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Triclosan (TCS) is a lipophilic antimicrobial agent present in commercial and healthcare products. Despite its beneficial properties, TCS disrupts thyroid hormone homeostasis and may be linked to metabolic disorders, cardiotoxicity, and increased cancer risk. Evidence on prenatal TCS exposure and adverse neurobehavioral outcomes is limited. This systematic review aimed to verify whether prenatal exposure to TCS is associated with neurobehavioral impairments. Observational studies with pregnant women exposed to TCS during pregnancy were included. The MEDLINE, EMBASE, Scopus, Web of Science, and LILACS databases were searched for studies up to February 27, 2024. Titles and abstracts were first screened, followed by full-text readings by two independent reviewers. Data extraction was performed independently, with conflicts resolved by consensus with a third reviewer. The included studies were assessed using an adapted Downs and Black tool and qualitatively synthesized. Certainty of evidence was assessed by GRADE. The study protocol was registered with PROSPERO (CRD42024526426). Among 17 studies, 14 cohort studies met the inclusion criteria. The sample size ranged from 193 to 794 pairs of pregnant women and children. Exposure to TCS throughout pregnancy resulted in median concentrations from 0.40 ng/mL to 28.2 ng/mL. Four studies suggested a potential association between prenatal TCS exposure and neurodevelopmental deficits, such as externalizing problems, attention issues, hyperactivity, somatization, emotional symptoms, social awareness, and communication; in contrast, eight studies found no significant effect. The studies had low certainty of evidence. Considering the heterogeneity and confounding factors, further investigation is required to confirm that prenatal TCS exposure leads to neurobehavioral disorders.

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The case involves a 61-year-old female patient with a history of systemic lupus erythematosus, who sought urgent medical attention due to abdominal pain and an abdominal tomography consistent with colonic obstruction. Exploratory laparotomy followed by transverse colectomy was performed. The pathological examination of the specimen revealed a colonic diaphragmatic ring secondary to chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs). This condition primarily affects elderly women exposed to chronic NSAID therapy. It results from mucosal ulceration followed by submucosal inflammation and fibrosis. Management involves, in addition to discontinuation of the medication, surgical resection in acute cases, or diagnostic-therapeutic endoscopy in uncomplicated cases.

Se presenta el caso de una paciente de 61 años con antecedente de lupus eritematoso sistémico, quien acudióal sistema médico de urgencias por dolor abdominal y una tomografía de abdomen compatible con oclusión colónica. Se realizólaparotomía exploradora seguida de colectomía transversa. La anatomía de la pieza arrojócomo resultado un anillo diafragmático colónico secundario al consumo crónico de antiinflamatorios no esteroideos. Esta afección se presenta principalmente en mujeres de edad avanzada expuestas a dicha medicación de forma crónica. La misma es secundaria a ulceración de la mucosa, seguida de inflamación y fibrosis de la submucosa. El abordaje implica, además de la supresión de la medicación, una resección quirúrgica en los casos agudos, o una endoscopía diagnóstico-terapéutica en aquellos casos no complicados.

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Phlegmonous gastritis in an uncommon bacterial infection of the gastric wall, predominantly affects immunocompromised patients, with high mortality rates despite appropriate treatment. Various risk factors compromising gastric mucosal integrity have been described. Symptoms are typically nonspecific and may manifest as acute abdomen, therefore, imaging studies gain special value. Proper treatment requires appropriate antibiotic therapy and surgical intervention may be considered in some cases. Available literature on patients with oncohematological diseases or undergoing chemotherapy who develop phlegmonous gastritis, is limited. We present the case of a female patient with relapsed acute lymphoblastic leukemia who developed phlegmonous gastritis during the neutropenic period following chemotherapy.

La gastritis flemonosa es una infección bacteriana de la pared gástrica poco frecuente, que afecta a pacientes inmunocomprometidos con una alta mortalidad a pesar del tratamiento adecuado. Se han descrito diferentes factores de riesgo que comprometen la integridad de la mucosa gástrica. Los síntomas son generalmente inespecíficos, y puede presentarse como un abdomen agudo, por lo que los estudios por imágenes cobran especial importancia. El tratamiento requiere de una terapia antibiótica adecuada y, en ocasiones, de intervención quirúrgica. La bibliografía disponible sobre pacientes con enfermedades oncohematológicas o bajo tratamiento quimioterápico que desarrollan gastritis flemonosa, es limitada. Presentamos el caso de una paciente con leucemia linfoblástica aguda con recaída que desarrollóuna gastritis flemonosa durante el período de neutropenia posterior a la quimioterapia.

