Ferritin heavy chain supports stability and function of the regulatory T cell lineage.

Regulatory T (TREG) cells develop via a program orchestrated by the transcription factor forkhead box protein P3 (FOXP3). Maintenance of the TREG cell lineage relies on sustained FOXP3 transcription via a mechanism involving demethylation of cytosine-phosphate-guanine (CpG)-rich elements at conserved non-coding sequences (CNS) in the FOXP3 locus. This cytosine demethylation is catalyzed by the ten-eleven translocation (TET) family of dioxygenases, and it involves a redox reaction that uses iron (Fe) as an essential cofactor. Here, we establish that human and mouse TREG cells express Fe-regulatory genes, including that encoding ferritin heavy chain (FTH), at relatively high levels compared to conventional T helper cells. We show that FTH expression in TREG cells is essential for immune homeostasis. Mechanistically, FTH supports TET-catalyzed demethylation of CpG-rich sequences CNS1 and 2 in the FOXP3 locus, thereby promoting FOXP3 transcription and TREG cell stability. This process, which is essential for TREG lineage stability and function, limits the severity of autoimmune neuroinflammation and infectious diseases, and favors tumor progression. These findings suggest that the regulation of intracellular iron by FTH is a stable property of TREG cells that supports immune homeostasis and limits the pathological outcomes of immune-mediated inflammation.

Targeting circulating labile heme as a defense strategy against malaria.

Severe presentations of malaria emerge as Plasmodium (P.) spp. parasites invade and lyse red blood cells (RBC), producing extracellular hemoglobin (HB), from which labile heme is released. Here, we tested whether scavenging of extracellular HB and/or labile heme, by haptoglobin (HP) and/or hemopexin (HPX), respectively, counter the pathogenesis of severe presentations of malaria. We found that circulating labile heme is an independent risk factor for cerebral and non-cerebral presentations of severe P. falciparum malaria in children. Labile heme was negatively correlated with circulating HP and HPX, which were, however, not risk factors for severe P. falciparum malaria. Genetic Hp and/or Hpx deletion in mice led to labile heme accumulation in plasma and kidneys, upon Plasmodium infection This was associated with higher incidence of mortality and acute kidney injury (AKI) in ageing but not adult Plasmodium-infected mice, and was corroborated by an inverse correlation between heme and HPX with serological markers of AKI in P. falciparum malaria. In conclusion, HP and HPX act in an age-dependent manner to prevent the pathogenesis of severe presentation of malaria in mice and presumably in humans.

Effects of Calendula officinalis extract on liver histopathology, lipid profile, and oxidative stress in rats submitted to a diet rich in cholesterol and carbohydrates.

PURPOSE: To evaluate the modulatory properties of Calendula officinalis L. (Asteraceae) (C. officinalis) extract on cafeteria diet-fed rats. METHODS: A cafeteria diet was administered ad libitum for 45 days to induce dyslipidemia. Then, the rats were treated with the formulations containing C. officinalis in the doses of 50, 100, and 150 mg/kg or only with the vehicle formulation; the control group received a commercial ration. RESULTS: The cafeteria diet decreased glutathione S-transferase activity and high-density lipoprotein plasmatic levels and damaged the hepatic architecture. The C. officinalis extract was able to reduce lipid infiltration in liver tissue and to modulate oxidative stress and lipid profile markers. CONCLUSIONS: The correlations between the variables suggest a pathological connection between oxidative stress markers and serum lipid profile.

