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1.
Cardiovasc Diabetol ; 19(1): 164, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33004045

RESUMO

BACKGROUND: Cardiometabolic disorders may worsen Covid-19 outcomes. We investigated features and Covid-19 outcomes for patients with or without diabetes, and with or without cardiometabolic multimorbidity. METHODS: We collected and compared data retrospectively from patients hospitalized for Covid-19 with and without diabetes, and with and without cardiometabolic multimorbidity (defined as ≥ two of three risk factors of diabetes, hypertension or dyslipidaemia). Multivariate logistic regression was used to assess the risk of the primary composite outcome (any of mechanical ventilation, admission to an intensive care unit [ICU] or death) in patients with diabetes and in those with cardiometabolic multimorbidity, adjusting for confounders. RESULTS: Of 354 patients enrolled, those with diabetes (n = 81), compared with those without diabetes (n = 273), had characteristics associated with the primary composite outcome that included older age, higher prevalence of hypertension and chronic obstructive pulmonary disease (COPD), higher levels of inflammatory markers and a lower PaO2/FIO2 ratio. The risk of the primary composite outcome in the 277 patients who completed the study as of May 15th, 2020, was higher in those with diabetes (Adjusted Odds Ratio (adjOR) 2.04, 95%CI 1.12-3.73, p = 0.020), hypertension (adjOR 2.31, 95%CI: 1.37-3.92, p = 0.002) and COPD (adjOR 2.67, 95%CI 1.23-5.80, p = 0.013). Patients with cardiometabolic multimorbidity were at higher risk compared to patients with no cardiometabolic conditions (adjOR 3.19 95%CI 1.61-6.34, p = 0.001). The risk for patients with a single cardiometabolic risk factor did not differ with that for patients with no cardiometabolic risk factors (adjOR 1.66, 0.90-3.06, adjp = 0.10). CONCLUSIONS: Patients with diabetes hospitalized for Covid-19 present with high-risk features. They are at increased risk of adverse outcomes, likely because diabetes clusters with other cardiometabolic conditions.


Assuntos
Betacoronavirus , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/epidemiologia , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/epidemiologia , Pneumonia Viral/diagnóstico , Pneumonia Viral/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Doenças Cardiovasculares/metabolismo , Infecções por Coronavirus/metabolismo , Diabetes Mellitus/metabolismo , Feminino , Seguimentos , Humanos , Masculino , Doenças Metabólicas/diagnóstico , Doenças Metabólicas/epidemiologia , Doenças Metabólicas/metabolismo , Pessoa de Meia-Idade , Multimorbidade/tendências , Pandemias , Pneumonia Viral/metabolismo , Prognóstico , Estudos Retrospectivos , Fatores de Risco
2.
Nat Commun ; 11(1): 5165, 2020 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-33057007

RESUMO

Angiotensin-converting enzyme 2 (ACE2) has been identified as the host entry receptor for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for the COVID-19 pandemic. ACE2 is a regulatory enzyme of the renin-angiotensin system and has protective functions in many cardiovascular, pulmonary and metabolic diseases. This review summarizes available murine models with systemic or organ-specific deletion of ACE2, or with overexpression of murine or human ACE2. The purpose of this review is to provide researchers with the genetic tools available for further understanding of ACE2 biology and for the investigation of ACE2 in the pathogenesis and treatment of COVID-19.


Assuntos
Doenças Cardiovasculares/patologia , Modelos Animais de Doenças , Pneumopatias/patologia , Peptidil Dipeptidase A/metabolismo , Animais , Betacoronavirus/fisiologia , Doenças Cardiovasculares/metabolismo , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Humanos , Pneumopatias/metabolismo , Doenças Metabólicas/metabolismo , Doenças Metabólicas/patologia , Camundongos , Camundongos Mutantes , Pandemias , Peptidil Dipeptidase A/genética , Pneumonia Viral/metabolismo , Pneumonia Viral/patologia , Pneumonia Viral/virologia
3.
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
4.
Nat Commun ; 11(1): 4150, 2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32811819

