Brazilian Journal of Medical and Biological Research最新文献

Cervical cancer remains a leading cause of cancer-related mortality among women worldwide, despite treatment advances. The most common form is squamous cell cervical carcinoma, primarily associated with human papillomavirus (HPV) type 16. Chrysin (5,7-dihydroxyflavone) is a natural flavonoid with promising anticancer properties both in vitro and in vivo. The aim of this study was to evaluate the antiproliferative, anti-migratory, and anti-invasive effects of chrysin on the SiHa human cervical cancer cell line (HPV-16-positive) using a 3D cell culture model with spheroids. Cell viability was assessed using the resazurin assay, while cytostatic effects were monitored by measuring spheroid size through imaging. Migration was evaluated with the spheroid migration assay. The expression of matrix metalloproteinase (MMP)-2, MMP-9, and vascular endothelial growth factor (VEGF) was quantified by immunoenzymatic assays. Chrysin treatment exhibited concentration-dependent cytotoxic and cytostatic effects, reducing cell proliferation and decreasing SiHa spheroid size. Additionally, chrysin inhibited cell migration and invasion, potentially reducing metastatic potential, primarily by decreasing the production of MMP-2 and VEGF. These findings suggest that chrysin has therapeutic potential for squamous cell cervical carcinoma and warrants further in vivo preclinical studies.

This study aimed to evaluate the effects of the ketamine-xylazine (KX) anesthetic mixture on autonomic and cardiovascular functions in normotensive rats (Wistar) and spontaneously hypertensive rats (SHR), using both spectral and symbolic analyses. Male Wistar (n=22) and SHR (n=28) rats were intramuscularly anesthetized with KX, and their femoral artery and vein were cannulated for pulsatile arterial pressure recording and drug administration. Autonomic function was assessed 24 and 48 h post-surgery through spectral and symbolic analyses of heart rate (HR) and systolic arterial pressure (SAP) variability. KX anesthesia significantly decreased mean arterial pressure (MAP) 24 h post-surgery in both Wistar and SHR rats. Spectral analysis revealed increased sympathetic modulation in the vascular bed of SHR 48 h post-surgery. In Wistar rats, there was a significant reduction in parasympathetic modulation at 48 h, as indicated by root mean square of successive RR interval differences (RMSSD) and high frequency (HF) (nu) indices. Symbolic analysis, however, detected no significant changes in autonomic modulation. These data are consistent with the notion that KX anesthesia significantly impacts autonomic and cardiovascular functions, with differential effects observed between Wistar and SHR rats. Spectral analysis proved more effective than symbolic analysis in detecting these changes. These findings highlight the need for careful consideration of anesthetic effects in experimental research and suggest that optimizing anesthetic protocols could improve clinical outcomes by minimizing adverse autonomic impact.

Serum biomarkers are crucial for identifying complications of obesity. This study evaluated serum levels of leptin, vascular endothelial growth factor (VEGF), myeloperoxidase (MPO), C-reactive protein (CRP), oxidized low-density lipoprotein (OXLDL), low-density lipoprotein (LDL), and other biochemical parameters in a rat model of high-fat diet (HFD)-induced obesity to investigate potential relationships between these biomarkers and microvascular function. Rats in the HFD group were fed a high-fat diet for 23 weeks, whereas control rats received a standard diet. Microvascular function was assessed using the post-occlusive reactive hyperemia (PORH) test; PORH responses were measured in the right forelimbs using laser Doppler flowmetry. Serum samples were then collected to measure the aforementioned biomarkers. Results showed decreased PORH responses in the HFD group, indicating impaired microvascular function. Serum levels of leptin, MPO, CRP, LDL, and OXLDL were significantly higher in the HFD group. Strong correlations were observed between microvascular dysfunction and LDL, OXLDL, MPO, and CRP. No significant changes were found in VEGF or HDL levels. These findings suggest that increased LDL oxidation to OXLDL in obesity contributes to vascular impairment, likely due to increased oxidative stress and inflammation mediated by elevated MPO and CRP. Further research focusing on the roles of LDL, OXLDL, MPO, and CRP may provide deeper insights into the mechanisms underlying microvascular dysfunction in obesity.

