👤 Tatiana Lins Carvalho

Peripheral nerve injuries (PNI) often lead to long-term functional impairment. Mesenchymal stem cells (MSCs) and cannabidiol (CBD) have shown anti-inflammatory and neuroprotective effects in vitro, which may be relevant for PNI research. The aim of this study was to evaluate CBD-rich cannabis extract’s potential to induce anti-inflammatory and neurotrophic gene expression in equine adipose tissue-derived MSCs (EqAT-MSCs) in an inflammatory in vitro environment. The morphology and metabolic activity of EqAT-MSCs ( 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

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

Currently, Alzheimer's disease (AD) is one of the most frequent forms of dementia. From a molecular perspective, the molecular characteristics that better define this disease consist of abnormal protein deposits between neuronal cells, namely senile plaques (SPs) and neurofibrillary tangles (NFTs), consisting of protein aggregates of amyloid- Show less

In this study, we analyzed over 500 ST30 genomes from diverse sources, including Brazilian strains sequenced by our team, using genomic, pangenomic, phylogenetic, and time-calibrated phylogenetic analyses. We traced key evolutionary events, estimating that the specialization of PT80/81 and SWP occurred after a divergence around 1868, forming a group of PT80/81-related strains and another group formed by SWP-related strains. Our findings highlight major events involving gene acquisition and loss, as well as mobile genetic elements (MGE). Notably, PT80/81 lost most Our study revises the evolutionary history of ST30 Show less

Dyslipidemia is described in several autoimmune conditions. Lipoprotein lipase (LPL) is responsible for triglyceride breakdown. Anti-LPL antibodies have been described. To review articles on anti-LPL antibodies in autoimmune and non-autoimmune diseases. Twenty-two articles were found: 9 case reports and 13 observational studies. In 5 of 9 case reports, hypertriglyceridemia normalized after immunosuppressive treatment. The observational studies showed the prevalence and associations of anti-LPL antibodies: systemic lupus erythematosus, found in 37.8 % to 71 % of patients and associated with nephritis, disease activity, and the presence of anti-dsDNA antibodies. In myositis, the prevalence ranged from 4 % to 43 % without any reported association. In scleroderma, they were found in 35 % to 42 % and associated with skin and lung fibrosis, heart involvement, and the presence of anti-topoisomerase-1 antibodies. In Sjögren's syndrome and rheumatoid arthritis, they were found in a minority of individuals. They were absent in Behçet's disease, antiphospholipid antibody syndrome, juvenile idiopathic arthritis, juvenile dermatomyositis, and Takayasu arteritis. Three studies were conducted on dyslipidemic patients without autoimmune conditions, and in one of them, anti-LPL antibodies were associated with necrosis in atherosclerotic plaques. Anti-LPL antibodies were detected in several autoimmune and non-autoimmune diseases, mainly connective tissue diseases, and were associated with increased triglyceride levels. These antibodies may contribute to the accelerated atherogenesis seen in these patients. Show less

What is the contribution of genetic defects in Portuguese patients with congenital hypogonadotropic hypogonadism (CHH)? Approximately one-third of patients with CHH were found to have a genetic cause for their disorder, with causal pathogenic and likely pathogenic germline variants distributed among 10 different genes; cases of oligogenic inheritance were also included. CHH is a rare and genetically heterogeneous disorder characterized by deficient production, secretion, or action of GnRH, LH, and FSH, resulting in delayed or absent puberty, and infertility. Genetic screening was performed on a cohort of 81 Portuguese patients with CHH (36 with Kallmann syndrome and 45 with normosmic hypogonadotropic hypogonadism) and 263 unaffected controls. The genetic analysis was performed by whole-exome sequencing followed by the analysis of a virtual panel of 169 CHH-associated genes. The main outcome measures were non-synonymous rare sequence variants (population allele frequency <0.01) classified as pathogenic, likely pathogenic, and variants of uncertain significance (VUS). A genetic cause was identified in 29.6% of patients. Causal pathogenic and likely pathogenic variants were distributed among 10 of the analysed genes. The most frequently implicated genes were N/A. The identification of a large number of VUS presents challenges in interpretation and these may require reclassification as more evidence becomes available. Non-coding and copy number variants were not studied. Functional studies of the variants were not undertaken. This study highlights the genetic heterogeneity of CHH and identified several novel variants that expand the mutational spectrum of the disorder. A significant proportion of patients remained without a genetic diagnosis, suggesting the involvement of additional genetic, epigenetic, or environmental factors. The high frequency of VUS underscores the importance of cautious variant interpretation. These findings contribute to the understanding of the genetic architecture of CHH and emphasize the need for further studies to elucidate the underlying mechanisms and identify additional causes of CHH. This research was funded by the Portuguese Foundation for Science and Technology (grant numbers PTDC/SAU-GMG/098419/2008, UIDB/00709/2020, CEECINST/00016/2021/CP2828/CT0002, and 2020.04924.BD) and by Sidra Medicine-a member of the Qatar Foundation (grant number SDR400038). The authors declare no competing interests. Show less

