The Amazonian Camu-Camu Fruit Modulates the Development of Drosophila melanogaster and the Neural Function of Adult Flies under Oxidative Stress Conditions.

Camu-camu (Myrciaria dubia) is known for its antioxidant properties, although little is known about its developmental safety effects, particularly on adult neural function under basal redox and oxidative stress conditions. Therefore, this study sought to address this gap by conducting three complementary protocols using Drosophila melanogaster to investigate these effects. The initial assays revealed that second-stage larvae consumed diets supplemented with various concentrations of camu-camu uniformly, establishing a 50% lethal concentration at 4.799 mg/mL. Hence, non-lethal (0.1, 0.5, and 1 mg/mL) and sub-lethal (5 and 10 mg/mL) concentrations were then chosen to evaluate the effects of camu-camu on preimaginal development and adult neural function. Our observations showed that camu-camu impacts the expression of antioxidant enzymes, reactive species, and lipoperoxidation. Notably, sub-lethal concentrations decreased preimaginal viability and locomotor activity, negatively influenced geotaxis and acetylcholinesterase activity, and increased reactive species, catalase, and glutathione S-transferase activity in flies. Additionally, the protective effects of camu-camu against oxidative stress induced by iron (20 mM) were assessed. Flies supplemented with 0.5 mg/mL of camu-camu during the larval period showed improved neural viability and function, and this supplementation was found to protect against oxidative stress. These findings are instrumental in evaluating the safety and efficacy of commercial supplements based on camu-camu, offering significant insights for future research and application.

VDR, SOD-2, and CYP24A1 Gene Expression in Different Genotypes of BsmI SNP of the Vitamin D Receptor Gene in Individuals with Hypovitaminosis.

BACKGROUND: Hypovitaminosis D is a public health problem due to its implications for various diseases. Vitamin D has numerous functions, such as modulating the metabolism of cellular tissues, and it is expressed through the vitamin D receptor (VDR) gene that may influence gene expression modulation, which plays an important role in vitamin D metabolism. OBJECTIVE: To evaluate the effect of the genotypes of BsmI single nucleotide polymorphism (SNP) of the VDR gene on VDR, SOD2, and CYP24A1 gene expression in individuals with low serum vitamin D levels. METHODS: This was a cross-sectional analytical study. After signing the informed consent form, individuals were invited to participate and answered a structured questionnaire with identification data. Blood was collected for biochemical analysis, and vitamin D was measured by chemiluminescence; BsmI polymorphism was determined using real-time polymerase chain reaction (PCR) assays with TaqMan allelic discrimination, and gene expression was conducted by qRT-PCR using QuantiFast SYBR® Green PCR Master Mix. Data were analyzed using the SPSS 20.0 software, and differences were considered significant at p < 0.05. RESULTS: 98 individuals with vitamin D ≤ 20 ng/dL were evaluated, and the BsmI SNP of the VDR gene showed CYP24A1 overexpression and low SOD2 expression. CONCLUSION: BsmI SNP of the VDR gene can modulate the expression of the genes evaluated without interfering with serum levels.

The Protective Effect of Lithium Against Rotenone may be Evolutionarily Conserved: Evidence from Eisenia fetida, a Primitive Animal with a Ganglionic Brain.

Chronic exposure to stress is a non-adaptive situation that is associated with mitochondrial dysfunction and the accumulation of reactive oxygen species (ROS), especially superoxide anion (SA). This accumulation of ROS produces damage-associated molecular patterns (DAMPs), which activate chronic inflammatory states and behavioral changes found in several mood disorders. In a previous study, we observed that an imbalance of SA triggered by rotenone (Ro) exposure caused evolutionarily conserved oxi-inflammatory disturbances and behavioral changes in Eisenia fetida earthworms. These results supported our hypothesis that SA imbalance triggered by Ro exposure could be attenuated by lithium carbonate (LC), which has anti-inflammatory properties. The initial protocol exposed earthworms to Ro (30 nM) and four different LC concentrations. LC at a concentration of 12.85 mg/L decreased SA and nitric oxide (NO) levels and was chosen to perform complementary assays: (1) neuromuscular damage evaluated by optical and scanning electron microscopy (SEM), (2) innate immune inefficiency by analysis of Eisenia spp. extracellular neutrophil traps (eNETs), and (3) behavioral changes. Gene expression was also evaluated involving mitochondrial (COII, ND1), inflammatory (EaTLR, AMP), and neuronal transmission (nAchR α5). LC attenuated the high melanized deposits in the circular musculature, fiber disarrangement, destruction of secretory glands, immune inefficiency, and impulsive behavior pattern triggered by Ro exposure. However, the effects of LC and Ro on gene expression were more heterogeneous. In summary, SA imbalance, potentially associated with mitochondrial dysfunction, appears to be an evolutionary component triggering oxidative, inflammatory, and behavioral changes observed in psychiatric disorders that are inhibited by LC exposure.

Rotenone-exposure as cytofunctional aging model of human dermal fibroblast prior replicative senescence.

