Purinergic exposure induces epigenomic and transcriptomic-mediated preconditioning resembling epilepsy-associated microglial states.

Microglia play a crucial role in a range of neuropathologies through exacerbated activation. Microglial inflammatory responses can be influenced by prior exposures to noxious stimuli, like increased levels of extracellular adenosine and ATP. These are characteristic of brain insults like epileptic seizures and could potentially shape subsequent responses through epigenetic regulation. We investigated DNA methylation and expression changes in human microglia-like cells differentiated from monocytes following ATP-mediated preconditioning. We demonstrate that microglia-like cells display homeostatic microglial features, shown by surface markers, transcriptome, and DNA methylome. After exposure to ATP, TLR-mediated activation leads to an exacerbated pro-inflammatory response. These changes are accompanied by methylation and transcriptional reprogramming associated with enhanced immune-related functions. The reprogramming associated with ATP-mediated preconditioning leads to profiles found in microglial subsets linked to epilepsy. Purine-driven microglia immune preconditioning drives epigenetic and transcriptional changes that could contribute to altered functions of microglia during seizure development and progression.

Is terbinafine an effective treatment for feline sporotrichosis?

BACKGROUND: Terbinafine has been successfully used in the treatment of human sporotrichosis; however, its effectiveness in the treatment of feline sporotrichosis is unknown. Therefore, this study aimed to describe the use of terbinafine in the treatment of feline sporotrichosis. METHODS: A cohort study was conducted in cats with sporotrichosis to assess the effectiveness and safety of terbinafine (30‒60 mg/kg/day). Clinical examination and analysis of laboratory parameters were performed monthly until clinical signs resolved or terbinafine treatment was discontinued. RESULTS: Of the 54 cats with sporotrichosis included in the study, 19 were lost during follow-up and five were withdrawn from the study due to switching to treatment with another prescription drug. Of the remaining 30 cats, 10 achieved clinical cure, with a median treatment time of 18.5 weeks. Treatment failed in 18 cases, and two cats died. Twenty-two cats had adverse reactions to terbinafine treatment, and 10 cats showed elevation of serum transaminases. LIMITATION: Loss during follow-up was high, which makes it difficult to draw accurate conclusions regarding clinical outcomes. CONCLUSION: The low rate of clinical cure observed suggests that terbinafine does not represent an effective treatment option for cases of feline sporotrichosis.

Anxiolytic and Anticonvulsant Effects of Fisetin Isolated from Bauhinia pentandra on Adult Zebrafish (Danio rerio).

Anxiety and epilepsy are common worldwide and represent a primary global health concern. Fisetin, a flavonoid isolated from Bauhinia pentandra, has a wide range of biological activities may be a promising alternative to combat diseases related to the central nervous system (CNS). The present study aimed to investigate the anxiolytic and anticonvulsant effects of fisetin on adult zebrafish. Furthermore, molecular docking simulations were performed to improve the results. Fisetin did not present toxicity and caused anxiolytic behavior and delayed seizures in animals. This effect may occur through serotonin neurotransmission at 5-HT3A and/or 5-HT3B receptors. Molecular docking simulations showed that fisetin interacts with the orthosteric site of the 5-HT3A receptor with strong H-bond interactions with the Trp156 residue, with a strong contribution from the catechol ring, a behavior similar to that of the antagonist co-crystallized inhibitor granisetron (CWB). Fisetin may be a promising alternative to combat diseases related to the central nervous system. Keywords anxiety • Bauhinia pentandra • Danio rerio • epilepsy • fisetin.

Intergenerational consequences of violence: violence during pregnancy as a risk factor for infection in infancy.

Introduction: Psychosocial stress during pregnancy has long-lasting and important consequences in the following generations, as it can affect intrauterine development. The impact on the developing immune system is notoriously important due to the associated morbidity and mortality in the first years of life. Little attention has been given to the role of violence during pregnancy (VDP), especially its impact on infant infectious morbidity. Methods: We analyzed data from two Brazilian birth cohorts (n = 2,847) in two distinct cities (Ribeirão Preto and São Luís), collected during pregnancy and at the beginning of the second year of life. The association between VDP and infection in infancy was analyzed with structural equation modeling, using the WHO-VAW questionnaire as exposure and a latent variable for infection as the outcome. Results: VDP was reported by 2.48% (sexual), 11.56% (physical), and 45.90% (psychological) of the mothers. The models presented an adequate fit. In the city of São Luís, VDP was significantly associated with the latent construct for infection (standardized beta = 0.182; p = 0.022), while that was not the case for the Ribeirão Preto sample (standardized beta = 0.113; p = 0.113). Further analyses showed a gradient effect for the different dimensions of the exposure, from psychological to physical and sexual violence. Conclusion: Our results suggest an association of VDP with infant morbidity in a poorer socioeconomic setting, and highlight the importance of considering the different dimensions of intimate partner violence. These findings may have important implications for the comprehension of global health inequalities and of the effects of gender-based violence.

