Euterpe oleracea Mart. Bioactive Molecules: Promising Agents to Modulate the NLRP3 Inflammasome.

Inflammation is a vital mechanism that defends the organism against infections and restores homeostasis. However, when inflammation becomes uncontrolled, it leads to chronic inflammation. The NLRP3 inflammasome is crucial in chronic inflammatory responses and has become a focal point in research for new anti-inflammatory therapies. Flavonoids like catechin, apigenin, and epicatechin are known for their bioactive properties (antioxidant, anti-inflammatory, etc.), but the mechanisms behind their anti-inflammatory actions remain unclear. This study aimed to explore the ability of various flavonoids (isolated and combined) to modulate the NLRP3 inflammasome using in silico and in vitro models. Computer simulations, such as molecular docking, molecular dynamics, and MM/GBSA calculations examined the interactions between bioactive molecules and NLRP3 PYD. THP1 cells were treated with LPS + nigericin to activate NLRP3, followed by flavonoid treatment at different concentrations. THP1-derived macrophages were also treated following NLRP3 activation protocols. The assays included colorimetric, fluorometric, microscopic, and molecular techniques. The results showed that catechin, apigenin, and epicatechin had high binding affinity to NLRP3 PYD, similar to the known NLRP3 inhibitor MCC950. These flavonoids, particularly at 1 µg/mL, 0.1 µg/mL, and 0.01 µg/mL, respectively, significantly reduced LPS + nigericin effects in both cell types and decreased pro-inflammatory cytokine, caspase-1, and NLRP3 gene expression, suggesting their potential as anti-inflammatory agents through NLRP3 modulation.

Neural acetylcholinesterase and monoamine oxidase deregulation during streptozotocin-induced behavioral, metabolic and redox modification in Nauphoeta cinerea.

Genetic and environmental factors have been linked with neurodegeneration, especially in the elderly. Yet, efforts to impede neurodegenerative processes have at best addressed symptoms instead of underlying pathologies. The gap in the understanding of neuro-behavioral plasticity is consistent from insects to mammals, and cockroaches have been proven to be effective models for studying the toxicity mechanisms of various chemicals. We therefore used head injection of 74 and 740 nmol STZ in Nauphoeta cinerea to elucidate the mechanisms of chemical-induced neurotoxicity, as STZ is known to cross the blood-brain barrier. Neurolocomotor assessment was carried out in a new environment, while head homogenate was used to estimate metabolic, neurotransmitter and redox activities, followed by RT-qPCR validation of relevant cellular signaling. STZ treatment reduced the distance and maximum speed travelled by cockroaches, and increased glucose levels while reducing triglyceride levels in neural tissues. The activity of neurotransmitter regulators - AChE and MAO was exacerbated, with concurrent upregulation of glucose sensing and signaling, and increased mRNA levels of redox regulators and inflammation-related genes. Consequently, STZ neurotoxicity is conserved in insects, with possible implications for using N. cinerea to target the multi-faceted mechanisms of neurodegeneration and test potential anti-neurodegenerative agents.

High-Throughput Molecular Modeling and Evaluation of the Anti-Inflammatory Potential of Açaí Constituents against NLRP3 Inflammasome.

The search for bioactive compounds in natural products holds promise for discovering new pharmacologically active molecules. This study explores the anti-inflammatory potential of açaí (Euterpe oleracea Mart.) constituents against the NLRP3 inflammasome using high-throughput molecular modeling techniques. Utilizing methods such as molecular docking, molecular dynamics simulation, binding free energy calculations (MM/GBSA), and in silico toxicology, we compared açaí compounds with known NLRP3 inhibitors, MCC950 and NP3-146 (RM5). The docking studies revealed significant interactions between açaí constituents and the NLRP3 protein, while molecular dynamics simulations indicated structural stabilization. MM/GBSA calculations demonstrated favorable binding energies for catechin, apigenin, and epicatechin, although slightly lower than those of MCC950 and RM5. Importantly, in silico toxicology predicted lower toxicity for açaí compounds compared to synthetic inhibitors. These findings suggest that açaí-derived compounds are promising candidates for developing new anti-inflammatory therapies targeting the NLRP3 inflammasome, combining efficacy with a superior safety profile. Future research should include in vitro and in vivo validation to confirm the therapeutic potential and safety of these natural products. This study underscores the value of computational approaches in accelerating natural product-based drug discovery and highlights the pharmacological promise of Amazonian biodiversity.

Renal effects of selective cyclooxygenase-2 inhibitor anti-inflammatory drugs: A systematic review and meta-analysis.

