👤 Moysés Fagundes de Araújo Neto

Intrinsic Capacity (IC) is defined as the composite of physical and mental abilities an individual possesses, encompassing five domains: cognition, psychological health, sensory function, vitality, and locomotion. This construct is central to the World Health Organization's framework for assessing functional ability in older adults. Growing evidence highlights the critical role of the musculoskeletal system in maintaining these domains, while conditions such as sarcopenia, osteoporosis, and their coexistence as osteosarcopenia (OS) are increasingly associated with IC decline. This narrative review compiles current evidence on the modulatory role of muscles and bones in IC and the impacts of sarcopenia, osteoporosis, and OS. Most findings suggest that musculoskeletal tissues influence IC not only through biomechanical functions but also as secretory organs, releasing myokines and osteokines with endocrine, paracrine, and autocrine effects. Among the most studied are brain-derived neurotrophic factor, irisin, osteocalcin, and interleukin-6. Dysregulation of these pathways, along with biomechanical dysfunction and systemic inflammation, links sarcopenia, osteoporosis, and OS to IC impairment. Further research is needed to clarify the specific mechanisms involved, particularly in the sensory and vitality domains, to inform targeted interventions that promote healthy aging. Show less

Prior studies indicate sex-specific obesity-frailty interactions, with postmenopausal estrogen decline increasing sarcopenic obesity risk and inflammation in women. This study evaluated circulating cytokines (IL-6, TNF-α), adipokines (adiponectin, resistin), myokines (GDF-15, BDNF, myostatin), health-related biomarkers (IGF-1, IGFBP-3), and physical performance (five-times chair stand, grip strength) in pre-frail and frail older adult women classified as having low appendicular lean mass (LALM), obesity, or obesity plus LALM. In this cross-sectional study, community-dwelling women aged ≥65 years from São Paulo, Brazil were screened (July 2022-September 2023); among 280 eligible, 88 met Fried frailty criteria. Body composition was assessed by DXA and participants were categorized as LALM (<20th percentile of residuals, -1.45), obesity (body mass index, BMI ≥30 kg/m Among 88 frail women (72.7% pre-frail and 27.3% frail), obesity plus LALM showed lower IGFBP-3 and higher GDF-15 vs. LALM (P Among pre-frail and frail older adult women, obesity-with or without low lean mass-was associated with adverse metabolic/inflammatory profiles (higher resistin, GDF-15, insulin; lower IGFBP-3) in full and frail-only analyses, alongside a trend toward slower chair-stand performance. These cross-sectional findings highlight obesity-frailty interactions, warranting prospective validation. Show less

Lipid Nanoparticles (LDE) have been used as a drug delivery vehicle to treat various diseases. LDEs resemble the structure of human low-density lipoprotein (LDL), but lack apoliprotein B (apo-B). The aim of this study was to determine whether changes in the proportion of unesterified cholesterol (UC) or triacylglycerols (TG) affect the physical stability of LDE in aqueous solutions over a six-month observation period, as analysed by Ultra Small-angle X-ray Scattering (USAXS), Dynamic Light Scattering (DLS) and zeta potential measurements. It was shown that variations in UC or TG content in the initial lipid mixture did not alter the size of the resulting LDE nanoparticles, which remained within the 30-35 nm range. This particle size was maintained for up to three months in formulations with varying TG content and up to four months in those with varying UC content. Thereafter, a progressive increase in nanoparticle size was observed, which suggests enhanced aggregate formation and reduced of LDE stability between 3 and 6 months of storage. This loss of stability did not appear to be directly related to changes in UC or TG composition. Notably, USAXS and DLS measurements yielded comparable results, which reinforces the reliability of the data. In addition, the zeta potential remained close to zero for all seven nanoparticle compositions throughout the six months, indicating that all LDE formulations had electrostatic neutral potential and remain so when they progressively aggregate with time. Complementary analyses also showed that LDE particles are, on average, spherical in shape. Overall, these findings provide relevant insights for the rational design of lipid mixtures in the preparation of nanoemulsions for drug delivery applications. Show less

