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1.
Nutr Bull ; 48(4): 559-571, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37905391

RESUMO

Childhood dyslipidaemia is associated with the occurrence of cardiovascular diseases in adulthood, so evaluating whether an individual has a genetic predisposition to this pathology is of great importance for early action of prevention and treatment. This study aimed to evaluate the association between the FTO (rs9939609), MC4R (rs17782313) and MTMR9 (rs2293855) polymorphisms, the obesity-related genetic risk score and atherogenic risk in Brazilian children. This is a cross-sectional study conducted in 544 children aged 4-9 years in the city of Viçosa, Minas Gerais state, Brazil. The single nucleotide polymorphisms rs9939609, rs17782313 and rs2293855, were identified by the system TaqMan SNP genotyping and the obesity-related genetic risk score was determined. The lipid profile (serum total cholesterol [TC], high density lipoprotein [HDL] cholesterol, low density lipoprotein [LDL] cholesterol, triglycerides) was analysed and the atherogenic indices (Castelli I and II indices), atherogenic coefficient (AC), lipoprotein combined index (LCI) and plasma atherogenic index (PAI) were calculated. A semi-structured questionnaire was applied, obtaining data on the sociodemographic, economic and lifestyle characteristics of the children. Weight and height measurements were performed in all children, and body composition was evaluated by Dual-Energy X-ray Absorptiometry (DXA). 55.5% of the sample had dyslipidaemia, while 28.5% of the sample had at least one polymorphism and 2.2% had three polymorphisms. Children with the AG/AA genotypes in the rs2293855 polymorphism had lower HDL cholesterol levels and higher TC/HDL cholesterol, LDL/HDL cholesterol ratios and AC. Those with one or more polymorphisms (rs9939609, rs17782313 and rs2293855) in the genetic risk score had lower HDL cholesterol levels and higher TC/HDL cholesterol ratios, AC, LCI and PAI. In conclusion, the risk allele of the rs2293855 polymorphism and a higher obesity-related genetic risk score were positively associated with higher atherogenic risk in Brazilian children.


Assuntos
Dislipidemias , Obesidade , Criança , Humanos , HDL-Colesterol , Genótipo , Estudos Transversais , Índice de Massa Corporal , Polimorfismo de Nucleotídeo Único/genética , Colesterol , Lipoproteínas HDL/genética , Dislipidemias/epidemiologia , Proteínas Tirosina Fosfatases não Receptoras/genética , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética
2.
Bio Protoc ; 12(17)2022 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-36213105

RESUMO

Skeletal muscle stem cells differentiated from human-induced pluripotent stem cells (hiPSCs) serve as a uniquely promising model system for investigating human myogenesis and disease pathogenesis, and for the development of gene editing and regenerative stem cell therapies. Here, we present an effective and reproducible transgene-free protocol for derivation of human skeletal muscle stem cells, iMyoblasts, from hiPSCs. Our two-step protocol consists of 1) small molecule-based differentiation of hiPSCs into myocytes, and 2) stimulation of differentiated myocytes with growth factor-rich medium to activate the proliferation of undifferentiated reserve cells, for expansion and cell line establishment. iMyoblasts are PAX3 + /MyoD1 + myogenic stem cells with dual potential to undergo muscle differentiation and to self-renew as a regenerative cell population for muscle regeneration both ex vivo and in vivo . The simplicity and robustness of iMyoblast generation and expansion have enabled their application to model the molecular pathogenesis of Facioscapulohumeral Muscular Dystrophy and Limb-Girdle Muscular Dystrophies, to both ex vivo and in vivo muscle xenografts, and to respond efficiently to gene editing, enabling the co-development of gene correction and stem cell regenerative therapeutic technologies for the treatment of muscular dystrophies and muscle injury. Graphical abstract.