Background: Selective cyclooxygenase-2 inhibitor anti-inflammatory drugs (coxibs) are associated with the development of adverse events, mainly gastrointestinal and cardiovascular, but renal effects are less known. Objective: To assess the renal risks of coxibs compared to placebo by means of a systematic review and meta-analysis. Methods: Randomized controlled trials that assessed renal effects of coxibs (celecoxib, etoricoxib, lumiracoxib, parecoxib, and valdecoxib) were searched in PubMed, Embase, Scopus and other sources up to March 2024. Two independent reviewers performed study screening, data extraction, and risk of bias assessment. Random effect meta-analysis was employed to calculate the relative risks (RR) and 95% confidence intervals (CI) of renal effects of coxibs compared to placebo and inconsistency among studies (I 2 ). Certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation approach. Results: Out of 5284 retrieved records, 49 studies (comprising 46 reports) were included. Coxibs increased the risk of edema (RR 1.46; 95% CI 1.15, 1.86; I 2  = 0%; 34 studies, 19,754 participants; moderate-certainty evidence), and celecoxib increased hypertensive or renal events (RR 1.24; 95% CI 1.08, 1.43; I 2  = 0%; 2 studies, 3589 participants; moderate-certainty evidence). Etoricoxib increased the risk of hypertension (RR 1.98; 95% CI 1.14, 3.46; I 2  = 34%; 13 studies, 6560 participants; moderate-certainty evidence); no difference was observed when pooling all coxibs (RR 1.26; 95% CI 0.91, 1.76; I 2  = 26%; 30 studies, 16,173 participants; moderate-certainty evidence). Conclusions: Coxibs likely increase the renal adverse effects, including hypertension and edema. Awareness about the renal risks of coxibs should be increased, mainly in high-risk patient.

Unplanned Hospital Admissions in Patients With Solid Tumors in Brazil: Causes and Progressive Disease's Impact on Outcomes.

PURPOSE: Most patients with cancer will be hospitalized throughout the disease course. However, most evidence on the causes and outcomes of these hospitalizations comes from administrative data or small retrospective studies from high-income countries. METHODS: This study is a retrospective cohort of patients with solid tumors hospitalized from February 1, 2021, to December 31, 2021, in a tertiary cancer center in São Paulo, Brazil. We collected data on cancer diagnosis, symptoms at admission, hospitalization diagnosis, and survival clinical outcomes during in-hospital stay (in-hospital mortality) and after discharge (readmission rates and overall survival [OS]). Progressive disease (PD) diagnosis during admission was retrieved from manual chart review if explicitly stated by the attending physician. We modeled in-hospital mortality and postdischarge OS with logistic regression and Cox proportional hazards models, respectively. RESULTS: A total of 3,726 unique unplanned admissions were identified. The most common symptoms at admission were pain (40.6%), nausea (16.8%), and dyspnea (16.1%). PD (34.0%), infection (31.1%), and cancer pain (13.4%) were the most frequent reasons for admission. The in-hospital mortality rate was 18.9%. Patients with PD had a high in-hospital mortality rate across all tumor groups and higher odds of in-hospital death (odds ratio, 3.5 [95% CI, 3.0 to 4.2]). The 7-, 30-, and 90-day readmission rates were 11.9%, 33.5%, and 54%, respectively. The postdischarge median OS (mOS) was 12.6 months (95% CI, 11.6 to 13.7). Poorer postdischarge survival was observed among patients with PD (mOS, 5 months v 18 months; P < .001; hazard ratio, 2.4 [95% CI, 2.1 to 2.6]). CONCLUSION: PD is a common diagnosis during unplanned hospitalizations and is associated with higher in-hospital mortality rates and poorer OS after discharge. Oncologists should be aware of the prognostic implications of PD during admission and align goals of care with their patients.

Near Infrared Biomimetic Hybrid Magnetic Nanocarrier for MRI-Guided Thermal Therapy.

