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1.
Ideggyogy Sz ; 72(9-10): 325-336, 2019 Sep 30.
Artigo em Húngaro | MEDLINE | ID: mdl-31625699

RESUMO

With the acceptance of "The developmental origins of health and disease" concept in the 1990s, it became clear that epigenetic inheritance, which do not involve changes in the DNA sequence has important role in the pathogenesis of diseases. Epigenetic regulation serves the adaptation to the changing environment and maintains the reproductive fitness even on the drawback of increased risk of diseases in later life. The role of epigenetic mechanisms in chronic non-communicable diseases has been well established. Recent studies have revealed that epigenetic changes have also causal role in certain pediatric diseases. The review evaluates the recent epigenetic findings in the pathomechanism of common pediatric diseases. The wide range and long-lasting duration of epigenetic regulations give importance to the subject. Methods are already available to evaluate a part of the epigenetic changes in the clinical practice, presently aiming primarily the estimation of the disease risk or definition of diagnosis. Furthermore, there are already available limited means to influence the epigenetic regulation.


Assuntos
Metilação de DNA/fisiologia , Epigênese Genética , Cardiopatias , Infecção , Transtornos Mentais , Doenças Metabólicas , Efeitos Tardios da Exposição Pré-Natal , Criança , Pré-Escolar , Metilação de DNA/genética , Feminino , Cardiopatias/genética , Humanos , Infecção/genética , Transtornos Mentais/genética , Doenças Metabólicas/genética , Pediatria , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética
2.
An Bras Dermatol ; 94(3): 341-343, 2019 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-31365666

RESUMO

CHILD syndrome (Congenital Hemidysplasia, Ichthyosiform erythroderma, Limb Defects) is a rare X-linked dominant disease. The authors report a 2-month-old patient presenting with typical features of CHILD syndrome that was treated with a topical solution containing cholesterol and lovastatin, with complete clearance of her CHILD nevus. The changes in skin lipid metabolism that explain the CHILD ichthyosiform nevus and their correction through topical application of cholesterol and lovastatin are discussed.


Assuntos
Anormalidades Múltiplas/tratamento farmacológico , Anticolesterolemiantes/administração & dosagem , Colesterol/metabolismo , Doenças Genéticas Ligadas ao Cromossomo X/tratamento farmacológico , Eritrodermia Ictiosiforme Congênita/tratamento farmacológico , Deformidades Congênitas dos Membros/tratamento farmacológico , Lovastatina/administração & dosagem , Anormalidades Múltiplas/genética , Administração Tópica , Colesterol/biossíntese , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/genética , Humanos , Eritrodermia Ictiosiforme Congênita/genética , Lactente , Deformidades Congênitas dos Membros/genética , Doenças Metabólicas/genética
3.
J Agric Food Chem ; 67(32): 8735-8739, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31244204

RESUMO

The circadian clock is an intrinsic mechanism of biological adaptation to the cyclical changes of the environment. The circadian rhythm disorders affect the life activities of organisms. A variety of phytochemicals (e.g., polyphenols, flavonoids, alkaloids, and melatonin) reportedly can regulate the expression and rhythm of circadian clock genes and stabilize the internal environment. This perspective focuses on the relationship of circadian clock genes with oxidative stress, inflammatory response, and metabolic disorders and emphasizes the regulation of phytochemicals on the circadian clock. Potential mechanisms and applications of supplemental phytochemicals to improve metabolic disorders and circadian rhythm disorders are also discussed.


Assuntos
Relógios Circadianos , Doenças Metabólicas/fisiopatologia , Compostos Fitoquímicos/metabolismo , Animais , Humanos , Doenças Metabólicas/genética , Doenças Metabólicas/metabolismo , Estresse Oxidativo , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo
4.
Nat Genet ; 51(5): 804-814, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31043758

RESUMO

Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.


