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1.
Int J Mol Sci ; 22(4)2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33670113

RESUMO

The mechanistic target of rapamycin (mTOR) is a master regulator of cell growth, proliferation, and metabolism by integrating various environmental inputs including growth factors, nutrients, and energy, among others. mTOR signaling has been demonstrated to control almost all fundamental cellular processes, such as nucleotide, protein and lipid synthesis, autophagy, and apoptosis. Over the past fifteen years, mapping the network of the mTOR pathway has dramatically advanced our understanding of its upstream and downstream signaling. Dysregulation of the mTOR pathway is frequently associated with a variety of human diseases, such as cancers, metabolic diseases, and cardiovascular and neurodegenerative disorders. Besides genetic alterations, aberrancies in post-translational modifications (PTMs) of the mTOR components are the major causes of the aberrant mTOR signaling in a number of pathologies. In this review, we summarize current understanding of PTMs-mediated regulation of mTOR signaling, and also update the progress on targeting the mTOR pathway and PTM-related enzymes for treatment of human diseases.


Assuntos
Doenças Cardiovasculares/metabolismo , Doenças Metabólicas/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias/metabolismo , Doenças Neurodegenerativas/metabolismo , Processamento de Proteína Pós-Traducional , Serina-Treonina Quinases TOR/metabolismo , Doenças Cardiovasculares/genética , Proliferação de Células , Humanos , Doenças Metabólicas/genética , Proteínas de Neoplasias/genética , Neoplasias/genética , Doenças Neurodegenerativas/genética , Transdução de Sinais , Serina-Treonina Quinases TOR/genética
2.
Bratisl Lek Listy ; 122(3): 190-195, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33618527

RESUMO

AIM: Congenital disorders of glycosylation (CDG) belong to an expanding group of rare genetic metabolic disorders caused by defects in the complex chemical enzymatic process of glycosylation. The study is aimed at presenting a case report of a premature dysmorphic newborn, clinical presentation of the condition, the way it was diagnosed and treated, as well as its comparison with the known cases. RESULTS: The result of glycan analysis supports the assumption of a supposed glycosylation disorder and also specifies a specific subtype: CDG-1, subtype ALG12-CDG (Ig). CONCLUSION: CDG have an extremely wide clinical spectrum and should be considered in any child with unexplained developmental delay, failure to thrive, seizures, and abnormalities in liver enzymes, coagulation and immunologic factors. The treatment of most forms of CDG depends upon numerous factors such as specific symptoms present, severity of the disorder, age and overall health of the patients and tolerance to certain medications or procedures. For these reasons, the treatment is specific for every individual. It is based on the symptoms and requires a coordination of efforts of a team of specialists (Tab. 4, Fig. 3, Ref. 19).


Assuntos
Defeitos Congênitos da Glicosilação , Doenças Metabólicas , Criança , Defeitos Congênitos da Glicosilação/diagnóstico , Defeitos Congênitos da Glicosilação/genética , Glicosilação , Humanos , Recém-Nascido , Programas de Rastreamento , Doenças Metabólicas/diagnóstico , Doenças Metabólicas/genética
3.
Clin Sci (Lond) ; 135(3): 535-554, 2021 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-33533405

RESUMO

The renin-angiotensin system (RAS) has currently attracted increasing attention due to its potential function in regulating energy homeostasis, other than the actions on cellular growth, blood pressure, fluid, and electrolyte balance. The existence of RAS is well established in metabolic organs, including pancreas, liver, skeletal muscle, and adipose tissue, where activation of angiotensin-converting enzyme (ACE) - angiotensin II pathway contributes to the impairment of insulin secretion, glucose transport, fat distribution, and adipokines production. However, the activation of angiotensin-converting enzyme 2 (ACE2) - angiotensin (1-7) pathway, a novel branch of the RAS, plays an opposite role in the ACE pathway, which could reverse these consequences by improving local microcirculation, inflammation, stress state, structure remolding, and insulin signaling pathway. In addition, new studies indicate the protective RAS arm possesses extraordinary ability to enhance brown adipose tissue (BAT) activity and induces browning of white adipose tissue, and consequently, it leads to increased energy expenditure in the form of heat instead of ATP synthesis. Interestingly, ACE2 is the receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is threating public health worldwide. The main complications of SARS-CoV-2 infected death patients include many energy metabolism-related chronic diseases, such as diabetes. The specific mechanism leading to this phenomenon is largely unknown. Here, we summarize the latest pharmacological and genetic tools on regulating ACE/ACE2 balance and highlight the beneficial effects of the ACE2 pathway axis hyperactivity on glycolipid metabolism, as well as the thermogenic modulation.


