Histone deacetylase inhibition mitigates cognitive deficits and astrocyte dysfunction induced by amyloid-ß (Aß) oligomers.

BACKGROUND AND PURPOSE: Inhibitors of histone deacetylases (iHDACs) are promising drugs for neurodegenerative diseases. We have evaluated the therapeutic potential of the new iHDAC LASSBio-1911 in Aß oligomer (AßO) toxicity models and astrocytes, key players in neuroinflammation and Alzheimer's disease (AD). EXPERIMENTAL APPROACH: Astrocyte phenotype and synapse density were evaluated by flow cytometry, Western blotting, immunofluorescence and qPCR, in vitro and in mice. Cognitive function was evaluated by behavioural assays using a mouse model of intracerebroventricular infusion of AßO. KEY RESULTS: LASSBio-1911 modulates reactivity and synaptogenic potential of cultured astrocytes and improves synaptic markers in cultured neurons and in mice. It prevents AßO-triggered astrocytic reactivity in mice and enhances the neuroprotective potential of astrocytes. LASSBio-1911 improves behavioural performance and rescues synaptic and memory function in AßO-infused mice. CONCLUSION AND IMPLICATIONS: These results contribute to unveiling the mechanisms underlying astrocyte role in AD and provide the rationale for using astrocytes as targets to new drugs for AD.

Cardiac Output and Stroke Volume Assessments by Transthoracic Echocardiography and Pulse index Continuous Cardiac Output Monitor in Critically ill Adult Patients: A Comparative Study.

PURPOSE: Bedside transthoracic echocardiography (TTEcho) is a noninvasive cardiac output (CO) monitoring method that has grown recently. However, there are questions regarding its accuracy compared to invasive methods. We aimed to evaluate the agreement and correlation of TTEcho and pulse index continuous CO (PiCCO) monitor measurements for CO and systolic volume (SV) in critically ill patients. METHODS: This prospective experimental study included consecutive adult patients who required invasive hemodynamic monitoring admitted at an intensive care unit in the Federal District, Brazil, from January/2019 to January/2021. Correlation and agreement between SV and CO measurements by PiCCO and TTEcho were performed using the Spearman correlation and the Bland-Altman analysis. RESULTS: The study enrolled 29 patients, with adequate TTEcho evaluations in all patients. There were very strong correlations between CO-TTEcho and CO-PiCCO (r = 0.845, P < .001) and SV-TTEcho and SV-PiCCO (r = 0.800, P < .001). TTEcho estimations for CO and SV were feasible within the limits of agreement in 96.6% (28/29) compared to PiCCO. The mean difference between CO-PiCCO and CO-TTEcho was 0.250 L/min (limits of agreement: -1.083 to 1.583 L/min, percentage error: 21.0%), and between SV-PiCCO and SV-TTEcho was 2.000 mL (limits of agreement: -16.960 to 20.960, percentage error: 24.3%). The reduced cardiac index (CI) measurements by TTEcho showed an accuracy of 89.7% (95% IC: 72.6%-97.8%) and an F1 score of 92.7% (95% IC: 75.0%-98.0%), considering the CI-PiCCO as the gold standard. CONCLUSION: Echocardiographic measurements of CO and SV are comparable to measurements by PiCCO. These results reinforce echocardiography as a reliable tool to evaluate hemodynamics in critically ill patients.

DHA-rich fish oil plays a protective role against experimental cerebral malaria by controlling inflammatory and mechanical events from infection.