4.
Front Pharmacol ; 11: 258, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32226382

RESUMO

Hypertension is a major global health challenge, as it represents the main risk factor for stroke and cardiovascular disease. It is a multifactorial clinical condition characterized by high and sustained levels of blood pressure, likely resulting from a complex interplay of endogenous and environmental factors. The gut microbiota has been strongly supposed to be involved but its role in hypertension is still poorly understood. In an attempt to fill this gap, here we characterized the microbial composition of fecal samples from 48 hypertensive and 32 normotensive Brazilian individuals by next-generation sequencing of the 16S rRNA gene. In addition, the cytokine production of peripheral blood samples was investigated to build an immunological profile of these individuals. We identified a dysbiosis of the intestinal microbiota in hypertensive subjects, featured by reduced biodiversity and distinct bacterial signatures compared with the normotensive counterpart. Along with a reduction in Bacteroidetes members, hypertensive individuals were indeed mainly characterized by increased proportions of Lactobacillus and Akkermansia while decreased relative abundances of well-known butyrate-producing commensals, including Roseburia and Faecalibacterium within the Lachnospiraceae and Ruminococcaceae families. We also observed an inflamed immune profile in hypertensive individuals with an increase in TNF/IFN-γ ratio, and in TNF and IL-6 production when compared to normotensive ones. Our work provides the first evidence of association of hypertension with altered gut microbiota and inflammation in a Brazilian population. While lending support to the existence of potential microbial signatures of hypertension, likely to be robust to age and geography, our findings point to largely neglected bacteria as potential contributors to intestinal homeostasis loss and emphasize the high vulnerability of hypertensive individuals to inflammation-related disorders.

5.
Nat Commun ; 9(1): 4514, 2018 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-30375513

RESUMO

We characterize different tumour types in search for multi-tumour drug targets, in particular aiming for drug repurposing and novel drug combinations. Starting from 11 tumour types from The Cancer Genome Atlas, we obtain three clusters based on transcriptomic correlation profiles. A network-based analysis, integrating gene expression profiles and protein interactions of cancer-related genes, allows us to define three cluster-specific signatures, with genes belonging to NF-κB signaling, chromosomal instability, ubiquitin-proteasome system, DNA metabolism, and apoptosis biological processes. These signatures have been characterized by different approaches based on mutational, pharmacological and clinical evidences, demonstrating the validity of our selection. Moreover, we define new pharmacological strategies validated by in vitro experiments that show inhibition of cell growth in two tumour cell lines, with significant synergistic effect. Our study thus provides a list of genes and pathways that could possibly be used, singularly or in combination, for the design of novel treatment strategies.


Assuntos
Redes Reguladoras de Genes , Genômica , Neoplasias/tratamento farmacológico , Mapas de Interação de Proteínas , Proteômica , Apoptose/genética , Instabilidade Cromossômica/genética , DNA/metabolismo , Reposicionamento de Medicamentos , Genes Neoplásicos , Ensaios de Triagem em Larga Escala , Humanos , Terapia de Alvo Molecular , NF-kappa B/genética , NF-kappa B/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Complexo de Endopeptidases do Proteassoma/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Transdução de Sinais , Transcriptoma , Ubiquitina/genética , Ubiquitina/metabolismo
6.
Clin Nutr ; 37(4): 1286-1292, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-28579220

RESUMO

OBJECTIVE: Evaluate whether the polymorphism rs17782313 near MC4R gene influences long-term outcomes after bariatric surgery. METHODS: The rs16782313 polymorphism was genotyped in 217 individuals undergoing bariatric surgery and analyzed in detail in 141 women. Data for comorbidities, BMI, excess weight loss (EWL), and body composition were obtained before and during 60 months after surgery. RESULTS: The risk allele was found in 65 (47%) of the 141 women. Pre-surgical body weight and BMI were higher in carriers of the rs17782313 polymorphism (CC + CT group) than in non-carriers (TT group) (p = 0.039 and 0.047, respectively). The number of women who acquired surgical success (EWL > 50%), was lower in CC + CT group compared to TT group (p = 0.015). The minimum BMI seen during the 60 months of follow-up was higher in CC + CT group compared to TT group (p = 0.028). The number of women who presented BMI < 30 kg/m2 (no longer classified as obesity) after 24 months of surgery was inferior in CC + CT group (6 out 35 patients - 17%) than in TT group (19 out 49 patients - 37%, p = 0.043). Moreover, the number of patients maintaining BMI > 35 kg/m2 were higher carriers (18 out 35 patients - 51%) compare to non-carriers (16 out 49 patients - 32%, p = 0.045). CONCLUSION: Women with extreme obesity carrying rs17782313 MC4R polymorphism present a higher pre-surgical BMI, are more unlikely to reach non-obesity BMI (<30 kg/m2) and tend to maintain a BMI > 35 kg/m2 that characterize treatment failure.