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Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of midbrain dopaminergic neurons, leading to motor symptoms such as tremors, rigidity, and bradykinesia. Non-motor symptoms, including depression, hyposmia, and sleep disturbances, often emerge in the early stages of PD, but their mechanisms remain poorly understood. The 6-hydroxydopamine (6-OHDA) rodent model is a well-established tool for preclinical research, replicating key motor and non-motor symptoms of PD. In this review, we systematically analyzed 135 studies that used 6-OHDA rodent models of PD to investigate non-motor symptoms. The review process adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Our analysis highlights the growing use of 6-OHDA PD models for experimental research of non-motor symptoms. It also reveals significant variability in methodologies, including choices of brain target, toxin dosage, lesion verification strategies, and behavioral assessment reporting. Factors that hinder reproducibility and comparability of findings across studies. We highlight the need for standardization in 6-OHDA-based models with particular emphasis on consistent evaluation of lesion extent and reporting of the co-occurrence of non-motor symptoms. By fostering methodological coherence, this framework aims to enhance the reproducibility, reliability, and translational value of 6-OHDA models in PD non-motor symptom research.

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The prevalence of Parkinson's disease (PD) requires better characterized animal models, in particular of the PD prodrome. Since pesticide are well-established triggers of Parkinsonism, we now undertook a detailed characterization of the time-dependent onset of behavioural and neurochemical alterations after the repeated daily intraperitoneal administration to adult male rats of a low dose of rotenone (2.75 mg/kg) during weekdays for 21 days. The onset of motor (bradykinesia in the open field test) and coordination deficits (balance in the rotarod and rearing in the open field) occurred after 14 days of exposure to rotenone, linked to a nigrostriatal dopaminergic degeneration and increased accumulation of α-synuclein, which are key features of PD. Moreover, we identified several modifications pre-dating the onset of PD-like motor symptoms, encompassing gastrointestinal alterations and a modified whole-body composition together with olfactory dysfunction and memory and emotional impairments, which were typified by: i) a delayed gastric emptying of liquids (13CO2 analysis), which was evident from the third day of rotenone administration and was aggravated over subsequent days; ii) a loss of total, visceral and subcutaneous body fat and dehydration (bioimpedance spectroscopy); iii) olfactory dysfunction (discrimination test and food buried test). The characterization of this prodrome period in this robust model of PD offers a new window of opportunity to investigate the pathophysiological mechanisms of PD onset and to devise and test novel neuroprotective strategies.

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BACKGROUND: Vitamin K antagonists (VKA) represent an important therapeutic strategy offered by the Brazilian Unified Public Health System to patients with atrial fibrillation (AF). However, predictors of relevant clinical outcomes are understudied in the real world. OBJECTIVE: To determine the incidence and independent predictors of clinical outcomes in patients with valvular and nonvalvular AF treated with VKA. METHODS: This prospective cohort included patients with valvular and nonvalvular AF receiving VKA for ≥ 1 year. The primary outcomes were cardiovascular death, thromboembolic events, and major and clinically relevant non-major bleeding, separately and as a composite outcome. The outcomes were independently adjudicated. P values < 0.05 were considered statistically significant. RESULTS: The study included 1,350 patients, with a mean age of 69.2 (± 11.8) years, 53.6% female, followed up for 17 (15 - 19) months. The annual incidence of thromboembolic events and cardiovascular death was 4.4%, and predictors were prior thromboembolism (hazard ratio [HR] 2.12; 95% confidence interval [CI] 1.22 - 3.67), time in therapeutic range (TTR) < 50% (HR 1.98; 95% CI 1.16 - 3.37), and glomerular filtration rate (GFR) < 45 mL/min/1.73 m2 (HR 2.76; 95% CI 4.82 - 1.58). The rate of major and clinically relevant non-major bleeding was 3.24% per year (95% CI 2.47 - 4.14), and predictors were prior bleeding (HR 2.60; 95% CI 1.47 - 4.61) and mechanical prosthesis (HR 1.91; 95% CI 1.15 - 3.15). The composite outcome was 8.7% per year, and predictors were prior bleeding (HR 1.70; 95% CI 1.07 - 2.70), TTR < 41% (HR 1.79; 95% CI 1.11 - 2.86), and left atrial diameter > 44 mm (HR 1.97; 95% CI 3.26 - 1.19). CONCLUSIONS: Prior thromboembolism or bleeding, reduced GFR and TTR levels, and enlarged left atrium were predictors of clinical outcomes in patients with AF treated with VKA.