Rotenone (Ro), causes superoxide imbalance by inhibiting complex I of the mitochondrial electron transport chain, being able to serve as a model for functional skin aging by inducing cytofunctional changes in dermal fibroblasts prior to proliferative senescence. To test this hypothesis, we conducted an initial protocol to select a concentration of Ro (0.5, 1, 1.5, 2, 2.5, and 3 µM) that would induce the highest levels of the aging marker beta-galactosidase (ß-gal) in human dermal HFF-1 fibroblasts after 72 h of culture, as well as a moderate increase in apoptosis and partial G1 arrestment. We evaluated whether the selected concentration (1 µM) differentially modulated oxidative and cytofunctional markers of fibroblasts. Ro 1.0 µM increased ß-gal levels and apoptosis frequency, decreased the frequency of S/G2 cells, induced higher levels of oxidative markers, and presented a genotoxic effect. Fibroblasts exposed to Ro showed lower mitochondrial activity, extracellular collagen deposition, and fewer fibroblast cytoplasmic connections than controls. Ro triggered overexpression of the gene associated with aging (MMP-1), downregulation genes of collagen production (COL1A, FGF-2), and cellular growth/regeneration (FGF-7). The 1 µM concentration of Ro could serve as an experimental model for functional aging fibroblasts prior to replicative senescence. It could be used to identify causal aging mechanisms and strategies to delay skin aging events.

Epidemiological survey on the benefit of neuraminidase inhibitors on severe acute respiratory syndrome due to COVID-19 / Levantamento epidemiológico do benefício de inibidores de neuraminidase na síndrome respiratória aguda grave por COVID-19 / Encuesta epidemiológica del beneficio de inhibidores de neuraminidase en síndrome respiratorio agudo severo por COVID-19

Background and objectives: The COVID-19 pandemic and its consequent severe acute respiratory syndrome (SARS) have taken the lives of millions since 2020. The use of neuraminidase inhibitors is a promising alternative in treating this disease, with several studies on off-label use being conducted since the beginning of the pandemic, but none of them have a large sample size and analyze multiple risk factors. The purpose of this article is to identify possible associations between various factors and risk of hospitalization, need for ventilation and death, as well as the influence of the prescription of Zanamivir and Oseltamivir on these same indicators. Methods: In this transversal study, approximately 900,000 medical records from all regions of Brazil were collected from the Ministry of Health database, and after that, proper statistical analysis of the variables was performed. Results: Hospitalization was associated with gender, ethnicity, education, local urbanization, State, and its percentage of elderly, as well as the climate. The prescription of Zanamivir and Oseltamivir was associated with higher incidence of symptoms, lower hospitalization and death rate, and lower need for invasive and non-invasive ventilation. Medical records from146,160 patients were excluded due to SARS not caused by COVID-19. Conclusion: From this data, it is possible to draw a risk profile for hospitalization by SARS and consider the use of Zanamivir and Oseltamivir as a treatment for these patients.(AU)

Justificativa e objetivos: A pandemia de COVID-19 e sua consequente síndrome respiratória aguda grave (SRAG) levaram milhões de pessoas a óbito desde 2020. O uso de inibidores da neuraminidase é uma alternativa promissora no tratamento dessa doença, com vários estudos sobre o uso off-label sendo conduzidos desde o início da pandemia, mas nenhum que tenha um grande tamanho amostral e que analise vários fatores de risco. O objetivo deste artigo é identificar possíveis associações entre diversos fatores e risco de hospitalização, necessidade de ventilação e óbito, assim como a influência da prescrição de Zanamivir e Oseltamivir nos mesmos indicadores. Métodos: Neste estudo transversal, foi feito o levantamento de aproximadamente 900 mil prontuários de todas as regiões do Brasil, provenientes de dados do Ministério da Saúde, e em seguida foi realizado o tratamento estatístico adequado das variáveis. Resultados: A hospitalização foi associada a sexo, etnia, escolaridade, urbanização do local, Estado e porcentagem de idosos do mesmo, assim como o clima. Já a prescrição de Zanamivir e Oseltamivir foi associada a maior incidência de sintomas, menor taxa de hospitalização e óbito e menor necessidade de ventilação invasiva e não-invasiva. Foram excluídos 146.160 prontuários devido a SRAG não ocasionada pela COVID-19. Conclusão: Com esses dados, é possível traçar um perfil de risco para hospitalização por SRAG e considerar o uso de Zanamivir e Oseltamivir como tratamento para esses pacientes.(AU)