RESUMO

The systemic decline in autophagic activity with age impairs homeostasis in several tissues, leading to age-related diseases. A mechanistic understanding of adipocyte dysfunction with age could help to prevent age-related metabolic disorders, but the role of autophagy in aged adipocytes remains unclear. Here we show that, in contrast to other tissues, aged adipocytes upregulate autophagy due to a decline in the levels of Rubicon, a negative regulator of autophagy. Rubicon knockout in adipocytes causes fat atrophy and hepatic lipid accumulation due to reductions in the expression of adipogenic genes, which can be recovered by activation of PPARγ. SRC-1 and TIF2, coactivators of PPARγ, are degraded by autophagy in a manner that depends on their binding to GABARAP family proteins, and are significantly downregulated in Rubicon-ablated or aged adipocytes. Hence, we propose that age-dependent decline in adipose Rubicon exacerbates metabolic disorders by promoting excess autophagic degradation of SRC-1 and TIF2.


Assuntos
Adipócitos/metabolismo , Envelhecimento/fisiologia , Autofagia/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Doenças Metabólicas/metabolismo , Adipócitos/patologia , Adipogenia/genética , Tecido Adiposo/citologia , Tecido Adiposo/metabolismo , Adiposidade/genética , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Autofagia/fisiologia , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Técnicas de Inativação de Genes , Glucose/genética , Glucose/metabolismo , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Metabolismo dos Lipídeos/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/metabolismo , Coativador 1 de Receptor Nuclear/metabolismo , Coativador 2 de Receptor Nuclear/metabolismo , PPAR gama/metabolismo
5.
Nat Commun ; 11(1): 4337, 2020 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-32859897

RESUMO

Intracellular Na elevation in the heart is a hallmark of pathologies where both acute and chronic metabolic remodelling occurs. Here, we assess whether acute (75 µM ouabain 100 nM blebbistatin) or chronic myocardial Nai load (PLM3SA mouse) are causally linked to metabolic remodelling and whether the failing heart shares a common Na-mediated metabolic 'fingerprint'. Control (PLMWT), transgenic (PLM3SA), ouabain-treated and hypertrophied Langendorff-perfused mouse hearts are studied by 23Na, 31P, 13C NMR followed by 1H-NMR metabolomic profiling. Elevated Nai leads to common adaptive metabolic alterations preceding energetic impairment: a switch from fatty acid to carbohydrate metabolism and changes in steady-state metabolite concentrations (glycolytic, anaplerotic, Krebs cycle intermediates). Inhibition of mitochondrial Na/Ca exchanger by CGP37157 ameliorates the metabolic changes. In silico modelling indicates altered metabolic fluxes (Krebs cycle, fatty acid, carbohydrate, amino acid metabolism). Prevention of Nai overload or inhibition of Na/Camito may be a new approach to ameliorate metabolic dysregulation in heart failure.


Assuntos
Reprogramação Celular/fisiologia , Citoplasma/metabolismo , Insuficiência Cardíaca/metabolismo , Miocárdio/metabolismo , Sódio/metabolismo , Animais , Modelos Animais de Doenças , Metabolismo Energético , Técnicas de Introdução de Genes , Coração , Hipertrofia , Preparação de Coração Isolado , Masculino , Doenças Metabólicas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Ratos , Ratos Wistar , Sódio/sangue , Trocador de Sódio e Cálcio/efeitos dos fármacos , Tiazepinas/farmacologia
6.
Adv Exp Med Biol ; 1265: 39-56, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32761569