FUNDAMENTO: Antagonistas da vitamina K (AVK) representam uma importante estratégia terapêutica oferecida pelo Sistema Único de Saúde no Brasil aos pacientes com fibrilação atrial (FA). Entretanto, os preditores de desfechos clínicos relevantes são pouco estudados no mundo real. OBJETIVO: Determinar a incidência e os preditores independentes de desfechos clínicos em pacientes com FA valvar e não valvar tratados com AVK. MÉTODOS: Coorte prospectivo de pacientes com FA valvar e não valvar em uso ≥ 1 ano de AVK. Desfechos primários foram morte cardiovascular, eventos tromboembólicos, sangramento maior e não maior clinicamente relevante, separadamente e como desfecho composto, e adjudicados de modo independente. Valores de p < 0,05 foram considerados estatisticamente significantes. RESULTADOS: Incluídos 1.350 pacientes, idade média de 69,2 (± 11.8) anos e 53,6% do sexo feminino, seguidos por 17 (15 - 19) meses. Incidência anual de eventos tromboembólicos e morte cardiovascular foi 4,4% e preditores foram tromboembolismo prévio (hazard ratio [HR] 2,12; intervalo de confiança [IC] de 95% 1,22 - 3,67), tempo na faixa terapêutica (TFT) < 50% (HR 1,98; IC95% 1,16 - 3,37), e taxa de filtração glomerular (TFG) < 45 mL/min/1.73 m2 (HR 2,76; IC95% 4,82 - 1,58). Taxa de sangramento maior e não maior clinicamente relevante foram 3,24% por ano (IC95% 2,47 - 4,14) e preditores foram sangramento prévio (HR 2,60; IC95% 1,47 - 4,61) e prótese mecânica (HR 1,91; IC95% 1,15 - 3,15). O desfecho composto foi 8,7% por ano e preditores foram sangramento prévio (HR 1,70; IC95% 1,07 - 2,70), TFT < 41% (HR 1,79; IC95% 1,11 - 2,86) e diâmetro do átrio esquerdo > 44 mm (HR 1,97; IC95% 3,26 - 1,19). CONCLUSÕES: Tromboembolismo ou sangramento prévios, TFG e TFT reduzidos e átrio esquerdo aumentado foram preditores de desfechos clínicos em pacientes com FA tratados com AVK.

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The highly lipophilic nature and low aqueous solubility of cannabidiol (CBD) limit its oral bioavailability, resulting in poor intestinal absorption. To overcome these limitations, we proposed the production of a nanoemulsion with CBD to be included in the therapeutic treatment of autism spectrum disorder. The current study aimed to evaluate the effect of CBD-rich corn oil nanoemulsion treatment in male rats born to females exposed to valproic acid (VPA) during pregnancy on autistic-like behaviors and hippocampal histology. Offspring rats were treated orally twice daily with CBD nanoemulsions at different doses (1 and 2 mg/animal). The endpoints evaluated were anxiety, grooming time, exploratory activity, sociability, the social preference index, and hippocampal and cerebral cortex histology. All formulations were characterized as nanoemulsions and showed a reduced vesicle size (107.6 - 72.6 nm), low PDI (0.290-0.432), negative zeta potential (-40.6 mv), and good stability. Prenatal exposure to VPA increased anxiety and grooming time, and reduced exploratory activity, sociability, and the social preference index in the animals. Furthermore, VPA-exposed animals exhibited elevated neuronal death and a reduction in viable cells in the hippocampus. In conclusion, CBD nanoemulsion treatment reversed autistic-like behaviors, potentially by protecting against hippocampal neuronal death. The highly lipophilic nature and low aqueous solubility of cannabidiol (CBD) limit its oral bioavailability, resulting in poor intestinal absorption. To overcome these limitations, we proposed the production of a nanoemulsion with CBD to be included in the therapeutic treatment of autism spectrum disorder. The current study aimed to evaluate the effect of CBD-rich corn oil nanoemulsion treatment in male rats born to females exposed to valproic acid (VPA) during pregnancy on autistic-like behaviors and hippocampal histology. Offspring rats were treated orally twice daily with CBD nanoemulsions at different doses (1 and 2 mg/animal). The endpoints evaluated were anxiety, grooming time, exploratory activity, sociability, the social preference index, and hippocampal and cerebral cortex histology. All formulations were characterized as nanoemulsions and showed a reduced vesicle size (107.6 - 72.6 nm), low PDI (0.290-0.432), negative zeta potential (-40.6 mv), and good stability. Prenatal exposure to VPA increased anxiety and grooming time, and reduced exploratory activity, sociability, and the social preference index in the animals. Furthermore, VPA-exposed animals exhibited elevated neuronal death and a reduction in viable cells in the hippocampus. In conclusion, CBD nanoemulsion treatment reversed autistic-like behaviors, potentially by protecting against hippocampal neuronal death.