Cell-membrane hybrid nanoparticles (NPs) are designed to improve drug delivery, thermal therapy, and immunotherapy for several diseases. Here, we report the development of distinct biomimetic magnetic nanocarriers containing magnetic nanoparticles encapsulated in vesicles and IR780 near-infrared dyes incorporated in the membranes. Distinct cell membranes are investigated, red blood cell (RBC), melanoma (B16F10), and glioblastoma (GL261). Hybrid nanocarriers containing synthetic lipids and a cell membrane are designed. The biomedical applications of several systems are compared. The inorganic nanoparticle consisted of Mn-ferrite nanoparticles with a core diameter of 15 ± 4 nm. TEM images show many multicore nanostructures (∼40 nm), which correlate with the hydrodynamic size. Ultrahigh transverse relaxivity values are reported for the magnetic NPs, 746 mM-1s-1, decreasing respectively to 445 mM-1s-1 and 278 mM-1s-1 for the B16F10 and GL261 hybrid vesicles. The ratio of relaxivities r2/r1 decreased with the higher encapsulation of NPs and increased for the biomimetic liposomes. Therapeutic temperatures are achieved by both, magnetic nanoparticle hyperthermia and photothermal therapy. Photothermal conversion efficiency ∼25-30% are reported. Cell culture revealed lower wrapping times for the biomimetic vesicles. In vivo experiments with distinct routes of nanoparticle administration were investigated. Intratumoral injection proved the nanoparticle-mediated PTT efficiency. MRI and near-infrared images showed that the nanoparticles accumulate in the tumor after intravenous or intraperitoneal administration. Both routes benefit from MRI-guided PTT and demonstrate the multimodal theranostic applications for cancer therapy.

Episodic memory improvement in illiterate adults attending late-life education irrespective of low socioeconomic status: insights from the PROAME study.

The majority of people with dementia live in low or middle-income countries (LMICs) where resources that play a crucial role in brain health, such as quality education, are still not widely available. In Brazil, illiteracy remains a prevalent issue, especially in communities with lower socioeconomic status (SES). The PROAME study set out to explore basic education in illiterate adults as a means to improve cognitive reserve. Objective: This manuscript aims to explore the relationship between SES and learning, as well as cognitive outcomes, in an older illiterate population. Methods: This six-month clinical trial (NCT04473235) involved 108 participants, of which 77 concluded all assessments, enrolled in late-life basic education. SES assessments included Quality of Urban Living Index, Municipal Human Development Index and Household SES calculated for each participant. Cognitive assessments encompassed the Free and Cued Selective Reminding Test (FCSRT), a word list to assess reading, and the Beta III matrix. Results: The sample consisted primarily of women, with a mean age of 58.5. Participants improved their reading (p=0.01) and their FCSRT (p=0.003). Regarding episodic memory, women outperformed men (p=0.007) and younger participants improved more than their older counterparts (p=0.001). There was no association observed between SES and cognitive outcomes. Conclusion: Irrespective of SES, participants demonstrated positive outcomes after attending basic education. These findings highlight that late life education could be an important non-pharmacologic preventative measure, especially in LMICs.

A maioria das pessoas com demência vive em países de baixa/média renda, onde recursos essenciais para a saúde cerebral, como educação de qualidade, ainda não são amplamente acessíveis. No Brasil, o analfabetismo ainda é frequente, especialmente em comunidades de baixo nível socioeconômico. O estudo PROAME teve como objetivo explorar a educação básica tardia em pessoas analfabetas como ferramenta para o aumento da reserva cognitiva. Objetivo: Investigar a relação entre nível socioeconômico com aprendizado e com desempenho em testes cognitivos, em adultos analfabetos. Métodos: Este estudo clínico de seis meses (NCT04473235) contou com 108 participantes inscritos no projeto Educação para Jovens e Adultos (EJA), dos quais 77 completaram os testes. O nível socioeconômico de cada participante foi medido usando-se: o Índice de Qualidade de Vida Urbana, o Índice de Desenvolvimento Humano Municipal e o nível socioeconômico doméstico. Avaliações cognitivas incluíram: o Teste de Recordação Seletiva Livre e Guiada (TRSLG), uma lista de palavras para avaliar leitura e a matriz Beta III. Resultados: A amostra era predominantemente feminina, com idade média de 58,5. Os participantes melhoraram a leitura (p=0,01) e o TRSLG (p=0,003). Com relação à memoria episódica, as mulheres tiveram resultados superiores aos dos homens (p=0,007) e participantes mais jovens melhoraram mais que seus colegas mais velhos (p=0,001). Não foi observada nenhuma relação entre o nível socioeconômico e o desempenho cognitivo. Conclusão: Independentemente do nível socioeconômico, participantes obtiveram resultados positivos após frequentar a educação básica. Isso sugere que a educação tardia pode ser uma medida preventiva não farmacológica importante, especialmente em países de baixa/média renda.