Every year, thousands of children, particularly those under 5 years old, die because of cerebral malaria (CM). Following conventional treatment, approximately 25% of surviving individuals have lifelong severe neurocognitive sequelae. Therefore, improved conventional therapies or effective alternative therapies that prevent the severe infection are crucial. Omega-3 (Ω-3) polyunsaturated fatty acids (PUFAs) are known to have antioxidative and anti-inflammatory effects and protect against diverse neurological disorders, including Alzheimer's and Parkinson's diseases. However, little is known regarding the effects of Ω-3 PUFAs against parasitic infections. In this study, C57BL/6 mice received supplemental treatment of a fish oil rich in the Ω-3 PUFA, docosahexaenoic acid (DHA), which was started 15 days prior to infection with Plasmodium berghei ANKA and was maintained until the end of the study. Animals treated with the highest doses of DHA, 3.0 and 6.0 g/kg body weight, had 60 and 80% chance of survival, respectively, while all nontreated mice died by the 7th day postinfection due to CM. Furthermore, the parasite load during the critical period for CM development (5th to 11th day postinfection) was controlled in treated mice. However, after this period all animals developed high levels of parasitemia until the 20th day of infection. DHA treatment also effectively reduced blood-brain barrier (BBB) damage and brain edema and completely prevented brain hemorrhage and vascular occlusion. A strong anti-inflammatory profile was observed in the brains of DHA-treated mice, as well as, an increased number of neutrophil and reduced number of CD8+ T leukocytes in the spleen. Thus, this is the first study to demonstrate that the prophylactic use of DHA-rich fish oil exerts protective effects against experimental CM, reducing the mechanical and immunological events caused by the P. berghei ANKA infection.

Increased Neutrophil Percentage and Neutrophil-T Cell Ratio Precedes Clinical Onset of Experimental Cerebral Malaria.

Newly emerging data suggest that several neutrophil defense mechanisms may play a role in both aggravating and protecting against malaria. These exciting findings suggest that the balance of these cells in the host body may have an impact on the pathogenesis of malaria. To fully understand the role of neutrophils in severe forms of malaria, such as cerebral malaria (CM), it is critical to gain a comprehensive understanding of their behavior and functions. This study investigated the dynamics of neutrophil and T cell responses in C57BL/6 and BALB/c mice infected with Plasmodium berghei ANKA, murine models of experimental cerebral malaria (ECM) and non-cerebral experimental malaria, respectively. The results demonstrated an increase in neutrophil percentage and neutrophil-T cell ratios in the spleen and blood before the development of clinical signs of ECM, which is a phenomenon not observed in the non-susceptible model of cerebral malaria. Furthermore, despite the development of distinct forms of malaria in the two strains of infected animals, parasitemia levels showed equivalent increases throughout the infection period evaluated. These findings suggest that the neutrophil percentage and neutrophil-T cell ratios may be valuable predictive tools for assessing the dynamics and composition of immune responses involved in the determinism of ECM development, thus contributing to the advancing of our understanding of its pathogenesis.

Interplay Between the Immune and Nervous Cognitive Systems in Homeostasis and in Malaria.

The immune and nervous systems can be thought of as cognitive and plastic systems, since they are both involved in cognition/recognition processes and can be architecturally and functionally modified by experience, and such changes can influence each other's functioning. The immune system can affect nervous system function depending on the nature of the immune stimuli and the pro/anti-inflammatory responses they generate. Here we consider interactions between the immune and nervous systems in homeostasis and disease, including the beneficial and deleterious effects of immune stimuli on brain function and the impact of severe and non-severe malaria parasite infections on neurocognitive and behavioral parameters in human and experimental murine malaria. We also discuss the effect of immunization on the reversal of cognitive deficits associated with experimental non-severe malaria in a model susceptible to the development of the cerebral form of the illness. Finally, we consider the possibility of using human vaccines, largely exploited as immune-prophylactics for infectious diseases, as therapeutic tools to prevent or mitigate the expression of cognitive deficits in infectious and chronic degenerative diseases.

Self-care during the COVID-19 pandemic: Development of a virtual educational booklet for postmenopausal women with osteoporosis.

OBJECTIVE: To describe the development of a virtual educational booklet for self-care promotion of postmenopausal women with osteoporosis during the COVID-19 pandemics. METHOD: This methodological study was conducted in three steps: bibliographic search, development of virtual educational booklet by 12 evaluators and ten representatives of the target audience. A questionnaire adapted from the literature was used to evaluate the educational booklet. The questionnaire consisted of seven items: scientific accuracy, content, language, illustrations, specificity and comprehension, readability, and quality of information. A minimum score of 0.75 in the content validity index (CVI) of each questionnaire item and minimum agreement of 75% among positive responses of postmenopausal women were required to validate the virtual booklet. RESULTS: Health professionals and representatives of the target audience suggested changes regarding layout, illustrations, and content of the virtual booklet. CVI of the final version was 0.84 between health professionals and agreement among the target audience was 90%. CONCLUSION: The virtual educational booklet with exercises and instructions for postmenopausal women with osteoporosis was valid and should be used by health professionals for advice on self-care and health promotion during the COVID-19 pandemic.