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Immune checkpoint inhibitors (ICIs) are drugs that are being increasingly used in the field of oncology; due to their mechanism of action, they can present immune-related adverse effects (IRAEs), with various clinical manifestations, one of which is delirium. We present the case of a patient diagnosed with pleural mesothelioma that started combined palliative immunotherapy two months before admission. She was hospitalized for delirium with psychotic symptoms and a comprehensive neurological and etiological examination for this pathology was performed, revealing undetectable TSH levels, indicating the etiology of the condition as thyrotoxicosis in the context of autoimmune thyroiditis, secondary to treatment with ICIs. Symptomatic treatment with beta-blockers was initiated, leading to progressive improvement. This case brings awareness of impaired consciousness and neuropsychiatric symptoms as manifestation of IRAEs and the difficulty of their diagnosis: there may also be several other causes of impaired consciousness, so the characterization of delirium requires a multifaceted approach to determine the underlying cause, taking into account direct cancer-related complications and those stemming from the treatments received by this group of patients. Endocrinological immune-related adverse events (IRAEs), such as thyroid IRAEs, generally have a low lethality rate, do not necessarily require discontinuation of therapy, and are linked to a more favorable oncological prognosis. Conversely, neurological IRAEs, though rare, constitute a contraindication for further use of ICIs. This clinical case emphasizes the importance of the systematic study of consciousness impairment in cancer patients, and of considering multiple IRAEs that could lead to changes in oncological therapy when establishing possible etiologies.

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Methylmercury (MeHg) is the most harmful organic form of mercury to organisms, especially in the aquatic environment. Therefore, it is crucial to assess the effects of exposure to this contaminant on aquatic biota using multiple biomarkers. In this context, we aimed to analyze the morphophysiological and behavioral effects of sub-lethal exposure to MeHg in tadpoles of Physalaemus ephippifer. To achieve this, larvae of the model species were subjected to a toxicological assay, conducted across five treatments (control; 0.0004 µg/ml; 0.0007 µg/ml; 0.004 µg/ml; and 0.007 µg/ml of MeHg). Following exposure, the tadpoles were subjected to three behavioral assays: escape response, chemical perception, and visual perception. Subsequently, we performed electrocardiographic analysis, cardiac histology, and teratogenic analysis. In the chemical and visual perception assays, tadpoles exposed to MeHg exhibited anti-predator behavior even in the absence of predatory stimuli. Electrocardiographic analyses revealed cardiac hyperexcitability with an increase in heart rate, including tachycardia at the highest concentration, and histological analysis showed physiological cardiac hypertrophy. For teratogenic alterations, sub-lethal concentrations caused an increase in the occurrence of teratogenic effects, such as alterations in the oral apparatus, and body and intestinal morphology. Thus, it can be concluded that the combined data indicate that sub-lethal exposure to MeHg could generate behavioral and physiological changes similar to anxiety in P. ephippifer tadpoles. Therefore, such observed effects are capable of increasing the vulnerability of tadpoles exposed to MeHg, acting as one of the mechanisms leading to the population decline of anurans.

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A series of new tetrasubstituted α-aminophosphonate derivatives with a methylphosphoserine fragment were described. These compounds were synthesized by a three-component (3-CR) "Kabachnik-Fields reaction." The novel α-aminophosphonates were screened for in vivo anti-inflammatory activity through topical and oral administration routes. All compounds decreased TPA-induced ear edema in a dose-dependent fashion. In this test, compounds 2, 5, and 7 showed the same efficacy (≈ 90%) and higher potency than indomethacin and decreased the inflammatory marker neutrophil-to-lymphocyte ratio (NLR). Moreover, oral pretreatment and post-treatment with compounds 2-7 reduced CFA-induced paw edema, as did indomethacin or (S)-naproxen. Based on the promising in vivo anti-inflammatory results, we investigated their physicochemical and pharmacokinetics profiles in silico. The analysis also revealed that the novel tetrasubstituted α-aminophosphonates did not break Lipinski's rule of five and had drug-likeness and favorable ADME properties for oral and transdermal administration.