Assuntos
Obesidade , Receptor Tipo 4 de Melanocortina/genética , Redução de Peso/genética , Adulto , Cirurgia Bariátrica , Índice de Massa Corporal , Feminino , Humanos , Estudos Longitudinais , Pessoa de Meia-Idade , Obesidade/epidemiologia , Obesidade/genética , Obesidade/cirurgia , Polimorfismo de Nucleotídeo Único/genética , Estudos Retrospectivos
7.
Oncotarget ; 8(14): 23237-23245, 2017 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-28423572

RESUMO

Changes in blood epigenetic age have been associated with several pathological conditions and have recently been described to anticipate cancer development. In this work, we analyze a publicly available leukocytes methylation dataset to evaluate the relation between DNA methylation age and the prospective development of specific types of cancer. We calculated DNA methylation age acceleration using five state-of-the-art estimators (three multi-site: Horvath, Hannum, Weidner; and two CpG specific: ELOV2 and FHL2) in a cohort including 845 subjects from the EPIC-Italy project and we compared 424 samples that remained cancer-free over the approximately ten years of follow-up with 235 and 166 subjects who developed breast and colorectal cancer, respectively. We show that the epigenetic age estimated from blood DNA methylation data is statistically significantly associated to future breast and male colorectal cancer development. These results are corroborated by survival analysis that shows significant association between age acceleration and cancer incidence suggesting that the chance of developing age-related diseases may be predicted by circulating epigenetic markers, with a dependence upon tumor type, sex and age estimator. These are encouraging results towards the non-invasive and perspective usage of epigenetic biomarkers.


Assuntos
Neoplasias da Mama/sangue , Neoplasias da Mama/genética , Neoplasias Colorretais/sangue , Neoplasias Colorretais/genética , Leucócitos/patologia , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Neoplasias da Mama/patologia , Neoplasias Colorretais/patologia , Metilação de DNA , Epigenômica , Feminino , Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Fatores Sexuais
8.
J Heart Lung Transplant ; 36(7): 797-805, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28320630

RESUMO

BACKGROUND: Heart transplantation is a valuable therapeutic option for Chagas disease patients with severe cardiomyopathy. During patient follow-up, the differential diagnosis between cardiac transplant rejection and Chagas disease infection reactivation remains a challenging task, which hinders rapid implementation of the appropriate treatment. Herein we investigate whether polymerase chain reaction (PCR) strategies could facilitate early detection of Trypanosoma cruzi (T cruzi) in transplanted endomyocardial biopsies (EMBs). METHODS: In this study we analyzed 500 EMB specimens obtained from 58 chagasic cardiac transplant patients, using PCR approaches targeted to nuclear (rDNA 24Sα) and kinetoplastid (kDNA) markers, and compared the efficiency of these approaches with that of other tests routinely used. RESULTS: T cruzi DNA was detected in 112 EMB specimens derived from 39 patients (67.2%). The first positive result occurred at a median 1.0 month post-transplant. Conventional histopathologic, blood smear and hemoculture analyses showed lower sensitivity and higher median time to the first positive result. Patient follow-up revealed that 31 of 39 PCR-positive cases presented clinical reactivation of Chagas disease at different time-points after transplantation. PCR techniques showed considerable sensitivity (0.82) and specificity (0.60), with area under the receiver operating characteristic (ROC) curves of 0.708 (p = 0.001). Moreover, PCR techniques anticipated the clinical signs of Chagas disease reactivation by up to 36 months, with a median time of 6 months and an average of 9.1 months. CONCLUSIONS: We found a good association between the PCR diagnosis and the clinical signs of the disease, indicating that the PCR approaches used herein are suitable for early diagnosis of Chagas disease reactivation, with high potential to assist physicians in treatment decisions. For this purpose, an algorithm is proposed for surveillance based on the molecular tests.