Reconstrução da região superior do dorso com retalho musculocutâneo do trapézio em V-Y baseado na artéria dorsal da escápula / Reconstruction of the upper region of the back with a V-Y trapezius musculocutaneous flap based on the dorsal artery of the scapula

Introdução: Defeitos na região superior do dorso geralmente são de difícil tratamento, especialmente nos casos de exposição de vértebras, meninge ou material de síntese. O fechamento primário com retalho muscular ou musculocutâneo é a melhor escolha, mas a área doadora para tratar grandes defeitos pode requerer enxertia. A preservação da artéria dorsal da escápula parece assegurar um território cutâneo maior do que o do retalho musculocutâneo do trapézio clássico baseado apenas na artéria cervical transversa. Método: Foi concebida uma ampla ilha triangular de pele sobre o músculo trapézio baseado na artéria dorsal da escápula com transferência por movimento pendular e um procedimento tipo V-Y em cinco pacientes após a extirpação de tumores malignos. Resultados: Os defeitos e as áreas doadoras foram fechados primariamente com total viabilidade dos retalhos e não foram observadas complicações além da ocorrência de seroma. Conclusão: O retalho musculocutâneo do trapézio baseado na artéria dorsal da escápula oferece segurança no tratamento de exposição óssea na região superior do dorso.

Introduction: Defects in the upper region of the back are generally difficult to treat, especially in cases of exposure of vertebrae, meninges, or synthetic material. Primary closure with a muscular or musculocutaneous flap is the best choice, but the donor area to treat large defects may require grafting. Preservation of the dorsal artery of the scapula appears to ensure a larger cutaneous territory than that of the classic trapezius musculocutaneous flap based only on the transverse cervical artery. Method: A wide triangular island of skin was designed over the trapezius muscle based on the dorsal scapular artery with pendulum transfer and a V-Y type procedure in five patients after the extirpation of malignant tumors. Results: The defects and donor areas were closed primarily with full viability of the flaps and no complications were observed other than the occurrence of seroma. Conclusion: The trapezius musculocutaneous flap based on the dorsal artery of the scapula offers safety in the treatment of bone exposure in the upper back region.

Inhibition of the morphological transition of Candida spp. by riparins I-IV.

Candida spp. is an opportunistic pathogen capable of causing superficial to invasive infections. Morphological transition is one of the main virulence factors of this genus and, therefore, is an important variable to be considered in pharmacological interventions. Riparins I, II, III, and IV are alkamide-type alkaloids extracted from the unripe fruit of Aniba riparia, whose remarkable pharmacological properties were previously demonstrated. This work aimed to evaluate in silico and in vitro the inhibitory effects of Riparins on the morphological transition of Candida albicans, Candida tropicalis, and Candida krusei. Molecular docking was applied to analyze the inhibitory effects of riparins against proteins such as N-acetylglucosamine, CYP-51, and protein kinase A (PKA) using the Ramachandran plot. The ligands were prepared by MarvinSketch and Spartan software version 14.0, and MolDock Score and Rerank Score were used to analyze the affinity of the compounds. In vitro analyses were performed by culturing the strains in humid chambers in the presence of riparins or fluconazole (FCZ). The morphology was observed through optical microscopy, and the size of the hyphae was determined using the ToupView software. In silico analysis demonstrated that all riparins are likely to interact with the molecular targets: GlcNAc (>50%), PKA (>60%), and CYP-51 (>70%). Accordingly, in vitro analysis showed that these compounds significantly inhibited the morphological transition of all Candida strains. In conclusion, this study demonstrated that riparins inhibit Candida morphological transition and, therefore, can be used to overcome the pathogenicity of this genus.

Green manure (Crotalaria juncea L.) enhances Origanum vulgare L. biomass accumulation, essential oil yield, and phytochemical properties.

Green manure (GM) may reduce the use of chemical fertilizers, been an ecologically appropriate strategy to cultivation of medicinal plants. Crotalaria juncea, is one of the most used because it adapts to different climatic and high nitrogen content. Origanum vulgare. is widely used in cooking, pharmaceutical, cosmetic industries and food products. The objectives of this study were to evaluate the GM on biomass, essential oil (EO), phenolic and antioxidant. The experiment consisted: control; 150, 300, 450, and 600 g (Sh= leaves+steam) more 200 g roots (R); 600 g aerial part; 200 g roots; and soil with 300 g cattle manure per pot. The highest dry weights were observed in the presence of GM and cattle manure (90 days). The control had an EO production 75% lower in relation to the dose of 450 g GM (Sh+R). Principal component analysis showed that GM and cattle manure positively influenced the dry weight, content, yield, and EO constituents, and total flavonoids. The GM contributed to the accumulation of the major EO compounds (trans-sabinene hydrate, thymol, terpinen-4-ol). The GM management may be beneficial for cultivating, because it can increase the production of biomass and the active components, in addition to being an inexpensive resource.