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PURPOSE: This narrative review aims to provide the most updated knowledge regarding the treatment of adverse effects secondary to testosterone replacement therapy (TRT), such as gynecomastia, cardiovascular and hematologic risks, prostate health risk, and liver dysfunction risks. MATERIALS AND METHODS: An extensive literature review was conducted, incorporating guidelines from the American Urological Association and the Endocrine Society. The studies determined common adverse effects and their most common methods of management. RESULTS: TRT improves the quality of life, sexual function, and mood in hypogonadal men. Possible adverse effects associated with TRT include increased estrogen levels and gynecomastia, which are usually managed with aromatase inhibitors and tamoxifen. Cardiovascular risks from TRT include hypertension and erythrocytosis, which mandate periodic hematocrit and blood pressure monitoring; therapeutic phlebotomy is indicated if the hematocrit exceeds 52%. No significant concern regarding prostate cancer has been observed in the closely monitored patient. However, TRT should not be administered to individuals with active evidence of untreated prostate cancer, except under rare circumstances such as active surveillance for very low-risk disease. Older oral forms of TRT can affect liver function; therefore, transdermal, newer oral forms and injectables are generally favored in men with a history of liver disease. CONCLUSIONS: Monitoring and management of adverse effects are critical to maximize benefit and minimize the risks of TRT. Ongoing research will further elucidate the safety of TRT while advancing evidence-based practices in managing its associated adverse effects. Effective patient education and counseling are also essential to improve compliance and treatment outcomes.

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The scope of this study was to assess the ototoxic effects and general health of farmers exposed to pesticides in the Pontal do Paranapanema region, SP, Brazil. Participants of both sexes aged 18-40, 40-60 and >60 years were allocated into two groups: Non-Exposed Group (NEG) and Occupationally Exposed Group (OEG). A questionnaire of exposure and health, meatoscopy, pure tone audiometry, logoaudiometry and immittanciometry were assessed. Cypermethrin, chlorpyrifos and glyphosate were the most reported pesticides. The most frequently reported exposure times were 0-10, 31-40 and 51-60 years. Headaches, visual and spinal disorders were the most common complaints, as well as hypertension and gastric and renal disorders. Only 35% (18-40) and 30% (40-60) of the OEG had good hearing perception. Rotational dizziness, ear infection, tinnitus and otalgia were reported. There was an increase in conventional and high frequency hearing thresholds in EWGs, at almost all frequencies and ages, as well as an alteration in the stapedial reflex. It was concluded that occupational exposure to pesticides has ototoxic potential and can harm general health.

O objetivo do estudo foi avaliar os efeitos ototóxicos e saúde geral de agricultores expostos a agrotóxicos na região do Pontal do Paranapanema-SP. Participantes de ambos os sexos com idade entre 18-40, 40-60 e >60 anos, foram alocados em dois grupos: Grupo Não Exposto (GNE) e Grupo Ocupacionalmente Exposto (GOE). Foram avaliados questionário de exposição e saúde, meatoscopia, audiometria tonal liminar, logoaudiometria e imitanciometria. Cipermetrina, clorpirifós e glifosato foram os agrotóxicos mais notificados. Os tempos de exposição relatados em maior frequência foram 0-10, 31-40 e 51-60 anos. Cefaleia, distúrbios visuais e da coluna vertebral foram as queixas mais detectadas, além de hipertensão e distúrbios gástricos e renais. Apenas 35 (18-40) e 30% (40-60) dos GOE apresentaram boa percepção auditiva. Tontura rotatória, infecção de ouvido, zumbido e otalgia foram relatados. Houve aumento de limiares auditivos na frequência convencional e alta em GOE, em quase todas as frequências e idades, além de alteração do reflexo estapediano. Concluiu-se que a exposição ocupacional a agrotóxicos tem potencial ototóxico e pode prejudicar a saúde geral.

El objetivo del estudio fue evaluar los efectos ototóxicos y la salud general de agricultores expuestos a pesticidas en la región de Pontal do Paranapanema-SP, Brasil. Los participantes de ambos sexos con edades comprendidas entre 18-40, 40-60 y >60 años fueron asignados en dos grupos: grupo no expuesto (GNE) y grupo ocupacionalmente expuesto (GOE). Se evaluaron cuestionarios de exposición y salud, meatoscopia, audiometría de tonos puros, audiometría del habla y análisis de inmitancia. Los pesticidas más reportados fueron cipermetrina, clorpirifos y glifosato. Los tiempos de exposición reportados con mayor frecuencia fueron 0-10, 31-40 y 51-60 años. Los dolores de cabeza, los trastornos visuales y de la columna fueron los síntomas más frecuentes, además de la hipertensión y los trastornos gástricos y renales. Sólo el 35% (18-40) y el 30% (40-60) del GOE tenían buena percepción auditiva. Se han informado mareos rotacionales, infección de oído, tinnitus y otalgia. Hubo un aumento de los umbrales auditivos en frecuencias convencionales y altas en el GOE, en casi todas las frecuencias y edades, además de cambios en el reflejo estapedial. Se concluyó que la exposición ocupacional a plaguicidas tiene potencial ototóxico y puede perjudicar la salud general.