Justificación y objetivos: la pandemia Covid-19 y su consiguiente síndrome respiratorio agudo severo (SRAS) han muerto millones de personas desde 2020. El uso de inhibidores de la neuraminidasa es una alternativa prometedora en el tratamiento de esta enfermedad, con varios estudios sobre el uso off-label que se realiza desde el principio de la pandemia, pero ninguno que tenga un tamaño de muestra grande y analice múltiples factores de riesgo. El propósito de este artículo es identificar posibles asociaciones entre varios factores y el riesgo de hospitalización, necesidad de ventilación y muerte, así como la influencia de la prescripción de Zanamivir y Oseltamivir en los mismos indicadores. Métodos: En este estudio transversal, se encuestaron a los datos del Ministerio de Salud de aproximadamente 900,000 registros de todas las regiones de Brasil, después de que se realizó un tratamiento estadístico adecuado de las variables. Resultados: La hospitalización se asoció con género, etnia, educación, urbanización del sitio, Estado y porcentaje de ancianos, así como el clima. La prescripción de zanamivir y oseltamivir se asoció con la mayor incidencia de síntomas, menor hospitalización y tasa de mortalidad y menor necesidad de ventilación invasiva y no invasiva. Se excluyeron 146,160 registros médicos debido a SRAS no causado por Covid-19. Conclusión: con estos datos, es posible dibujar un perfil de riesgo para la hospitalización por SRAS y considerar el uso de zanamivir y oseltamivir como tratamiento para estos pacientes.(AU)

A coffee enriched with guarana, selenium, and l-carnitine (GSC) has nutrigenomic effects on oxi-inflammatory markers of relapsing-remitting multiple sclerosis patients: A pilot study.

Relapsing-remitting multiple sclerosis (RRMS) is the most common clinical course of multiple sclerosis (MS), characterized by a chronic inflammatory state and elevated levels of oxidative markers. Food supplements with potential anti-inflammatory, antioxidant and neuroprotective effects have been tested as possible adjuvants in the treatment of MS. In this sense, this pilot study was carried out with the aim of verifying whether a minimum daily dose of a guarana, selenium and l-carnitine (GSC) based multi supplement, mixed in cappuccino-type coffee, administered for 12 weeks to 28 patients with RRMS could differentially modulate oxidative blood markers (lipoperoxidation, protein carbonylation and DNA oxidation) and inflammatory blood markers (protein levels of cytokines IL-1ß, IL-6, TNF-α, IFN-γ, IL-10, gene expression of these cytokines, and NLRP3 and CASP-1 molecules, and C-reactive protein levels). The results indicate that a low concentration of GSC is capable of decreasing the plasma levels of oxidized DNA and pro-inflammatory cytokines of RRMS patients. The results support further research into the action of GSC on clinical symptoms, not only in patients with MS, but also with other neurological conditions.

Sobrevida de pessoas idosas hospitalizadas com uso prévio de medicamentos potencialmente inapropriados / Survival of hospitalized older adults with prior use of potentially inappropriate medicine

Resumo Objetivos Neste estudo prospectivo, avaliamos o impacto do uso de medicamentos potencialmente inapropriados prescritos antes da internação (PIM-ph) na mortalidade de idosos. Métodos Foram incluídos 318 pacientes com idade ≥ 65 anos que procuraram atendimento de emergência e foram internados por qualquer motivo clínico. As informações sobre os indicadores clínicos e sociais foram obtidas por meio de entrevistas estruturadas, 24 a 48 horas após a internação. Os medicamentos usados por esses pacientes foram registrados e o uso de PIM-ph foi identificado pela análise brasileira baseada em consenso de uso de PIM. A análise considerou a influência de todo conjunto de PIM-ph, bem como de alguns PIM-ph específicos. O impacto do uso de PIM-ph na sobrevida de idosos hospitalizados foi determinado por meio da análise multivariada de regressão de Cox. Resultados A prevalência de PIM-ph foi 49,7% (n = 158). Um total de 85 (26,7%) pacientes faleceram durante a internação ou até 30 dias após a alta. Dezoito classes farmacológicas de uso de PIM-ph foram identificadas. O uso de PIM-ph, benzodiazepínico (IC: 1.055-3.365, p= 0.032), digoxina (IC: 1.623-7.048, p=0.001) e diuréticos de alça (IC: 1.000-3.455, p=0.05) aumentou o risco relativo de mortalidade independente de sexo, idade, causas clínicas de hospitalização, risco de fragilidade, suporte social, presença de sintomas de confusão, polifarmácia e evolução intra-hospitalar de complicações geriátricas. Conclusão O uso de PIM-ph (Benzodiazepínicos, digoxina e diuréticos de alça) pode contribuir para o risco de mortalidade em idosos hospitalizados. Esses resultados podem ser relevantes no manejo e cuidado terapêutico de pacientes hospitalizados.