This systematic review investigates the effects of the ayahuasca beverage (Aya) in various animal models. Using the PRISMA protocol and adhering to the Cochrane Handbook for Systematic Reviews, a comprehensive selection of 2,359 documents was identified from the Web of Science, Medline, and Scopus databases between 2012 and 2022. Following the inclusion and exclusion criteria, 14 articles were included in the final analysis. The analysis revealed a diversity in the selection of animal models that included different developmental stages and various forms of Aya intoxication, including acute and chronic doses, and varying concentrations of the active principles. The studies revealed that Aya causes significant alterations in the motor and cognitive behavior of animals, especially associated with the serotonergic system, which seems to contribute to the negative symptoms also observed in schizophrenia and depression. Despite the evidence found, this review highlights the scarcity of more robust pre-clinical studies with methodological standardization to make more conclusive comparisons, especially given the need to identify potential toxic and neurochemical effects of Aya on organisms for a safer assessment of its therapeutic use.

The aim of this study was to evaluate the dynamic variations in the quantitative parameters of diffusion-weighted imaging (DWI) at different b-value combinations in a prostate cancer (PCa) mouse model for noninvasive monitoring of histopathological changes. Twenty-five male C57BL/6J mice were randomly allocated into a control group (n=5) or an experimental group (n=20). The experimental groups were used to establish the PCa model. On days 9, 12, 15, and 18 post-modeling, 5 mice were randomly selected for MRI, including T1WI, T2WI, T2WI SPIR, and DWI. The b-values were set at 0, 500, 1000, 1500, and 2000 s/mm2. Apparent diffusion coefficient (ADC) and exponential apparent diffusion coefficient (EADC) values from different b-value combinations were measured. Post-MRI, tumors were excised for histopathological analysis. DWI quantitative parameters, tumor nuclear fraction, and Ki-67 area fraction were compared on different days, along with correlation analysis. ADC values gradually decreased as tumor progressed, whereas EADC values gradually increased. Tumor nuclear fraction increased over time. Ki-67 increased first and then decreased. Tumor nuclear fraction was negatively correlated with the ADC value and positively correlated with the EADC value. The Ki-67 was positively correlated with the ADC value and negatively correlated with the EADC value. ADC values at b=1000, 1500 s/mm2 and the EADC values at b=0, 500 s/mm2 demonstrated the strongest correlations with the tumor nuclear fraction; the ADC and EADC values at b=500, 1000 s/mm2 were more strongly correlated with Ki-67, being potential noninvasive imaging biomarkers for monitoring changes in tumor histopathology.

Obesity is an independent risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD). Non-pharmacological strategies, such as strength training (ST), have been investigated for their effectiveness in attenuating MASLD. This study evaluated the effects of ST on hepatic fat accumulation in an experimental model of obesity. Thirty-day-old male Wistar rats (∼150 g) were assigned to either a standard diet (SD) or a high-fat diet (HFD). The experimental protocol lasted 26 weeks and was divided into two phases: 1) obesity induction and maintenance (16 weeks) and 2) ST intervention (10 weeks). After the 16th week, HFD-fed rats were further divided into sedentary obese (Ob) and obese trained (ObST) groups. The ST protocol consisted of 4-5 vertical ladder climbs with 60-s intervals, three times per week, using 50-100% of maximal load. Body weight (BW), fat pads, total body fat (BF), adiposity index (AI), and muscle strength were assessed, as were glycemic, lipid, inflammatory, and histological parameters. ST reduced BW, epididymal and visceral fat depots, triglycerides, total cholesterol, glucose, leptin, and tumor necrosis factor (TNF)-α levels while improving insulin resistance. In conclusion, ST significantly attenuated hepatic steatosis in obesity, promoting metabolic and anti-inflammatory benefits. These findings suggest that ST may be an effective therapeutic strategy for MASLD, and further studies are needed to elucidate its molecular mechanisms and clinical applications.

It is unclear who benefits the most from atherosclerotic cardiovascular disease (ASCVD) screening imaging. This study aimed to identify features associated with positive coronary artery calcium scores (CACS) in individuals with diabetes using machine learning (ML) techniques. ELSA-Brasil is a cohort study with 15,105 participants aged 35 to 74 years in six Brazilian cities. We analyzed 25 sociodemographic, medical history, symptom-related, and laboratory variables from 585 participants from the São Paulo investigation center with CACS data and no overt cardiovascular disease at baseline. We used six ML algorithms to build models to identify individuals with positive CACS. Feature importance was determined by SHapley Additive exPlanations (SHAP) values. The best performer ML algorithm was the XGBoost Classifier (accuracy: 94.8%). Age (SHAP: 0.220), systolic blood pressure (SHAP: 0.102), and body mass index (SHAP: 0.075) were the most important variables to identify ASCVD in individuals with diabetes in XGBoost models. Considering all ML models in our analysis, age, systolic blood pressure, and sex were frequently influential variables. We obtained high accuracy with our best model, using information generally present in current clinical practice. ML models may help clinicians select patients with characteristics most probably associated with a positive CAC. Age, systolic blood pressure, body mass index, and sex may be useful markers to identify those at higher risk for subclinical ASCVD.