Brain-derived neurotrophic factor (BDNF) levels in children and adolescents before and after stimulant use a systematic review and metanalysis.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder associated with cognitive, social, and academic impairment. Neurotrophins, particularly brain-derived neurotrophic factor (BDNF), have been implicated in the pathophysiology of ADHD and response to stimulant treatment. This review aims to investigate the relationship between BDNF levels in ADHD before and after treatment with stimulants in childhood. METHODS: This systematic review followed PRISMA-P guidelines and included 19 studies from PubMed, EMBASE, Cochrane, Capes Periodic, and Lilacs databases. The studies were evaluated for risk of bias and level of evidence. RESULTS: There was no significant difference in peripheral BDNF levels in ADHD children before or after methylphenidate treatment. Additionally, there was no statistically significant difference in BDNF levels between children with ADHD and controls. DISCUSSION: Understanding the role of BDNF in ADHD may provide insight into the disorder's pathophysiology and facilitate the development of biological markers for clinical use. CONCLUSION: Our findings suggest that BDNF levels are not significantly affected by methylphenidate treatment in ADHD children and do not differ from controls. SYSTEMATIC REVIEW REGISTRATION: "Brain-derived neurotrophic factor (BDNF) levels in children and adolescents before and after stimulant use: a systematic review". Number CRD42021261519.

Natural Coumarin Derivatives Targeting Melanoma.

In general, a cancerous process starts from uncontrolled cell growth, apoptosis, and rapid proliferation of cellular clones, as well as, reactive oxygen species (ROS) and imbalance of ROS-antioxidant production also could be involved in the genesis of the disease. Cancer has accounted for millions of deaths worldwide every year, representing a relevant threat to human lives. In this context, malignant melanoma represents the most aggressive and deadliest type of cancer, leading to increased rates of patient deaths. Natural active compounds have demonstrated their pharmacological benefits in several different studies. Among these compounds, coumarin analogs have demonstrated promising biological profiles, considering their efficacy and low toxicity. In this context, this phytochemical oxygenated core has been broadly investigated since it presents several biological properties of interest in the medicinal field. Herein, we reported a complete compilation of studies focused on natural coumarins against melanoma, as well as, tyrosinase since it is a cooper-catalyzed oxidase that performs an essential role during melanogenesis (Eu-melanins and Pheo-melanins), which is associated with melanoma. Thus, three different subclasses of natural coumarin were described in detail, such as simple coumarin core, furanocoumarins, pyranocoumarins, and pyrone-substituents. Additionally, insights on tyrosinase have been provided, allowing an overview of some structural/functional aspects of its enzyme, such as the presence of a binuclear type 3 cooper coordination at the binding site of this target, acting as cofactors. Posteriorly, several coumarin-based analogs with anti-tyrosinase activity also were reported and discussed. Finally, we believe that unprecedented review can be a valuable source of information, which can be used to design and develop novel coumarin-based analogs targeting melanoma and also tyrosinase enzyme, contributing to the advances in the field of natural products.

Consumption and Breakfast Patterns in Children and Adolescents with Congenital Heart Disease.

Little is known about skipping breakfast and breakfast patterns (BP) and their evaluation according to sociodemographic, clinical, lifestyle, cardiometabolic and nutritional data in children and adolescents with congenital heart disease (CHD). This cross-sectional study with 232 children and adolescents with CHD identified the prevalence and patterns of the breakfast, described these according to sociodemographic, clinical and lifestyle characteristics, and assessed their association with cardiometabolic and nutritional markers. Breakfast patterns were identified by principal components, and bivariate and linear regression analysis were applied. Breakfast consumption was observed in 73% of participants. Four BP were identified: pattern 1 "milk, ultra-processed bread, and chocolate milk", pattern 2 "margarine and processed bread", pattern 3 "cold meats/sausages, cheeses and butter/cream" and pattern 4 "fruits/fruit juices, breakfast cereals, yogurts, and homemade cakes/pies and sweet snacks". Family history for obesity and acyanotic CHD were associated with breakfast skipping. Younger participants and greater maternal education were associated with greater adherence to pattern 1 and pattern 4. Older participants and longer post-operative time showed greater adherence to pattern 3. No association between skipping breakfast or BP and cardiometabolic and nutritional markers was observed. Nonetheless, the findings reinforce the need for nutritional guidance for healthy breakfast, aiming to reduce the consumption of ultra-processed foods and to prioritize fresh and minimally processed foods.