A new trypsin inhibitor from Centrosema plumieri effective against digestive proteases from Tribolium castaneum, an eco-friendly alternative.

Tribolium castaneum, also known as the red flour beetle, is a polyphagous pest that seriously damages agricultural products, including stored and processed grains. Researchers have aimed to discover alternative pest control mechanisms that are less harmful to the ecosystem than those currently used. We conduct the purification and characterization of a protease inhibitor from C. plumieri seeds and an in vitro evaluation of its insecticidal potential against the insect pest T. castaneum. The trypsin inhibitor was isolated from C. plumieri seeds in a single-step DEAE-Sepharose column chromatography and had a molecular mass of 50 kDA. When analyzed for interaction with different proteolytic enzymes, the inhibitor exhibited specificity against trypsin and no activity against other serine proteases such as chymotrypsin and elastase-2. The isolated inhibitor was able to inhibit digestive enzymes of T. castaneum from extracts of the intestine of this insect. Therefore, we conclude that the new protease inhibitor, specific in tryptic inhibition, of protein nature from the seeds of C. plumieri was effective in inhibiting the digestive enzymes of T. castaneum and is a promising candidate in the ecological control of pests.

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.

HIV latency-reversing activity of latex from Euphorbia umbellata (Pax) Bruyns and three diterpenes isolated from this species.

Two unusual phorbol esters, namely 20-deoxyphorbol-3,4,12-triacetate-13-phenylacetate (1) and phorbol-3,4,12,13-tetraacetate-20-phenylacetate (2) plus ingol-3,8,12-triacetate-7-phenylacetate (3) were isolated from the latex of Euphorbia umbellata and identified by HRESIMS and 2D NMR. Compound 1 is herein described for the first time. Assignment of the phenylacetyl group at C-7 in compound 3 was suggested by the HMBC and NOESY spectra obtained in pyridine-d5. In addition to the latex and its distinct terpenoid fractions, the isolated compounds were tested as latent reversal agents against HIV-1-infected J-Lat cells, with reference to phorbol-12-myristate-13-acetate and ingenol-B. Compound 2 reverted 75-80% the viral latency on the GFP-positive cells, resulting EC50 3.70 µg/mL (SI 6.7), while 1 induced 34-40% reactivation at the same concentration range (4-20 µg/mL). The ingol derivative 3 was ineffective. Phorbol esters were confirmed as effective constituents in the latex since the fraction containing them was 2.4-fold more active than the lyophilised latex at the lowest concentration assayed.

Availability of Electroconvulsive Therapy in Public Health Services in the Last Decade in Brazil.

OBJECTIVE: To identify the current treatment options for electroconvulsive therapy (ECT) therapy in public services linked to the Unified Health System in Brazil and compare them with data published in 2012 based on their availability. METHODS: In this retrospective observational study, we mapped institutions that perform ECT under public health services in Brazil. A questionnaire was administered to active and inactive service centers between August 2022 and June 2023. RESULTS: We identified 16 institutions that performed ECT, including 12 linked to public universities and 4 with various links. In the last decade, 2 new public services that perform ECT in the country have emerged, whereas 4 services have ceased function. In 2022, the number of individuals treated with ECT per 100,000 population was 1.86, whereas the number of procedures performed per 100,000 people was 6.55. CONCLUSIONS: Although 2 new public ECT services have been identified, 4 have turned inactive. Most services are linked to public universities, and inactive service points to financial issues as the main factor in service interruption. Brazil has one of the lowest rates of individuals treated with ECT per 100,000 population compared with countries in North America and Europe. Thus, it is essential to raise awareness to improve ECT adoption rates and bring it out of the shadows in Brazil.

Internet-based self-administered intervention to reduce anxiety and depression symptomatology and improve well-being in 7 countries: protocol of a randomized control trial.