Assuntos
/metabolismo , Doenças Metabólicas/enzimologia , /genética , Animais , /metabolismo , Metabolismo Energético , Humanos , Doenças Metabólicas/genética , Doenças Metabólicas/metabolismo , Doenças Metabólicas/virologia , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Sistema Renina-Angiotensina , /fisiologia
4.
PLoS One ; 15(12): e0244826, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33382823

RESUMO

BACKGROUND: There is lots of evidence that maternal peri-gestational metabolic, genomic and environmental conditions are closely linked to metabolic and cardiovascular outcomes in their offspring later in life. Moreover, there is also lotsof evidence that underlining mechanisms, such as molecular as well as epigenetic changes may alter the intrauterine environment leading to cardio-metabolic diseases in their offspring postnatal. But, there is also increasing evidence that cardio-metabolic diseases may be closely linked to their paternal metabolic risk factors, such as obesity, Type 2 Diabetes and other risk factors. OBJECTIVE: To analyse the evidence as well as specific risk factors of paternal trans-generational programming of cardio-metabolic diseases in their offspring. METHODS: Within a systematic scoping review, we performed a literature search in MEDLINE (PubMed) and EMBASE databases in August 2020 considering original research articles (2000-2020) that examined the impact of paternal programming on metabolic and cardiovascular offspring health. Epidemiological, clinical and experimental studies as well as human and animal model studies were included. RESULTS: From n = 3.199 citations, n = 66 eligible studies were included. We selected n = 45 epidemiological as well as clinical studies and n = 21 experimental studies. In brief, pre-conceptional paternal risk factors, such as obesity, own birth weight, high-fat and low-protein diet, undernutrition, diabetes mellitus, hyperglycaemia, advanced age, smoking as well as environmental chemical exposure affect clearly metabolic and cardiovascular health of their offspring later in life. CONCLUSIONS: There is emerging evidence that paternal risk factors, such as paternal obesity, diabetes mellitus, nutritional habits, advanced age and exposure to environmental chemicals or cigarette smoke, are clearly associated with adverse effects in metabolic and cardiovascular health in their offspring. Compared to maternal programming, pre-conceptional paternal factors might also have also a substantial effect in the sense of trans-generational programming of their offspring and need further research.


Assuntos
Doenças Cardiovasculares/genética , Epigênese Genética , Desenvolvimento Fetal/fisiologia , Doenças Metabólicas/genética , Peso ao Nascer/genética , Pai , Feminino , Humanos , Masculino , Fatores de Risco
5.
Nat Commun ; 11(1): 5210, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-33060578

RESUMO

Human insulinomas are rare, benign, slowly proliferating, insulin-producing beta cell tumors that provide a molecular "recipe" or "roadmap" for pathways that control human beta cell regeneration. An earlier study revealed abnormal methylation in the imprinted p15.5-p15.4 region of chromosome 11, known to be abnormally methylated in another disorder of expanded beta cell mass and function: the focal variant of congenital hyperinsulinism. Here, we compare deep DNA methylome sequencing on 19 human insulinomas, and five sets of normal beta cells. We find a remarkably consistent, abnormal methylation pattern in insulinomas. The findings suggest that abnormal insulin (INS) promoter methylation and altered transcription factor expression create alternative drivers of INS expression, replacing canonical PDX1-driven beta cell specification with a pathological, looping, distal enhancer-based form of transcriptional regulation. Finally, NFaT transcription factors, rather than the canonical PDX1 enhancer complex, are predicted to drive INS transactivation.