Visceral leishmaniasis (VL) is an important tropical and neglected disease and represents a serious global health problem. The initial interaction between the phagocytes and the parasite is crucial to determine the pathogen's capacity to initiate infection and it shapes the subsequent immune response that will develop. While type-1 T-cells induce IL-6, IL-1β, TNF-α, and IL-12 production by monocytes/macrophages to fight the infection, type-2 T-cells are associated with a regulatory phenotype (IL-10 and TGF-β) and successful infection establishment. Recently, our group demonstrated the role of an important Th1/Th17 T-cell population, the mucosal-associated invariant T (MAIT) cells, in VL. MAIT cells can respond to Here, we describe the impact of the MR1-blockage on Overall, our data showed that VL patients presents higher percentage of activated neutrophils than asymptomatic and non-infected controls. In addition, MR1 blockade led to lower TNF-α and TGF-β production by non-activated neutrophils from asymptomatic individuals. Moreover, TNF-α and IL-10 production by monocytes was higher in VL patients. In the analysis of soluble mediators produced These data corroborate the hypothesis that MR1-restricted responses are associated to a protective role during Show less

Dimethyl fumarate (DMF, Tecfidera) is an oral drug utilized to treat relapsing-remitting multiple sclerosis (MS). DMF treatment reduces disease activity in MS. Gastrointestinal discomfort is a common adverse effect of the treatment with DMF. This study aimed to investigate the effect of DMF administration in the gut draining lymph nodes cells of C57BL6/J female mice with experimental autoimmune encephalomyelitis (EAE), an animal model of MS. We have demonstrated that the treatment with DMF (7.5 mg/kg) significantly reduces the severity of EAE. This reduction of the severity is accompanied by the increase of both proinflammatory and anti-inflammatory mechanisms at the beginning of the treatment. As the treatment progressed, we observed an increasing number of regulatory Foxp3 negative CD4 T cells (Tr1), and anti-inflammatory cytokines such as IL-27, as well as the reduction of PGE2 level in the mesenteric lymph nodes of mice with EAE. We provide evidence that DMF induces a gradual anti-inflammatory response in the gut draining lymph nodes, which might contribute to the reduction of both intestinal discomfort and the inflammatory response of EAE. These findings indicate that the gut is the first microenvironment of action of DMF, which may contribute to its effects of reducing disease severity in MS patients. Show less

Cross-language studies suggest more similarities than differences in how dysarthria affects the speech of people with Parkinson's disease (PwPD) who speak different languages. In this study, we aimed to identify the relative contribution of acoustic variables to distinguish PwPD from controls who spoke varieties of two Romance languages, French and Portuguese. This bi-national, cross-sectional, and case-controlled study included 129 PwPD and 124 healthy controls who spoke French or Portuguese. All participants underwent the same clinical examinations, voice/speech recordings, and self-assessment questionnaires. PwPD were evaluated French-speaking and Portuguese-speaking individuals were distinguished from each other with over 90% accuracy by five acoustic variables (the mean fundamental frequency and the shimmer of the sustained vowel /a/ production, the oral diadochokinesis performance index, the relative sound level pressure and the relative sound pressure level standard deviation of the text reading). A distinct set of parameters discriminated between controls and PwPD: for men, maximum phonation time and the oral diadochokinesis speech proportion were the most significant variables; for women, variables calculated from the oral diadochokinesis were the most discriminative. Acoustic variables related to phonation and voice quality distinguished between speakers of the two languages. Variables related to pneumophonic coordination and articulation rate were the more effective in distinguishing PwPD from controls. Thus, our research findings support that respiration and diadochokinesis tasks appear to be the most appropriate to pinpoint signs of dysarthria, which are largely homogeneous and language-universal. In contrast, identifying language-specific variables with the speech tasks and acoustic variables studied was less conclusive. Show less