Background: Online psychological interventions have emerged as a treatment alternative because they are accessible, flexible, personalized, and available to large populations. The number of Internet interventions in Latin America is limited, as are Randomized Controlled Trials (RCTs) of their effectiveness and a few studies comparing their effectiveness in multiple countries at the same time. We have developed an online intervention, Well-being Online, which will be available to the public free of charge in 7 countries: Mexico, Ecuador, Peru, Chile, Brazil, Spain, and the Netherlands. We expect a reduction in depression and anxiety symptoms and an increase in well-being of the participants. Methods: A multi-country, randomized controlled trial will be conducted. The intervention is multicomponent (Cognitive Behavioral Therapy, Behavioral Activation Therapy, Mindfulness, Acceptance and Commitment Therapy, and Positive Psychology), with 10 sessions. In each country, eligible participants will be randomized to one of three groups: Enriched Intervention (interactive web design with videos, infographics, text, audio, and forum), Text Intervention (text on the website), and Wait List (control group). Repeated measures will be obtained at 5-time points. Our primary outcomes will be anxiety symptomatology, depressive symptomatology, and mental well-being. MANOVA analysis will be used for our main analysis. Discussion: This protocol describes the design of a randomized trial to evaluate the efficacy of a web-based intervention to reduce anxiety and depression symptomatology and increase subjective well-being. The intervention will be made available in four languages (Spanish, Portuguese, Dutch, and English). Its results will contribute to the evidence of effectiveness in terms of randomized trials and Internet interventions, mainly in Latin America and Europe.

Therapy with bone marrow mesenchymal stem cells in bone regeneration in children with osteonecrosis secondary to sickle cell disease.

Introduction: This study aimed to describe the evolution of bone regeneration in children with hip osteonecrosis associated with sickle cell disease, treated with bone marrow-derived mesenchymal stem cell implants at the Professor Edgar Santos University Hospital Complex. Materials and methods: A non-randomized clinical trial was conducted with 48 patients of both sexes, aged between 11 and 18 years, diagnosed with femoral head osteonecrosis secondary to sickle cell disease. Patient selection was based on strict criteria, including confirmed diagnosis of sickle cell anemia and a stage of osteonecrosis compatible with the proposed treatment. Bone regeneration assessment was performed through radiographic examinations and magnetic resonance imaging, following the Ficat & Arlet criteria and the Salter-Thompson classification. Results: Statistical analysis revealed a significant association between the patients' age and positive treatment outcomes, suggesting that autologous bone marrow cell implantation is a safe and effective approach in the early stages of osteonecrosis. The majority of patients (87.5%) reported complete pain relief, while 10.42% experienced significant symptom improvement. Only one patient (2.08%) did not observe improvement. The results indicate that cell therapy can regenerate or slow the progression of bone necrosis, reducing the need for more invasive surgical procedures. Conclusion: The study demonstrates the potential of bone marrow-derived mesenchymal stem cell implantation in treating hip osteonecrosis in children with sickle cell disease, emphasizing the importance of long-term monitoring of bone structure stability.

Biomimetic Chemical Reactions with Natural Products Using Metalloporphyrins and Salen Complexes as Catalysts: A Brief Review.

The cytochrome P450 is a superfamily of hemoproteins mainly present in the liver and are versatile biocatalysts. They participate in the primary metabolism and biosynthesis of various secondary metabolites. Chemical catalysts are utilized to replicate the activities of enzymes. Metalloporphyrins and Salen complexes can contribute to the products' characterization and elucidate biotransformation processes, which are investigated during pre-clinical trials. These catalysts also help discover biologically active compounds and get better yields of products of industrial interest. This review aims to investigate which natural product classes are being investigated by biomimetic chemical models and the functionalities applied in the use of these catalysts. A limited number of studies were observed, with terpenes and alkaloids being the most investigated natural product classes. The research also revealed that Metalloporphyrins are still the most popular in the studies, and the identity and yield of the products obtained depend on the reaction system conditions.

Tropane Alkaloid Isolated from Erythroxylum bezerrae Exhibits Neuropharmacological Potential in an Adult Zebrafish (Danio rerio) Model.

This study carried out to investigate the anti-inflammatory and antinociceptive effect of tropane alkaloid (EB7) isolated from E. bezerrae. It evaluated the toxicity and possible involvement of ion channels in the antinociceptive effect of EB7, as well as its anti-inflammatory effect in adult zebrafish (Zfa). Docking studies with EB7 and COX-1 and 2 were also performed. The tested doses of EB7 (4, 20 and 40 mg/kg) did not show any toxic effect on Zfa during the 96h of analysis (LD50>40 mg/kg). They did not produce any alteration in the locomotor behavior of the animals. Furthermore, EB7 showed promising pharmacological effects as it prevented the nociceptive behavior induced by hypertonic saline, capsaicin, formalin and acid saline. EB7 had its analgesic effect blocked by amiloride involving the neuromodulation of ASICs in Zfa. In evaluating the anti-inflammatory activity, the edema induced by κ-carrageenan 3.5 % was reduced by the dose of 40 mg/kg of EB7 observed after the fourth hour of analysis, indicating an effect similar to that of ibuprofen. Molecular docking results indicated that EB7 exhibited better affinity energy when compared to ibuprofen control against the two evaluated targets binding at different sites in the cocrystallized COX-1 and 2 inhibitors.

