👤 Sérgio Leite

The effects of different exercise intensities on cognitive outcomes and brain-derived neurotrophic factor (BDNF) concentrations in adolescents with overweight/obesity are not yet fully elucidated. This study aimed: (a) to compare the prevalence of responders to cognitive function and BDNF concentration in adolescents with overweight/obesity participating in a 12-week intervention with high-intensity interval training (HIIT) or moderate-intensity continuous training (MICT), and (b) to analyze whether cardiorespiratory fitness (CRF) can explain differences in inter-individual variability between responders and non-responders. Adolescents with overweight/obesity were assigned to HIIT (n = 15), MICT (n = 14), or CG (n = 24). Anthropometrics, body composition, CRF, basal BDNF, and cognitive performance (Trial Making Test (TMT) and Stroop Test (ST)) were evaluated pre- and post-intervention. Training was performed on stationary bikes (3×/week for 12 weeks). The prevalence of responders in ST and TMT was higher in the HIIT group than in CG (93-62%, p = 0.029; 67-33%, p = 0.043), with no differences in MICT. No group differences were found for BDNF responders (HIIT:73%-MICT:71%-CG:46%, p = 0.263). ST and TMT responders had greater CRF improvements than non-responders. HIIT elicited a higher prevalence of cognitive responders than CG. CRF improvements may partially explain individual variability in responsiveness to cognitive outcomes. This is the first study to examine and compare inter-individual variability in cognitive function and BDNF levels following MICT and HIIT interventions in adolescents with overweight/obesity; Exercise intensity and improvements in cardiorespiratory fitness are key factors for optimizing the cognitive effects of interventions in youth with overweight; Twelve weeks of supervised HIIT and MICT training led to increased rates of cognitive responders among adolescents with overweight/obesity. Show less

Sex and racial or ancestral disparities in Alzheimer disease remain incompletely understood; autopsy studies that examine amyloid, tau, and genetic factors are scarce. To test whether neuritic plaque burden and cognitive outcomes differ by sex and whether sex modifies the effects of apolipoprotein E ε4 (APOEε4), informant-reported race, and African ancestry. This was a cross-sectional study using postmortem neuropathological data from the Biobank for Aging Studies, University of São Paulo, São Paulo, Brazil. A total of 2268 autopsies from a population-based, diverse clinicopathological sample were collected between April 2004 and March 2025. Sex, informant-reported race (Black, White), African ancestry proportion, and APOEε4 carrier status. Neuritic plaque burden (Consortium to Establish a Registry for Alzheimer's Disease [CERAD] score), and cognitive function (Clinical Dementia Rating-Sum of Boxes [CDR-SB]). Ordinal logistic regression examined association of sex with CERAD scores and 2- and 3-way interactions among sex, race, ancestry, and APOEε4; adjusting for age, education, vascular factors, and Braak stages. Linear models related pathology to CDR-SB, adding copathologies. The analysis included 2268 autopsies (median [IQR] age, 74.8 [63.8-83.3] years; 1152 [51% male] and 1116 [49%] female; 802 [35%] Black and 1466 [65%] White; other race groups not included owing to small numbers); female individuals were older than male individuals and more likely to exhibit cognitive impairment (CDR global score ≥0.5). Female individuals had higher plaque burden than male individuals (unadjusted odds ratio [OR], 1.97; 95% CI, 1.67-2.29; P < .001), and this association remained significant in adjusted models for sociodemographic and vascular factors and APOEε4 status (adjusted OR, 1.65; 95% CI, 1.33-2.20; P < .001). APOEε4 carriers of both sexes had an approximately 4-fold greater odds of plaques. Significant 2-way interactions were found between sex, APOEε4 status, race, and ancestry on CERAD scores. Black noncarriers (OR, 0.47; 95% CI, 0.34-0.67) and noncarriers of African ancestry (OR, 0.57; 95% CI, 0.43-0.76) were least likely to have high plaque burden, whereas this protection was weakened in ε4 carriers. No significant 3-way interaction was detected. Among individuals with a CERAD score of 2 or higher, female individuals were more likely than male individuals to reach Braak stage V-VI than male individuals (probability ratio, 1.25; 95% CI, 1.13-1.38; P = .002). Adding Braak stage to multivariable models attenuated the female-male difference in plaques and interaction of sex and plaque on CDR-SB was no longer significant. The findings indicate that female sex, APOEε4, and both race and African ancestry were jointly associated with amyloid in this study population. Excess amyloid among women may partly explain their greater tau burden and steeper cognitive decline. These findings highlight the importance of incorporating sex, race, and ancestry into biomarker thresholds, risk stratification, and the design of preventive or disease-modifying trials for Alzheimer disease. Show less