Coumarin-Based Compounds as Inhibitors of Tyrosinase/Tyrosine Hydroxylase: Synthesis, Kinetic Studies, and In Silico Approaches.

Cancer represents the main cause of morbidity and mortality worldwide, constituting a serious health problem. In this context, melanoma represents the most aggressive and fatal type of skin cancer, with death rates increasing every year. Scientific efforts have been addressed to the development of inhibitors targeting the tyrosinase enzyme as potential anti-melanoma agents due to the importance of this enzyme in melanogenesis biosynthesis. Coumarin-based compounds have shown potential activity as anti-melanoma agents and tyrosinase inhibitors. In this study, coumarin-based derivatives were designed, synthesized, and experimentally evaluated upon tyrosinase. Compound FN-19, a coumarin-thiosemicarbazone analog, exhibited potent anti-tyrosinase activity, with an IC50 value of 42.16 ± 5.16 µM, being more active than ascorbic acid and kojic acid, both reference inhibitors. The kinetic study showed that FN-19 acts as a mixed inhibitor. Still, for this compound, molecular dynamics (MD) simulations were performed to determine the stability of the complex with tyrosinase, generating RMSD, RMSF, and interaction plots. Additionally, docking studies were performed to elucidate the binding pose at the tyrosinase, suggesting that the hydroxyl group of coumarin derivative performs coordinate bonds (bidentate) with the copper(II) ions at distances ranging from 2.09 to 2.61 Å. Then, MM/PBSA calculations revealed that van der Waals interactions are the most relevant intermolecular forces for complex stabilization. Furthermore, it was observed that FN-19 has a binding energy (ΔEMM) value similar to tropolone, a tyrosinase inhibitor. Therefore, the data obtained in this study will be useful for designing and developing novel coumarin-based analogs targeting the tyrosinase enzyme.

Changes in lifestyle behaviors during the COVID-19 pandemic in children and adolescents with congenital heart disease.

OBJECTIVE: To describe the changes in lifestyle behaviors during the COVID-19 pandemic in children and adolescents with congenital heart disease and to investigate the association of congenital heart disease complexity with lifestyle behavior changes. METHODS: Cross-sectional study with 127 children and adolescents with congenital heart disease, who underwent cardiac procedure (mean postoperative time: 10.11±3.13 years), conducted between December 2020 and January 2021. Lifestyle behaviors, such as dietary intake, physical activity, sedentary behavior, and sleep, were assessed through telephone interview based on validated questionnaires. Dietary patterns were identified using principal component analysis. Frequency of general and specific combinations of healthy and unhealthy lifestyle behavior changes was evaluated. Multinomial logistic regressions were used to test the association between congenital heart disease complexity and changes in lifestyle behavior. RESULTS: The main lifestyle behaviors acquired during pandemic were: 83.5% decreased physical activity; 37.0% increased sedentary behavior; 26.0% slept more than usual; and 23.6% adopted a less-healthy dietary pattern. Almost half of the participants (41.8%) had at least one unhealthy change in lifestyle behavior. Complex congenital heart diseases were associated with increased sedentary behavior (OR 3.49, 95%CI 1.23-9.90). CONCLUSIONS: Children and adolescents with congenital heart disease had unhealthy lifestyle behavior during the pandemic, mainly in the form of reduced physical activity and increased sedentary behavior.

Renal control of life-threatening malarial anemia.

Iron recycling prevents the development of anemia under homeostatic conditions. Whether iron recycling was co-opted as a defense strategy to prevent the development of anemia in response to infection is unclear. We find that in severe Plasmodium falciparum malaria, the onset of life-threatening anemia is associated with acute kidney injury (AKI), irrespective of parasite load. Using a well-established experimental rodent model of malaria anemia, we identify a transcriptional response that endows renal proximal tubule epithelial cells (RPTECs) with the capacity to store and recycle iron during P. chabaudi chabaudi (Pcc) infection. This response encompasses the induction of ferroportin 1/SLC40A1, which exports iron from RPTECs and counteracts AKI while supporting compensatory erythropoiesis and preventing the onset of life-threatening malarial anemia. Iron recycling by myeloid cells is dispensable to this protective response, suggesting that RPTECs provide an iron-recycling salvage pathway that prevents the pathogenesis of life-threatening malarial anemia.