Miniaturizing and integrating atomic vapor cells is widely investigated for the purposes of fundamental measurements and technological applications such as quantum sensing. Extending such platforms to the realm of molecular physics is a fascinating prospect that paves the way for compact frequency metrology as well as for exploring light-matter interactions with complex quantum objects. Here, we perform molecular rovibrational spectroscopy in a thin-cell of micrometric thickness, comparable to excitation wavelengths. We operate the cell in two distinct regions of the electromagnetic spectrum, probing ν Show less

Hypertrophic cardiomyopathy (HCM) is the most prevalent inherited cardiomyopathy and a leading cause of sudden death. Genetic testing and familial cascade screening play a pivotal role in the clinical management of HCM patients. However, conventional genetic tests primarily focus on the detection of exonic and canonical splice site variation. Oversighting intronic non-canonical splicing variants potentially contributes to a proportion of HCM patients remaining genetically undiagnosed. Here, using a non-integrative reprogramming strategy, we generated induced pluripotent stem cell (iPSC) lines from four individuals carrying one of two variants within intronic regions of MYBPC3: c.1224-52G > A and c.1898-23A > G. Upon differentiation to iPSC-derived cardiomyocytes (iPSC-CMs), mis-spliced mRNAs were identified in cells harbouring these variants. Both abnormal mRNAs contained a premature termination codon (PTC), fitting the criteria for activation of nonsense mediated decay (NMD). However, the c.1898-23A > G transcripts escaped this mRNA quality control mechanism, while the c.1224-52G > A transcripts were degraded. The newly generated iPSC lines represent valuable tools for studying the functional consequences of intronic variation and for translational research aimed at reversing splicing abnormalities to prevent disease progression. Show less

Hypertrophic cardiomyopathy (HCM) is frequently caused by mutations in the MYPBC3 gene, which encodes the cardiac myosin-binding protein C (cMyBP-C). Most pathogenic variants in MYPBC3 are either nonsense mutations or result in frameshifts, suggesting that the primary disease mechanism involves reduced functional cMyBP-C protein levels within sarcomeres. However, a subset of MYPBC3 variants are missense mutations, and the molecular mechanisms underlying their pathogenicity remain elusive. Upon in vitro differentiation into cardiomyocytes, induced pluripotent stem cells (iPSCs) derived from HCM patients represent a valuable resource for disease modeling. In this study, we generated two iPSC lines from peripheral blood mononuclear cells (PBMCs) of a female with early onset and severe HCM linked to the MYBPC3: c.772G > A variant. Although this variant was initially classified as a missense mutation, recent studies indicate that it interferes with splicing and results in a frameshift. The generated iPSC lines exhibit a normal karyotype and display hallmark characteristics of pluripotency, including the ability to undergo trilineage differentiation. These novel iPSCs expand the existing repertoire of MYPBC3-mutated cell lines, broadening the spectrum of resources for exploring how diverse mutations induce HCM. They additionally offer a platform to study potential secondary genetic elements contributing to the pronounced disease severity observed in this individual. Show less

Familial hypertrophic cardiomyopathy (HCM) stands as a predominant heart condition, characterised by left ventricle hypertrophy in the absence of any associated loading conditions, with affected individuals having an increased risk of developing heart failure and sudden cardiac death (SCD). Two induced pluripotent stem cell (iPSC) lines were derived from peripheral blood mononuclear cells obtained from two unrelated individuals with previously reported nonsense mutations in the MYBPC3 gene. The first individual is a 48-year-old male (F26) with the MYBPC3 c.1731G > A HCM mutation, whereas the second individual is a 43-year-old female (F82) carrying the MYBPC3 c.2670G > A HCM mutation. The generated iPSCs exhibit appropriate expression of pluripotency markers, trilineage differentiation capacity and a normal karyotype. This resource contributes to gaining deeper insights into the pathophysiological mechanisms that underlie HCM. Show less