Dihydromyricetin (DMY) presents itself as a promising therapeutic candidate due to its inhibitory effects on various receptor tyrosine kinases, prompting an investigation of its structural characteristics, molecular interactions, and biological activity across the FGFR, HER, PDGFR, and VEGFR families. Protein sequences and structures for FGFR1/2, HER2/3, PDGFRA/B, and VEGFR1/2 were retrieved from UniProt/PDB. DMY and reference inhibitors were docked to each kinase using AutoDock Vina. Anti-angiogenic activity was measured by HET-CAM assay with vessel metrics quantified via IKOSA CAM. MTT determined cytotoxicity (IC₅₀) and tumor-selectivity index in 4T1 and L929 cells; data (mean ± SEM) were analyzed by one-way ANOVA with Tukey's test (p < 0.005). DMY exhibited docking scores comparable to established inhibitors, achieved over 45 % inhibition of neovascularization in the HET-CAM assay at nanomolar concentrations, displayed a tumor-selectivity index of less than one in 4T1 versus L929 cells (mirroring many clinical chemotherapeutics), and, notably, coadministration with doxorubicin reduced in vitro cardiotoxicity markers. The high-affinity, multi-kinase binding profile and significant anti-angiogenic efficacy underscore DMY's multifunctional potential, while its tumor-selectivity index aligns with accepted therapeutic risk-benefit balances and its cardioprotective effect suggests a way to mitigate anthracycline toxicity. These findings indicate that DMY is a multifunctional agent exhibiting both antiangiogenic and cytotoxic properties, warranting further preclinical and clinical investigation. Show less

Lipoprotein(a) [Lp(a)] is recognized as an independent risk factor for coronary disease owing to its atherogenic, proinflammatory, and prothrombotic properties. Current guidelines recommend a single measurement in adults to refine cardiovascular (CV) risk assessment. We aimed to characterize Lp(a) levels in patients with acute coronary syndrome (ACS) and explore associations with sex, age, comorbidities, and traditional cardiovascular risk factors. We conducted a cross-sectional study of patients with ACS admitted to our center between January 2022 and December 2023, with Lp(a) measured at admission. Patients were stratified into two groups: Lp(a) >100 nmol/L and ≤100 nmol/L. Demographic and clinical data, including traditional cardiovascular risk factors (dyslipidemia, diabetes mellitus, arterial hypertension, smoking, and obesity), were collected from hospital records. Chi-square and independent t or Mann-Whitney U tests were used to compare categorical and quantitative variables; linear regression analysis assessed associations between continuous Lp(a) values and independent variables. Among 903 patients admitted with ACS during the study period, Lp(a) was measured in 388 (42%). Median Lp(a) level was 62.0 [18.4, 153.8] nmol/L. Of these, 38.7% had Lp(a) >100 nmol/L. Women had higher Lp(a) than men (p-trend=0.014). Lp(a) levels were similar across traditional cardiovascular risk factors categories. Among patients without traditional cardiovascular risk factors, women also had higher Lp(a) than men (p=0.003). Elevated Lp(a) was associated with history of coronary artery disease (p-trend=0.003) and with treatment with high-intensity statins alone (p-trend=0.032) or in combination with ezetimibe (p-trend=0.014). Lp(a) levels showed a heterogeneous distribution and was not associated with traditional cardiovascular risk factors or other lipid parameters. This reinforces Lp(a) as an independent risk factor, supporting active screening in patients with ACS, particularly in women not affected by traditional cardiovascular risk factors. Show less