Assuntos
Regulação Neoplásica da Expressão Gênica , Insulina/genética , Insulina/metabolismo , Insulinoma/genética , Insulinoma/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Adulto , Idoso , Sítios de Ligação , Biologia Computacional , Metilação de DNA , Feminino , Proteínas de Homeodomínio/metabolismo , Humanos , Células Secretoras de Insulina/metabolismo , Masculino , Doenças Metabólicas/genética , Doenças Metabólicas/metabolismo , Pessoa de Meia-Idade , Regiões Promotoras Genéticas , Transativadores/metabolismo , Fatores de Transcrição/química , Fatores de Transcrição/metabolismo , Adulto Jovem
6.
Am J Chin Med ; 48(6): 1409-1433, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32907360

RESUMO

Scutellaria baicalensis (SB), a herbal medicine, is commonly used to treat metabolic diseases, while Metformin (MF) is a widely used drug for type 2 diabetes. The purpose of this study was to investigate whether co-treatment of SB with MF could produce a potential therapeutic effect on high-fat and high-fructose diet (HFFD)-induced metabolic dysregulation. First, we optimized the dose of SB (100, 200, 400, and 800[Formula: see text]mg/kg) with MF (200[Formula: see text]mg/kg) in HFFD-induced C57BL6J mice. Next, the optimized dose of SB (400[Formula: see text]mg/kg) was co-administered with MF (50, 100, and 200[Formula: see text]mg/kg) in a similar animal model to find the effective combinations of SB and MF. Metabolic markers were determined in serum and tissues using different assays, histology, gene expression, and gut microbial population. The SB and MF co-treatment significantly decreased the body, liver, and VAT weights. The outcome of OGTT was improved, and the fasting insulin, HbA1c, TG, TC, LDL-c, AST, and ALT were decreased, while HDL-c was significantly increased. Histological analyses revealed maintained the integrity of liver, adipose tissue, and intestine prevented lipid accumulation in the liver and intestine and combated neuronal damage in the brain. Importantly, controlled the expression of PPAR[Formula: see text], and IL-6 genes in the liver, and expression of BDNF, Glut1, Glut3, and Glut4 genes in the brain. Treatment-specific gut microbial segregation was observed in the PCA chart. Our findings indicate that SB and MF co-treatment is an effective therapeutic approach for HFFD-induced metabolic dysregulation which is operated through the gut-liver-brain axis.


Assuntos
Encéfalo/metabolismo , Microbioma Gastrointestinal , Fígado/metabolismo , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/metabolismo , Metformina/administração & dosagem , Metformina/farmacologia , Fitoterapia , Extratos Vegetais/administração & dosagem , Extratos Vegetais/farmacologia , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Dieta da Carga de Carboidratos/efeitos adversos , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Quimioterapia Combinada , Transportador de Glucose Tipo 1/genética , Transportador de Glucose Tipo 1/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Doenças Metabólicas/genética , Doenças Metabólicas/microbiologia , Camundongos Endogâmicos C57BL , PPAR gama/genética , PPAR gama/metabolismo
8.
Nat Commun ; 11(1): 3861, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32737316

RESUMO

Integrating results from genome-wide association studies (GWASs) and gene expression studies through transcriptome-wide association study (TWAS) has the potential to shed light on the causal molecular mechanisms underlying disease etiology. Here, we present a probabilistic Mendelian randomization (MR) method, PMR-Egger, for TWAS applications. PMR-Egger relies on a MR likelihood framework that unifies many existing TWAS and MR methods, accommodates multiple correlated instruments, tests the causal effect of gene on trait in the presence of horizontal pleiotropy, and is scalable to hundreds of thousands of individuals. In simulations, PMR-Egger provides calibrated type I error control for causal effect testing in the presence of horizontal pleiotropic effects, is reasonably robust under various types of model misspecifications, is more powerful than existing TWAS/MR approaches, and can directly test for horizontal pleiotropy. We illustrate the benefits of PMR-Egger in applications to 39 diseases and complex traits obtained from three GWASs including the UK Biobank.