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Increased oxidative stress and apoptosis are key mechanisms of thymic atrophy induced by cyclophosphamide (CYP). Atrophy leads to changes in the thymic microenvironment and disrupts T cell maturation. The hormone melatonin displays antioxidant and antiapoptotic effects. Here, we tested the hypothesis that melatonin would act as a cytoprotective agent against the harmful effects of CYP in the thymus. A single dose of CYP (300 mg/kg; ip) was injected in male C57BL/6 mice pretreated or not with melatonin (10 mg/kg/day, ip) for 4 days. Atrophy, oxidative stress and apoptosis markers, and T cell subpopulations were evaluated in the thymus 24 h after CYP injection. Melatonin partially prevented atrophy and the increase in caspase 3 activity induced by CYP. Augmented lipoperoxidation and generation of NADPH-oxidase derived superoxide (O2 •-), as well as decreased superoxide dismutase (SOD) activity, were detected in the thymus of CYP-injected mice. Pretreatment with melatonin abrogated these responses. CYP reduced the number of double-positive (CD4+CD8+) cells, activated single-positive (CD8+ and CD4+) cells, and regulatory CD4+FoxP3+ (Treg) cells in the thymus. None of these effects were reversed by melatonin. In conclusion, melatonin partially prevented thymic atrophy, possibly by reducing apoptosis and oxidative stress. However, melatonin did not abrogate the immunomodulatory effect of CYP on T cell populations. The lack of effect of melatonin on CYP-induced reduction in Treg cells may be of interest since these cells reduce antitumor immunity.

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Purinergic signaling plays a major role in aging and neurodegenerative diseases, which are associated with memory decline. Blackcurrant (BC), an anthocyanin-rich berry, is renowned for its antioxidant and neuroprotective activities. However, evidence on the effects of BC on purinergic signaling is lacking. This study investigated the effects of BC and its association with Donepezil (DNPZ) on learning and memory, on the modulation of purinergic signaling, pro-inflammatory responses, and oxidative markers in a mouse model of cognitive impairment chronically induced by scopolamine (SCO). Animals were divided into twelve groups and treated with BC (50 or 100 mg/kg), and/or DNPZ (5 mg/kg), and/or SCO (1 mg/kg). Results showed that SCO decreased spatial learning and memory as assessed by the Morris Water Maze test, and treatment with BC and/or DNPZ restored these effects. Furthermore, BC and/or DNPZ treatments also prevented changes in ecto-nucleoside triphosphate diphosphohydrolase (NTPDase) and adenosine deaminase (ADA) activities and restored the increased density of P2X7 and A2A receptors in synaptosomes of the cerebral cortex of SCO-induced mice. Moreover, the increased Nod-like receptor protein 3 (NLRP3) and interleukin-1ß expression, and the oxidative stress markers levels were reduced by BC and/or DNPZ treatments, compared with the SCO group. Overall, BC and/or DNPZ treatments ameliorated SCO-induced cognitive decline, alleviated oxidative stress and pro-inflammatory responses, and improved purinergic signaling. These findings underscore the potential of BC, especially when in combination with DNPZ, as a therapeutic agent for the prevention of memory deficits associated with aging or neurological diseases.

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Chronic kidney disease (CKD) is one of the leading health problems in the world. It is silent in the early stages and gradually progresses, inducing renal physiological and structural alterations. Moreover, CKD is associated with impaired life quality, increased risk for cardiovascular diseases, and reduced life expectancy. Different CKD animal models differ in underlying etiology, time of onset, and associated diseases. The 0.25% adenine diet induces progressive kidney damage, constituting an adequate model mimicking human CKD. Vasopressin (VP) was postulated as a mediator of CKD, mainly acting through its V2 receptors. However, the molecular mechanisms involved in the pathogenesis of this condition and its progression still are not entirely understood. This study aimed to evaluate if AQP2 expression is altered in an adenine-induced model of CKD in rats at early stages of development (two weeks) and to assess a potential beneficial effect of Tolvaptan (a V2 receptor antagonist) treatment. We showed an increased renal medullary AQP2 expression at two weeks of adenine administration. This increase was mainly cytoplasmic, explaining the increased urinary volume of CKD rats and suggesting a possible non-canonical role for AQP2. In addition, Tolvaptan effectively inhibited the V2 receptor in both control and CKD rats, decreasing AQP2 expression and increasing diuresis. Moreover, Tolvaptan slightly reduced BUN and plasma creatinine. On the other hand, the renal alterations induced by adenine in CKD rats were not prevented by Tolvaptan.