Abstract Objectives We aimed to evaluate the impact of potentially inappropriate medications prescribed prior to hospitalization (PIM-ph) on the mortality Methods We included 318 patients, aged ≥65 who sought emergency care and were hospitalized for any clinical reasons. Information on patients' clinical and social indicators was obtained via structured interviews conducted 24 to 48 hours after hospitalization. All medications used by older adults prior to hospitalization were recorded, and PIM-ph were identified using the Brazilian PIM Consensus. The study considered the influence of the entire set of PIM-ph and specific PIM-ph used by these patients. The impact of PIM-ph use during hospitalization and after 30 days of this event was statistically determined by multivariable Cox proportional hazard regression analysis, which included sex, age, and other clinical and functional indicators as intervening variables. Results The prevalence of PIM-ph use was 49.7% (n=158). A total of 85 (26.7%) patients died during hospitalization or within 30 days after discharge. Eighteen pharmacological classes of PIM-ph use were identified. The use of total PIM-ph, benzodiazepines (IC: 1.055-3.365, p= 0.032), digoxin(IC: 1.623-7.048, p=0.001), and loop diuretics (IC: 1.000-3.455, p=0.05) increased the relative risk of mortality independent of sex, age, clinical causes of hospitalization, frailty risk, social support, presence of confusion symptoms, polypharmacy, and in-hospital evolution of geriatric complications. Conclusion PIM-ph use, especially benzodiazepines, digoxin, and loop diuretics, could contribute to mortality risk in hospitalized older adults. These results could be relevant in the management and therapeutic care of hospitalized patients.

Superoxide-imbalance Pharmacologically Induced by Rotenone Triggers Behavioral, Neural, and Inflammatory Alterations in the Eisenia fetida Earthworm.

BACKGROUND: Some studies have suggested that mitochondrial dysfunction and a superoxide imbalance could increase susceptibility to chronic stressful events, contributing to the establishment of chronic inflammation and the development of mood disorders. The mitochondrial superoxide imbalance induced by some molecules, such as rotenone, could be evolutionarily conserved, causing behavioral, immune, and neurological alterations in animals with a primitive central nervous system. OBJECTIVE: Behavioral, immune, and histological markers were analyzed in Eisenia fetida earthworms chronically exposed to rotenone for 14 days. METHODS: Earthworms were placed in artificial soil containing 30 nM of rotenone distributed into a plastic cup that allowed the earthworms to leave and return freely into the ground. Since these organisms prefer to be buried, the model predicted that the earthworms would necessarily have to return to the rotenone-contaminated medium, creating a stressful condition. The effect on survival behavior in the immune and histological body wall and ventral nervous ganglia (VNG) structures, as well as gene expression related to inflammation and mitochondrial and neuromuscular changes. RESULTS: Rotenone-induced loss of earthworm escape behavior and immune alterations indicated a chronic inflammatory state. Some histological changes in the body wall and VNG indicated a possible earthworm reaction aimed at protecting against rotenone. Overexpression of the nicotinic acetylcholine receptor gene (nAChR α5) in neural tissues could also help earthworms reduce the degenerative effects of rotenone on dopaminergic neurons. CONCLUSION: These data suggest that mitochondrial dysfunction could be an evolutionarily conserved element that induces inflammatory and behavioral changes related to chronic stress.

Amazonian Guarana- and Açai-Conjugated Extracts Improve Scratched Fibroblast Healing and Eisenia fetida Surgical Tail Amputation by Modulating Oxidative Metabolism.

Background: Previous studies have suggested that guarana (Paullinia cupana) and açai (Euterpe oleracea) have antioxidant, anti-inflammatory, and proliferative properties, indicating their potential therapeutic action in wound healing. We produced a conjugated guarana-açai (GA) extract and tested its healing action on earthworms (Eisenia fetida) subjected to tail amputation by surgical incision. Methods: Extract from roasted guarana seeds and fresh açai seed berries was produced. The antioxidant and genoprotective capacity of GA extract was tested. The concentration with the most remarkable healing potential was used in subsequent tests. The last three posterior segments of the clitellate earthworm tail reared under standardized conditions were surgically amputated. Next, topical PBS or GA extract was applied to the surgical wound. The rate of cell migration and tissue regeneration at the local wound site was histologically evaluated after the procedure. Expression of the SOX4 gene that acts in epithelial-to-mesenchymal transition was determined by RT-qPCR. Results: Sixteen bioactive molecules, including some previously described substances, were identified. All tested concentrations exhibited antioxidant and genoprotective effects. The GA extract accelerated the healing processes as observed through macroscopic and histological analyses and increased expression of SOX4. Conclusion: The GA extract has a potential role in the healing of surgically induced wounds.

Supplementation with açaí (Euterpe Oleracea Martius) for the treatment of chronic tinnitus: effects on perception, anxiety levels and oxidative metabolism biomarkers. / Suplementação com açaí (Euterpe Oleracea Martius) para o tratamento do zumbido crônico: efeitos na percepção, níveis de ansiedade e biomarcadores de metabolismo oxidativo.