Assuntos
Cardiomiopatia Chagásica/diagnóstico , Cardiomiopatia Chagásica/cirurgia , Endocárdio/parasitologia , Transplante de Coração , Trypanosoma cruzi/isolamento & purificação , Adulto , DNA de Protozoário , Feminino , Humanos , Masculino , Valor Preditivo dos Testes , Curva ROC , Reação em Cadeia da Polimerase em Tempo Real
9.
Oncotarget ; 8(8): 12820-12830, 2017 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-28086223

RESUMO

Colorectal cancer is among the leading causes of cancer death worldwide. Despite numerous molecular characterizations of the phenomenon, the exact dynamics of its onset and progression remain elusive. Colorectal cancer onset has been characterized by changes in DNA methylation profiles, that, owing to the stability of their patterns, are promising candidates to shed light on the molecular events laying at the base of this phenomenon.To exploit this stability and reinforce it, we conducted a meta-analysis on publicly available DNA methylation datasets generated on: normal colorectal, adenoma (ADE) and adenocarcinoma (CRC) samples using the Illumina 450k array, in the systems medicine frame, searching for tumor gene episignatures, to produce a carefully selected list of potential drivers, markers and targets of the disease. The analysis proceeds from a differential meta-analysis of the methylation profiles using an analytical pipeline recently developed by our group [1], through network reconstruction, topological and functional analyses, to finally highlight relevant epigenomic features. Our results show that genes already highlighted for their genetic or transcriptional alteration in colorectal cancer are also differentially methylated, reinforcing -regardless of the level of cellular control- their role in the complex of alterations involved in tumorigenesis.These findings were finally validated in an independent cohort from The Cancer Genome Atlas (TCGA).


Assuntos
Adenocarcinoma/genética , Neoplasias Colorretais/genética , Metilação de DNA/genética , Análise por Conglomerados , Humanos
10.
PLoS One ; 9(1): e83926, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24416183

RESUMO

The Brazilian population was formed by extensive admixture of three different ancestral roots: Amerindians, Europeans and Africans. Our previous work has shown that at an individual level, ancestry, as estimated using molecular markers, was a poor predictor of color in Brazilians. We now investigate if SNPs known to be associated with human skin pigmentation can be used to predict color in Brazilians. For that, we studied the association of fifteen SNPs, previously known to be linked with skin color, in 243 unrelated Brazilian individuals self-identified as White, Browns or Blacks from Rio de Janeiro and 212 unrelated Brazilian individuals self-identified as White or Blacks from São Paulo. The significance of association of SNP genotypes with self-assessed color was evaluated using partial regression analysis. After controlling for ancestry estimates as covariates, only four SNPs remained significantly associated with skin pigmentation: rs1426654 and rs2555364 within SLC24A5, rs16891982 at SLC45A2 and rs1042602 at TYR. These loci are known to be involved in melanin synthesis or transport of melanosomes. We found that neither genotypes of these SNPs, nor their combination with biogeographical ancestry in principal component analysis, could predict self-assessed color in Brazilians at an individual level. However, significant correlations did emerge at group level, demonstrating that even though elements other than skin, eye and hair pigmentation do influence self-assessed color in Brazilians, the sociological act of self-classification is still substantially dependent of genotype at these four SNPs.


Assuntos
Estudos de Associação Genética , Variação Genética , Pigmentação/genética , Brasil , Análise por Conglomerados , Genealogia e Heráldica , Genoma Humano/genética , Genótipo , Humanos , Desequilíbrio de Ligação/genética , Polimorfismo de Nucleotídeo Único/genética , Análise de Componente Principal , Análise de Regressão , Software
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