5,6-tetrahydrobenzo[7,8]chromene[5,6-d]imidazole (the product of the reaction of ß-lapachone with paraformaldehyde) by its reaction with halo-alkanes were prepared and evaluated against the parasite and peritoneal macrophages. The N1-n-hexyl and N3-n-hexyl naphthoimidazoles were 2.2 and 3.2 times more active than the standard drug benznidazole with selectivity indices of 2.7 and 13.4, respectively.

Stairway to Heaven or Hell? Perspectives and Limitations of Chagas Disease Chemotherapy.

In this review, we intend to provide a general view of the evolution of experimental studies in the area of chemotherapy for Chagas disease. We can follow the process of drug development through three phases. The first phase began almost at the same time as the discovery made by Carlos Chagas and proceeds to 1970, during which time an extensive list of compounds was subjected to preclinical and clinical trials. The second phase began with the introduction of nifurtimox and benznidazole into the clinical setting, followed with the search for alternative drugs. In this phase, a dichotomy existed between rational and empirical approaches in preclinical studies. The third phase began with the unravelling of the T. cruzi genome. The development of transgenic parasites has allowed the development of solid HTS protocols, and the establishment of bioluminescent T. cruzi has allowed in vivo drug evaluations using a reduced number of animals. Among the wide variety of compounds subjected to preclinical studies, we have discovered azolic and non-azolic inhibitors of sterol C14α-demethylase (CYP51) and nitro compounds. Two compounds evaluated during the second phase, namely, MK-436 and allopurinol, could be revisited. Clinical studies of posaconazole and E1224 yielded disappointing results, and it is critical to understand the reason for their failure as a monotherapy. Currently, the combination and repositioning of drugs with different mechanisms of action are complementary approaches. The use of drug combinations, particularly those of nitro compounds with CYP51 inhibitors, is considered a real alternative for the treatment of Chagas disease.