Assuntos
Peso ao Nascer/genética , Adulto , Pressão Sanguínea/genética , Estatura/genética , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/genética , Feminino , Desenvolvimento Fetal/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Cardiopatias/etiologia , Cardiopatias/genética , Humanos , Recém-Nascido , Masculino , Herança Materna/genética , Troca Materno-Fetal/genética , Doenças Metabólicas/etiologia , Doenças Metabólicas/genética , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Gravidez , Fatores de Risco
5.
Int J Mol Sci ; 20(8)2019 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-31003407

RESUMO

A growing body of evidence suggests that meal timing is an important factor for metabolic regulation and that the circadian clock tightly interacts with metabolic functions. The proper functioning of the circadian clock is critical for maintaining metabolic health. Therefore, chrononutrition, a novel discipline which investigates the relation between circadian rhythms, nutrition, and metabolism, has attracted increasing attention in recent years. Circadian rhythms are strongly affected by obesity, type 2 diabetes, and other dietary-induced metabolic diseases. With increasing age, the circadian system also undergoes significant changes which contribute to the dysregulation of metabolic rhythms. Metabolic diseases are a major health concern, particularly in light of a growing aging population, and effective approaches for their prevention and treatment are urgently needed. Recently, animal studies have impressively shown beneficial effects of several dietary patterns (e.g., caloric restriction or time-restricted feeding) on circadian rhythms and metabolic outcomes upon nutritional challenges. Whether these dietary patterns show the same beneficial effects in humans is, however, less well studied. As indicated by recent studies, dietary approaches might represent a promising, attractive, and easy-to-adapt strategy for the prevention and therapy of circadian and metabolic disturbances in humans of different age.


Assuntos
Envelhecimento/genética , Restrição Calórica , Relógios Circadianos/genética , Doenças Metabólicas/dietoterapia , Envelhecimento/fisiologia , Animais , Humanos , Doenças Metabólicas/genética , Doenças Metabólicas/fisiopatologia , Avaliação Nutricional
6.
J Genet ; 982019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30945673

RESUMO

Elevated C-reactive protein (CRP) serves as an independent biomarker for acute and chronic inflammation, and is also associated with metabolic diseases. Genomewide loci regulating CRP level in Indian population, a high-risk group for metabolic illness, is unexplored. Therefore, we aimed to discover common polymorphisms associated with plasma CRP level in 4493 Indians of Indo-European origin using genomewide association study. Genomewide strong associations of two known intronic variants in hepatocyte nuclear factor-1 α gene (HNF1A) were identified among Indian subjects. We also detected prior associations of several variants in/near metabolic and inflammatory process genes: APOC1, LEPR, CRP, HNF4A, IL6R and APOE with modest associations. This study confirms that Indians from Indo-European origin display similar core universal genetic factors for CRP levels.


Assuntos
Biomarcadores/análise , Proteína C-Reativa/análise , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Estudo de Associação Genômica Ampla , Inflamação/genética , Doenças Metabólicas/genética , Polimorfismo de Nucleotídeo Único , Adulto , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Índia/epidemiologia , Inflamação/sangue , Inflamação/patologia , Masculino , Doenças Metabólicas/sangue , Doenças Metabólicas/patologia , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco
7.
Dis Model Mech ; 12(3)2019 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-30858282

RESUMO

Five years after the launch of the Disease Models & Mechanisms (DMM) Special Issue on zebrafish as a disease model, the field has progressed significantly. Zebrafish have been used to precisely model human genetic variants, to unpick the mechanisms of metabolic and other diseases, to study infection, inflammation and cancer, and to develop and test new therapeutic approaches. In this Editorial, we highlight recent research published in DMM that uses zebrafish to develop new experimental tools and to provide new insight into disease mechanism and therapy. The broad spectrum of subjects and approaches covered in these articles underscores the versatility of zebrafish in translational research. Further, it highlights the zebrafish community's ethos of creativity and collaboration in translating basic biological research into clinically relevant advances affecting how we understand and treat human disease.