Clusters of lifestyle behaviors associated with atherosclerosis risk factors in children and adolescents with congenital heart disease: Floripa CHild Study.

Secondary cardiovascular disease is the main cause of mortality in congenital heart disease (CHD) patients. The cardiovascular risk could be widely prevented with adherence to a healthy lifestyle; however, clusters of lifestyle behaviors related to atherosclerosis risk factors in children and adolescents with CHD remain unclear. We aimed to describe the clusters of lifestyle behaviors of children and adolescents with CHD and to evaluate their association with atherosclerosis risk factors. We conducted a cross-sectional study on 227 children and adolescents with CHD (median age:10.02 [IQR:7.08-13.02] years). Dietary intake, physical activity (PA), and sedentary behavior (SB) were evaluated. Clusters of lifestyle behaviors were determined using a two-step cluster analysis. Atherosclerosis risk factors evaluated include body fat mass, central obesity, blood pressure, lipid parameters, glucose, C-reactive protein, and carotid intima-media thickness (cIMT). Multiple logistic regressions were used. The "unhealthy: high SB + low PA" cluster was associated with elevated body fat mass, central obesity, and elevated cIMT. Furthermore, the "unhealthy: low PA + unhealthy eating habits" cluster was associated with elevated body fat mass, central obesity, and elevated glucose. The unhealthier lifestyle behavior clusters were associated with atherosclerosis risk factors in children and adolescents with CHD. Multidisciplinary strategies to promote healthy behaviors are needed to prevent cardiovascular disease in later life.

Changes in lifestyle behaviors during the COVID-19 pandemic in children and adolescents with congenital heart disease / Mudanças nos comportamentos de estilo de vida durante a pandemia COVID-19 em crianças e adolescentes com cardiopatia congênita

Abstract Objective: To describe the changes in lifestyle behaviors during the COVID-19 pandemic in children and adolescents with congenital heart disease and to investigate the association of congenital heart disease complexity with lifestyle behavior changes. Methods: Cross-sectional study with 127 children and adolescents with congenital heart disease, who underwent cardiac procedure (mean postoperative time: 10.11±3.13 years), conducted between December 2020 and January 2021. Lifestyle behaviors, such as dietary intake, physical activity, sedentary behavior, and sleep, were assessed through telephone interview based on validated questionnaires. Dietary patterns were identified using principal component analysis. Frequency of general and specific combinations of healthy and unhealthy lifestyle behavior changes was evaluated. Multinomial logistic regressions were used to test the association between congenital heart disease complexity and changes in lifestyle behavior. Results: The main lifestyle behaviors acquired during pandemic were: 83.5% decreased physical activity; 37.0% increased sedentary behavior; 26.0% slept more than usual; and 23.6% adopted a less-healthy dietary pattern. Almost half of the participants (41.8%) had at least one unhealthy change in lifestyle behavior. Complex congenital heart diseases were associated with increased sedentary behavior (OR 3.49, 95%CI 1.23-9.90). Conclusions: Children and adolescents with congenital heart disease had unhealthy lifestyle behavior during the pandemic, mainly in the form of reduced physical activity and increased sedentary behavior.