Effect of Cinnamaldehyde Chalcone on Behavior in Adult Zebrafish (Danio rerio): In Silico Approach.

The study focuses on the anxiolytic potential of chalcone (2E,4E)-1-(2-hydroxyphenyl)-5-phenylpenta-2,4-dien-1-one (CHALCNM) in adult zebrafish. Successfully synthesized in 58 % yield, CHALCNM demonstrated no toxicity after 96 h of exposure. In behavioral tests, CHALCNM (40 mg/kg) reduced locomotor activity and promoted less anxious behavior in zebrafish, confirmed by increased permanence in the light zone of the aquarium. Flumazenil reversed its anxiolytic effect, indicating interaction with GABAA receptors. Furthermore, CHALCNM (4 and 20 mg/kg) preserved zebrafish memory in inhibitory avoidance tests. Virtual screening and ADMET profile studies suggest high oral bioavailability, access to the CNS, favored by low topological polarity (TPSA≤75 Å2) and low incidence of hepatotoxicity, standing out as a promising pharmacological agent against the GABAergic system. In molecular coupling, CHALCNM demonstrated superior affinity to diazepam for the GABAA receptor. These results reinforce the therapeutic potential of CHALCNM in the treatment of anxiety, highlighting its possible future clinical application.

Dereplication Tools for Rhizophora mangle Extracts from Different Mangrove Areas and their Potential Against Staphylococcus aureus.

Rhizophora extracts have several potential biological activities, and their metabolites can be used in the pharmaceutical industry. Extracts of Rhizophora species obtained from mangroves have shown prospective activity against Staphylococcus aureus. This study aimed to investigate the chemical profile of Rhizophora mangle leaves from fringe, basin, and transition mangrove zones and their bactericidal/bacteriostatic potential against S. aureus. R. mangle leaves were collected monthly in 2018 from litterfall in three different zones of the mangrove of Guaratiba State Reserve: fringe, basin, and transition. Extracts were prepared from the material collected in October and December for LC-HRMS/MS analysis, and dereplication was performed using a molecular library search and the classical molecular networking GNPS platform. The minimum inhibitory concentrations (MICs) of the aqueous extract of R. mangle against S. aureus were determined. No S. aureus growth was observed compared to the control for extracts collected from September to December. Different compounds were annotated in each region, yet a marked presence of phenolic compounds was noted, among them glycosylated flavonoid derivatives of quercetin and kaempferol. The results suggest bactericidal/bacteriostatic activity for extracts of R. mangle leaves collected in 2018 from three mangrove forest zones.

Identification and Characterization of Rotigotine Degradation Products by HPLC Coupled DAD and CAD Detectors and HRMS Through Q-Orbitrap and Electrospray Ionization.

Rotigotine (RTG) is a dopamine agonist used in the treatment of Parkinson's disease. As it is susceptible to oxidation, stability studies must be carefully designed for the identification and characterization of all possible degradation products. Here, RTG degradation was evaluated according to the International Conference on Harmonization guidelines under various stress conditions, including acidic and basic hydrolysis, oxidative, metallic, photolytic, and thermal conditions. Additionally, more severe stress conditions were applied to induce RTG degradation. Significant degradation was only observed under oxidative and photolytic conditions. The samples were analyzed by high performance liquid chromatography coupled to photodiode array detectors, charged aerosol, and high-resolution mass spectrometry. Chromatographic analyses revealed the presence of eight substances related to RTG, four of which were already described and were qualified impurities (impurities B, C, K and E) and four new degradation products (DP-1 - DP-4), whose structures were characterized by high-resolution mass spectrometry through Q-Orbitrap and electrospray ionization. In the stress testing of the active pharmaceutical ingredient in solid form, significant RTG degradation was observed in the presence of the oxidative matrix. The results corroborate the literature that confirm the high susceptibility of RTG to oxidation and the importance of using different detectors to detect degradation products in forced degradation studies.

Association between breast feeding and food consumption according to the degree of processing in Brazil: a cohort study.