Assuntos
Pesquisa Médica Translacional , Peixe-Zebra/metabolismo , Animais , Modelos Animais de Doenças , Descoberta de Drogas , Genética Humana , Doenças Metabólicas/genética
8.
Nat Commun ; 10(1): 1209, 2019 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-30872577

RESUMO

Sparse profiling of CpG methylation in blood by microarrays has identified epigenetic links to common diseases. Here we apply methylC-capture sequencing (MCC-Seq) in a clinical population of ~200 adipose tissue and matched blood samples (Ntotal~400), providing high-resolution methylation profiling (>1.3 M CpGs) at regulatory elements. We link methylation to cardiometabolic risk through associations to circulating plasma lipid levels and identify lipid-associated CpGs with unique localization patterns in regulatory elements. We show distinct features of tissue-specific versus tissue-independent lipid-linked regulatory regions by contrasting with parallel assessments in ~800 independent adipose tissue and blood samples from the general population. We follow-up on adipose-specific regulatory regions under (1) genetic and (2) epigenetic (environmental) regulation via integrational studies. Overall, the comprehensive sequencing of regulatory element methylomes reveals a rich landscape of functional variants linked genetically as well as epigenetically to plasma lipid traits.


Assuntos
Doenças Cardiovasculares/genética , Ilhas de CpG/genética , Epigênese Genética , Doenças Metabólicas/genética , Sequências Reguladoras de Ácido Nucleico/genética , Tecido Adiposo/metabolismo , Adulto , Idoso , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/metabolismo , Metilação de DNA , Epigenômica/métodos , Feminino , Perfilação da Expressão Gênica , Genoma Humano , Estudo de Associação Genômica Ampla , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Lipídeos/sangue , Masculino , Doenças Metabólicas/sangue , Doenças Metabólicas/metabolismo , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA/métodos
9.
Clin Chim Acta ; 494: 106-111, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30904546

RESUMO

To evaluate the incidence, disease spectrum, and genetic characteristics of inherited metabolic disorders (IMDs) of newborns in Quanzhou area, China. We analyze the expanded newborn screening results of IMDs detected by tandem mass spectrometry (MS/MS) during 5 years. Suspected positive patients were diagnosed through next-generation sequencing and validated by Sanger sequencing. In addition, multiplex ligation-dependent probe amplification technology has also been applied to assist in diagnosis of diseases with deletion or duplication mutations. A total of 364,545 newborns were screened, 130 IMDs were identified yielding an incidence of 1:2804. In addition, 9 cases of maternal disorders were also identified by our MS/MS newborn screening program. There were 42 newborns with amino acid disorders (1:8680), 39 with organic acid disorders (1:9347), and 49 with fatty acid oxidation disorders (1:7440). Unlike other studies, our study indicated that fatty acid oxidation disorder has the highest proportion (37.7%), particularly primary carnitine deficiency (PCD) with incidence up to 1:10,126 was the most common disorder in the region. The recurrent mutations of relatively common diseases like PCD, phenylalanine hydroxylase deficiency, short-chain acyl-CoA dehydrogenase deficiency, citrin deficiency, glutaric acidemia type I, isobutyryl-CoA dehydrogenase deficiency, and multiple acyl-CoA dehydrogenase deficiency in this region were also clearly elucidated. Therefore, our data indicated that IMDs are never uncommon in Quanzhou, the disease spectrum and genetic backgrounds were clearly elucidated, contributing to the treatment and prenatal genetic counseling of these disorders in this region.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Doenças Metabólicas/genética , Triagem Neonatal , China , Feminino , Humanos , Recém-Nascido , Masculino , Mutação , Espectrometria de Massas em Tandem
10.
PLoS Genet ; 15(2): e1007970, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30768595

RESUMO

Identifying regulatory mechanisms that influence inflammation in metabolic tissues is critical for developing novel metabolic disease treatments. Here, we investigated the role of microRNA-146a (miR-146a) during diet-induced obesity in mice. miR-146a is reduced in obese and type 2 diabetic patients and our results reveal that miR-146a-/- mice fed a high-fat diet (HFD) have exaggerated weight gain, increased adiposity, hepatosteatosis, and dysregulated blood glucose levels compared to wild-type controls. Pro-inflammatory genes and NF-κB activation increase in miR-146a-/- mice, indicating a role for this miRNA in regulating inflammatory pathways. RNA-sequencing of adipose tissue macrophages demonstrated a role for miR-146a in regulating both inflammation and cellular metabolism, including the mTOR pathway, during obesity. Further, we demonstrate that miR-146a regulates inflammation, cellular respiration and glycolysis in macrophages through a mechanism involving its direct target Traf6. Finally, we found that administration of rapamycin, an inhibitor of mTOR, was able to rescue the obesity phenotype in miR-146a-/- mice. Altogether, our study provides evidence that miR-146a represses inflammation and diet-induced obesity and regulates metabolic processes at the cellular and organismal levels, demonstrating how the combination of diet and miRNA genetics influences obesity and diabetic phenotypes.