PURPOSE: To investigate the effects of antioxidant supplementation with açaí extract on the discomfort with chronic tinnitus and the relationship with the levels of anxiety and oxidative metabolism, not excluding the overlap of diseases. METHODS: Randomized, placebo-controlled clinical trial. 30 individuals participated, with an average of 50.5 years, 14 males and 16 females, with normal hearing thresholds or sensorineural hearing loss up to mild degree, divided into two groups: Placebo Group (without active) and, Açaí Group (100mg of açaí extract). The following procedures were applied before and after three months of treatments: Tinnitus Handicap Inventory (THI), Beck's Anxiety Inventory (BAI) and blood samples for evaluation of oxidative stress biomarkers (Lipid Peroxidation and Protein Carbonylation). RESULTS: There was a reduction in the discomfort of tinnitus for the açaí group verified through THI (p = 0.006). Significant differences were found in the score of common symptoms for anxiety disorders in the placebo group (p = 0.016), however, the same was not observed for oxidative metabolism biomarkers, although there was a decrease in post-treatment values for all groups. CONCLUSION: Oral antioxidant supplementation, with açaí extract, showed favorable effects on tinnitus, reducing discomfort with the symptom, regardless of the underlying etiology, and can be considered a treatment modality. However, the effect of this supplementation on anxiety symptoms and oxidative stress biomarkers needs further investigation.

OBJETIVO: Investigar os efeitos da suplementação antioxidante com extrato de açaí no incômodo com o zumbido crônico e a relação com os níveis de ansiedade e metabolismo oxidativo, não excluindo a sobreposição de enfermidades. MÉTODO: Ensaio clínico, randomizado, controlado por placebo. Participaram 30 indivíduos, com média de 50,5 anos, 14 do sexo masculino e 16 do feminino, com limiares auditivos normais ou perda auditiva sensorioneural até grau leve bilateralmente, divididos em dois grupos: Grupo Placebo (sem ativo) e Grupo Açaí (100mg de extrato de açaí). Aplicaram-se os seguintes procedimentos antes e após três meses dos tratamentos: Tinnitus Handicap Inventory (THI), Inventário de Ansiedade de Beck (BAI) e amostras de sangue para avaliação de biomarcadores de estresse oxidativo (Peroxidação Lipídica e Carbonilação de proteínas). RESULTADOS: Houve redução do incômodo do zumbido para o grupo açaí, verificado por meio do THI (p=0,006). Diferenças significativas foram constatadas na pontuação dos sintomas comuns para os quadros de ansiedade no grupo placebo (p=0,016) porém, o mesmo não foi observado para os biomarcadores de metabolismo oxidativo, apesar de haver uma diminuição dos valores pós-tratamento para os grupos. CONCLUSÃO: A suplementação antioxidante oral, com extrato de açaí, manifestou efeitos favoráveis no zumbido, reduzindo o desconforto com o sintoma, independente da etiologia de base, podendo ser considerada uma modalidade de tratamento. Entretanto, o efeito dessa suplementação nos sintomas de ansiedade e em biomarcadores de estresse oxidativo precisa de maior investigação.

Suplementação com açaí (Euterpe Oleracea Martius) para o tratamento do zumbido crônico: efeitos na percepção, níveis de ansiedade e biomarcadores de metabolismo oxidativo / Supplementation with açaí (Euterpe Oleracea Martius) for the treatment of chronic tinnitus: effects on perception, anxiety levels and oxidative metabolism biomarkers

RESUMO Objetivo Investigar os efeitos da suplementação antioxidante com extrato de açaí no incômodo com o zumbido crônico e a relação com os níveis de ansiedade e metabolismo oxidativo, não excluindo a sobreposição de enfermidades. Método Ensaio clínico, randomizado, controlado por placebo. Participaram 30 indivíduos, com média de 50,5 anos, 14 do sexo masculino e 16 do feminino, com limiares auditivos normais ou perda auditiva sensorioneural até grau leve bilateralmente, divididos em dois grupos: Grupo Placebo (sem ativo) e Grupo Açaí (100mg de extrato de açaí). Aplicaram-se os seguintes procedimentos antes e após três meses dos tratamentos: Tinnitus Handicap Inventory (THI), Inventário de Ansiedade de Beck (BAI) e amostras de sangue para avaliação de biomarcadores de estresse oxidativo (Peroxidação Lipídica e Carbonilação de proteínas). Resultados Houve redução do incômodo do zumbido para o grupo açaí, verificado por meio do THI (p=0,006). Diferenças significativas foram constatadas na pontuação dos sintomas comuns para os quadros de ansiedade no grupo placebo (p=0,016) porém, o mesmo não foi observado para os biomarcadores de metabolismo oxidativo, apesar de haver uma diminuição dos valores pós-tratamento para os grupos. Conclusão A suplementação antioxidante oral, com extrato de açaí, manifestou efeitos favoráveis no zumbido, reduzindo o desconforto com o sintoma, independente da etiologia de base, podendo ser considerada uma modalidade de tratamento. Entretanto, o efeito dessa suplementação nos sintomas de ansiedade e em biomarcadores de estresse oxidativo precisa de maior investigação.