Resumo Objetivo: Descrever as mudanças nos estilos de vida durante a pandemia em crianças e adolescentes com cardiopatia congênita e investigar a associação da complexidade da cardiopatia congênita com as mudanças de estilo de vida. Métodos: Estudo transversal com 127 crianças e adolescentes com cardiopatia congênita, que realizaram procedimento cardíaco (tempo médio de pós-operatório: 10,11 (3,13) anos), realizado entre dezembro de 2020 e janeiro de 2021. O estilo de vida (alimentação, atividade física, comportamento sedentário e sono) foi avaliado por entrevista telefônica, com base em questionários validados. Padrões alimentares foram identificados por meio da análise de componentes principais. Frequência de combinações gerais e específicas de mudanças de estilo de vida saudável e não saudável foram avaliadas. Regressões logísticas multinominais foram utilizadas para testar associações. Resultados: Os principais comportamentos de estilo de vida adquiridos durante a pandemia foram: 83,5% reduziram a atividade física, 37,0% aumentaram o comportamento sedentário, 26,0% dormiram mais e 23,6% mudaram para um padrão alimentar menos saudável. Quase metade (41,8%) dos participantes teve pelo menos uma mudança não saudável no estilo de vida. Cardiopatias congênitas complexas foram associadas ao aumento do comportamento sedentário durante a pandemia (odds ratio 3,49, IC95% 1,23-9,90). Conclusões: Crianças e adolescentes com cardiopatia congênita apresentaram estilo de vida não saudável durante a pandemia, principalmente na forma de redução da atividade física e aumento do comportamento sedentário.

Effects of Calendula officinalis extract on liver histopathology, lipid profile, and oxidative stress in rats submitted to a diet rich in cholesterol and carbohydrates

ABSTRACT Purpose: To evaluate the modulatory properties of Calendula officinalis L. (Asteraceae) (C. officinalis) extract on cafeteria diet-fed rats. Methods: A cafeteria diet was administered ad libitum for 45 days to induce dyslipidemia. Then, the rats were treated with the formulations containing C. officinalis in the doses of 50, 100, and 150 mg/kg or only with the vehicle formulation; the control group received a commercial ration. Results: The cafeteria diet decreased glutathione S-transferase activity and high-density lipoprotein plasmatic levels and damaged the hepatic architecture. The C. officinalis extract was able to reduce lipid infiltration in liver tissue and to modulate oxidative stress and lipid profile markers. Conclusions: The correlations between the variables suggest a pathological connection between oxidative stress markers and serum lipid profile.

Inserção de médicas na formação de especialidades da comissão de residência médica do Hospital Geral Roberto Santos / Inclusion of female physicians in the HGRS medical residency committee's medical specialties / Inserción de médicas en la formación de la especialidad del comité de residencia médica del Hospital General Roberto Santos

A inserção das mulheres na medicina tem sido progressiva, com média de 5,2% de aumento a cada década nos últimos trinta anos. As mulheres já são maioria entre as faixas etárias até 34 anos (55,3%) e até 29 anos, representando 58,5% dos graduandos, segundo o Conselho Federal de Medicina. A abordagem do tipo quantiqualitativa e exploratória, com levantamento e análise de dados secundários, buscou evidenciar uma amostra temporal sobre a inserção das mulheres na formação de especialidades médicas da Comissão de Residência Médica (Coreme) do Hospital Geral Roberto Santos (HGRS). Apesar da formação da graduação ser equânime e da entrada das médicas na residência no HGRS permanecer com média de 69,2%, os quantitativos de preceptoras, supervisoras e coordenadoras de serviço relacionados aos programas de residência médica na instituição são bem inferiores (40,5%; 17,4% e 26,1%, respectivamente), não oportunizando a progressão das médicas para os espaços de decisão e gestão. Quanto à coordenação da Coreme, não há registro de mulheres médicas na função da instituição. Trabalhar as questões de gênero em unidade hospitalar no contexto da medicina, profissão surgida da hegemonia masculina e patriarcal, enquanto cultura, não é simples, mas necessário. O estudo traz uma reflexão para o diálogo sobre a construção de políticas de desenvolvimento na gestão do trabalho, que envolva equidade e justiça social quanto ao gênero no ensino da residência médica, com equiparação de direitos e valores que possam beneficiar a igualdade no desenvolvimento social nos dias atuais.