Assuntos
Pleiotropia Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Análise da Randomização Mendeliana/estatística & dados numéricos , Modelos Genéticos , Transcriptoma , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/patologia , Simulação por Computador , Bases de Dados Factuais , Gastroenteropatias/diagnóstico , Gastroenteropatias/genética , Gastroenteropatias/patologia , Humanos , Doenças do Sistema Imunitário/diagnóstico , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/patologia , Funções Verossimilhança , Doenças Metabólicas/diagnóstico , Doenças Metabólicas/genética , Doenças Metabólicas/patologia , Herança Multifatorial , Neoplasias/diagnóstico , Neoplasias/genética , Neoplasias/patologia , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia
9.
Am J Hum Genet ; 107(4): 596-611, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32853555

RESUMO

Newborn screening (NBS) was established as a public health program in the 1960s and is crucial for facilitating detection of certain medical conditions in which early intervention can prevent serious, life-threatening health problems. Genomic sequencing can potentially expand the screening for rare hereditary disorders, but many questions surround its possible use for this purpose. We examined the use of exome sequencing (ES) for NBS in the North Carolina Newborn Exome Sequencing for Universal Screening (NC NEXUS) project, comparing the yield from ES used in a screening versus a diagnostic context. We enrolled healthy newborns and children with metabolic diseases or hearing loss (106 participants total). ES confirmed the participant's underlying diagnosis in 15 out of 17 (88%) children with metabolic disorders and in 5 out of 28 (∼18%) children with hearing loss. We discovered actionable findings in four participants that would not have been detected by standard NBS. A subset of parents was eligible to receive additional information for their child about childhood-onset conditions with low or no clinical actionability, clinically actionable adult-onset conditions, and carrier status for autosomal-recessive conditions. We found pathogenic variants associated with hereditary breast and/or ovarian cancer in two children, a likely pathogenic variant in the gene associated with Lowe syndrome in one child, and an average of 1.8 reportable variants per child for carrier results. These results highlight the benefits and limitations of using genomic sequencing for NBS and the challenges of using such technology in future precision medicine approaches.


Assuntos
Neoplasias da Mama/diagnóstico , Testes Genéticos/estatística & dados numéricos , Perda Auditiva/diagnóstico , Doenças Metabólicas/diagnóstico , Síndrome Oculocerebrorrenal/diagnóstico , Neoplasias Ovarianas/diagnóstico , Neoplasias da Mama/genética , Pré-Escolar , Feminino , Genoma Humano , Perda Auditiva/genética , Heterozigoto , Humanos , Lactente , Recém-Nascido , Masculino , Doenças Metabólicas/genética , Triagem Neonatal , North Carolina , Síndrome Oculocerebrorrenal/genética , Neoplasias Ovarianas/genética , Saúde Pública/métodos , Sequenciamento Completo do Exoma
10.
Nutr Metab Cardiovasc Dis ; 30(10): 1609-1621, 2020 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-32682747

RESUMO

BACKGROUND AND AIMS: Studies of twins can reduce confounding and provide additional evidence about the causes of disease, due to within-pair matching for measured and unmeasured factors. Although findings from twin studies are typically applicable to the general population, few studies have taken full advantage of the twin design to explore the developmental origins of cardiometabolic health outcomes. We aimed to systematically review the evidence from twin studies and generate pooled estimates for the effects of early-life risk factors on later-life cardiometabolic health. METHODS AND RESULTS: An initial search was conducted in March 2018, with 55 studies of twins included in the review. Risk of bias was assessed using the Newcastle-Ottawa Scale, and eligible studies were included in a meta-analysis, where pooled estimates were calculated. Twenty-six studies analysed twins as individuals, and found that higher birthweight was associated with lower SBP (ß = -2.02 mmHg, 95%CI: -3.07, -0.97), higher BMI (ß = 0.52 kg/m2, 95%CI: 0.20, 0.84) and lower total cholesterol (ß = -0.07 mmol/L, 95%CI: -0.11, -0.04). However, no associations were reported in studies which adjusted for gestational age. Few of the included studies separated their analyses into within-pair and between-pair associations. CONCLUSIONS: Early-life risk factors were associated with cardiometabolic health outcomes in twin studies. However, many estimates from studies in this review were likely to have been confounded by gestational age, and few fully exploited the twin design to assess the developmental origins of cardiometabolic health outcomes.