Assuntos
Inflamação/prevenção & controle , Doenças Metabólicas/prevenção & controle , MicroRNAs/genética , MicroRNAs/metabolismo , Animais , Glicemia/metabolismo , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Feminino , Expressão Gênica , Humanos , Hiperglicemia/genética , Hiperglicemia/metabolismo , Hiperglicemia/prevenção & controle , Inflamação/genética , Inflamação/metabolismo , Insulina/sangue , Gordura Intra-Abdominal/metabolismo , Gordura Intra-Abdominal/patologia , Macrófagos/metabolismo , Masculino , Doenças Metabólicas/genética , Doenças Metabólicas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/antagonistas & inibidores , NF-kappa B/metabolismo , Obesidade/genética , Obesidade/metabolismo , Obesidade/prevenção & controle , Proteínas Proto-Oncogênicas c-akt/genética , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/genética , Ganho de Peso/efeitos dos fármacos , Ganho de Peso/genética
11.
Nat Genet ; 51(4): 600-605, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30778224

RESUMO

Microbiome-wide association studies on large population cohorts have highlighted associations between the gut microbiome and complex traits, including type 2 diabetes (T2D) and obesity1. However, the causal relationships remain largely unresolved. We leveraged information from 952 normoglycemic individuals for whom genome-wide genotyping, gut metagenomic sequence and fecal short-chain fatty acid (SCFA) levels were available2, then combined this information with genome-wide-association summary statistics for 17 metabolic and anthropometric traits. Using bidirectional Mendelian randomization (MR) analyses to assess causality3, we found that the host-genetic-driven increase in gut production of the SCFA butyrate was associated with improved insulin response after an oral glucose-tolerance test (P = 9.8 × 10-5), whereas abnormalities in the production or absorption of another SCFA, propionate, were causally related to an increased risk of T2D (P = 0.004). These data provide evidence of a causal effect of the gut microbiome on metabolic traits and support the use of MR as a means to elucidate causal relationships from microbiome-wide association findings.


Assuntos
Ácidos Graxos Voláteis/genética , Microbioma Gastrointestinal/genética , Doenças Metabólicas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Diabetes Mellitus Tipo 2/genética , Feminino , Genótipo , Teste de Tolerância a Glucose/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos , Adulto Jovem
13.
World J Gastroenterol ; 25(7): 859-869, 2019 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-30809085

RESUMO

BACKGROUND: Disorders of primary bile acid synthesis may be life-threatening if undiagnosed, or not treated with primary bile acid replacement therapy. To date, there are few reports on the management and follow-up of patients with Δ4-3-oxosteroid 5ß-reductase (AKR1D1) deficiency. We hypothesized that a retrospective analysis of the responses to oral bile acid replacement therapy with chenodeoxycholic acid (CDCA) in patients with this bile acid synthesis disorder will increase our understanding of the disease progression and permit evaluation of this treatment regimen as an alternative to the Food and Drug Administration (FDA) approved drug cholic acid, which is currently unavailable in China. AIM: To evaluate the therapeutic responses of patients with AKR1D1 deficiency to oral bile acid therapy, specifically CDCA. METHODS: Twelve patients with AKR1D1 deficiency, confirmed by fast atom bombardment ionization-mass spectrometry analysis of urine and by gene sequencing for mutations in AKR1D1, were treated with differing doses of CDCA or ursodeoxycholic acid (UDCA). The clinical and biochemical responses to therapy were monitored over a period ranging 0.5-6.4 years. Dose adjustment, to optimize the therapeutic dose, was based on changes in serum biochemistry parameters, notably liver function tests, and suppression of the urinary levels of atypical hepatotoxic 3-oxo-Δ4-bile acids measured by mass spectrometry. RESULTS: Physical examination, serum biochemistry parameters, and sonographic findings improved in all 12 patients during bile acid therapy, except one who underwent liver transplantation. Urine bile acid analysis confirmed a significant reduction in atypical hepatotoxic 3-oxo-Δ4 bile acids concomitant with clinical and biochemical improvements in those patients treated with CDCA. UDCA was ineffective in down-regulating endogenous bile acid synthesis as evidenced from the inability to suppress the urinary excretion of atypical 3-oxo-Δ4-bile acids. The dose of CDCA required for optimal clinical and biochemical responses varied from 5.5-10 mg/kg per day among patients based on maximum suppression of the atypical bile acids and improvement in serum biochemistry parameters, and careful titration of the dose was necessary to avoid side effects from CDCA. CONCLUSION: The primary bile acid CDCA is effective in treating AKR1D1 deficiency but the therapeutic dose requires individualized optimization. UDCA is not recommended for long-term management.