Women have been progressively integrating medicine programs, with an average increase of 5.2% each decade in the past 30 years. Female physicians are already the majority among the age groups of up to 34 years (55.3%) and up to 29 years, representing 58.5% of undergraduates, according to the Federal Council of Medicine. This quantitative, qualitative and exploratory research, based on survey and analysis of secondary data, sought to highlight a temporal sample on the inclusion of women in the medical specialties of the Geral Roberto Santos Hospital's (HGRS) Medical Residency Committee (Coreme). Despite an equanimous graduation education and a fixed average entry of female physicians (69.2%) into the HGRS residency, the number of female preceptors, supervisors and service coordinators related to the residency programs are much lower (40.5%,17.4% and 26.1%, respectively), hindering their carrier progression to decision and management roles. As for the Coreme coordination, there is no record of female physicians exercising this role. Discussing gender issues in medicine­ a profession that emerged from male and patriarchal hegemony­within a hospital setting as a cultural phenomenon is complex and necessary. The study reflects on the development of management policies to include gender-based equity and social justice in medical residency, fostering equal rights and values in today's society.

La creciente inserción de la mujer en la medicina ha sido progresiva, con un aumento promedio del 5,2% cada década en los últimos 30 años. Las mujeres predominan entre los grupos de edad de los 34 años (55,3%) y de los 29 años, y representa el 58,5% de los estudiantes de grado según el Consejo Federal de Medicina. El enfoque cuantitativo-cualitativo, exploratorio, con encuesta y análisis de datos secundarios, buscó destacar una muestra temporal sobre la inclusión de mujeres en la formación de especialidades médicas de la Comisión de Residencia Médica (Coreme) del Hospital General Roberto Santos (HGRS). A pesar de que la formación de graduación es ecuánime y de que el ingreso de médicas a la residencia en el HGRS se mantiene en un promedio del 69,2%, el número de preceptoras, supervisoras y coordinadoras de servicios relacionado con los programas de residencia en la institución es muy inferior (el 40,5%; el 17,4% y el 26,1%, respectivamente), lo que no permite la progresión de las médicas a los espacios de decisión y gestión. En cuanto a la coordinación del Coreme, no existe registro de mujeres médicas en el rol de la institución. No es sencillo sino necesario trabajar temas de género en una unidad del hospital en el contexto de la medicina, una profesión que surgió de la hegemonía masculina patriarcal como cultura. Este estudio permite reflexionar sobre el diálogo de la formación de políticas de desarrollo en la gestión del trabajo, que incluya la equidad y la justicia social respecto al género en la enseñanza de residencia médica, con igualdad de derechos y valores que pueden favorecer la igualdad al desarrollo social en la actualidad.

HDL-Cholesterol in Children and Adolescents with Congenital Heart Disease

Abstract Background Children and adolescents with congenital heart disease may be more likely to develop atherogenic cardiovascular diseases in adulthood. Therefore, the early identification of risk factors and intervention in childhood may be crucial for a good quality of life and longevity. Objectives To describe the distribution of high-density lipoprotein-cholesterol (HDL-c) levels and its association with socioeconomic, clinical and cardiovascular risk factors in children and adolescents with congenital heart disease. Methods Cross-sectional study with children and adolescents aged between 5 and 18 years, with congenital heart disease. Socioeconomic, clinical and cardiovascular risk factors were evaluated. HDL-c concentrations were evaluated by the direct method and categorized as desirable (>45 mg/dL), borderline (40-45 mg/dL) and low (<40 mg/dL). We also assessed the "undesirable" levels, consisting of the sum of "borderline" and "low" values for comparative purposes. The multivariate logistic regression analysis was used to evaluate the factor associated with undesirable HDL-c levels. A p<0.05 value was adopted as statistically significant. Results Mean HDL-c was 51.2 mg/dL (SD 12.6), with a prevalence of 33.2% of undesirable HDL-c. In the multivariate analysis, C-reactive protein levels ≥ 3mg/dL (OR 3.26; 95% CI 1.32-8.04), age ≥ 10 years old (OR: 2.11; 95% CI 1.12-3.99) and undesirable levels of triglycerides (OR 2.21; 95% CI 1.13-4.75) were associated with undesirable HDL-c. Conclusion In this sample of children and adolescents with congenital heart disease, almost one third presented low or borderline HDL-c levels. Age ≥10 years, C-reactive protein and triglycerides were associated with undesirable HDL-c levels. These factors should be considered in the prevention of cerebrovascular diseases in adulthood in this population.