Central nervous system demyelinating diseases: glial cells at the hub of pathology.

Inflammatory demyelinating diseases (IDDs) are among the main causes of inflammatory and neurodegenerative injury of the central nervous system (CNS) in young adult patients. Of these, multiple sclerosis (MS) is the most frequent and studied, as it affects about a million people in the USA alone. The understanding of the mechanisms underlying their pathology has been advancing, although there are still no highly effective disease-modifying treatments for the progressive symptoms and disability in the late stages of disease. Among these mechanisms, the action of glial cells upon lesion and regeneration has become a prominent research topic, helped not only by the discovery of glia as targets of autoantibodies, but also by their role on CNS homeostasis and neuroinflammation. In the present article, we discuss the participation of glial cells in IDDs, as well as their association with demyelination and synaptic dysfunction throughout the course of the disease and in experimental models, with a focus on MS phenotypes. Further, we discuss the involvement of microglia and astrocytes in lesion formation and organization, remyelination, synaptic induction and pruning through different signaling pathways. We argue that evidence of the several glia-mediated mechanisms in the course of CNS demyelinating diseases supports glial cells as viable targets for therapy development.

A short history of innate immunity.

Innate immunity refers to the mechanisms responsible for the first line of defense against pathogens, cancer cells and toxins. The innate immune system is also responsible for the initial activation of the body's specific immune response (adaptive immunity). Innate immunity was studied and further developed in parallel with adaptive immunity beginning in the first half of the 19th century and has been gaining increasing importance to our understanding of health and disease. In the present overview, we describe the main findings and ideas that contributed to the development of innate immunity as a continually expanding branch of modern immunology. We start with the toxicological studies by Von Haller and Magendie, in the late 18th and early 19th centuries, and continue with the discoveries in invertebrate immunity that supported the discovery and characterization of lipopolysaccharide (LPS) and pattern recognition receptors that led to the development of the pattern recognition and danger theory.

Malaria and leishmaniasis: Updates on co-infection.

Malaria and leishmaniasis are endemic parasitic diseases in tropical and subtropical countries. Although the overlap of these diseases in the same host is frequently described, co-infection remains a neglected issue in the medical and scientific community. The complex relationship of concomitant infections with Plasmodium spp. and Leishmania spp. is highlighted in studies of natural and experimental co-infections, showing how this "dual" infection can exacerbate or suppress an effective immune response to these protozoa. Thus, a Plasmodium infection preceding or following Leishmania infection can impact the clinical course, accurate diagnosis, and management of leishmaniasis, and vice versa. The concept that in nature we are affected by concomitant infections reinforces the need to address the theme and ensure its due importance. In this review we explore and describe the studies available in the literature on Plasmodium spp. and Leishmania spp. co-infection, the scenarios, and the factors that may influence the course of these diseases.

Age-Associated Upregulation of Glutamate Transporters and Glutamine Synthetase in Senescent Astrocytes In Vitro and in the Mouse and Human Hippocampus.