Alzheimer's Disease (AD) is a progressive neurodegenerative disorder and the leading cause of cognitive decline in older adults. Several biomarkers of AD have been identified, but its pathogenesis has not yet been completely elucidated. One of the most relevant hypotheses proposed to explain the cognitive impairment caused by this disease is the cholinergic hypothesis, which postulates that loss of cholinergic neurons is one of its causes and that the subsequent reduction of acetylcholine levels in the synaptic cleft can be compensated through the inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Another well-known hypothesis is the amyloid-beta hypothesis, which explains the disease as being caused by the formation and accumulation of amyloid plaques in a cascade of enzymatic events starting with the cleavage of an amyloid precursor protein (APP) by beta-secretase 1 (BACE-1). Previous studies have shown that silodosin has the structural requirements for the inhibition of those three enzymes (AChE, BuChE, and BACE-1), which suggests that it can be useful as a multitarget candidate to treat Alzheimer patients. This study aims to assess the effect of silodosin on cellular viability, measure the inhibitory activity against AChE, BuChE, and BACE-1, and evaluate the molecular behavior of all three inhibitor-enzyme systems by molecular dynamics (MD) simulations. Cell viability assays through the MTT method showed that silodosin concentrations of less than 10 μM are safe to be used. Enzymatic assays revealed AChE inhibitory activity at high micromolar levels (IC50 >500.0 μM) but inhibited BuChE at low micromolar levels (IC50 = 3.02 ± 0.05 μM). BACE-1 inhibition assays have shown significant reduction at three micromolar. MD simulations demonstrated that silodosin promotes late stabilization of the AChE complex, but the simulations involving BuChE and BACE-1 revealed that the compound promotes system stabilization at early stages and has the structural requirements to inhibition. Show less

The present study aimed to compare photobiomodulation (PBMT) and the use of a non-steroidal anti-inflammatory drug (NSAID), after surgical removal of lower lip lesions with a high-power diode laser. This was a series of 13 cases, in which all subjects were treated with high-power diode laser (808 nm) in continuous mode, with a power between 2.0 and 2.5 W. In the experimental group (G1) (n = 7), the subjects underwent PBMT using a low-power laser (LPL) (660 nm, 1 J, 40 mW, spot area of ​​0.04 cm², punctual), on the first, third and seventh post-surgery day. In the control group (G2) (n = 6), a NSAID (nimesulide 100 mg, every 12 h, for five days) was prescribed, and the LPL device was positioned, without being activated, to mimic the PBMT. The visual analogue scale (VAS) was applied to assess postoperative pain. The size of the surgical wound was measured immediately after surgery, as well as after two, seven, 15 and 30 days. For statistical analysis, the significance level was set at p < 0.05. Most subjects were male (53.8%) with a mean age of 44.7 years. Subjects in G1 reported less pain during follow-ups than those in G2, but with no significant differences between groups in all experimental times (p > 0.05). In the analysis, after seven days, the G1 presented a smaller surgical wound (p = 0.017). PBMT can be an alternative in relation to the use of nimesulide, allowing for less painful symptoms and optimization of the healing process. Show less

Alzheimer's disease causes chronic neurodegeneration and is the leading cause of dementia in the world. The causes of this disease are not fully understood but seem to involve two essential cerebral pathways: cholinergic and amyloid. The simultaneous inhibition of AChE, BuChE, and BACE-1, essential enzymes involved in those pathways, is a promising therapeutic approach to treat the symptoms and, hopefully, also halt the disease progression. This study sought to identify triple enzymatic inhibitors based on stereo-electronic requirements deduced from molecular modeling of AChE, BuChE, and BACE-1 active sites. A pharmacophore model was built, displaying four hydrophobic centers, three hydrogen bond acceptors, and one positively charged nitrogen, and used to prioritize molecules found in virtual libraries. Compounds showing adequate overlapping rates with the pharmacophore were subjected to molecular docking against the three enzymes and those with an adequate docking score ( Show less

Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive loss of cognitive functions, and it is the most prevalent type of dementia worldwide, accounting for 60 to 70% of cases. The pathogenesis of AD seems to involve three main factors: deficiency in cholinergic transmission, formation of extracellular deposits of β-amyloid peptide, and accumulation of deposits of a phosphorylated form of the TAU protein. The currently available drugs are prescribed for symptomatic treatment and present adverse effects such as hepatotoxicity, hypertension, and weight loss. There is urgency in finding new drugs capable of preventing the progress of the disease, controlling the symptoms, and increasing the survival of patients with AD. This study aims to present new multipurpose compounds capable of simultaneously inhibiting acetylcholinesterase (AChE), butyrylcholinesterase (BChE)-responsible for recycling acetylcholine in the synaptic cleft-and beta-secretase 1 (BACE-1)-responsible for the generation of amyloid-β plaques. AChE, BChE, and BACE-1 are currently considered the best targets for the treatment of patients with AD. Virtual hierarchical screening based on a pharmacophoric model for BACE-1 inhibitors and a dual pharmacophoric model for AChE and BChE inhibitors were used to filter 214,446 molecules by QFIT Show less

Alzheimer's Disease (AD) is a neurodegenerative condition characterized by progressive memory loss and other affected cognitive functions. Pharmacological therapy of AD relies on inhibitors of the enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), offering only a palliative effect and being incapable of stopping or reversing the neurodegenerative process. However, recent studies have shown that inhibiting the enzyme β-secretase 1 (BACE-1) may be able to stop neurodegeneration, making it a promising target. Considering these three enzymatic targets, it becomes feasible to apply computational techniques to guide the identification and planning of molecules capable of binding to all of them. After virtually screening 2119 molecules from a library, 13 hybrids were built and further screened by triple pharmacophoric model, molecular docking, and molecular dynamics (t = 200 ns). The selected hybrid G meets all stereo-electronic requirements to bind to AChE, BChE, and BACE-1 and offers a promising structure for future synthesis, enzymatic testing, and validation. Show less

Cardiovascular diseases (CVD) are major causes of mortality worldwide, leading to premature deaths, loss of quality of life, and extensive socioeconomic impacts. Alterations in normal plasma lipid concentrations comprise important risk factors associated with CVD due to mechanisms involved in the pathophysiology of atherosclerosis. Genetic markers such as single nucleotide polymorphisms (SNPs) are known to be associated with lipid metabolism, including variants in the cholesteryl ester transfer protein (CETP) gene. Thus, the study's objective was to assess the relationship among lipid profile, socioeconomic and demographic characteristics, health status, inflammatory biomarkers, and CETP genetic variants in individuals living in a highly admixed population. The study comprises an analysis of observational cross-sectional data representative at the population level from a highly admixed population, encompassing 901 individuals from three age groups (adolescents, adults, and older adults). Socioeconomic, demographic, health, and lifestyle characteristics were collected using semi-structured questionnaires. In addition, biochemical markers and lipid profiles were obtained from individuals' blood samples. After DNA extraction, genotyping, and quality control according to Affymetrix's guidelines, information on 15 SNPs in the CETP gene was available for 707 individuals. Lipid profile and CVD risk factors were evaluated by principal component analysis (PCA), and associations between lipid traits and those factors were assessed through multiple linear regression and logistic regression. There were low linear correlations between lipid profile and other individuals' characteristics. Two principal components were responsible for 80.8 % of the total variance, and there were minor differences in lipid profiles among individuals in different age groups. Non-HDL-c, total cholesterol, and LDL-c had the highest loadings in the first PC, and triacylglycerols, VLDL-c and HDL-c were responsible for a major part of the loading in the second PC;, whilst HDL-c and LDL-c/HDL-c ratio were significant in the third PC. In addition, there were minor differences between groups of individuals with or without dyslipidemia regarding inflammatory biomarkers (IL-1β, IL- 6, IL-10, TNF-α, CRP, and MCP-1). Being overweight, insulin resistance, and lifestyle characteristics (calories from solid fat, added sugar, alcohol and sodium, leisure physical activity, and smoking) were strong predictors of lipid traits, especially HDL-c and dyslipidemia (p < 0.05). The CETP SNPs rs7499892 and rs12691052, rs291044, and rs80180245 were significantly associated with HDL-c (p < 0.05), and their inclusion in the multiple linear regression model increased its accuracy (adjusted R This study identified correlations between lipid traits and other CVD risk factors. In addition, similar lipid and inflammatory profiles across age groups in the population suggested that adolescents might already present a significant risk for developing cardiovascular diseases in the population. The risk can be primarily attributed to decreased HDL-c concentrations, which appear to be influenced by genetic factors, as evidenced by associations between SNPs in the CETP gene and HDL-c concentrations, as well as potential gene-diet interactions. Our findings underscore the significant impact of genetic and lifestyle factors on lipid profile within admixed populations in developing countries. Show less