Familial hypertrophic cardiomyopathy (HCM) is the most common inherited heart condition. HCM patients show left ventricle hypertrophy without any associated loading conditions, being at risk for heart failure and sudden cardiac death. Two induced pluripotent stem cell (iPSC) lines were generated from peripheral blood mononuclear cells obtained from two unrelated individuals, a 54-year-old male (F81) and a 44-year-old female (F93), both carrying the MYBPC3 c.1484G>A HCM mutation. iPSCs show expression of pluripotency markers, trilineage differentiation capacity and a normal karyotype. This resource enables further assessment of the pathophysiological development of HCM. Show less

MicroRNAs are small regulatory molecules that control gene expression. An emerging property of muscle miRNAs is the cooperative regulation of transcriptional and epitranscriptional events controlling muscle phenotype. miR-155 has been related to muscular dystrophy and muscle cell atrophy. However, the function of miR-155 and its molecular targets in muscular dystrophies remain poorly understood. Through in silico and in vitro approaches, we identify distinct transcriptional profiles induced by miR-155-5p in muscle cells. The treated myotubes changed the expression of 359 genes (166 upregulated and 193 downregulated). We reanalyzed muscle transcriptomic data from dystrophin-deficient patients and detected overlap with gene expression patterns in miR-155-treated myotubes. Our analysis indicated that miR-155 regulates a set of transcripts, including 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

To describe the phenotype of CLN-associated retinal dystrophy in a subset of patients at the Columbia University Medical Center, United States, and the Hospital das Clínicas de Pernambuco, Brazil, in comparison to the published literature. Eleven patients with confirmed biallelic variants in the CLN genes were evaluated via dilated fundus examination, clinical imaging, and full-field electroretinogram. A thorough literature search was conducted to determine previously published variants and associated phenotypes. Genetic testing confirmed the presence of variants in CLN3, CLN7/MFSD8, CLN8, and GRN/CLN11. Five novel variants were identified, and four novel phenotypes of previously published alleles were described. The phenotype differed among patients with variants in the same gene and sometimes among patients with the same allele. Substantial phenotypic variability among variants in the CLN genes makes identification of genotype-phenotype or allele-phenotype correlations challenging. Further study is required to establish an extensive database for adequate patient counseling. Show less

Biological aging can be described as accumulative, prolonged metabolic stress and is the major risk factor for cognitive decline and Alzheimer's disease (AD). Recently, we identified and described a quinone reductase 2 (QR2) pathway in the brain, in which QR2 acts as a removable memory constraint and metabolic buffer within neurons. QR2 becomes overexpressed with age, and it is possibly a novel contributing factor to age-related metabolic stress and cognitive deficit. We found that, in human cells, genetic removal of QR2 produced a shift in the proteome opposing that found in AD brains while simultaneously reducing oxidative stress. We therefore created highly specific QR2 inhibitors (QR2is) to enable evaluation of chronic QR2 inhibition as a means to reduce biological age-related metabolic stress and cognitive decline. QR2is replicated results obtained by genetic removal of QR2, while local QR2i microinjection improved hippocampal and cortical-dependent learning in rats and mice. Continuous consumption of QR2is in drinking water improved cognition and reduced pathology in the brains of AD-model mice (5xFAD), with a noticeable between-sex effect on treatment duration. These results demonstrate the importance of QR2 activity and pathway function in the healthy and neurodegenerative brain and what we believe to be the great therapeutic potential of QR2is as first-in-class drugs. Show less