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Given ketamine's conflicting impacts on the central nervous system, investigating its effects within an inflammatory context becomes crucial. This study aimed to assess the impact of varying ketamine doses on neurotrophin and inflammatory cytokine levels within the brains of rats submitted to the sepsis model. Wistar rats were submitted to the cecal ligation and puncture (CLP) model of sepsis. Intraperitoneal ketamine injections (5, 15, or 25 mg/kg) or saline were administered daily for seven days, thirty days post-CLP. Rats were euthanized thirty minutes following the last injection for analysis of IL-1ß, IL-6, IL-10, TNF-α, BDNF, NGF, NT-3, and GDNF levels in the frontal cortex, hippocampus, and striatum. CLP-induced elevated IL-1𝛽, IL-6, IL-10, and TNF-α levels in the frontal cortex and hippocampus of rats, with reduced BDNF levels across all structures examined. Furthermore, reduced NGF and GDNF levels were observed solely in the hippocampus. Ketamine at 5 mg/kg normalized CLP-induced alterations and, in Sham animals, increased BDNF and NGF levels in the frontal cortex and/or hippocampus. At 15 mg/kg, ketamine elevated BDNF and NGF levels in Sham animals, while at 25 mg/kg, it exacerbated the inflammatory response initiated by CLP. These findings suggest variable effects of ketamine within a context of systemic inflammation, emphasizing the importance of considering individual inflammatory backgrounds when utilizing ketamine.

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BACKGROUND: Angiotensin II, is critical in regulating the sympathetic and neuroendocrine systems through angiotensin II type 1 receptors (AT1-R). Angiotensin II intracerebral administration increases water and sodium intake, as well as renal sodium excretion. Previously, our group has shown that AT1-R is involved in behavioral and neurochemical sensitization induced by amphetamine. We aimed to assess the physiological output, behavioral, and neurochemical responses to intracerebral angiotensin II administration, via the AT1-R, twenty-one days after amphetamine administration. MATERIAL AND METHODS: Male Wistar rats received daily vehicle or AT1-R antagonist (oral) for 10 days, and amphetamine or saline intraperitoneal (i.p.) from day 6 to 10. On day 25 they were implanted with an intracerebral cannula. On day 32, the animals received intracerebral angiotensin II. First group: the animals were tested in a free choice paradigm for 2% NaCl and water intake, and sacrificed for neuronal activity assessment via c-Fos immunohistochemistry. Second group: urine samples were collected for electrolyte determination. Third group: the animals were tested in the plus maze or the hole board for anxiety and working memory evaluation, respectively, and sacrificed for c-Fos immunohistochemistry. RESULTS: Amphetamine exposure blunted the increase in sodium intake (p = 0.0022), and potentiated the natriuretic (p = 0.0043) and kaliuretic effect (p = 0.0002) induced by angiotensin II. Moreover, amphetamine exposure prevented the expression of the anxiogenic effect (drug effect p < 0.0001) and the memory deficit (p = 0.1314) induced by cerebral angiotensin II administration. Amph decreased c-Fos immunoreactivity in nucleus tractus solitarii (NTS) p = 0.0037; paraventricular nucleus (PVN) p = 0.0047; Central amygdala (CeA) p = 0.0008; Basolateral amygdala (BLA) p = 0.0018; increased in hippocampus region CA1 p = 0.0043; CA3 p = 0.026; and dentate gyrus (DG) p = 0.0057. The blockade of AT1-R prevented these alterations (sodium intake p = 0.0421 natriuresis p = 0.019; kaliuresis p = 0.196; working memory (p < 0.0001); but no the anxiogenic response to angiotensin II (drug effect p < 0.0001); as well as the c-Fos changes (NTS p = 0.0052; PVN p = 0.029; CeA p = 0.0002; BLA p = 0.0021; CA1 p = 0.0026; CA3 p = 0.022; and DG p = 0.0016). CONCLUSION: Most of the long-lasting AT1-R altered responses to brain angiotensin II administration induced by repeated amphetamine exposure could be prevented by AT1-R blockade.