Harnessing Brazilian biodiversity database: identification of flavonoids as potential inhibitors of SARS-CoV-2 main protease using computational approaches and all-atom molecular dynamics simulation.

SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) is the etiological agent responsible for the global outbreak of COVID-19 (Coronavirus Disease 2019). The main protease of SARS-CoV-2, Mpro, is a key enzyme that plays a vital role in mediating viral replication and transcription. In this study, a comprehensive computational approach was employed to investigate the binding affinity, selectivity, and stability of natural product candidates as potential new antivirals acting on the viral polyprotein processing mediated by SARS-CoV-2 Mpro. A library of 288 flavonoids extracted from Brazilian biodiversity was screened to select potential Mpro inhibitors. An initial filter based on Lipinski's rule of five was applied, and 204 compounds that did not violate any of the Lipinski rules were selected. The compounds were then docked into the active site of Mpro using the GOLD program, and the poses were subsequently re-scored using MM-GBSA (Molecular Mechanics Generalized Born Surface Area) binding free energy calculations performed by AmberTools23. The top five flavonoids with the best MM-GBSA binding free energy values were selected for analysis of their interactions with the active site residues of the protein. Next, we conducted a toxicity and drug-likeness analysis, and non-toxic compounds were subjected to molecular dynamics simulation and free energy calculation using the MM-PBSA (Molecular Mechanics Poisson-Boltzmann Surface Area) method. It was observed that the five selected flavonoids had lower MM-GBSA binding free energy with Mpro than the co-crystal ligand. Furthermore, these compounds also formed hydrogen bonds with two important residues, Cys145 and Glu166, in the active site of Mpro. Two compounds that passed the drug-likeness filter showed stable conformations during the molecular dynamics simulations. Among these, NuBBE_867 exhibited the best MM-PBSA binding free energy value compared to the crystallographic inhibitor. Therefore, this study suggests that NuBBE_867 could be a potential inhibitor against the main protease of SARS-CoV-2 and may be further examined to confirm our results.

Diphenyl Diselenide Attenuates Mitochondrial Damage During Initial Hypoxia and Enhances Resistance to Recurrent Hypoxia.

Hypoxia plays a significant role in the development of various cerebral diseases, many of which are associated with the potential risk of recurrence due to mitochondrial damage. Conventional drug treatments are not always effective for hypoxia-related brain diseases, necessitating the exploration of alternative compounds. In this study, we investigated the potential of diphenyl diselenide [(PhSe)2] to ameliorate locomotor impairments and mitigate brain mitochondrial dysfunction in zebrafish subjected to hypoxia. Additionally, we explored whether these improvements could confer resistance to recurrent hypoxia. Through a screening process, an appropriate dose of (PhSe)2 was determined, and animals exposed to hypoxia received a single intraperitoneal injection of 100 mg/kg of the compound or vehicle. After 1 h from the injection, evaluations were conducted on locomotor deficits, (PhSe)2 content, mitochondrial electron transport system, and mitochondrial viability in the brain. The animals were subsequently exposed to recurrent hypoxia to assess the latency time to hypoxia symptoms. The findings revealed that (PhSe)2 effectively crossed the blood-brain barrier, attenuated locomotor deficits induced by hypoxia, and improved brain mitochondrial respiration by modulating complex III. Furthermore, it enhanced mitochondrial viability in the telencephalon, contributing to greater resistance to recurrent hypoxia. These results demonstrate the beneficial effects of (PhSe)2 on both hypoxia and recurrent hypoxia, with cerebral mitochondria being a critical target of its action. Considering the involvement of brain hypoxia in numerous pathologies, (PhSe)2 should be further tested to determine its effectiveness as a potential treatment for hypoxia-related brain diseases.

Investigation of the cytotoxicity, genotoxicity and antioxidant prospects of JM-20 on human blood cells: A multi-target compound with potential therapeutic applications.