The innate immune response and cytokine milieu in airway mucosa, mediated by bronchial epithelial cells, are critical in determining susceptibility or protection against cryptococcosis. In experimental models, Th2 and Th1 responses are linked to susceptibility and protection, respectively, while the roles of other cytokines remain less understood. To evaluate the in vitro effects of IL-4, IFN-γ, and IL-27 (100ng/mL) on human bronchial epithelial cells (BEAS-2B) infected with a strain of Cryptococcus neoformans sensu stricto (multiplicities of infection [MOI] 1-100). Cells were stimulated with each cytokine, followed by C. neoformans infection (MOI 100). After 24h, supernatants were collected to measure CCL2, IL-6, and IL-8 production. STAT1 and STAT6 activation was analyzed by flow cytometry. Phagocytosis and colony-forming unit assays assessed fungal internalization and growth. Cytokine-stimulated, infected cells displayed reduced IL-6 and/or CCL2 production and decreased STAT6 activation (IL-4) or STAT1 activation (IL-27, IFN-γ) compared with cells stimulated with C. neoformans sensu stricto or cytokines alone. IL-27 reduced fungal internalization, while IL-4 and IFN-γ increased it. All cytokines promoted higher fungal growth. The interaction of bronchial epithelial cells stimulated with IL-4, IFN-γ, or IL-27, with yeasts of C. neoformans induced an anti-inflammatory profile in the cells that impaired STAT activation and favored fungal proliferation. These findings suggest that certain cytokine environments within the airway epithelium may create conditions conducive to C. neoformans persistence, potentially influencing the progression of the infection. Show less

This study aimed to compare the accuracy of IFN-τ stimulated gene abundance (ISGs) in peripheral blood mononuclear cells (PBMCs), CL blood perfusion by Doppler ultrasound (Doppler-US), plasma concentration of P4 on Day 21 and pregnancy-associated glycoproteins (PAGs) test on Day 25 after timed-artificial insemination (TAI) for early pregnancy diagnosis in dairy cows and heifers. Holstein cows (n = 140) and heifers (n = 32) were subjected to a hormonal synchronization protocol and TAI on Day 0. On Day 21 post-TAI, blood samples were collected for PBMC isolation and plasma concentration of P4. The CL blood perfusion was evaluated by Doppler-US. Plasma samples collected on Day 25 were assayed for PAGs. The abundance of ISGs (ISG15 and RSAD2) in PBMCs was determined by RT-qPCR. Pregnancy was confirmed on Days 32 and 60 post-TAI by B-mode ultrasonography. Statistical analyses were performed by ANOVA using the MIXED procedure and GLIMMIX in SAS software. The pregnancy biomarkers were used to categorize the females as having undergone late luteolysis (LL); early embryonic mortality (EEM); late embryonic mortality (LEM); or late pregnancy loss (LPL). The abundance of ISGs, CL blood perfusion by Doppler-US, and concentrations of P4 on Day 21, and PAGs test on Day 25 were significant (P < 0.05) predictors of early pregnancy in dairy cows and heifers. Dairy cows had a greater (P = 0.01) occurrence of LL than heifers, but there was no difference (P > 0.1) for EEM, LEM, and LPL in heifers compared to cows. Cows with postpartum reproductive issues had a greater (P = 0.008) rate of LEM and a lesser (P = 0.01) rate of LPL compared to cows without reproductive issues. In summary, the CL blood perfusion by Doppler-US had the highest accuracy and the least number of false negatives, suggesting it is the best predictor of pregnancy on Day 21 post-TAI. The PAGs test was the most reliable indicator of pregnancy status on Day 25 post-TAI in dairy heifers and cows. The application of machine learning, specifically the MARS algorithm, shows promise in enhancing the accuracy of predicting early pregnancies in cows. Show less

Accurate and fast dose calculation is crucial in modern radiation therapy. Four dose calculation algorithms (AAA, AXB, CCC, and MC) are available in Varian Eclipse and RaySearch Laboratories RayStation Treatment Planning Systems (TPSs). This study aims to evaluate and compare dosimetric accuracy of the four dose calculation algorithms applying to homogeneous and heterogeneous media, VMAT plans (based on AAPM TG-119 test cases), and the surface and buildup regions. The four algorithms are assessed in homogeneous (IAEA-TECDOCE 1540) and heterogeneous (IAEA-TECDOC 1583) media. Dosimetric evaluation accuracy for VMAT plans is then analyzed, along with the evaluation of the accuracy of algorithms applying to the surface and buildup regions. Tests conducted in homogeneous media revealed that all algorithms exhibit dose deviations within 5% for various conditions, with pass rates exceeding 95% based on recommended tolerances. Additionally, the tests conducted in heterogeneous media demonstrate high pass rates for all algorithms, with a 100% pass rate observed for 6 MV and mostly 100% pass rate for 15 MV, except for CCC, which achieves a pass rate of 94%. The results of gamma index pass rate (GIPR) for dose calculation algorithms in IMRT fields show that GIPR (3% /3 mm) for all four algorithms in all evaluated tests based on TG119, are greater than 97%. The results of the algorithm testing for the accuracy of superficial dose reveal variations in dose differences, ranging from -11.9% to 7.03% for 15 MV and -9.5% to 3.3% for 6 MV, respectively. It is noteworthy that the AXB and MC algorithms demonstrate relatively lower discrepancies compared to the other algorithms. This study shows that generally, two dose calculation algorithms (AXB and MC) that calculate dose in medium have better accuracy than other two dose calculation algorithms (CCC and AAA) that calculate dose to water. 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