Assuntos
Ácido Quenodesoxicólico/administração & dosagem , Fármacos Gastrointestinais/administração & dosagem , Doenças Metabólicas/tratamento farmacológico , Oxirredutases/deficiência , Ácido Ursodesoxicólico/administração & dosagem , Administração Oral , Ácido Quenodesoxicólico/efeitos adversos , Análise Mutacional de DNA , Progressão da Doença , Relação Dose-Resposta a Droga , Feminino , Fármacos Gastrointestinais/efeitos adversos , Humanos , Recém-Nascido , Masculino , Doenças Metabólicas/genética , Doenças Metabólicas/urina , Mutação , Oxirredutases/genética , Estudos Retrospectivos , Resultado do Tratamento , Ácido Ursodesoxicólico/efeitos adversos
14.
N C Med J ; 80(1): 49-53, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30622207

RESUMO

This commentary traces the expansion of newborn screening for inherited metabolic disorders during the past 55 years, from the first simple test for phenylketonuria to the current panel of over 35 conditions. Emphasis is placed on the role played by technology and the contributions made by researchers in North Carolina.


Assuntos
Tecnologia Biomédica , Triagem Neonatal , Humanos , Recém-Nascido , Doenças Metabólicas/diagnóstico , Doenças Metabólicas/genética , North Carolina , Fenilcetonúrias/diagnóstico
15.
Biomed Pharmacother ; 111: 657-665, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30611990

RESUMO

A microRNA (miRNA) is a single-stranded, small and non-coding RNA molecule that contains 20-25 nucleotides. More than 2000 miRNAs have been identified in human genes since the first miRNA was discovered in Caenorhabditis elegans in the early 1990s. miRNAs play a crucial role in various biological processes by regulating gene expression through post-transcriptional mechanisms. The alterations of their levels are associated with various diseases, such as glucometabolic disorder and lipid metabolism disorder. In recent years, miRNAs have been proved to be involved in regulating the functions of pancreatic ß-cells, insulin resistance and other biological behaviors related to glucometabolic disorder and the pathogenesis of diabetes mellitus (DM). This review summarized specific miRNAs, including miRNA-375 (miR-375), miRNA-155 (miR-155), miRNA-21 (miR-21), miRNA-33 (miR-33), the let-7 family and some other miRNAs related to glucometabolic regulation, introduced the obstacles and challenges in miRNA therapy, and discussed the prospect of new treatment methods for glucometabolic disorder.


Assuntos
Glucose/metabolismo , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/metabolismo , MicroRNAs/metabolismo , Animais , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/genética , Diabetes Mellitus/metabolismo , Glucose/genética , Humanos , Hiperglicemia/tratamento farmacológico , Hiperglicemia/genética , Hiperglicemia/metabolismo , Insulina/genética , Insulina/metabolismo , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Doenças Metabólicas/genética , MicroRNAs/administração & dosagem , MicroRNAs/genética
16.
J Gastroenterol Hepatol ; 34(2): 330-345, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30550622