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Mimosa tenuiflora ("jurema-preta") is traditionally used in folk medicine for various diseases. The study investigated the neuropharmacological potential of Mimosa tenuiflora bark fraction (FATEM) in adult zebrafish. This included the acute toxicity (LC50) of FATEM (0.01; 0.05; 0.1; 0.5; 1.0 and 5.0 mg/mL; i.p.) and the effects on behavioral tests, such as open field, light & dark and zebrafish tail immobilization test (ZTI). The anxiolytic response induced by alcohol withdrawal and the seizure induced by pentylenetetrazole were also tested. The possible mechanisms of anxiolytic and antidepressant actions of FATEM were evaluated through the administration of specific antagonists (Flumazenil, Cyproheptadine, Pizotifen or Granisetron). Furthermore, the study investigated the ADME profile and molecular docking simulations of the major FATEM compound, Benzyloxyamine, with GABAergic and serotonergic receptors. FATEM did not present acute toxicity and caused a reduction in locomotor activity (p < 0.0001 vs. Control) similar (p< 0.0001) to Diazepam, indicating a sedative/anxiolytic effect. The anxiolytic activity in the light & dark test was similar to Diazepam (p < 0.0001), prevented by GABA and serotonergic antagonists. FATEM also prevented anxious behaviors induced by alcohol withdrawal and exhibited an antidepressant effect in the ZTI (p < 0.0001 vs. Control) similar (p < 0.0001) to the effect of Fluoxetine, which was reversed by serotonergic antagonists. In silico evaluations indicated favorable pharmacokinetic properties and affinity of FATEM with GABAergic and serotonergic receptors. The study reveals that FATEM has adequate physicochemical characteristics to act on the CNS with specific affinity for GABAA and serotonergic receptors, indicating its potential as a treatment for anxiety and depression.

RESUMO

Epilepsy is a chronic neurological disorder that affects nearly 50 million people worldwide. Experimental evidence suggests that epileptic neurons are linked to the endocannabinoid system and that inhibition of the FAAH enzyme could have neuroprotective effects by increasing the levels of endogenous endocannabinoid anandamide. In this context, the use of macamides as therapeutic agents in neurological diseases has increased in recent years. With a similar structure to anandamide, several theories point to the FAAH-macamide interaction as a possible cause of FAAH enzymatic inhibition. In this work, we used in silico and in vivo techniques to analyze the potential therapeutic effect of three synthetic macamides in the treatment of epilepsy: N-3-methoxybenzyl-oleamide (3-MBO), N-3-methoxybenzyl-linoleamide (3-MBL), and N-3-methoxybenzyl-linolenamide (3-MBN). In the first stage, an in silico analysis was conducted to explore the energetic affinity of these macamides with rFAAH and their potential inhibitory effect. MD simulations, molecular docking, and MM/PBSA calculations were used for these purposes. Based on our results, we selected the two best macamides and performed an in vivo study to analyze their therapeutic effect in male Sprague Dawley rat models. Rats were subjected to an in vivo induction of epileptic status by the intraperitoneal injection of pilocarpine and analyzed according to the Racine scale. In silico results showed an energetic affinity of three macamides and a possible "plugging" effect of the membrane access channel to the active site as a potential cause of FAAH inhibition. On the other hand, the in vivo results showed an anticonvulsant effect of both macamides, with 3-MBL being the most active, resulting in a higher survival probability in the rats. This work represents one of the first studies on the use of macamides for the treatment of epilepsy.

RESUMO

BACKGROUND: Considering that peripheral blood biomarkers are prognostic predictors for several human tumors, this study aimed to comparatively analyze the association of hematological alterations with the incidence of epithelial dysplasia (ED) and oral squamous cell carcinoma (OSCC) in male and female mice treated with 4-nitroquinoline-N-oxide (4NQO) and ethanol (EtOH). METHODS: 120 C57Bl/6J mice (60 males and 60 females) were allocated to four groups (n = 15). They were treated firstly either with 5 mg/mL propylene glycol (PPG) or 100 µg/mL 4NQO in the drinking water for 10 weeks, followed by sterilized water (H2O) or 8% EtOH (v/v) for 15 weeks, as follows: PPG/H2O, PPG/EtOH, 4NQO/H2O, and 4NQO/EtOH (CEUA-UFU, #020/21). After killing, tongues were collected for histopathological analysis of ED and OSCC. Blood samples were processed for complete blood count and calculation of neutrophil-to-lymphocyte ratio (NLR) and systemic immune-inflammation index (SII). RESULTS: The incidence of OSCC in females from the 4NQO/EtOH group (60%) was lower when compared to males (93%). Neutrophils, NLR, and SII increased from control animals (PPG/H2O and PPG/EtOH) to ED and OSCC-bearing male and female mice (4NQO/H2O and 4NQO/EtOH), while lymphocytes decreased. Females from the 4NQO/H2O group with ED also had higher neutrophils, NRL, and SII values than females with normal tongues. CONCLUSION: The low incidence of 4NQO- and ethanol-induced OSCC in females indicates that the sex bias in OSCC may not be associated with extrinsic risk factors alone. Neutrophil and lymphocyte counts, NRL, and SII were significantly altered during multistep carcinogenesis and thus could be explored as biomarkers for ED and OSCC development.