👤 Frederico G S Toledo

Chia (Salvia hispanica L.) is a functional food that can help control the metabolic changes caused by unbalanced diets. The aim of this study was to investigate the effects of chia flour (CF) and chia oil (CO) on satiety, inflammation, and antioxidant potential in the brain of rats fed a high-fat high-fructose diet (HFHF). Male Wistar rats were divided into two groups: AIN-93M (n = 8) and HFHF (n = 24) for 8 wk. Subsequently, HFHF-fed animals were subdivided (n = 8) into: HFHF, HFHF+CF, and HFHF+CO for 10 wk. Gene expression of satiety and inflammation-related proteins was analyzed by RT-qPCR; leptin and adiponectin levels were quantified by ELISA; and antioxidant potential was assessed via SOD and CAT activity. In silico analysis was performed using molecular docking, and the correlations were evaluated via Pearson's analyses. The HFHF+CO group showed higher POMC/CART gene expression, as well as reduced leptin levels compared to the HFHF+CF and AIN-93M groups. Both chia flour and oil reduced NPY, LEP-r, and NF-κB gene expressions compared to the HFHF group. The HFHF+CF group showed increased Nrf2 gene expression compared to the HFHF group. All main phenolic acids found in chia flour showed good interactions with the analyzed markers LEP-r, MC4R, and NPY-Y1. Main positive correlations were observed beteween adiponectin and SOD, phenolics consumption and ALA, MC4R and NPY, NPY and AgRP, and AgRP and MC4R. Thus, this study highlights chia flour and oil as potential modulators of satiety and inflammatory response in the brain, in addition to reinforcing the antioxidant effect of flour. Show less

Hydroxychloroquine (HCQ) is an immunomodulatory agent used in autoimmune conditions. Observational studies suggest that HCQ may lower circulating cholesterol and triglyceride levels, indicating a potential cardiovascular benefit. However, the specific changes in lipoprotein particle concentrations driving these effects have not been characterized in detail. To evaluate the effects of HCQ on circulating lipids and on lipoprotein concentration and composition. A post hoc analysis was conducted within a randomized, placebo-controlled, double-blind trial investigating the effects of HCQ on glucose metabolism in adults at risk for type 2 diabetes. Outcomes were analyzed as changes from baseline (placebo-adjusted) using mixed-effects models, with adjustments for sex, age, body mass index, and statin use. Compared with placebo, HCQ reduced total cholesterol (10.4%), low-density lipoprotein (LDL) cholesterol (12.9%), and non-high-density lipoprotein (HDL) cholesterol (15.0%). LDL particle concentration decreased by 15.1% and apolipoprotein B (ApoB) by 9.7%. HCQ had no effect on HDL cholesterol, HDL particle concentration, or apolipoproteinA1 (ApoA1). However, small HDL particle concentrations fell by 20.0%, while large HDL particle concentrations increased by 17.1%. HCQ reduced triglycerides by 27.8%, which was associated with a 20.6% reduction in triglyceride content per very low-density lipoprotein (VLDL) particle. Lipoprotein(a) levels were unaffected. HCQ changes lipoprotein concentration and composition, though the effects are distinct for each lipoprotein class. Our results suggest that HCQ lowers total cholesterol by reducing LDL particle concentration, decreases triglyceride by reducing the triglyceride content of VLDL particles, and alters the relative distribution of small vs large HDL particle concentration. These findings suggest protective benefits against atherosclerosis that warrant further investigation. Show less

Declines in skeletal muscle and cognitive function in older adults have been linked to abnormalities in abdominal subcutaneous adipose tissue (ASAT), yet the underlying molecular mediators remain poorly understood. Here, leveraging ASAT transcriptomics and explant-conditioned media proteomics from participants in the Study of Muscle, Mobility and Aging (SOMMA; age ≥70 years, n = 229), we identified ASAT gene clusters and secreted proteins strongly associated with comprehensive assessments of physical and cognitive function in older adults. ASAT inflammation and secreted immunoglobulins were identified as key signatures of aging-associated physical and cognitive performance limitations. Systems genetics analysis confirmed secreted-SERPINF1 as a negative regulator of skeletal muscle contraction and highlighted its potential role in inducing inflammation in the heart in silico. Additionally, novel ASAT-secreted proteins such as NID2 and APOA4 were implicated in mediating ASAT crosstalk with skeletal muscle and brain in silico. Our framework provides insights into ASAT-driven tissue crosstalk underlying physical and cognitive performance in older adults and offers a valuable resource for understanding the role of ASAT in human aging. Show less