Sarcomas are a rare and diverse group of cancers occurring mainly in young individuals for which an underlying germline genetic cause remains unclear in most cases. Germline DNA from 177 children, adolescents and young adults with soft tissue or bone sarcomas was tested using multigene panels with 113 or 126 cancer predisposing genes (CPGs) to describe the prevalence of germline pathogenic/likely pathogenic variants (GPVs). Subsequent testing of a subset of tumours for loss of heterozygosity (LOH) evaluation was performed to investigate the clinical and molecular significance of these variants. GPVs were detected in 21.5% (38/177) of the patients (15.8% in children and 21.6% in adolescents and young adults), with dominant CPGs being altered in 15.2% overall. These variants were found in genes previously associated with the risk of developing sarcomas ( Our findings reveal that a high proportion of young patients with sarcomas presented a GPV in a CPG, underscoring the urgency of establishing appropriate genetic screening strategies for these individuals and their families. Show less

Mitochondria are organelles known primarily for generating ATP via the oxidative phosphorylation process. Environmental signals are sensed by whole organisms or cells and markedly affect this process, leading to alterations in gene transcription and, consequently, changes in mitochondrial function and biogenesis. The expression of mitochondrial genes is finely regulated by nuclear transcription factors, including nuclear receptors and their coregulators. Among the best-known coregulators is the nuclear receptor corepressor 1 (NCoR1). Muscle-specific knockout of NCoR1 in mice induces an oxidative phenotype, improving glucose and fatty acid metabolism. However, the mechanism by which NCoR1 is regulated remains elusive. In this work, we identified the poly(A)-binding protein 4 (PABPC4) as a new NCoR1 interactor. Unexpectedly, we found that silencing of PABPC4 induced an oxidative phenotype in both C2C12 and MEF cells, as indicated by increased oxygen consumption, mitochondria content, and reduced lactate production. Mechanistically, we demonstrated that PABPC4 silencing increased the ubiquitination and consequent degradation of NCoR1, leading to the derepression of PPAR-regulated genes. As a consequence, cells with PABPC4 silencing had a greater capacity to metabolize lipids, reduced intracellular lipid droplets, and reduced cell death. Interestingly, in conditions known to induce mitochondrial function and biogenesis, both mRNA expression and PABPC4 protein content were markedly reduced. Our study, therefore, suggests that the lowering of PABPC4 expression may represent an adaptive event required to induce mitochondrial activity in response to metabolic stress in skeletal muscle cells. As such, the NCoR1-PABPC4 interface might be a new road to the treatment of metabolic diseases. Show less

The polymorphisms of fatty acid desaturase genes FADS1 and FADS2 have been associated with an increase in weight gain. We investigated FADS1 and FADS2 gene polymorphisms and the relation between ω-3 and ω-6 fatty acid plasma concentrations and gestational weight gain. A prospective cohort study of 199 pregnant women was followed in Santo Antônio de Jesus, Brazil. Plasma levels of polyunsaturated fatty acids (PUFAs) were measured at baseline and gestational weight gain during the first, second, and third trimesters. Fatty acid recognition was carried out with the aid of gas chromatography. Single nucleotide polymorphisms (SNPs) were genotyped using real-time PCR. Statistical analyses included Structural Equation Modelling. A direct effect of FADS1 and FADS2 gene polymorphisms on gestational weight was observed; however, only the SNP rs174575 (FADS2) showed a significant positive direct effect on weight over the course of the pregnancy (0.106; Show less

The Th1 cytokines production associated to signal transducer and activator of transcription 4 (STAT4) signaling amplifies the pro-inflammatory response in acute respiratory distress syndrome (ARDS). The anti-inflammatory action of commensal bacteria has been described as a secondary effect dependent on IL-10- secreting Treg cells that can act in organs far from the gut, including the lung. Despite it, no data is showing whether the previous reported anti-inflammatory action of probiotics is associated with its immunomodulatory effect dependent on Treg cells in a murine model of ARDS. Therefore, herein we focused on the short-term pretreatment effect with Lacticaseibacillus rhamnosus (Lr) in STAT4-associated Th1 cytokines as well as in population of IL-10- secreting Treg cells in a murine model of ARDS. Assays were performed in experimental groups divided into control, LPS, and Lr + LPS. Total and differential cells from bronchoalveolar lavage fluid (BALF) were counted through microscopy and the IL-10, IL-12, IL-17, IL-18, IL-22, IL-23, IL-27, IFN-γ, MMP-9, and TIMP were measured by ELISA. The peribronchial neutrophils were assessed using morphometry and for pulmonary edema was measured by Evans blue dye extravasation. The gene expression for STAT4, T-bet, STAT3, RORɣt, STAT5, and Foxp3 were measured by Real-Time PCR. Population of IL-10-secreting Treg cells was performed by flow cytometer. Data showed that pretreatment with Lr attenuated the number of inflammatory cells, secretion of both Th1 and Th17 cytokines, expression of STAT4/T-bet and STAT3/RORɣt in lung as well as alterations in lung morphometry. Otherwise, Lr was not efficient to restore mRNA expression for STAT5 and Foxp3 expression and population of IL-10-secreting Treg cells. Thus, beneficial effect of short-term pretreatment with Lr in murine model of ARDS is not dependent on an increased immunomodulatory action of IL-10-secreting Treg cells, however the anti-inflammatory effect of Lr has as target the Th1 and Th17 cytokines as well as signaling involving the STAT4/T-bet and STAT3/RORɣt. Show less