ABSTRACT Purpose To investigate the effects of antioxidant supplementation with açaí extract on the discomfort with chronic tinnitus and the relationship with the levels of anxiety and oxidative metabolism, not excluding the overlap of diseases. Methods Randomized, placebo-controlled clinical trial. 30 individuals participated, with an average of 50.5 years, 14 males and 16 females, with normal hearing thresholds or sensorineural hearing loss up to mild degree, divided into two groups: Placebo Group (without active) and, Açaí Group (100mg of açaí extract). The following procedures were applied before and after three months of treatments: Tinnitus Handicap Inventory (THI), Beck's Anxiety Inventory (BAI) and blood samples for evaluation of oxidative stress biomarkers (Lipid Peroxidation and Protein Carbonylation). Results There was a reduction in the discomfort of tinnitus for the açaí group verified through THI (p = 0.006). Significant differences were found in the score of common symptoms for anxiety disorders in the placebo group (p = 0.016), however, the same was not observed for oxidative metabolism biomarkers, although there was a decrease in post-treatment values for all groups. Conclusion Oral antioxidant supplementation, with açaí extract, showed favorable effects on tinnitus, reducing discomfort with the symptom, regardless of the underlying etiology, and can be considered a treatment modality. However, the effect of this supplementation on anxiety symptoms and oxidative stress biomarkers needs further investigation.

Açaí (Euterpe oleracea Mart.) reduces the inflammatory response triggered in vitro by the antipsychotic drug olanzapine in RAW 264.7 macrophage cells.

BACKGROUND: Açaí (Euterpe oleracea Mart), a Brazilian fruit, is considered a "superfruit" due its energetic properties and bioactive compounds. The açai's anti-inflammatory effects could attenuate the undesirable metabolic and pro-inflammatory side effects triggered by some antipsychotic drugs, such as Olanzapine (OLZ). It is possible to infer that açai supplement could potentially minimize the adverse effects of OLZ. Aim. This study tested the potential in vitro effects of açai hydroalcoholic extract on the inflammatory activation of the RAW 264.7 macrophage line triggered by OLZ antipsychotic drugs. METHODS: An in vitro protocol was performed using commercial RAW 264.7 macrophages, cultured under sterile conditions at 37°C with 5% CO2 saturation. Initially, a pharmacological curve was defined to determine the concentration of Olanzapine to be used. After this, the cells were supplemented with different concentrations of hydroalcoholic extract of açaí, which had been previously chemically characterized. After 24 and 72 hours of treatment, oxidative and inflammatory tests were performed. Therefore, the aim of this study was to verify whether the hydroalcoholic extract of açaí can modulate the oxy-inflammatory response of olanzapine in vitro. RESULTS: From a preliminary analysis, the açai extract at 5 mg/mL presented higher activity against inflammation triggered by OLZ (0.03 µg/mL). At this concentration, açai was able to reduce several oxidative and inflammatory markers triggered by OLZ (0.03 µg/mL) exposure, such as nitric oxide (NO), reactive oxygen species (ROS), and pro-inflammatory cytokine levels (IL-1b, IL-6, TNF-a, IFN-g) caused by OLZ (0.03 µg/mL). Moreover, açaí reverted the levels of anti-inflammatory cytokine IL-10 that had been dropped by OLZ exposure to their pre-exposure treatments. CONCLUSIONS: The results suggest that açai extract could be useful in attenuating the peripheral inflammatory states triggered by OLZ. Additional pre-clinical and clinical investigations could be useful in testing therapeutic açai extract supplements.

Safety indicators of a novel multi supplement based on guarana, selenium, and L-carnitine: Evidence from human and red earthworm immune cells.

Neurodegenerative diseases are associated with chronic inflammatory states. There is evidence to support the design of novel supplements based on guarana (G) (Paullinia cupana), selenium (S), and L-carnitine (C), the use of which, potentially attenuates neuro oxi-inflammatory conditions. Therefore, this study analyzed the cytotoxic and redox effects of GSC on human leucocytes, the inflammatory activation of microglia BV-2 cells, and effect on mortality, oxidative metabolism, and the immune modulation of red earthworms (Eisenia fetida). The GSC concentrations tested in cell culture were in the range of 0.04-2.1 mg/mL. All the GSC-supplemented samples tested, reverted H2O2 oxidation in DNA molecules, suggesting its genoprotective potential. GSC did not induce mortality in leucocyte cultures. On the contrary, a reduction in the levels of oxidation of lipids, proteins, and cell apoptosis was observed, via downregulation of caspase 3 and 8 genes. GSC showed a dual effect on microglia, decreasing the cellular proliferation at lower concentrations (<0.24 mg/mL) and increasing the cellular proliferation mainly at concentrations > 1.0 mg/mL. GSC did not have a toxic effect on red earthworms, but induced an increase in amoebocyte cells and in brown body formation, indicating immune response activation. The results suggest that GSC could be safe for human consumption.

Avocado oil (Persea americana) protects SH-SY5Y cells against cytotoxicity triggered by cortisol by the modulation of BDNF, oxidative stress, and apoptosis molecules.