Aging is marked by complex and progressive physiological changes, including in the glutamatergic system, that lead to a decline of brain function. Increased content of senescent cells in the brain, such as glial cells, has been reported to impact cognition both in animal models and human tissue during normal aging and in the context of neurodegenerative disease. Changes in the glutamatergic synaptic activity rely on the glutamate-glutamine cycle, in which astrocytes handle glutamate taken up from synapses and provide glutamine for neurons, thus maintaining excitatory neurotransmission. However, the mechanisms of glutamate homeostasis in brain aging are still poorly understood. Herein, we showed that mouse senescent astrocytes in vitro undergo upregulation of GLT-1, GLAST, and glutamine synthetase (GS), along with the increased enzymatic activity of GS and [3H]-D-aspartate uptake. Furthermore, we observed higher levels of GS and increased [3H]-D-aspartate uptake in the hippocampus of aged mice, although the activity of GS was similar between young and old mice. Analysis of a previously available RNAseq dataset of mice at different ages revealed upregulation of GLAST and GS mRNA levels in hippocampal astrocytes during aging. Corroborating these rodent data, we showed an increased number of GS + cells, and GS and GLT-1 levels/intensity in the hippocampus of elderly humans. Our data suggest that aged astrocytes undergo molecular and functional changes that control glutamate-glutamine homeostasis upon brain aging.

Towards chemical characterization and possible applications of juçara fruit: an approach to remove Euterpe edulis Martius from the extinction list.

Juçara (Euterpe edulis Martius) is a palm widely distributed in the Atlantic Forest. It produces a non-climacteric, black-violet small fruit similar to the Amazonian açaí (Euterpe precatoria). The fruit is known as superfruit because it presents chemical characteristics of great importance, such as anthocyanins content. Regarding bioactive compounds and antioxidant scavenging capacity, it presents high anthocyanin (634.26 to 2,929 mg of cyanidin-3-glucoside 100 g-1) and total phenolic compounds (415.1 to 9,778.20 mg equivalents of gallic acid 100 g-1) contents. The soluble solid content ranges from 3.0 to 4.9% and its pH is higher than other tropical fruits (4.8 to 5.6). Despite the rich bioactive compound content of juçara fruits, this plant has been traditionally used for palm heart production. The accelerated and illegal palm heart exploitation, without the use of an adequate management has led to the risk of extinction of this species. In order to prevent this species from vanishing, several studies have valued the health characteristics of juçara fruit chemical composition. An economical approach has been the production of juçara pulp described as a source of bioactive compounds, which has attracted the attention of industrial field aiming the production of functional foods, foodstuff, cosmetics and pharmaceutical products. A full botanical and chemical characterization of juçara tree and fruit is presented in this paper, as well as suggestions to increase the use of this tropical fruit and derivatives. Supplementary Information: The online version contains supplementary material available at 10.1007/s13197-021-05342-8.

Immunomodulation through vaccination as a promising therapeutic strategy to mitigate malaria-related neurocognitive sequelae.

Malaria, an ancient infectious parasitic disease, is caused by protozoa of the genus Plasmodium, whose erythrocytic cycle is accompanied by fever, headache, sweating and chills and a systemic inflammation that can progress to severe forms of disease, including cerebral malaria. Approximately 25% of survivors of this syndrome develop sequelae that may include neurological, neurocognitive, behavioral alterations and poor school performance. Furthermore, some outcomes have also been recorded following episodes of non-severe malaria, which correspond to the most common clinical form of the disease worldwide. There is a body of evidence that neuroinflammation, due to systemic inflammation, plays an important role in the neuropathogenesis of malaria culminating in these cognitive dysfunctions. Preclinical studies suggest that vaccination with type 2 immune response elicitors, such as the tetanus-diphtheria (Td) vaccine, may exert a beneficial immunomodulatory effect by alleviating neuroinflammation. In this viewpoint article, vaccination is proposed as a therapy approach to revert or mitigate neurocognitive deficits associated with malaria.

A short history of innate immunity

Innate immunity refers to the mechanisms responsible for the first line of defense against pathogens, cancer cells and toxins. The innate immune system is also responsible for the initial activation of the body's specific immune response (adaptive immunity). Innate immunity was studied and further developed in parallel with adaptive immunity beginning in the first half of the 19th century and has been gaining increasing importance to our understanding of health and disease. In the present overview, we describe the main findings and ideas that contributed to the development of innate immunity as a continually expanding branch of modern immunology. We start with the toxicological studies by Von Haller and Magendie, in the late 18th and early 19th centuries, and continue with the discoveries in invertebrate immunity that supported the discovery and characterization of lipopolysaccharide (LPS) and pattern recognition receptors that led to the development of the pattern recognition and danger theory.