Melatonin is a hormone related to circadian rhythms and has potential clinical applications. Our objectives were to verify the effect of melatonin on the liver of zebrafish exposed to fructose and evaluate the expression of appetite-related genes (leptin, ghrelin, and melanocortin receptor 4 [MC4R]). Animals were divided into three groups: control (CG, Show less

Given the reports made about geographical differences in Colorectal Cancer (CRC) occurrence, suggesting a link between dietary habits, genes and cancer risk, we hypothesise that there are four fundamental metabolic pathways involved in diet-genes interactions, directly implicated in colorectal carcinogenesis: folate metabolism; lipid metabolism; oxidative stress response; and inflammatory response. Supporting this hypothesis are the evidence given by the significant associations between several diet-genes polymorphisms and CRC, namely: MTHFR, MTR, MTRR and TS (involved in folate metabolism); NPY, APOA1, APOB, APOC3, APOE, CETP, LPL and PON1 (involved in lipid metabolism); MNSOD, SOD3, CAT, GSTP1, GSTT1 and GSTM1 (involved in oxidative stress response); and IL-1, IL-6, TNF-α, and TGF-β (involved in inflammatory response). We also highlight the association between some foods/nutrients/nutraceuticals that are important in CRC prevention or treatment and the four metabolic pathways proposed, and the recent results of genome-wide association studies, both assisting our hypothesis. Finally, we propose a new line of investigation with larger studies, using accurate dietary biomarkers and investigating the four metabolic pathways genes simultaneously. This line of investigation will be essential to understand the full complexity of the association between nature and nurture in CRC and perhaps in other types of cancers. Only with this in-depth knowledge will it be possible to make personalised nutrition recommendations for disease prevention and management. Show less

Ultraviolet light exposure and cutaneous pigmentation are important host risk factors for cutaneous melanoma (CM), and it is well known that inherited ability to produce melanin varies in humans. The study aimed to identify single-nucleotide variants (SNVs) on pigmentation-related genes with importance in risk and clinicopathological aspects of CM. The study was conducted in two stages. In stage 1, 103 CM patients and 103 controls were analyzed using Genome-Wide Human SNV Arrays in order to identify SNVs in pigmentation-related genes, and the most important SNVs were selected for data validation in stage 2 by real-time polymerase-chain reaction in 247 CM patients and 280 controls. ADCY3 c.675+9196T>G, CREB1 c.303+373G>A, and MITF c.938-325G>A were selected for data validation among 74 SNVs. Individuals with CREB1 GA or AA genotype and allele "A" were under 1.79 and 1.47-fold increased risks of CM than others, respectively. Excesses of CREB1 AA and MITF AA genotype were seen in patients with tumors at Clark levels III to V (27.8% versus 13.7%) and at III or IV stages (46.1% versus 24.9%) compared to others, respectively. When compared to others, patients with ADCY3 TT had 1.89 more chances of presenting CM progression, and those with MITF GA or AA had 2.20 more chances of evolving to death by CM. Our data provide, for the first time, preliminary evidence that inherited abnormalities in ADCY3, CREB1, and MITF pigmentation-related genes, not only can increase the risk to CM, but also influence CM patients' clinicopathological features. Show less