Keratinocyte hyperproliferation and excessive inflammatory responses are associated with psoriasis pathogenesis. Trifolirhizin has anti-inflammatory and anti-proliferation effects. The purpose of the study was to investigate the role of trifolirhizin in psoriasis-like skin lesions and its molecular mechanism. Imiquimod-induced psoriasis-like mouse models were treated with trifolirhizin. Skin lesions and inflammatory factors were assessed. In vitro, human HaCaT keratinocytes were stimulated by a mixture of interleukin (IL)-1α, IL-17, IL-22, tumor necrosis factor (TNF)-α, and oncostatin M (M5) to establish a psoriatic keratinocyte model. Cell viability and cycle were assessed via CCK-8 assay and flow cytometry. Inflammatory factors, autophagy levels, and AMPK-mTOR pathway activation were detected by western blot. Trifolirhizin dose-dependently inhibited epidermal layer erythema, scaling, and thickening and reduced epidermal thickness and IL-12 level in an imiquimod-induced psoriasis-like mouse model. Trifolirhizin also inhibited cell viability, PCNA expression, and excessive synthesis and secretion of IL-8 and IL-12 in HaCaT keratinocytes induced by M5. Furthermore, the inhibition of autophagy and AMPK-mTOR pathway could be reversed by trifolirhizin in M5-induced HaCaT keratinocytes and skin lesions from imiquimod-mediated psoriasis-like mouse model. The improvement effects of trifolirhizin could be inhibited by the autophagy inhibitor chloroquine. Trifolirhizin up-regulated autophagy through the AMPK-mTOR pathway, improved the hyperproliferation and excessive inflammatory responses of keratinocytes, thus alleviating psoriatic skin lesions. Trifolirhizin may have therapeutic potential in improving the progression of psoriasis.

Statins have been shown to have antifibrotic effects on various tissues and organs, but their ability to improve chronic colitis-associated intestinal fibrosis and their mechanisms of action remain unclear. The objective of this study was to investigate the role of pitavastatin in chronic colitis-associated intestinal fibrosis and its possible mechanisms. We established a mouse model of chronic colitis-associated intestinal fibrosis through repeated administration of dextran sodium sulfate (DSS) and treated the mice with pitavastatin. The severity of intestinal fibrosis, serum inflammatory factor levels, and expression levels of intestinal fibrosis-related genes in mice were assessed using pathological histological staining, immunohistochemical staining, reverse-transcription PCR, RNA sequencing, and enzyme-linked immunosorbent assay. In vitro, we treated a human colon fibroblast cell line (CCD-18Co) with or without transforming growth factor-β1 stimulation using pitavastatin. Western blot, Cell Counting Kit-8 assay, and Transwell assay were used to analyze the activation of colonic fibroblasts, protein expression levels of genes related to intestinal fibrosis, and cell proliferation and migration abilities. Pitavastatin significantly attenuated DSS-induced chronic colitis and intestinal fibrosis. In vitro, pitavastatin concentration-dependently inhibited the activation of CCD-18Co cells, significantly reduced the expression levels of the intestinal fibrosis-related proteins Col1A1, IGF-1, IGF-1R, MMP-3, and TIMP-1, and significantly inhibited cell proliferation and migration while markedly increasing MMP-9 protein expression. Additionally, after silencing the IGF-1 and IGF-1R genes in CCD-18Co cells, the promotion of MMP-9 expression by pitavastatin was significantly inhibited. These findings suggest that pitavastatin may be a promising antifibrotic drug for future treatment of intestinal fibrosis.

This study aimed to systematically evaluate the risk of drug-induced pulmonary edema (DIPE) using the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database. This retrospective pharmacovigilance study utilized FAERS data from the first quarter of 2004 to the second quarter of 2024. We identified drugs with at least 10 reported DIPE cases as primary suspects (PS). The DIPE signals were assessed using four methods: Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Empirical Bayes Geometric Mean (EBGM). Multivariate logistic regression was employed to control for confounding factors, and the timing of DIPE onset was statistically analyzed. Out of 173 target drugs, 37 were identified with DIPE risk. The top five drugs were naloxone, dasatinib, nifedipine, anti-thymocyte globulin, and pioglitazone. Multivariate logistic regression indicated that all except pioglitazone were independent risk factors for DIPE. The onset time of DIPE varied by age and gender for some drugs. This study is the first to identify the DIPE risk systematically associated with multiple drugs. It highlights the need for clinicians and pharmacists to be aware of these high-risk drugs and to monitor high-risk populations closely to ensure medication safety.