Assuntos
Doenças Cardiovasculares/etiologia , Doenças em Gêmeos/etiologia , Doenças Metabólicas/etiologia , Gêmeos , Adiposidade , Adolescente , Adulto , Idoso , Biomarcadores/sangue , Peso ao Nascer , Glicemia/metabolismo , Pressão Sanguínea , Índice de Massa Corporal , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/fisiopatologia , Criança , Pré-Escolar , Colesterol/sangue , Doenças em Gêmeos/sangue , Doenças em Gêmeos/genética , Doenças em Gêmeos/fisiopatologia , Feminino , Idade Gestacional , Nível de Saúde , Humanos , Insulina/sangue , Masculino , Doenças Metabólicas/sangue , Doenças Metabólicas/genética , Doenças Metabólicas/fisiopatologia , Pessoa de Meia-Idade , Estudos Observacionais como Assunto , Fatores de Risco , Estudos em Gêmeos como Assunto , Adulto Jovem
11.
Vet Clin North Am Equine Pract ; 36(2): 341-352, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32534851

RESUMO

A role for a genetic contribution to equine metabolic syndrome (EMS) and pars pituitary intermedia dysfunction (PPID) has been hypothesized. Heritability estimates of EMS biochemical measurements were consistent with moderately to highly heritable traits. Further, genome-wide association analyses have identified hundreds of regions of the genome contributing to EMS and candidate variants have been identified. The genetics of PPID has not yet been proven. Continued research for the specific genetic risk factors for both EMS and PPID is crucial for gaining a better understanding of the pathophysiology of both conditions and allowing development of genetic tests.


Assuntos
Doenças do Sistema Endócrino/veterinária , Doenças dos Cavalos/genética , Doenças Metabólicas/veterinária , Animais , Doenças do Sistema Endócrino/genética , Estudo de Associação Genômica Ampla/veterinária , Cavalos , Doenças Metabólicas/genética
12.
Maturitas ; 135: 6-26, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32252966

RESUMO

Sex is a major determinant of cardiometabolic risk. DNA methylation (DNAm), an important epigenetic mechanism that differs between sexes, has been associated with cardiometabolic diseases. Therefore, we aimed to systematically review studies in adults investigating sex-specific associations of DNAm with intermediate cardiometabolic traits and incident cardiovascular disease including stroke, myocardial infarction (MI) and coronary heart disease (CHD). Five bibliographic databases were searched from inception to 15 July 2019. We selected 35 articles (based on 30 unique studies) from 17,023 references identified, with a total of 14,020 participants of European, North American or Asian ancestry. Four studies reported sex differences between global DNAm and blood lipid levels and stroke risk. In 25 studies that took a genome wide or candidate gene approach, DNAm at 31 gene sites was associated with sex differences in cardiometabolic diseases. The identified genes were PLA2G7, BCL11A, KDM6A, LIPC, ABCG1, PLTP, CETP, ADD1, CNN1B, HOOK2, GFBP-7,PTPN1, GCK, PTX3, ABCG1, GALNT2, CDKN2B, APOE, CTH, GNASAS, INS, PON1, TCN2, CBS, AMT, KDMA6A, FTO, MAP3K13, CCDC8, MMP-2 and ER-α. Prioritized pathway connectivity analysis associated these genes with biological pathways such as vitamin B12 metabolism, statin pathway, plasma lipoprotein, plasma lipoprotein assembly, remodeling and clearance and cholesterol metabolism. Our findings suggest that DNAm might be a promising molecular strategy for understanding sex differences in the pathophysiology of cardiometabolic diseases and that future studies should investigate the effects of sex on epigenetic mechanisms in cardiometabolic risk. In addition, we emphasize the gap between the translational potential and the clinical utilization of cardiometabolic epigenetics.