RESUMO

Cardiovascular disease is the major cause of global mortality and disability. Abundant evidence indicates that amino acids play a fundamental role in cardiovascular physiology and pathology. Decades of research established the importance of L-arginine in promoting vascular health through the generation of the gas nitric oxide. More recently, L-glutamine, L-tryptophan, and L-cysteine have also been shown to modulate vascular function via the formation of a myriad of metabolites, including a number of gases (ammonia, carbon monoxide, hydrogen sulfide, and sulfur dioxide). These amino acids and their metabolites preserve vascular homeostasis by regulating critical cellular processes including proliferation, migration, differentiation, apoptosis, contractility, and senescence. Furthermore, they exert potent anti-inflammatory and antioxidant effects in the circulation, and block the accumulation of lipids within the arterial wall. They also mitigate known risk factors for cardiovascular disease, including hypertension, hyperlipidemia, obesity, and diabetes. However, in some instances, the metabolism of these amino acids through discrete pathways yields compounds that fosters vascular disease. While supplementation with amino acid monotherapy targeting the deficiency has ameliorated arterial disease in many animal models, this approach has been less successful in the clinic. A more robust approach combining amino acid supplementation with antioxidants, anti-inflammatory agents, and/or specific amino acid enzymatic pathway inhibitors may prove more successful. Alternatively, supplementation with amino acid-derived metabolites rather than the parent molecule may elicit beneficial effects while bypassing potentially harmful pathways of metabolism. Finally, there is an emerging recognition that circulating levels of multiple amino acids are perturbed in vascular disease and that a more holistic approach that targets all these amino acid derangements is required to restore circulatory function in diseased blood vessels.


Assuntos
Aminoácidos/metabolismo , Sistema Cardiovascular/metabolismo , Saúde , Animais , Doenças Cardiovasculares/metabolismo , Endotélio Vascular/metabolismo , Humanos , Doenças Metabólicas/metabolismo , Óxido Nítrico/metabolismo
7.
Nat Metab ; 2(7): 572-585, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32694793

RESUMO

For infectious-disease outbreaks, clinical solutions typically focus on efficient pathogen destruction. However, the COVID-19 pandemic provides a reminder that infectious diseases are complex, multisystem conditions, and a holistic understanding will be necessary to maximize survival. For COVID-19 and all other infectious diseases, metabolic processes are intimately connected to the mechanisms of disease pathogenesis and the resulting pathology and pathophysiology, as well as the host defence response to the infection. Here, I examine the relationship between metabolism and COVID-19. I discuss why preexisting metabolic abnormalities, such as type 2 diabetes and hypertension, may be important risk factors for severe and critical cases of infection, highlighting parallels between the pathophysiology of these metabolic abnormalities and the disease course of COVID-19. I also discuss how metabolism at the cellular, tissue and organ levels might be harnessed to promote defence against the infection, with a focus on disease-tolerance mechanisms, and speculate on the long-term metabolic consequences for survivors of COVID-19.


Assuntos
Infecções por Coronavirus/complicações , Infecções por Coronavirus/metabolismo , Doenças Metabólicas/etiologia , Doenças Metabólicas/metabolismo , Pneumonia Viral/complicações , Pneumonia Viral/metabolismo , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/fisiopatologia , Humanos , Hipertensão/complicações , Hipertensão/fisiopatologia , Pandemias , Fatores de Risco
8.
Medicine (Baltimore) ; 99(27): e21140, 2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32629750

RESUMO

INTRODUCTION: Treating blood stasis is effective in treating obesity and metabolic diseases in traditional Korean medicine. The aim of this prospective observational study is to determine the effectiveness of the diagnosis index for metabolic diseases with blood stasis by analyzing clinical data and blood samples. METHODS AND ANALYSIS: We will perform a prospective observational study. Participants who meet the inclusion criteria will be recruited from the Dongguk university Ilsan Oriental hospital. The outcomes are resistin, serum amyloid P component, C-reactive protein, D-dimer, and blood stasis scores. In addition, the blood pressure, ankle-brachial pressure index, brachial-ankle pulse wave velocity, body mass index, waist circumference, and levels of blood lipid will be assessed. DISCUSSION: Through this study, we could collect specific data for diagnosing metabolic diseases with blood stasis. Therefore, the findings of this study will provide a summary of the current state of evidence regarding the effectiveness of the diagnosis index in managing metabolic disease with blood stasis. ETHICS AND DISSEMINATION: The study was approved by the Institutional Review Board of the Dongguk University Ilsan Oriental Hospital (DUIOH-2018-09-001-007). The results will be published in a peer-reviewed journal and will be disseminated electronically and in print. TRIAL REGISTRATION NUMBER: Clinical Research Information Service: KCT0003548.