Declines in skeletal muscle and cognitive function in older adults have been linked to abnormalities in abdominal subcutaneous adipose tissue (ASAT), yet the underlying molecular mediators remain poorly understood. Here, leveraging ASAT transcriptomics and explant-conditioned media proteomics from participants in the Study of Muscle, Mobility and Aging (SOMMA; age ≥70 years, n = 229), we identified ASAT gene clusters and secreted proteins strongly associated with comprehensive assessments of physical and cognitive function in older adults. ASAT inflammation and secreted immunoglobulins were identified as key signatures of aging-associated physical and cognitive performance limitations. Systems genetics analysis confirmed secreted-SERPINF1 as a negative regulator of skeletal muscle contraction and highlighted its potential role in inducing inflammation in the heart Show less

Stroke embolic source have an unknown origin in 30-40% of cases. Mechanical thrombectomy for acute large vessel occlusion stroke has provided us with a method to directly retrieve the thrombi from patients for analysis. By collecting stroke-causing thrombi from known sources, we can then use high-throughput RNA sequencing (RNAseq) technology to directly measure the gene expression signatures of these clots. This may allow us to identify genetic markers to predict the cause of cryptogenic embolism. This is a prospective study in which RNAseq was used to analyze cerebral thrombi retrieved by mechanical thrombectomy devices in acute ischemic stroke patients. Samples were separated into two groups based on known stroke thrombus etiology, including Carotid group (patients with ipsilateral >70% carotid stenosis) and Atrial fibrillation (AF) group (patients with atrial fibrillation). Gene expression was compared by RNAseq analysis between the groups. From October 2016 to September 2017, 8 thrombi (4 in Carotid group, 4 in Afib group) were included in this study. There were 131 genes that were significantly up- or down-regulated between the two groups defined as a false discovery rate ≤ 0.05 and a fold change ≥ 2. Twenty-six genes were selected as candidate gene biomarkers based on the criteria in the methods section. Candidate genes HSPA1B, which encodes a heatshock protein, and GPRC5B, which encodes a G-protein, showed the greatest fold differences in expression between the two groups. This study has shown that RNA sequencing of acute ischemic stroke thrombi is feasible and indentified potential novel biomarkers for identifying stroke-causing thrombi origin, especially in cryptogenic stroke. Show less

The cholesterol-ester transfer protein (CETP) exchanges lipids between high-density lipoproteins (HDLs) and low-density lipoproteins (LDLs). The excessive transport of lipids from HDLs to LDLs mediated by this protein can cause an alteration in the deposition of lipoproteins onto the arterial walls, thus promoting the development of arteriosclerosis. Different CETP inhibitors have been tested in recent years, but none has been confirmed as being effectively palliative for the disease. We employed in silico databases and molecular docking as a computational method to predict how potential CETP inhibitors could interact with the active site of the CETP protein. Upon previously comparing two computer software packages to determine which generated a greater number of accurate CETP-inhibitor-complex structures, we chose the more appropriate program for our studies. We then abstracted a series of databases of known CETP inhibitors and noninhibitors exhibiting different 50% concentrations of CETP-inhibitory (INH) activity, to generate virtual structures for docking with different combinations of the CETP receptor. From this process, we obtained as the most suitable structure 4F2A₁OB_C_PCW-it accordingly having a greater area under the receiver operating characteristic curve. The molecular docking of known compounds in comparison with the respective conformation of this inhibitor enabled us to obtain ΔGs (in kcal/mol) from which data we made a first exploration of unknown compounds for CETP-INH activity. Thus, the 4F2A₁OB_C_PCW structure was docked with DrugBank-Approved commercial compounds in an extensive database, whose status had already been established from pharmacokinetics and toxicology. In this study, we present a group of potential compounds as CETP-inhibitor candidates. Show less

Liver X receptors (Lxrα and Lxrβ) are ligand-dependent nuclear receptors critical for ventral midbrain neurogenesis in vivo. However, no endogenous midbrain Lxr ligand has so far been identified. Here we used LC/MS and functional assays to identify cholic acid as a new Lxr ligand. Moreover, 24(S),25-epoxycholesterol (24,25-EC) was found to be the most potent and abundant Lxr ligand in the developing mouse midbrain. Both Lxr ligands promoted neural development in an Lxr-dependent manner in zebrafish in vivo. Notably, each ligand selectively regulated the development of distinct midbrain neuronal populations. Whereas cholic acid increased survival and neurogenesis of Brn3a-positive red nucleus neurons, 24,25-EC promoted dopaminergic neurogenesis. These results identify an entirely new class of highly selective and cell type-specific regulators of neurogenesis and neuronal survival. Moreover, 24,25-EC promoted dopaminergic differentiation of embryonic stem cells, suggesting that Lxr ligands may thus contribute to the development of cell replacement and regenerative therapies for Parkinson's disease. Show less