JM-20 is a 1,5-benzodiazepine compound fused to a dihydropyridine fraction with different pharmacological properties. However, its potential toxic effects on blood cells have not yet been reported. Thus, the present study aimed to investigate, for the first time, the possible cytotoxicity of JM-20 through cell viability, cell cycle, morphology changes, reactive species (RS) to DCFH-DA, and lipid peroxidation in human leukocytes, its hemolytic effect on human erythrocytes, and its potential DNA genotoxicity using plasmid DNA in vitro. Furthermore, the compound's ability to reduce the DPPH radical was also measured. Human blood was obtained from healthy volunteers (30 ± 10 years old), and the leukocytes or erythrocytes were immediately isolated and treated with different concentrations of JM-20. A cytoprotective effect was exhibited by 10 µM JM-20 against 1 mM tert-butyl hydroperoxide (t-but-OOH) in the leukocytes. However, the highest tested concentrations of the compound (20 and 50 µM) changed the morphology and caused a significant decrease in the cell viability of leukocytes (p < 0.05, in comparison with Control). All tested concentrations of JM-20 also resulted in a significant increase in intracellular RS as measured by DCFH-DA in these cells (p < 0.05, in comparison with Control). On the other hand, the results point out a potent antioxidant effect of JM-20, which was similar to the classical antioxidant α-tocopherol. The IC50 value of JM-20 against the lipid peroxidation induced by (FeII) was 1.051 µM ± 0.21, while the IC50 value of α-tocopherol in this parameter was 1.065 µM ± 0.34. Additionally, 50 and 100 µM JM-20 reduced the DPPH radical in a statistically similar way to the 100 µM α-tocopherol (p < 0.05, in comparison with the control). No significant hemolysis in erythrocytes, no cell cycle changes in leukocytes, and no genotoxic effects in plasmid DNA were induced by JM-20 at any tested concentration. The in silico pharmacokinetic and toxicological properties of JM-20, derivatives, and nifedipine were also studied. Here, our findings demonstrate that JM-20 and its putative metabolites exhibit similar characteristics to nifedipine, and the in vitro and in silico data support the low toxicity of JM-20 to mammals.

Influence of Limosilactobacillus fermentum IAL 4541 and Wickerhamomyces anomalus IAL 4533 on the growth of spoilage fungi in bakery products.

Fungi are the main microorganisms responsible for the spoilage of bakery products, and their control and subsequent reduction of food waste are significant concerns in the agri-food industry. Synthetic preservatives are still the most used compounds to reduce bakery product spoilage. On the other hand, studies have shown that biopreservation can be an attractive approach to overcoming food and feed spoilage and increasing their shelf-life. However, limited studies show the preservation effects on real food matrices. Therefore, this study aimed to investigate the influence of microorganisms such as lactic acid bacteria (LAB) and yeasts on the growth of spoilage filamentous fungi (molds) on bread and panettones. In general, on conventional and multigrain bread, treatments containing Limosilactobacillus fermentum IAL 4541 and Wickerhamomyces anomalus IAL 4533 showed similar results when compared to the negative control (calcium propionate) in delaying the fungal growth of the tested species (Aspergillus chevalieri, Aspergillus montevidensis, and Penicillium roqueforti). Different from bread, treatments with W. anomallus in panettones delayed the A. chevalieri growth up to 30 days, 13 days longer than observed on negative control (without preservatives). This study showed that biopreservation is a promising method that can extend bakery products' shelf-life and be used as an alternative to synthetic preservatives.

Should ebselen be considered for the treatment of mercury intoxication? A minireview.

Mercury is a ubiquitous environmental contaminant and can be found in inorganic (Hg0, Hg+ and Hg2+) and organic forms (chiefly CH3Hg+ or MeHg+). The main route of human, mammals and bird exposure occurs via predatory fish ingestion. Occupational exposure to Hg0 (and Hg2+) can also occur; furthermore, in gold mining areas the exposure to inorganic Hg can also be high. The toxicity of electrophilic forms of Hg (E+Hg) is mediated by disruption of thiol (-SH)- or selenol (-SeH)-containing proteins. The therapeutic approaches to treat methylmercury (MeHg+), Hg0 and Hg2+ are limited. Here we discuss the potential use of ebselen as a potential therapeutic agent to lower the body burden of Hg in man. Ebselen is a safe drug for humans and has been tested in clinical trials (for instance, brain ischemia, noise-induce hearing loss, diabetes complications, bipolar disorders) at doses varying from 400 to 3600 mg per day. Two clinical trials with ebselen in moderate and severe COVID are also approved. Ebselen can be metabolized to an intermediate with -SeH (selenol) functional group, which has a greater affinity to electrophilic Hg (E+Hg) forms than the available thiol-containing therapeutic agents. Accordingly, as observed in vitro and rodent models in vivo, Ebselen exhibited protective effects against MeHg+, indicating its potential as a therapeutic agent to treat MeHg+ overexposure. The combined use of ebselen with thiol-containing molecules (e.g. N-acetylcysteine and enaramide)) is also commented, because they can have synergistic protective effects against MeHg+.