Assuntos
Medicina Tradicional Coreana/métodos , Doenças Metabólicas/diagnóstico , Doenças Metabólicas/terapia , Língua/irrigação sanguínea , Adulto , Idoso , Índice Tornozelo-Braço/métodos , Pressão Sanguínea/fisiologia , Índice de Massa Corporal , Feminino , Humanos , Lipídeos/sangue , Masculino , Doenças Metabólicas/complicações , Doenças Metabólicas/metabolismo , Pessoa de Meia-Idade , Estudos Prospectivos , Análise de Onda de Pulso/métodos , República da Coreia/epidemiologia , Língua/patologia , Circunferência da Cintura/fisiologia
9.
Nat Commun ; 11(1): 2758, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32488069

RESUMO

Human beige adipocytes (BAs) have potential utility for the development of therapeutics to treat diabetes and obesity-associated diseases. Although several reports have described the generation of beige adipocytes in vitro, their potential utility in cell therapy and drug discovery has not been reported. Here, we describe the generation of BAs from human adipose-derived stem/stromal cells (ADSCs) in serum-free medium with efficiencies >90%. Molecular profiling of beige adipocytes shows them to be similar to primary BAs isolated from human tissue. In vitro, beige adipocytes exhibit uncoupled mitochondrial respiration and cAMP-induced lipolytic activity. Following transplantation, BAs increase whole-body energy expenditure and oxygen consumption, while reducing body-weight in recipient mice. Finally, we show the therapeutic utility of BAs in a platform for high-throughput drug screening (HTS). These findings demonstrate the potential utility of BAs as a cell therapeutic and as a tool for the identification of drugs to treat metabolic diseases.


Assuntos
Adipócitos Bege/metabolismo , Terapia Baseada em Transplante de Células e Tecidos/métodos , Descoberta de Drogas/métodos , Doenças Metabólicas/metabolismo , Adipócitos Bege/citologia , Animais , Peso Corporal , Avaliação Pré-Clínica de Medicamentos , Metabolismo Energético , Feminino , Ensaios de Triagem em Larga Escala , Humanos , Masculino , Células-Tronco Mesenquimais , Doenças Metabólicas/tratamento farmacológico , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Mitocôndrias/metabolismo , Consumo de Oxigênio , Células Estromais , Transplante
11.
Int J Mol Sci ; 21(10)2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32429235

RESUMO

We live and to do so we must breathe and eat, so are we a combination of what we eat and breathe? Here, we will consider this question, and the role in this respect of the AMP-activated protein kinase (AMPK). Emerging evidence suggests that AMPK facilitates central and peripheral reflexes that coordinate breathing and oxygen supply, and contributes to the central regulation of feeding and food choice. We propose, therefore, that oxygen supply to the body is aligned with not only the quantity we eat, but also nutrient-based diet selection, and that the cell-specific expression pattern of AMPK subunit isoforms is critical to appropriate system alignment in this respect. Currently available information on how oxygen supply may be aligned with feeding and food choice, or vice versa, through our motivation to breathe and select particular nutrients is sparse, fragmented and lacks any integrated understanding. By addressing this, we aim to provide the foundations for a clinical perspective that reveals untapped potential, by highlighting how aberrant cell-specific changes in the expression of AMPK subunit isoforms could give rise, in part, to known associations between metabolic disease, such as obesity and type 2 diabetes, sleep-disordered breathing, pulmonary hypertension and acute respiratory distress syndrome.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Oxigênio/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Animais , Dieta , Humanos , Doenças Metabólicas/metabolismo , Doenças Metabólicas/patologia , Isoformas de Proteínas/metabolismo , Respiração , Transtornos Respiratórios/metabolismo , Transtornos Respiratórios/patologia , Termogênese
12.
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
13.
Mol Cell ; 78(4): 584-596, 2020 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-32234490

RESUMO

Many genomic studies have revealed associations between the gut microbiota composition and host metabolism. These observations led to the idea that a causal relationship could exist between the microbiota and metabolic diseases, a concept supported by studies showing compositional changes in the microbial community in metabolic diseases and transmissibility of host phenotype via microbiota transfer. Accumulating data suggest that the microbiota may affect host metabolic phenotypes through the production of metabolites. These bioactive microbial metabolites, sensitive fingerprints of microbial function, can act as inter-kingdom signaling messengers via penetration into host blood circulation and tissues. These fingerprints may be used for diagnostic purposes, and increased understanding of strain specificity in producing microbial metabolites can identify bacterial strains or specific metabolites that can be used for therapeutic purposes. Here, we will review data supporting the causal role of the gut microbiota in metabolism and discuss mechanisms and potential clinical implications.