Morphophysiological alterations in fruit-eating bats after oral exposure to deltamethrin.

Deltamethrin (DTM) is a synthetic pyrethroid widely used in the cultivation and management of several crops due to its insecticidal action. Application to crops of pyrethroids such as DTM can result in the exposure of water and fruit consumed by fruit bats having a high pyrethroid content which may be harmful. Therefore the objective of this study was to evaluate the effects of short-term oral exposure of the fruit-eating bats (Artibeus lituratus) to two concentrations of DTM (0.02 and 0.04 mg/kg of papaya) on histopathology of the intestine, liver and kidney. The intestine of the animals exposed to both concentrations showed inflammatory infiltrate, degeneration, necrosis and goblet cell hyperplasia as the most frequent pathologies. Besides, the acid mucins showed an increase in the frequency of non-viable cells. The liver showed hepatocyte vacuolizatio and nuclear enlargement, as well as inflammatory infiltrate and steatosis. The kidneys of the exposed animals showed and inflammatory infiltrate, benign nephrosclerosis, vacuolization and necrosis. Also, DTM reduced nitric oxide synthesis, decreased glomerular diameter and increased glycogen percentage in the proximal tubules. Our results suggest that acute exposure to DTM at low concentrations has the potential to induce pronounced histopathological changes in vital organs, such as intestine, liver and kidney of fruit-eating bats.

Protective immunity triggered by ectonucleoside triphosphate diphosphohydrolase-based biopharmaceuticals attenuates cardiac parasitism and prevents mortality in Trypanosoma cruzi infection.

Chagas disease is a potentially fatal infection in 21 endemic Latin America countries for which the effectiveness of reference antiparasitic chemotherapy is limited. Thus, we developed three biopharmaceuticals and evaluated the effectiveness of different immunization strategies (recombinant protein NTPDase-1 [rNTPDase-1], DNA plasmid encoding Trypanosoma cruzi NTPDase-1 [TcNTPDase-1] and DNA-NTPDase-1 prime/rNTPDase-1 boost [Prime-boost]) based on the surface ecto-nucleoside triphosphate diphosphohydrolase (ecto-NTPDase) enzyme of T. cruzi in animals challenged with a virulent strain (Y) of this parasite. BALB/c mice were immunized three times at 30 days intervals, challenged with T. cruzi 15 days after the last immunization, and euthanized 30 days after T. cruzi challenge. Our results showed limited polarization of specific anti-ecto-NTPDase immunoglobulins in mice receiving both immunization protocols. Conversely, the Prime-boost strategy stimulated the Th1 protective phenotype, upregulating TNF-α and downregulating IL-10 production while increasing the activation/distribution of CD3+/CD8+, CD4+/CD44hi and CD8+/CD44hi/CD62L cells in immunized and infected mice. Furthermore, IL-6 and IL10 levels were reduced, while the distribution of CD4+/CD44hi and CD3+/CD8+ cells was increased from rNTPDase-1 and DNA-NTPDase1-based immunization strategies. Animals receiving DNA-NTPDase1 and Prime-boost protocols before T. cruzi challenged exhibited an enhanced immunological response associated with IL-17 upregulation and remarkable downregulation of heart parasitism (T. cruzi DNA) and mortality. These findings indicated that NTPDase-1 with Prime-boost strategy induced a protective and sustained Th17 response, enhancing host resistance against T. cruzi. Thus, ecto-NTPDase is a potentially relevant and applicable in the development of biopharmaceuticals with greater immunoprophylactic potential for Chagas disease.