BACKGROUND: The benefits of breast feeding may be associated with better formation of eating habits beyond childhood. This study was designed to verify the association between breast feeding and food consumption according to the degree of processing in four Brazilian birth cohorts. METHODS: The duration of exclusive, predominant and total breast feeding was evaluated. The analysis of the energy contribution of fresh or minimally processed foods (FMPF) and ultra-processed foods (UPF) in the diet was evaluated during childhood (13-36 months), adolescence (11-18 years) and adulthood (22, 23 and 30 years). RESULTS: Those who were predominantly breastfed for less than 4 months had a higher UPF consumption (ß 3.14, 95% CI 0.82 to 5.47) and a lower FMPF consumption (ß -3.47, 95% CI -5.91 to -1.02) at age 22 years in the 1993 cohort. Exclusive breast feeding (EBF) for less than 6 months was associated with increased UPF consumption (ß 1.75, 95% CI 0.25 to 3.24) and reduced FMPF consumption (ß -1.49, 95% CI -2.93 to -0.04) at age 11 years in the 2004 cohort. In this same cohort, total breast feeding for less than 12 months was associated with increased UPF consumption (ß 1.12, 95% CI 0.24 to 2.19) and decreased FMPF consumption (ß -1.13, 95% CI -2 .07 to -0.19). Children who did not receive EBF for 6 months showed an increase in the energy contribution of UPF (ß 2.36, 95% CI 0.53 to 4.18) and a decrease in FMPF (ß -2.33, 95% CI -4 .19 to -0.48) in the diet at 13-36 months in the 2010 cohort. In this cohort, children who were breastfed for less than 12 months in total had higher UPF consumption (ß 2.16, 95% CI 0.81 to 3.51) and lower FMPF consumption (ß -1.79, 95% CI -3.09 to -0.48). CONCLUSION: Exposure to breast feeding is associated with lower UPF consumption and higher FMPF consumption in childhood, adolescence and adulthood.

Knowledge and perceived confidence of Brazilian psychiatrists about eating disorders´ diagnosis and treatment recommendations.

OBJECTIVE: To investigate Brazilian psychiatrists ́ knowledge and perceived confidence, both in diagnosis and in evidence-based treatments for eating disorders (ED). METHODS: In this cross-sectional study, 259 psychiatrists filled out an online form including: sociodemographic data, questions about ED diagnosis and management based on standard guidelines. Descriptive statistics described sample characteristics and levels of ED knowledge and perceived confidence. RESULTS: Sample was composed mainly by women (65,64%), with mean age of 42.86, from the Southeast of Brazil (56,37%), working predominantly in private practice (59,85%), with less than ten years of experience in Psychiatry (51,74%). We found that 33.21% of participants correctly chose diagnostic criteria for anorexia nervosa (AN); 29.73% for bulimia nervosa (BN), and 38.22% for binge eating disorder (BED). Correct answers for therapeutic options were similar in BN and BED (20.8%), being considerably lower for AN (2.7%). Additionally, reported ED training were: 15.1% during medical school; 59.8% during medical residency/postgraduate studies; 58.7% as complementary training. Only 8.89% felt satisfied with their ED training; 50.97% felt confident diagnosing ED and 37.07% in managing ED patients. CONCLUSION: These results demonstrated an important gap in ED knowledge of Brazilian psychiatrists, and its consequences on their confidence and competence in managing ED patients.

Social support and suicidality during the COVID-19 pandemic among Brazilian healthcare workers: a longitudinal assessment of an online repeated cross-sectional survey.

INTRODUCTION: Healthcare workers (HCWs) are at an increased risk of suicide compared to non-healthcare workers. This study aims to investigate the association between social support and suicidal ideation and behavior (SIB) during the COVID-19 pandemic among Brazilian HCWs. METHODS: This study utilizes data from 10,885 participants who answered the first (time point 1 - between May and June of 2020) and second (time point 2 - between December 2020 and February 2021) assessments of an online repeated cross-sectional survey for evaluating mental health and quality of life of HCWs during the COVID-19 pandemic in Brazil. Logistic regression analysis was conducted to investigate the relationship between social support as the independent variable (time point 1) and SIB as the outcomes (time point 2). RESULTS: Higher social support was associated with a significantly lower chance of reporting SIB in the month prior to follow-up assessment (adjusted odds ratio [AOR]: 0.71, CI 95% 0.66 - 0.76 and AOR 0.61, CI 95% 0.54 - 0.68, respectively). These associations were independent of sex, age, feelings of loneliness, and self-reported psychiatric disorders. CONCLUSION: Social support is associated with a lower chance of suicidality among HCWs, a protective role that is probably more evident for suicidal behavior.