Assuntos
Bactérias/metabolismo , Bactérias/patogenicidade , Microbioma Gastrointestinal , Doenças Metabólicas/etiologia , Humanos , Doenças Metabólicas/metabolismo , Doenças Metabólicas/patologia
14.
Science ; 368(6489)2020 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-32327570

RESUMO

Protein quality control is essential for the proper function of cells and the organisms that they make up. The resulting loss of proteostasis, the processes by which the health of the cell's proteins is monitored and maintained at homeostasis, is associated with a wide range of age-related human diseases. Here, we highlight how the integrated stress response (ISR), a central signaling network that responds to proteostasis defects by tuning protein synthesis rates, impedes the formation of long-term memory. In addition, we address how dysregulated ISR signaling contributes to the pathogenesis of complex diseases, including cognitive disorders, neurodegeneration, cancer, diabetes, and metabolic disorders. The development of tools through which the ISR can be modulated promises to uncover new avenues to diminish pathologies resulting from it for clinical benefit.


Assuntos
Fator de Iniciação 2 em Eucariotos/metabolismo , Proteostase , Estresse Fisiológico , Fatores de Complexo Ternário/metabolismo , Acetamidas/química , Acetamidas/farmacologia , Animais , Cicloexilaminas/química , Cicloexilaminas/farmacologia , Fator de Iniciação 2 em Eucariotos/antagonistas & inibidores , Humanos , Imunidade , Doenças Metabólicas/metabolismo , Camundongos , Neoplasias/metabolismo , Fosfotransferases/metabolismo
15.
J Endocrinol ; 245(2): R11-R22, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32130201

RESUMO

The physiological mineralisation of skeletal tissues, as well as the pathological mineralisation of soft tissues involves a fine balance between regulators that either promote or inhibit the process. In recent years, several studies have advocated a non-skeletal role for some of these mineralisation regulators in a range of human diseases, including diabetes, cardiovascular disease, obesity and neurodegenerative disease. This is an emerging area of interest and the functional roles and mechanisms of action of these various endocrine factors, phosphatases and phosphodiesterase's in important pathologies are the focus of this review. Mechanistic insight of the pathways through which these acknowledged regulators of skeletal mineralisation act beyond the skeleton has the potential to identify druggable targets for commonly experienced morbidities, notably those related to metabolism and metabolic syndrome.


Assuntos
Biomineralização/fisiologia , Diester Fosfórico Hidrolases/metabolismo , Monoéster Fosfórico Hidrolases/metabolismo , Animais , Humanos , Doenças Metabólicas/metabolismo
16.
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
17.
Pharmacol Rev ; 72(2): 466-485, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32144120

RESUMO

The solute carrier family 16 (SLC16) is comprised of 14 members of the monocarboxylate transporter (MCT) family that play an essential role in the transport of important cell nutrients and for cellular metabolism and pH regulation. MCTs 1-4 have been extensively studied and are involved in the proton-dependent transport of L-lactate, pyruvate, short-chain fatty acids, and monocarboxylate drugs in a wide variety of tissues. MCTs 1 and 4 are overexpressed in a number of cancers, and current investigations have focused on transporter inhibition as a novel therapeutic strategy in cancers. MCT1 has also been used in strategies aimed at enhancing drug absorption due to its high expression in the intestine. Other MCT isoforms are less well characterized, but ongoing studies indicate that MCT6 transports xenobiotics such as bumetanide, nateglinide, and probenecid, whereas MCT7 has been characterized as a transporter of ketone bodies. MCT8 and MCT10 transport thyroid hormones, and recently, MCT9 has been characterized as a carnitine efflux transporter and MCT12 as a creatine transporter. Expressed at the blood brain barrier, MCT8 mutations have been associated with an X-linked intellectual disability, known as Allan-Herndon-Dudley syndrome. Many MCT isoforms are associated with hormone, lipid, and glucose homeostasis, and recent research has focused on their potential roles in disease, with MCTs representing promising novel therapeutic targets. This review will provide a summary of the current literature focusing on the characterization, function, and regulation of the MCT family isoforms and on their roles in drug disposition and in health and disease. SIGNIFICANCE STATEMENT: The 14-member solute carrier family 16 of monocarboxylate transporters (MCTs) plays a fundamental role in maintaining intracellular concentrations of a broad range of important endogenous molecules in health and disease. MCTs 1, 2, and 4 (L-lactate transporters) are overexpressed in cancers and represent a novel therapeutic target in cancer. Recent studies have highlighted the importance of MCTs in glucose, lipid, and hormone homeostasis, including MCT8 in thyroid hormone brain uptake, MCT12 in carnitine transport, and MCT11 in type 2 diabetes.