Dynamics and immunomodulation of cognitive deficits and behavioral changes in non-severe experimental malaria.

Data recently reported by our group indicate that stimulation with a pool of immunogens capable of eliciting type 2 immune responses can restore the cognitive and behavioral dysfunctions recorded after a single episode of non-severe rodent malaria caused by Plasmodium berghei ANKA. Here we explored the hypothesis that isolated immunization with one of the type 2 immune response-inducing immunogens, the human diphtheria-tetanus (dT) vaccine, may revert damages associated with malaria. To investigate this possibility, we studied the dynamics of cognitive deficits and anxiety-like phenotype following non-severe experimental malaria and evaluated the effects of immunization with both dT and of a pool of type 2 immune stimuli in reversing these impairments. Locomotor activity and long-term memory deficits were assessed through the open field test (OFT) and novel object recognition task (NORT), while the anxiety-like phenotype was assessed by OFT and light/dark task (LDT). Our results indicate that poor performance in cognitive-behavioral tests can be detected as early as the 12th day after the end of antimalarial treatment with chloroquine and may persist for up to 155 days post infection. The single immunization strategy with the human dT vaccine showed promise in reversal of long-term memory deficits in NORT, and anxiety-like behavior in OFT and LDT.

The Flavonol Quercitrin Hinders GSK3 Activity and Potentiates the Wnt/ß-Catenin Signaling Pathway.

The Wnt/ß-catenin signaling pathway dictates cell proliferation and differentiation during embryonic development and tissue homeostasis. Its deregulation is associated with many pathological conditions, including neurodegenerative disease, frequently downregulated. The lack of efficient treatment for these diseases, including Alzheimer's disease (AD), makes Wnt signaling an attractive target for therapies. Interestingly, novel Wnt signaling activating compounds are less frequently described than inhibitors, turning the quest for novel positive modulators even more appealing. In that sense, natural compounds are an outstanding source of potential drug leads. Here, we combine different experimental models, cell-based approaches, neuronal culture assays, and rodent behavior tests with Xenopus laevis phenotypic analysis to characterize quercitrin, a natural compound, as a novel Wnt signaling potentiator. We find that quercitrin potentiates the signaling in a concentration-dependent manner and increases the occurrence of the Xenopus secondary axis phenotype mediated by Xwnt8 injection. Using a GSK3 biosensor, we describe that quercitrin impairs GSK3 activity and increases phosphorylated GSK3ß S9 levels. Treatment with XAV939, an inhibitor downstream of GSK3, impairs the quercitrin-mediated effect. Next, we show that quercitrin potentiates the Wnt3a-synaptogenic effect in hippocampal neurons in culture, which is blocked by XAV939. Quercitrin treatment also rescues the hippocampal synapse loss induced by intracerebroventricular injection of amyloid-ß oligomers (AßO) in mice. Finally, quercitrin rescues AßO-mediated memory impairment, which is prevented by XAV939. Thus, our study uncovers a novel function for quercitrin as a Wnt/ß-catenin signaling potentiator, describes its mechanism of action, and opens new avenues for AD treatments.

Lycopene-rich watermelon concentrate used as a natural food colorant: Stability during processing and storage.

A lycopene-rich watermelon (Citrullus lanatus) concentrate was incorporated into snack cracker, fusilli pasta, and extruded snacks for coloring purposes. Changes in the L* and a* color coordinates and in the lycopene content were evaluated before and after thermal processes and monitored through 90 days of storage at ambient temperature. The products with the maximum lycopene degradation during processing were snack cracker and extruded snack (between 30 and 45%) whereas no degradation was observed in the fusilli pasta, except during cooking into boiling water (reduction up to 41%). The change in color during processing varied substantially depending on the product, but, in general, thermal treatments applied reduced the a* values (less reddish). The degradation kinetics of the lycopene and the color during storage followed first-order kinetics, with a half-life time of 25 to 315 days for lycopene content and 65 to 210 days for a* coordinate. Snack cracker was the most stable and had more than a 4-month period before losing half of the pigment content.