RESUMO

We aimed to review the epidemiologic literature examining lifestyle and metabolic risk factors, and blood-based biomarkers including multi-omics (genomics, proteomics, and metabolomics) and to discuss how these predictive markers can inform early diagnosis of pancreatic ductal adenocarcinoma (PDAC). A search of the PubMed database was conducted in June 2018 to review epidemiologic studies of (i) lifestyle and metabolic risk factors for PDAC, genome-wide association studies, and risk prediction models incorporating these factors and (ii) blood-based biomarkers for PDAC (conventional diagnostic markers, metabolomics, and proteomics). Prospective cohort studies have reported at least 20 possible risk factors for PDAC, including smoking, heavy alcohol drinking, adiposity, diabetes, and pancreatitis, but the relative risks and population attributable fractions of individual risk factors are small (mostly < 10%). High-throughput technologies have continued to yield promising genetic, metabolic, and protein biomarkers in addition to conventional biomarkers such as carbohydrate antigen 19-9. Nonetheless, most studies have utilized a hospital-based case-control design, and the diagnostic accuracy is low in studies that collected pre-diagnostic samples. Risk prediction models incorporating lifestyle and metabolic factors as well as other clinical parameters have shown good discrimination and calibration. Combination of traditional risk factors, genomics, and blood-based biomarkers can help identify high-risk populations and inform clinical decisions. Multi-omics investigations can provide valuable insights into disease etiology, but prospective cohort studies that collect pre-diagnostic samples and validation in independent studies are warranted.


Assuntos
Biomarcadores Tumorais/sangue , Carcinoma Ductal Pancreático/sangue , Carcinoma Ductal Pancreático/epidemiologia , Detecção Precoce de Câncer/métodos , Estilo de Vida , Doenças Metabólicas/sangue , Doenças Metabólicas/epidemiologia , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/genética , Feminino , Predisposição Genética para Doença , Genômica , Humanos , Masculino , Doenças Metabólicas/diagnóstico , Doenças Metabólicas/genética , Metabolômica , Pessoa de Meia-Idade , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Valor Preditivo dos Testes , Medição de Risco , Fatores de Risco
17.
Trends Mol Med ; 25(1): 3-5, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30528119

RESUMO

The potential of mRNA to produce therapeutic and protective protein levels is a promising approach for the treatment of a large number of diseases. In a recent study published in Nature Medicine (Published online October 8, 2018. doi.org/10.1038/s41591-018-0199-z), the intravenous delivery of human porphobilinogen deaminase (PBGD) mRNA, targeting the liver, demonstrated its efficacy and safety to replace the defective PBGD protein in preclinical models of acute intermittent porphyria.


Assuntos
Doenças Metabólicas/terapia , Porfiria Aguda Intermitente/terapia , RNA Mensageiro/genética , Animais , Modelos Animais de Doenças , Fígado/metabolismo , Doenças Metabólicas/genética , Nanopartículas/química , Porfiria Aguda Intermitente/genética
18.
Acta Biochim Biophys Sin (Shanghai) ; 51(1): 88-96, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30544157

RESUMO

Propamocarb (PM) is a pesticide that is widely used to protect cucumbers and other plants from downy mildew. Recently, some studies indicated that PM exposure had potential toxic effects in animals. In this study, adult male zebrafish were exposed to 100 and 1000 µg/l PM for 7 days to assess its effects on metabolism and the gut microbiota. We observed a significant decrease in triglyceride (TG) in the livers of zebrafish that were exposed to 1000 µg/l PM for 7 days. At the same time, some genes related to glycolysis and lipid metabolism in the livers of zebrafish, including hexokinase-1 (HK1), pyruvate kinase (PK), acyl-CoA oxidase (Aco), peroxisome proliferator activated receptor alpha (Ppar-α), apolipoprotein A-IV-like (Apo), Acetyl CoA carboxylase-1 (Acc1), diacylglycerol acyltransferase (Dgat), and fatty acid synthase (Fas), were also decreased significantly after PM exposure. Based on GC-MS metabolomics analysis, a total of 48 metabolites changed significantly in the 1000 µg/l PM treatment group in comparison with the control group. These altered metabolites were mainly associated with the glycolysis, amino acid metabolism, and lipid metabolism pathways. Interestingly, we further found that the 1000 µg/l PM treatment group also showed significant elevations in Proteobacteria, Bacteroidetes, and Firmicutes at the phylum level. Sequencing of the 16S rRNA gene in the V3-V4 region also showed a significant change in the abundance and diversity of the gut microbiota in the 1000 µg/l PM treatment group. Our results indicated that exposure to PM for a short time could induce hepatic metabolic disorders and gut microbiota dysbiosis in adult male zebrafish.