Assuntos
Transportadores de Ácidos Monocarboxílicos/metabolismo , Animais , Humanos , Doenças Metabólicas/metabolismo , Transportadores de Ácidos Monocarboxílicos/antagonistas & inibidores , Transportadores de Ácidos Monocarboxílicos/química , Transportadores de Ácidos Monocarboxílicos/genética , Relação Estrutura-Atividade , Distribuição Tecidual , Transcrição Genética
18.
Arch Endocrinol Metab ; 64(1): 71-81, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32187264

RESUMO

Objective Provide a comprehensive view of the events surrounding the sugar consumption, under conditions of energy equivalence; through the analysis of behavioral aspects of intake, and of biochemical, metabolic and physiological parameters, as well as the effect of this nutrient on the plasticity of adipose tissue. Materials and methods Newly weaned male Wistar rats were classified in two groups and subjected to the following normocaloric diets: standard chow diet or to high-sugar diet (HSD) ad libitum for 18 weeks. Results The animals submitted to the HSD were associated with a lower caloric intake during the 18 weeks of experimentation. However, the HSD induced a significant increase in body weight, white adipose tissue weight, adiposity index, Lee index, and the levels of triglycerides and very low-density lipoprotein in the serum. In addition, it induced glucose intolerance, insulin resistance and compensatory increase of insulin secretion by pancreatic ß-cells. Also increased heart rate and induced hyperplasia, and hypertrophy of retroperitoneal visceral adipose tissue. In the liver, the HSD was associated with increased hepatic lipid content (i.e., triglycerides and cholesterol) and hepatomegaly. Conclusion The post-weaning consumption of HSD induces an adaptive response in metabolism; however, such an event is not enough to reverse the homeostatic imbalance triggered by the chronic consumption of this macronutrient, leading to the development of metabolic syndrome, irrespective of caloric intake. These findings corroborate recent evidence indicating that sugar is a direct contributor to metabolic diseases independent of a positive energy balance. Arch Endocrinol Metab. 2020;64(1):71-81.


Assuntos
Tecido Adiposo/metabolismo , Açúcares da Dieta/metabolismo , Ingestão de Energia , Metabolismo Energético , Doenças Metabólicas/metabolismo , Obesidade/metabolismo , Animais , Açúcares da Dieta/efeitos adversos , Açúcares da Dieta/sangue , Masculino , Doenças Metabólicas/sangue , Obesidade/sangue , Obesidade/etiologia , Ratos , Ratos Wistar
19.
DNA Cell Biol ; 39(5): 733-737, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32181687

RESUMO

Ceramides have emerged as important regulators of tissue metabolism that play essential roles in cardiometabolic disease. They are potent biomarkers of diabetes and heart disease and are now being measured clinically as predictors of major adverse cardiac events. Moreover, studies in rodents reveal that inhibitors of ceramide synthesis prevent or reverse the pathogenic features of type 2 diabetes, nonalcoholic fatty liver disease, atherosclerosis, and cardiomyopathy. Herein the authors discuss inhibition of dihydroceramide desaturase-1, the final enzyme in the ceramide biosynthesis pathway, as a potential therapeutic approach to lower ceramides and combat cardiometabolic disease.


Assuntos
Metabolismo dos Lipídeos , Doenças Metabólicas/metabolismo , Oxirredutases/metabolismo , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/enzimologia , Oxirredutases/antagonistas & inibidores
20.
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
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