Screening for Differentially Expressed Memory Genes on a Diabetes Model Induced by High-Sugar Diet in Drosophila melanogaster: Potential Markers for Memory Deficits.

Type 2 diabetes mellitus (T2DM) has been shown to affect a series of cognitive processes including memory, increasing the risk for dementia, particularly Alzheimer's disease (AD). Although increasing evidence has supported that both diseases share common features, the pathophysiological mechanisms connecting these two disorders remain to be fully elucidated. Herein, we used Drosophila melanogaster fed on a high-sugar diet (HSD) to mimic T2DM, and investigate its effects on memory as well as identify potential molecular players associated with the memory deficits induced by HSD. Flies hatched from and reared on HSD for 7 days had a substantial decrease in short-term memory (STM). The screening for memory-related genes using transcriptome data revealed that HSD altered the expression of 33% of memory genes in relation to the control. Among the differentially expressed genes (DEGs) with a fold change (FC) higher than two, we found five genes, related to synapse and memory trace formation, that could be considered strong candidates to underlie the STM deficits in HSD flies: Abl tyrosine kinase (Abl), bruchpilot (Brp), minibrain (Mnb), shaker (Sh), and gilgamesh (Gish). We also analyzed genes from the dopamine system, one of the most relevant signaling pathways for olfactory memory. Interestingly, the flies fed on HSD presented a decreased expression of the Tyrosine hydroxylase (Ple) and Dopa decarboxylase (Ddc) genes, signals of a possible dopamine deficiency. In this work, we present promising biomarkers to investigate molecular networks shared between T2DM and AD.

Episodic memory improvement in illiterate adults attending late-life education irrespective of low socioeconomic status: insights from the PROAME study / Melhoria da memória episódica em adultos analfabetos que frequentam educação tardia, independentemente do baixo nível socioeconômico: considerações do estudo PROAME

ABSTRACT The majority of people with dementia live in low or middle-income countries (LMICs) where resources that play a crucial role in brain health, such as quality education, are still not widely available. In Brazil, illiteracy remains a prevalent issue, especially in communities with lower socioeconomic status (SES). The PROAME study set out to explore basic education in illiterate adults as a means to improve cognitive reserve. Objective: This manuscript aims to explore the relationship between SES and learning, as well as cognitive outcomes, in an older illiterate population. Methods: This six-month clinical trial (NCT04473235) involved 108 participants, of which 77 concluded all assessments, enrolled in late-life basic education. SES assessments included Quality of Urban Living Index, Municipal Human Development Index and Household SES calculated for each participant. Cognitive assessments encompassed the Free and Cued Selective Reminding Test (FCSRT), a word list to assess reading, and the Beta III matrix. Results: The sample consisted primarily of women, with a mean age of 58.5. Participants improved their reading (p=0.01) and their FCSRT (p=0.003). Regarding episodic memory, women outperformed men (p=0.007) and younger participants improved more than their older counterparts (p=0.001). There was no association observed between SES and cognitive outcomes. Conclusion: Irrespective of SES, participants demonstrated positive outcomes after attending basic education. These findings highlight that late life education could be an important non-pharmacologic preventative measure, especially in LMICs.

RESUMO A maioria das pessoas com demência vive em países de baixa/média renda, onde recursos essenciais para a saúde cerebral, como educação de qualidade, ainda não são amplamente acessíveis. No Brasil, o analfabetismo ainda é frequente, especialmente em comunidades de baixo nível socioeconômico. O estudo PROAME teve como objetivo explorar a educação básica tardia em pessoas analfabetas como ferramenta para o aumento da reserva cognitiva. Objetivo: Investigar a relação entre nível socioeconômico com aprendizado e com desempenho em testes cognitivos, em adultos analfabetos. Métodos: Este estudo clínico de seis meses (NCT04473235) contou com 108 participantes inscritos no projeto Educação para Jovens e Adultos (EJA), dos quais 77 completaram os testes. O nível socioeconômico de cada participante foi medido usando-se: o Índice de Qualidade de Vida Urbana, o Índice de Desenvolvimento Humano Municipal e o nível socioeconômico doméstico. Avaliações cognitivas incluíram: o Teste de Recordação Seletiva Livre e Guiada (TRSLG), uma lista de palavras para avaliar leitura e a matriz Beta III. Resultados: A amostra era predominantemente feminina, com idade média de 58,5. Os participantes melhoraram a leitura (p=0,01) e o TRSLG (p=0,003). Com relação à memoria episódica, as mulheres tiveram resultados superiores aos dos homens (p=0,007) e participantes mais jovens melhoraram mais que seus colegas mais velhos (p=0,001). Não foi observada nenhuma relação entre o nível socioeconômico e o desempenho cognitivo. Conclusão: Independentemente do nível socioeconômico, participantes obtiveram resultados positivos após frequentar a educação básica. Isso sugere que a educação tardia pode ser uma medida preventiva não farmacológica importante, especialmente em países de baixa/média renda.