Is There a Connection between the Metabolism of Copper, Sulfur, and Molybdenum in Alzheimer's Disease? New Insights on Disease Etiology.

Alzheimer's disease (AD) and other forms of dementia was ranked 3rd in both the Americas and Europe in 2019 in a World Health Organization (WHO) publication listing the leading causes of death and disability worldwide. Copper (Cu) imbalance has been reported in AD and increasing evidence suggests metal imbalance, including molybdenum (Mo), as a potential link with AD occurrence.We conducted an extensive literature review of the last 60 years of research on AD and its relationship with Cu, sulfur (S), and Mo at out of range levels.Weanalyzed the interactions among metallic elements' metabolisms;Cu and Mo are biological antagonists, Mo is a sulfite oxidase and xanthine oxidase co-factor, and their low activities impair S metabolism and reduce uric acid, respectively. We found significant evidence in the literature of a new potential mechanism linking Cu imbalance to Mo and S abnormalities in AD etiology: under certain circumstances, the accumulation of Cu not bound to ceruloplasmin might affect the transport of Mo outside the blood vessels, causing a mild Mo deficiency that might lowerthe activity of Mo and S enzymes essential for neuronal activity. The current review provides an updated discussion of the plausible mechanisms combining Cu, S, and Mo alterations in AD.

Ultra-processed food intake is associated with children and adolescents with congenital heart disease clustered by high cardiovascular risk factors.

The excessive intake of ultra-processed foods (UPF) is associated with an increase in cardiovascular risk. However, the effect of UPF intake on cardiovascular health in children and adolescents with congenital heart disease (CHD) is unknown. The aim of the present study was to describe UPF intake and evaluate associations with isolated cardiovascular risk factors and children and adolescents with CHD clustered by cardiovascular risk factors. A cross-sectional study was conducted involving 232 children and adolescents with CHD. Dietary intake was assessed using three 24-hour recalls. UPFs were categorized using the NOVA classification. The cardiovascular risk factors evaluated were central adiposity, elevated high-sensitivity C-reactive protein (hs-CRP) and subclinical atherosclerosis. The clustering of cardiovascular risk factors (waist circumference, hs-CRP and carotid intima-media thickness) was performed, allocating the participants to two groups (high versus low cardiovascular risk). UPFs contributed 40.69% (SD 6.21) to total energy intake. The main UPF groups were ready-to-eat and take-away/fast foods (22.2% energy from UPFs). The multivariable logistic regression revealed that an absolute increase of 10% in UPF intake (OR=1.90; 95% CI: 1.01;3.58) was associated with central adiposity. An absolute increase of 10% in UPF intake (OR=3.77; 95% CI: 1.80;7.87) was also associated with children and adolescents with CHD clustered by high cardiovascular risk after adjusting for confounding factors. Our findings demonstrate that UPF intake should be considered a modifiable risk factor for obesity and its cardiovascular consequences in children and adolescents with CHD.

A hypometabolic defense strategy against malaria.

Hypoglycemia is a clinical hallmark of severe malaria, the often-lethal outcome of Plasmodium falciparum infection. Here, we report that malaria-associated hypoglycemia emerges from a non-canonical resistance mechanism, whereby the infected host reduces glycemia to starve Plasmodium. This hypometabolic response is elicited by labile heme, a byproduct of hemolysis that induces illness-induced anorexia and represses hepatic glucose production. While transient repression of hepatic glucose production prevents unfettered immune-mediated inflammation, organ damage, and anemia, when sustained over time it leads to hypoglycemia, compromising host energy expenditure and adaptive thermoregulation. The latter arrests the development of asexual stages of Plasmodium via a mechanism associated with parasite mitochondrial dysfunction. In response, Plasmodium activates a transcriptional program associated with the reduction of virulence and sexual differentiation toward the generation of transmissible gametocytes. In conclusion, malaria-associated hypoglycemia represents a trade-off of a hypometabolic-based defense strategy that balances parasite virulence versus transmission.