Amyloidosis is a group of disorders characterised by the accumulation of extracellular deposits of insoluble protein aggregates. Clinical management depends on the accurate identification of the amyloid precursor and underlying cause. We describe a rare case of apolipoprotein A-IV cardiac amyloidosis, the diagnosis of which required mass spectrometry-based proteomic analysis. To be able to perform the differential diagnosis of cardiac amyloidosis subtypes using imaging methods, analytical results and tissue analysis.To recognise the added value of mass spectrometry (MS)-based proteomic analysis. Show less

The histology-based Gleason score (GS) of prostate cancer (PCa) tissue biopsy is the most accurate predictor of disease aggressiveness and an important measure to guide treatment strategies and patient management. The variability associated with PCa tumor sampling and the subjective determination of the GS are challenges that limit accurate diagnostication and prognostication. Thus, novel molecular signatures are needed to distinguish between indolent and aggressive forms of PCa for better patient management and outcomes. Herein, label-free LC-MS/MS proteomics is used to profile the proteome of 50 PCa tissues spanning five grade groups (n = 10 per group) relative to tissues from individuals with benign prostatic hyperplasia (BPH). Over 2000 proteins are identified albeit at different levels between and within the patient groups, revealing biological processes associated with specific grades. A panel of 11 prostate-derived proteins including IGKV3D-20, RNASET2, TACC2, ANXA7, LMOD1, PRCP, GYG1, NDUFV1, H1FX, APOBEC3C, and CTSZ display the potential to stratify patients from low and high PCa grade groups. Parallel reaction monitoring of the same sample cohort validate the differential expression of LMOD1, GYG1, IGKV3D-20, and RNASET2. The four proteins associated with low and high PCa grades reported here warrant further exploration as candidate biomarkers for PCa aggressiveness. Show less

Sudden cardiac death (SCD) risk stratification in dilated cardiomyopathy (DCM) has been based on left ventricular ejection fraction (LVEF), even though SCD may occur with LVEF > 35%. Family history of unexplained SCD, especially in the young, raises concern about potential inheritable risk factors. It remains largely unknown how genetic tests can be integrated into clinical practice, particularly in the selection of implantable cardioverter defibrillator (ICD) candidates. We aimed to assess the diagnostic yield of genetic testing in DCM patients with a class I recommendation for ICD implantation, based on current guidelines. We included ambulatory stable adult patients with idiopathic or familial DCM with previously implanted ICD. Molecular analysis included 15 genes ( We evaluated 21 patients, 12 (57%) males and 9 (43%) with familial DCM, including 3 (14%) with a family history of premature unexplained SCD. Mean age at DCM diagnosis was 40 ± 2 years, and mean age at ICD implantation was 50 ± 12 years. LVEF was 27 ± 9%, and LV end-diastolic diameter was 65 ± 7 mm. Genetic variants were found in six (29%) patients, occurring in 5 genes: In patients with DCM and ICD, genetic variants could be identified in a significant proportion of patients in several genes, highlighting the potential role of genetics in DCM SCD risk stratification. Show less