Chronic psycho-environmental stress can induce neurological dysfunction due to an increase in cortisol levels. It is possible that some food supplements could attenuate its negative impact, such as avocado oil (AO), which is rich in fatty acids with beneficial effects on the brain. This hypothesis was tested by an in vitro model using undifferentiated neuroblastoma cells (SH-SY5Y) exposed to hydrocortisone (HC), an active cortisol molecule with and without AO-supplementation. Cortisol can induce oxidative stress, apoptosis events, and a lowering effect on brain-derived neurotrophic factor (BDNF), a neurogenic molecule. As AO protective effects on HC-exposed cells could involve these routes, some markers of these routes were compared among neuroblastoma cultures. In the first assay, the range concentrations of HC exposure that trigger cell mortality and range AO-concentrations that could revert the HC effect. AO at all concentrations tested (2-30 µg/ml) did not present a cytotoxic effect on SH-SY5Y cells, whereas HC at 0.3-10 ng/ml had a dose-dependent cytotoxic effect on these cells. From these results, HC at 10 ng/ml and AO at 5 µg/ml were chosen for mechanistic analysis. AO was able to decrease the oxidative molecules; however, both AO- and HC-induced differential and varied gene expression modulation of these enzymes. AO partially reverted the protein and gene expression of apoptotic markers that were higher in HC-exposed cells. AO also increases the BDNF levels, which are lower HC-exposed cultures. The results indicate that AO could be a beneficial supplement in situations where cortisol levels are elevated, including chronic psycho-environmental stress. PRACTICAL APPLICATIONS: Psychological chronic stress that induces high cortisol exposure has been linked to premature aging and decreased healthy life expectancy. Neurobiological models involving cortisol have suggested a neurotoxic effect of this molecule, increasing the risk of psychiatric and other CNTDs. This effect can have a high impact mainly in infants and elderly people. In child abuse situations, chronic cortisol exposure could induce extensive apoptosis events, causing impairment in synaptogenesis. In both age groups, chronic cortisol exposure increased the risk of psychiatric conditions, especially anxiety and major depression. However, it is possible that the negative effects associated with chronic cortisol exposure could be attenuated by some food supplements. This is the case for molecules acquired through diet, such as polyunsaturated fatty acids (PUFAs), including omega-3. As inadequate omega-3 levels in the brain can increase the risk factor for neuropsychiatric disorders, it is possible to infer that some from food supplements, such as avocado oil, could attenuate the neurotoxic effects of chronic cortisol exposure. This hypothesis was tested using an exploratory in vitro protocol, and the results suggested that avocado oil could be used as a cytoprotective food supplement by decreasing the oxidative stress and apoptotic events induced by cortisol.

Superoxide-anion triggers impairments of immune efficiency and stress response behaviors of Eisenia fetida earthworms.

Superoxide-hydrogen peroxide (S-HP), triggered by Val16Ala-SOD2 human polymorphism, may influence the risk of depression. Therefore, it is plausible that higher basal S-anion levels and chronic inflammatory states associated with the VV-SOD2 genotype can negatively modulate the stress response associated with resilience in various species, from primitive species to humans. To test this hypothesis, Eisenia fetida earthworms were exposed for 24 h to 30 nM rotenone, which causes mitochondrial dysfunction by generating high S-anion levels (known as the "VV-like phenotype"), and 10 µM porphyrin, a SOD2-like compound, which generates elevated HP levels (known as the "AA-like phenotype"). The results suggested that both S-anion and HP acted as signaling molecules, differentially altering the immune function and acute hydric stressful response. Although the AA-like phenotype improved the immune and stress response efficiencies, the VV-like phenotype showed a downregulated expression of the toll-like receptor (EaTLR, JX898685) and antimicrobial peptide (AMP) (AF060552) genes, which triggered the impairment of encapsulation and earthworms extracellular trap (EET) processes used by earthworms to trap and destroy microorganisms. When exposed to adverse environments and dangerous hydric stress, VV-like earthworms exhibited an impulsive behavior and failed to quickly identify and migrate to a protected environment, unlike control earthworms and AA-like earthworms. All results corroborated that the S-anion imbalance could concomitantly induce alterations in immune function and stress behavior related to earthworm survival. From a human perspective, this information may corroborate the potential specific role of superoxide anion in the modulation of the stress response, resilience, and risk of depression.

Molecular markers associated with the outcome of tamoxifen treatment in estrogen receptor-positive breast cancer patients: scoping review and in silico analysis.

Tamoxifen (TMX) is used as adjuvant therapy for estrogen receptor-positive (ER+) breast cancer cases due to its affinity and inhibitory effects. However, about 30% of cases show drug resistance, resulting in recurrence and metastasis, the leading causes of death. A literature review can help to elucidate the main cellular processes involved in TMX resistance. A scoping review was performed to find clinical studies investigating the association of expression of molecular markers profiles with long-term outcomes in ER+ patients treated with TMX. In silico analysis was performed to assess the interrelationship among the selected markers, evaluating the joint involvement with the biological processes. Forty-five studies were selected according to the inclusion and exclusion criteria. After clustering and gene ontology analysis, 23 molecular markers were significantly associated, forming three clusters of strong correlation with cell cycle regulation, signal transduction of proliferative stimuli, and hormone response involved in morphogenesis and differentiation of mammary gland. Also, it was found that overexpression of markers in selected clusters is a significant indicator of poor overall survival. The proposed review offered a better understanding of independent data from the literature, revealing an integrative network of markers involved in cellular processes that could modulate the response of TMX. Analysis of these mechanisms and their molecular components could improve the effectiveness of TMX.