Assuntos
Carbamatos/toxicidade , Disbiose/fisiopatologia , Microbioma Gastrointestinal/efeitos dos fármacos , Fígado/efeitos dos fármacos , Doenças Metabólicas/fisiopatologia , Animais , Bactérias/classificação , Bactérias/genética , Disbiose/induzido quimicamente , Disbiose/genética , Microbioma Gastrointestinal/genética , Microbioma Gastrointestinal/fisiologia , Expressão Gênica/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Doenças Metabólicas/induzido quimicamente , Doenças Metabólicas/genética , Metabolômica/métodos , RNA Ribossômico 16S/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Fatores de Tempo , Testes de Toxicidade , Peixe-Zebra
19.
Environ Pollut ; 246: 45-52, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30529940

RESUMO

Exposure to airborne particulate matter (PM) 2.5 induced various adverse health effects, such as metabolic syndrome, systemic inflammation and respiratory infection. However, a global influence of PM2.5-induced metabolic and proteomic disorders remains confusing, and the underlying mechanism is still under-explored. Herein, LC-MS/MS-based metabolomics, lipidomics and isobaric tags for relative and absolute quantification (iTRAQ)-based proteomics were applied to analyze the toxicological characteristics of PM2.5 from Taiyuan City in China (Taiyuan-PM2.5) on human lung carcinoma cells (A549) after the 24-h treatment. Metabolites, lipids and proteins that have distinctive differences were screened by SIEVE, LipidSearch and Proteome Discoverer, respectively. The abundance of 56 metabolites (40 increased and 16 decreased), 22 lipids (19 increased and 3 decreased) and 81 proteins (55 up-regulated and 26 down-regulated) were significantly changed upon the PM2.5 treatment. Among the proteomics analysis, 16 proteins were specifically related to RNA splicing, mainly including up-regulated serine/arginine-rich splicing factor 1 (SRSF1), SRSF2, small nuclear ribonucleoprotein 70 kDa (snRNP70), small nuclear ribonucleoprotein polypeptide B (SNRPB), SNRPC, SNRPE and down-regulated heterogeneous nuclear ribonucleoprotein U-like 2 (hnRNP UL2). At the metabolic level, PM2.5 exposure significantly altered the sphingolipid metabolism, including ceramide, serine, sphingosine and sphingomyelin. It was proposed that excessive accumulation of ceramide and expression of key enzymes (ceramide synthases, phingomyelinase, sphingosine kinase types 2 and protein phosphatase-1) induced the secretion of pro-inflammatory cytokines, generation of lipotoxicity and alterations of RNA splicing in PM2.5-treated A549  cells. In general, our results demonstrated that ceramide accumulation and altered RNA splicing could becritical contributors to PM2.5-induced cytotoxicity at metabolic and proteomic level, which might be considered as potential markers for toxicological evaluation of PM2.5 samples.


Assuntos
Poluentes Atmosféricos/toxicidade , Doenças Metabólicas/etiologia , Material Particulado/toxicidade , Células A549 , Expressão Gênica/efeitos dos fármacos , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Doenças Metabólicas/genética , Doenças Metabólicas/metabolismo , Metabolômica , Proteômica , Fatores de Processamento de RNA/genética
20.
Int J Mol Sci ; 19(12)2018 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-30567372

RESUMO

The regulation of cellular metabolism is coordinated through a tissue cross-talk by hormonal control. This leads to the establishment of specific transcriptional gene programs which adapt to environmental stimuli. On the other hand, recent advances suggest that metabolic pathways could directly signal into chromatin modifications and impact on specific gene programs. The key metabolites acetyl-CoA or S-adenosyl-methionine (SAM) are examples of important metabolic hubs which play in addition a role in chromatin acetylation and methylation. In this review, we will discuss how intermediary metabolism impacts on transcription regulation and the epigenome with a particular focus in metabolic disorders.


Assuntos
Cromatina/genética , Epigênese Genética , Doenças Metabólicas/genética , Redes e Vias Metabólicas/genética , Acetilação , Cromatina/metabolismo , Regulação da Expressão Gênica/genética , Histonas/genética , Histonas/metabolismo , Humanos , Doenças Metabólicas/patologia , Metilação
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