Meibomian gland dysfunction and dry eye in keratoconus / Disfunção de glândulas de Meibomius e olho seco em ceratocone

ABSTRACT The objective of this report is to describe a case of meibomian gland dysfunction associated with keratoconus and to examine the importance of treatment for evaporative dry eye in cases of corneal ectasia. A 45-year-old man diagnosed as having keratoconus complained of burning, tearing, itching, and red eye. He had a history of penetrating corneal transplantation and wearing rigid contact lenses. The meibography revealed a severe meibomian gland dropout and normal tear meniscus height in both eyes. Objective propaedeutic tests are important tools for dry eye diagnosis and proper evaluation of ocular surface and tear film. In older patients, the classic signs of atopic conjunctivitis are not always present, and the causes of chronic rubbing must be further investigated. Treatment of underlying chronic inflammation such as dry eye, meibomian gland dysfunction, and blepharitis might be important to prevent keratoconus progression and guarantee symptom relief.

RESUMO O objetivo é relatar um caso de associação entre disfunção de glândulas de meibomius (DGM) e ceratocone, assim como ressaltar a importância do tratamento do olho seco evaporativo em casos de ectasia corneana. Paciente do sexo masculino de 45 anos com ceratocone e queixas de ardência, lacrimejamento, prurido e olho vermelho. O mesmo tem histórico de transplante de córnea penetrante e uso de lentes de contato rígidas. A meibografia revelou severa perda de glândulas de meibomius e menisco lacrimal normal em ambos os olhos. Testes propedêuticos objetivos são importantes ferramentas para diagnóstico de olho seco e apropriada avaliação da superfície ocular e filme lacrimal. Em pacientes mais velhos, os sinais clássicos de atopia não estão sempre presentes e investigações adicionais das causas de prurido crônico são necessárias. O tratamento da inflamação crônica subjacente como olho seco, disfunção de glândulas de meibomius e blefarite podem ser importantes para prevenir a progressão do ceratocone e garantir alívio dos sintomas.

Contribution of Müller Cells in the Diabetic Retinopathy Development: Focus on Oxidative Stress and Inflammation.

Diabetic retinopathy is a neurovascular complication of diabetes and the main cause of vision loss in adults. Glial cells have a key role in maintenance of central nervous system homeostasis. In the retina, the predominant element is the Müller cell, a specialized cell with radial morphology that spans all retinal layers and influences the function of the entire retinal circuitry. Müller cells provide metabolic support, regulation of extracellular composition, synaptic activity control, structural organization of the blood-retina barrier, antioxidant activity, and trophic support, among other roles. Therefore, impairments of Müller actions lead to retinal malfunctions. Accordingly, increasing evidence indicates that Müller cells are affected in diabetic retinopathy and may contribute to the severity of the disease. Here, we will survey recently described alterations in Müller cell functions and cellular events that contribute to diabetic retinopathy, especially related to oxidative stress and inflammation. This review sheds light on Müller cells as potential therapeutic targets of this disease.

Malaria Related Neurocognitive Deficits and Behavioral Alterations.

Typical of tropical and subtropical regions, malaria is caused by protozoa of the genus Plasmodium and is, still today, despite all efforts and advances in controlling the disease, a major issue of public health. Its clinical course can present either as the classic episodes of fever, sweating, chills and headache or as nonspecific symptoms of acute febrile syndromes and may evolve to severe forms. Survivors of cerebral malaria, the most severe and lethal complication of the disease, might develop neurological, cognitive and behavioral sequelae. This overview discusses the neurocognitive deficits and behavioral alterations resulting from human naturally acquired infections and murine experimental models of malaria. We highlighted recent reports of cognitive and behavioral sequelae of non-severe malaria, the most prevalent clinical form of the disease worldwide. These sequelae have gained more attention in recent years and therapies for them are required and demand advances in the understanding of neuropathogenesis. Recent studies using experimental murine models point to immunomodulation as a potential approach to prevent or revert neurocognitive sequelae of malaria.