Assuntos
Doenças Cardiovasculares/genética , Metilação de DNA , Doenças Metabólicas/genética , Caracteres Sexuais , Humanos
13.
Nat Commun ; 11(1): 1914, 2020 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-32313051

RESUMO

Obesity is associated with the activation of cellular responses, such as endoplasmic reticulum (ER) stress. Here, we show that leptin-deficient ob/ob mice display elevated hypothalamic ER stress as early as postnatal day 10, i.e., prior to the development of obesity in this mouse model. Neonatal treatment of ob/ob mice with the ER stress-relieving drug tauroursodeoxycholic acid (TUDCA) causes long-term amelioration of body weight, food intake, glucose homeostasis, and pro-opiomelanocortin (POMC) projections. Cells exposed to ER stress often activate autophagy. Accordingly, we report that in vitro induction of ER stress and neonatal leptin deficiency in vivo activate hypothalamic autophagy-related genes. Furthermore, genetic deletion of autophagy in pro-opiomelanocortin neurons of ob/ob mice worsens their glucose homeostasis, adiposity, hyperphagia, and POMC neuronal projections, all of which are ameliorated with neonatal TUDCA treatment. Together, our data highlight the importance of early life ER stress-autophagy pathway in influencing hypothalamic circuits and metabolic regulation.


Assuntos
Autofagia/fisiologia , Estresse do Retículo Endoplasmático/fisiologia , Metabolismo Energético/fisiologia , Hipotálamo/metabolismo , Leptina/metabolismo , Neurogênese/fisiologia , Adiposidade , Animais , Antivirais/farmacologia , Autofagia/efeitos dos fármacos , Autofagia/genética , Proteína 7 Relacionada à Autofagia/genética , Peso Corporal/efeitos dos fármacos , Peso Corporal/fisiologia , Colagogos e Coleréticos/farmacologia , Modelos Animais de Doenças , Ingestão de Alimentos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/genética , Comportamento Alimentar , Homeostase , Hiperfagia/metabolismo , Leptina/genética , Masculino , Doenças Metabólicas/genética , Doenças Metabólicas/metabolismo , Camundongos , Camundongos Endogâmicos , Camundongos Knockout , Neuroendocrinologia , Neurogênese/efeitos dos fármacos , Obesidade/metabolismo , Pró-Opiomelanocortina/metabolismo , Ácido Tauroquenodesoxicólico
14.
Nat Med ; 26(4): 549-557, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32273609

RESUMO

Polygenic risk scores (PRSs) have shown promise in predicting susceptibility to common diseases1-3. We estimated their added value in clinical risk prediction of five common diseases, using large-scale biobank data (FinnGen; n = 135,300) and the FINRISK study with clinical risk factors to test genome-wide PRSs for coronary heart disease, type 2 diabetes, atrial fibrillation, breast cancer and prostate cancer. We evaluated the lifetime risk at different PRS levels, and the impact on disease onset and on prediction together with clinical risk scores. Compared to having an average PRS, having a high PRS contributed 21% to 38% higher lifetime risk, and 4 to 9 years earlier disease onset. PRSs improved model discrimination over age and sex in type 2 diabetes, atrial fibrillation, breast cancer and prostate cancer, and over clinical risk in type 2 diabetes, breast cancer and prostate cancer. In all diseases, PRSs improved reclassification over clinical thresholds, with the largest net reclassification improvements for early-onset coronary heart disease, atrial fibrillation and prostate cancer. This study provides evidence for the additional value of PRSs in clinical disease prediction. The practical applications of polygenic risk information for stratified screening or for guiding lifestyle and medical interventions in the clinical setting remain to be defined in further studies.


Assuntos
Doenças Cardiovasculares , Predisposição Genética para Doença , Doenças Metabólicas , Herança Multifatorial , Neoplasias , Adulto , Idade de Início , Biomarcadores/análise , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Feminino , Finlândia/epidemiologia , Marcadores Genéticos/genética , Predisposição Genética para Doença/epidemiologia , Estudo de Associação Genômica Ampla , Humanos , Masculino , Doenças Metabólicas/diagnóstico , Doenças Metabólicas/epidemiologia , Doenças Metabólicas/genética , Pessoa de Meia-Idade , Neoplasias/diagnóstico , Neoplasias/epidemiologia , Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Valor Preditivo dos Testes , Prognóstico , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/genética , Medição de Risco , Fatores de Risco , Adulto Jovem
15.
Biochim Biophys Acta Mol Basis Dis ; 1866(6): 165761, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32169503