Exploring Natural Alkaloids from Brazilian Biodiversity as Potential Inhibitors of the Aedes aegypti Juvenile Hormone Enzyme: A Computational Approach for Vector Mosquito Control.

This study explores the potential inhibitory activity of alkaloids, a class of natural compounds isolated from Brazilian biodiversity, against the mJHBP enzyme of the Aedes aegypti mosquito. This mosquito is a significant vector of diseases such as dengue, zika, and chikungunya. The interactions between the ligands and the enzyme at the molecular level were evaluated using computational techniques such as molecular docking, molecular dynamics (MD), and molecular mechanics with generalized Born surface area (MMGBSA) free energy calculation. The findings suggest that these compounds exhibit a high binding affinity with the enzyme, as confirmed by the binding free energies obtained in the simulation. Furthermore, the specific enzyme residues that contribute the most to the stability of the complex with the compounds were identified: specifically, Tyr33, Trp53, Tyr64, and Tyr129. Notably, Tyr129 residues were previously identified as crucial in the enzyme inhibition process. This observation underscores the significance of the research findings and the potential of the evaluated compounds as natural insecticides against Aedes aegypti mosquitoes. These results could stimulate the development of new vector control agents that are more efficient and environmentally friendly.

Computational analysis of the interactions between Ebselen and derivatives with the active site of the main protease from SARS-CoV-2.

The main protease (Mpro) of the novel coronavirus SARS-CoV-2 is a key target for developing antiviral drugs. Ebselen (EbSe) is a selenium-containing compound that has been shown to inhibit Mpro in vitro by forming a covalent bond with the cysteine (Cys) residue in the active site of the enzyme. However, EbSe can also bind to other proteins, like albumin, and low molecular weight compounds that have free thiol groups, such as Cys and glutathione (GSH), which may affect its availability and activity. In this study, we analyzed the Mpro interaction with EbSe, its analogues, and its metabolites with Cys, GSH, and albumin by molecular docking. We also simulated the electronic structure of the generated molecules by density functional theory (DFT) and explored the stability of EbSe and one of its best derivatives, EbSe-2,5-MeClPh, in the catalytic pocket of Mpro through covalent docking and molecular dynamics. Our results show that EbSe and its analogues bound to GSH/albumin have larger distance between the selenium atom of the ligands and the sulfur atom of Cys145 of Mpro than the other compounds. This suggests that EbSe and its GSH/albumin-analogues may have less affinity for the active site of Mpro. EbSe-2,5-MeClPh was found one of the best molecules, and in molecular dynamics simulations, it showed to undergo more conformational changes in the active site of Mpro, in relation to EbSe, which remained stable in the catalytic pocket. Moreover, this study also reveals that all compounds have the potential to interact closely with the active site of Mpro, providing us with a concept of which derivatives may be promising for in vitro analysis in the future. We propose that these compounds are potential covalent inhibitors of Mpro and that organoselenium compounds are molecules that should be studied for their antiviral properties.

Impact of Colored Shade Nets on Biomass Production, Essential Oil Composition and Orientin and Isoorientin Content in Lippia gracilis Schauer.

The objective of this study was to evaluate the effect of ChromatiNet on vegetative growth, total antioxidant capacity, phenolic and essential oils (EOs) composition of Lippia gracilis. The plants were cultivated under full sunlight, black, blue and red ChromatiNet. The flavonoid content and antioxidant capacity were quantified spectrophotometrically. The C-glycosylflavone isomers (orientin and isoorientin) were isolated and identified by conventional spectroscopic techniques and measured using high-performance liquid chromatography-diode array detection. The EO was analysed by gas chromatography and gas chromatography-mass spectrometry. Environment influenced growth, total antioxidant capacity and phytochemical levels. Shoot dry weight, thymol, carvacrol and (E)-caryophyllene were favoured under red and black ChromatiNet. Root growth, EOs, caryophyllene oxide, p-cymene, flavonoids, orientin and isoorientin were favoured in sunlight. Growth and accumulation of EOs, flavonoids and photosynthetic pigments increased under blue ChromatiNet. Therefore, Lippia gracilis plants have plasticity related to the spectral quality of light and it cultivate depends of the phytochemicals of interest.