Unmetabolized quetiapine exerts an in vitro effect on innate immune cells by modulating inflammatory response and neutrophil extracellular trap formation.

Quetiapine is an antipsychotic drug that is used to treat psychiatric and neurological disorders. Despite its efficiency and low-toxicity, quetiapine administration has been associated with undesirable side effects such as the development of low-grade inflammatory disorders and neutropenia states. As the liver rapidly metabolizes quetiapine to metabolites, the non-metabolized part of this molecule might play a role in immune alterations. In an in vitro study, this hypothesis was tested by exposing activated and inactivated RAW-264.7 macrophages and human neutrophils to unmetabolized quetiapine (u-QUE). Based on our findings, u-QUE was not cytotoxic to these cells. u-QUE differentially modulates macrophages according to their activation states. In inactivated macrophages, u-QUE induced a proinflammatory state as observed by an increase in cellular proliferation; increased levels of oxidative molecules (nitric oxide and superoxide), protein levels, and gene overexpression of proinflammatory cytokines (IL-1ß, IL-6, and TNF-α); and decreased levels of IL-10, an anti-inflammatory cytokine. Conversely, on phytohemagglutinin (PHA)-activated macrophages, u-QUE exerted an anti-inflammatory effect. u-QUE induced neutrophil extracellular trap (NET) formation and increased the sensitivity of the neutrophils previously activated by exposure to dead yeast cells for NET formation. These results confirm the effect of quetiapine on macrophage and neutrophil function, which may be associated with the side effects of this psychopharmaceutical agent.

In Vitro Biological Properties of Solanum sessiliflorum (Dunal), an Amazonian Fruit.

Solanum sessiliflorum is an Amazonian fruit (cubiu) that has been domesticated since pre-Colombian era. It is also used in folk medicine to treat some clinical conditions. This investigation chemically characterized and analyzed the in vitro antioxidant and antitumoral effect of a cubiu pulp/seed hydroalcoholic extract. Cubiu extract was chemically characterized by high-performance liquid chromatography with diode array detector (HPLC-DAD), its antioxidant capacity measured by 2.2-diphenyl-1-picrylhydrazyl (DPPH) assay, and the following complementary in vitro protocols were performed: (1) cytoprotective effect of cubiu on human peripheral blood mononuclear cells (PBMCs) exposed to H2O2, a genotoxic and procarcinogen molecule; (2) effect of cubiu on low density lipoproteins oxidation; and (3) cytotoxic and antiproliferative effect on breast (MCF-7) and colorectal (HT-29) cancer cell lines. Biochemical and flow cytometry analyses were conducted in these protocols. Cubiu extract presented high concentrations of caffeic and gallic acids, beta-carotene, catechin, quercetin, and rutin, and its antioxidant capacity was confirmed. Cubiu attenuated H2O2 cytotoxicity on PBMCs, presented lowering effect on LDL oxidation, and induced mortality and proliferative inhibition of colorectal cancer cells. In cancer cells, cubiu extract at 10 µg/mL showed similar effects to 5-fluorouracil chemo drug reducing its viability and frequency of S-phase, indicating that cells are undergoing mitosis. In summary, despite the limitations of in vitro protocols, our results suggest that cubiu has several biological properties that affect human health.

Superoxide imbalance triggered by Val16Ala-SOD2 polymorphism increases the risk of depression and self-reported psychological stress in free-living elderly people.

BACKGROUND: Oxidative stress and chronic inflammatory states triggered by a single-nucleotide polymorphism (SNP) in superoxide dismutase manganese-dependent gene (Val16Ala-SOD2) have been associated with the risk of developing several chronic, nontransmissible diseases. However, it is still not clear whether the VV-SOD2 genotype that causes higher basal superoxide anion levels has any impact on the risk for depression and self-reported psychological stress in elderly people. METHODS: In the present study, we tested this hypothesis using a case-control study where depression was detected using the Geriatric Depression Scale-15 (GDS-15). A total of 612 Brazilian free-living elderly subjects with a mean age of 67.1 ± 7.1 years old (number of controls, C = 497, and depressive individuals, D = 115) were included in this study. All participants had similar social, health, and lifestyle variables, with the exception of polypharmacy (≥5 medicines daily intake), which was higher in the D group, compared to C subjects. RESULTS: Our results showed that the VV-SOD2 genotype significantly increased the risk for depression and psychological stress in the elderly subjects, independently of sex/gender, age, and other prior diseases and health indicators (depression risk = 1.842, 1.109-3.061 95% CI, p = .018). VV-subjects also had a higher daily intake of antidepressants, anxiolytics, and anti-inflammatory drugs than A-allele subjects. CONCLUSION: Our findings support the hypothesis that genetically induced oxidative superoxide-hydrogen peroxide imbalance may be involved in an increased risk for developing depression and psychological stress in free-living elderly people without other chronic nontransmissible diseases.