RESUMO

It is well-known that mitochondrial DNA (mtDNA) can escape to intracellular or extracellular compartments under different stress conditions, yet understanding their escape mechanisms remains a challenge. Although Bax/Bak pores and VDAC oligomers are the strongest possibilities, other mechanisms may be involved. For example, mitochondria permeability transition, altered mitophagy, and mitochondrial dynamics are associated with intracellular mtDNA escape, while extracellular traps and extracellular vesicles can participate in extracellular mtDNA escape. The evidence suggests that mtDNA escape is a complex event with more than one mechanism involved. In addition, once the mtDNA is outside the mitochondria, the effects can be complex. Different danger signal sensors recognize the mtDNA as a damage-associated molecular pattern, triggering an innate immune inflammatory response that can be observed in multiple metabolic diseases characterized by chronic inflammation, including autoimmune diseases, diabetes, cancer, and cardiovascular disorders. For these reasons, we will review the most recent evidence regarding mtDNA escape mechanisms and their impact on different metabolic diseases.


Assuntos
DNA Mitocondrial/genética , Doenças Metabólicas/genética , Mitocôndrias/genética , Estresse Oxidativo/genética , Humanos , Inflamação/genética , Doenças Metabólicas/imunologia , Doenças Metabólicas/metabolismo , Doenças Metabólicas/patologia , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Transdução de Sinais/genética
16.
Mutat Res ; 783: 108295, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32192649

RESUMO

Increasing evidence suggests that early-life events can predispose the newborn to a variety of health issues in later life. In adverse pre- and perinatal conditions, oxidative stress appears to play an important role in the development of future pathological outcomes. From a molecular point of view, oxidative stress can result in genome damage and changes in DNA methylation that can in turn prime pathogenic mechanisms. Interestingly, both alterations have been related to a reciprocal regulation of oxidative stress. The aim of this review is to give a brief overview of the complex relationship linking oxidative stress to DNA damage and methylation and to go through the different sources of exposure that a neonate can encounter in utero or shortly after birth. In this context, the setup of methodologies to monitor the extent of oxidative stress, genomic damage and instability or the presence of altered methylation patterns contributes to the understanding on how the complex events occurring in early life can lead to either a healthy status or a pathological condition.


Assuntos
Dano ao DNA , Metilação de DNA , Estresse Oxidativo , Exposição Ambiental/efeitos adversos , Epigênese Genética , Feminino , Humanos , Recém-Nascido , Doenças Metabólicas/genética , Doenças Metabólicas/metabolismo , Gravidez , Complicações na Gravidez/genética , Complicações na Gravidez/metabolismo , Nascimento Prematuro
17.
Molecules ; 25(6)2020 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-32204420

RESUMO

In mammals, a family of three inositol hexakisphosphate kinases (IP6Ks) synthesizes the inositol pyrophosphate 5-IP7 from IP6. Genetic deletion of Ip6k1 protects mice from high fat diet induced obesity, insulin resistance and fatty liver. IP6K1 generated 5-IP7 promotes insulin secretion from pancreatic ß-cells, whereas it reduces insulin signaling in metabolic tissues by inhibiting the protein kinase Akt. Thus, IP6K1 promotes high fat diet induced hyperinsulinemia and insulin resistance in mice while its deletion has the opposite effects. IP6K1 also promotes fat accumulation in the adipose tissue by inhibiting the protein kinase AMPK mediated energy expenditure. Genetic deletion of Ip6k3 protects mice from age induced fat accumulation and insulin resistance. Accordingly, the pan IP6K inhibitor TNP [N2-(m-trifluorobenzyl), N6-(p-nitrobenzyl)purine] ameliorates obesity, insulin resistance and fatty liver in diet induced obese mice by improving Akt and AMPK mediated insulin sensitivity and energy expenditure. TNP also protects mice from bone loss, myocardial infarction and ischemia reperfusion injury. Thus, the IP6K pathway is a potential target in obesity and other metabolic diseases. Here, we summarize the studies that established IP6Ks as a potential target in metabolic diseases. Further studies will reveal whether inhibition of this pathway has similar pleiotropic benefits on metabolic health of humans.