Anaplastic thyroid carcinomas (ATCs) are among the most lethal malignancies, for which there is no effective treatment. In the present study, we aimed to elucidate the molecular alterations contributing to ATC development and to identify novel therapeutic targets. We profiled the global gene expression of five ATCs and validated differentially expressed genes by quantitative RT-PCR in an independent set of tumors. In a series of 26 ATCs, we searched for pathogenic alterations in genes involved in the most deregulated cellular processes, including the hot spot regions of RAS, BRAF, TP53, CTNNB1 (β-catenin), and PIK3CA genes, and, for the first time, a comprehensive analysis of components involved in the cell cycle [cyclin-dependent kinase (CDK) inhibitors (CDKI): CDKN1A (p21(CIP1)); CDKN1B (p27(KIP1)); CDKN2A (p14(ARF), p16(INK4A)); CDKN2B (p15(INK4B)); CDKN2C (p18(INK4C))], cell adhesion (AXIN1), and proliferation (PTEN). Mutational analysis was also performed in 22 poorly differentiated thyroid carcinomas (PDTCs). Expression profiling revealed that ATCs were characterized by the underexpression of epithelial components and the up regulation of mesenchymal markers and genes from TGF-β pathway, as well as, the overexpression of cell cycle-related genes. In accordance, the up regulation of the SNAI2 gene, a TGF-β-responsive mesenchymal factor, was validated. CDKN3, which prevents the G1/S transition, was significantly up regulated in ATCs and PDTCs and aberrantly spliced in ATCs. Mutational analysis showed that most mutations were present in TP53 (42% of ATCs; 27% of PDTCs) or RAS (31% of ATCs; 18% of PDTCs). TP53 and RAS alterations showed evidence of mutual exclusivity (P = .0354). PIK3CA, PTEN, and CDKI mutations were present in 14%-20% of PDTCs, and in 10%-14% of ATCs. BRAF, CTNNB1, and AXIN1 mutations were rarely detected. Overall, this study identified crucial roles for TP53, RAS, CDKI, and TGF-β pathway, which may represent feasible therapeutic targets for ATC and PDTC treatment. Show less

Thyroid nodules are a common clinical problem, and fine-needle aspiration biopsy (FNAB) is widely used for its evaluation. Only 5% are malignant, being papillary carcinoma (PC) the most frequent neoplasia. Approximately 20% are classified as indeterminate or suspicious for malignancy. Gene-expression pattern may be useful for diagnosing PC in difficult or ambiguous cases. In our prior study, we were able to apply RT-PCR method in a series of routinely performed FNAB of thyroid nodules using individual, residual samples. In this study, a total of 70 thyroid samples were evaluated for the expression of MPPED2, H/HBA2, MET, FN1, GALE, and QPCT genes, including 24 cases of frozen thyroid tissue, 12 nodular hyperplasia and 12 PC, and the 46 consecutive thyroid FNAB samples, previously analyzed (3 positive, 10 indeterminate and 32 negative for malignancy, and 1 insufficient). FN1, GALE, MET, and QPCT mRNA expression were significantly different in benign and malignant samples, with similar pattern of overexpression in aspirates compared to frozen tissue. H/HBA2 and MPPED2 expression varied. Histological correlation was possible in five indeterminate cases, revealing one PC and four benign lesions. In conclusion, FN1, GALE, MET, and QPCT were significantly overexpressed in thyroid PC. RT-PCR method could be applied to routine FNAB, showing a similar pattern of overexpression. Despite the small number of cases evaluated, our results suggest that molecular analysis may be of assistance in patients with indeterminate/suspicious cytology, adding elements for preoperative diagnosis and better management of these patients. Show less