The melanocortinergic pathway orchestrates the energy homeostasis and impairments in this system often lead to an increase in body weight. Rare variants in the This study included 163 unrelated probands with Body Mass Index (BMI) ≥ 35 kg/m Significant anthropometric differences between the groups were observed. Higher body weight and BMI medians were found in patients with childhood-onset or adolescence/youth-onset when compared to the adulthood-onset obesity group. A total of five mutations were identified, including four missense variants: p.Ser36Thr, p.Val103Ile, p.Ala175Thr, and p.Ile251Leu. Additionally, we observed one synonymous variant (p.Ile198=). The p.Ala175Thr variant was identified in a female case with severe obesity and adulthood-onset. This variant was previously described as a partial loss-of-function mutation, in which the minor allele poses dominant-negative effect, probably resulting in reduced cAMP activity. This study showed a prevalence of common and rare variants in a cohort of Brazilian adults with severe obesity and candidates to bariatric surgery. We have identified a rare potentially pathogenic Show less

We have examined the role of a novel targeted cytokine, interleukin-27 (IL-27), modified at the C terminus with a dual targeting and therapeutic heptapeptide, in treating prostate cancer. IL-27 has shown promise in halting tumor growth and mediating tumor regression in several cancer models, including prostate cancer. We describe our findings on the effects of targeted IL-27 gene delivery on prostate cancer cells Show less

Interleukin-27 (IL-27) has shown promise in halting tumor growth and mediating tumor regression in several models, including prostate cancer. We describe our findings on the effects of IL-27 on the gene expression changes of TC2R prostate adenocarcinoma cells. We utilized RNAseq to assess profile differences between empty vector control, vector delivering IL-27 modified at its C-terminus with a non-specific peptide, and IL-27 modified at the C-terminus with a peptide targeting the IL-6-Rα. The targeted IL-27 had higher bioactivity and activity in vivo in a recent study by our group, but the mechanisms underlying this effect had not been characterized in detail at the gene expression level on tumor cells. In the present work, we sought to examine potential mechanisms for targeted IL-27 enhanced activity directly on tumor cells. The targeted IL-27 appeared to modulate several changes that would be consistent with an anti-tumor effect, including upregulation in the Interferon (IFN) and Interferon regulatory factor (IRF), oxidative phosphorylation, Janus kinase/Signal transducers and activators of transcription (JAK/STAT), and eukaryotic initiation factor 2 (EIF2) signaling. Of these signaling changes predicted by ingenuity pathway analyses (IPA), the novel form also with the highest significance (-log(Benjamini-Hochberg (B-H)) Show less

This study comprised 157 adult participants, stratified according to the period of obesity onset. The first group included 97 patients with childhood-onset obesity (0-11 years) and the second group comprised 60 subjects with adolescence/youth-onset obesity (12-21 years). The entire coding region of As a result, five previously described variants (Met1?, Ser36Thr, Val103Ile, Ile98=, and Phe202Leu) were identified. Met1? is a start lost codon variant, which affects the translation of This study showed the prevalence of Show less

Contradictory results are reported for the role of angiopoietin-like 4 (ANGPTL-4) in the development of cancer-cachexia and inflammation, given its importance in angiogenesis and inflammatory signaling. Our aim was to analyze the levels of ANGPTL-4 in colorectal cancer patients with a stable weight and those with cachexia in order to establish a relationship between ANGPTL-4 and the inflammatory process. Plasma and tumor levels of ANGPTL-4 were higher in CC in comparison to other groups. A positive association was verified between plasmatic ANGPTL-4 and NFκB levels in tumor from CC. In WSC, we identified an association between the plasmatic ANGPTL-4, IL-15, and IL-10 in tumor and IL-15 in MES. Increased levels of NFκB and TNF-R1 in MES were detected in CC in comparison to WSC. Specifically in CC-group, a positive correlation was found between ANGPTL-4 levels and those of IL-1β, TNF-α, and NFκB in tumor, along with an association between ANGPTL-4 levels with IL-1β and MCP-1 levels in tumor; and ANGPTL-4 and IL-1β levels in MES. We studied 102 patients, who were divided into three groups: control patients (C, n=37), cancer patients with a stable weight (WSC, n=23), and cancer-cachexia patients (CC, n=42). Samples of plasma, tumor, mesenteric (MES) and subcutaneous adipose tissue were removed for the determination of ANGPTL-4 levels and other proinflammatory factors. ANGPTL-4 levels were higher in plasma and tumor of CC-group, and positively associated with pro-inflammatory and pro-tumorigenic factors. Our results suggest an opposite effect of ANGPTL-4 depending on the concentration and presence of cachexia. Show less