Assuntos
Inibidores Enzimáticos/farmacologia , Doenças Metabólicas/genética , Fosfotransferases (Aceptor do Grupo Fosfato)/genética , Animais , Metabolismo Energético/efeitos dos fármacos , Inibidores Enzimáticos/uso terapêutico , Humanos , Fosfatos de Inositol/metabolismo , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/metabolismo , Camundongos , Terapia de Alvo Molecular , Fosfotransferases (Aceptor do Grupo Fosfato)/antagonistas & inibidores , Fosfotransferases (Aceptor do Grupo Fosfato)/metabolismo , Ácido Fítico/metabolismo
18.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(4): 367-372, 2020 Apr 10.
Artigo em Chinês | MEDLINE | ID: mdl-32219815

RESUMO

Follow-up is a crucial step for the screening of neonatal genetic and metabolic diseases, which can directly influence the detection, diagnosis, efficacy of treatment, as well as the quality of neonatal screening. In view of the lack of follow-up, full understanding, and inconsistent requirement between various agencies and personnel in China, there is an urgent need for standardization. The Committee for Proficiency Testing of the Neonatal Genetic Metabolic Disease Screening Center of the National Health Committee of China has organized the writing of expert consensus for follow-up of neonatal genetic and metabolic disease screening after thorough discussion, so as to guide the follow-up work and improve its quality.


Assuntos
Doenças Genéticas Inatas/diagnóstico , Doenças Metabólicas , Triagem Neonatal , China , Consenso , Seguimentos , Humanos , Recém-Nascido , Doenças Metabólicas/diagnóstico , Doenças Metabólicas/genética
19.
Biochim Biophys Acta Mol Basis Dis ; 1866(6): 165716, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32061776

RESUMO

Thiosulfate sulfurtransferase (TST, EC 2.8.1.1), also known as Rhodanese, is a mitochondrial enzyme which catalyzes the transfer of sulfur in several molecular pathways. After its initial identification as a cyanide detoxification enzyme, it was found that its functions also include sulfur metabolism, modification of iron­sulfur clusters and the reduction of antioxidants glutathione and thioredoxin. TST deficiency was shown to be strongly related to the pathophysiology of metabolic diseases including diabetes and obesity. This review summarizes research related to the enzymatic properties and functions of TST, to then explore the association between the effects of TST on mitochondria and development of diseases such as diabetes and obesity.


Assuntos
Antioxidantes/metabolismo , Doenças Metabólicas/genética , Enxofre/metabolismo , Tiossulfato Sulfurtransferase/genética , Glutationa/metabolismo , Humanos , Proteínas com Ferro-Enxofre/genética , Doenças Metabólicas/enzimologia , Doenças Metabólicas/patologia , Selênio/metabolismo , Tiorredoxinas/genética , Tiorredoxinas/metabolismo , Tiossulfato Sulfurtransferase/metabolismo
20.
Nutrients ; 12(2)2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31973214

RESUMO

Interactions of diet, gut microbiota, and host genetics play essential roles in the development of metabolic diseases. A/J and C57BL/6J (C57) are two mouse strains known to display different susceptibilities to metabolic disorders. In this context, we analyzed gut microbiota composition in A/J and C57 mice, and assessed its responses to high-fat diet (HFD) and antibiotic (AB) treatment. We also exchanged the gut microbiota between the two strains following AB treatment to evaluate its impact on the metabolism. We showed that A/J and C57 mice have different microbiome structure and composition at baseline. Moreover, A/J and C57 microbiomes responded differently to HFD and AB treatments. Exchange of the gut microbiota between the two strains was successful as recipients' microbiota resembled donor-strain microbiota. Seven weeks after inoculation, the differences between recipients persisted and were still closer from the donor-strain microbiota. Despite effective microbiota transplants, the response to HFD was not markedly modified in C57 and A/J mice. Particularly, body weight gain and glucose intolerance in response to HFD remained different in the two mouse strains whatever the changes in microbiome composition. This indicated that genetic background has a much stronger impact on metabolic responses to HFD than gut microbiome composition.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Microbioma Gastrointestinal/genética , Patrimônio Genético , Doenças Metabólicas/genética , Doenças Metabólicas/microbiologia , Animais , Antibacterianos/farmacologia , Predisposição Genética para Doença/genética , Doenças Metabólicas/etiologia , Camundongos , Camundongos Endogâmicos C57BL
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