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1.
Biochem Med (Zagreb) ; 30(1): 010701, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31839721

RESUMO

Introduction: Chronic obstructive pulmonary disease (COPD) is a complex inflammatory condition that can affect haemostasis. This study aimed to determine differences in platelet-related parameters between controls and COPD subjects. The hypothesis was that platelet indices are disturbed in COPD patients, and this would be accompanied by increased C-reactive protein (CRP), fibrinogen (Fbg) and white blood cells (WBC). Therefore, platelet count (Plt), platelet-related parameters - mean platelet volume (MPV), platelet distribution width (PDW), plateletcrit (Pct), their ratios (MPV/Plt, MPV/Pct, PDW/Plt, PDW/Pct), platelet to lymphocyte ratio (PLR), Plt index as well as CRP, Fbg and WBC were assessed. Materials and methods: Study included 109 patients with stable COPD and 95 control subjects, recruited at Clinical Department for Lung Diseases Jordanovac, University Hospital Centre Zagreb (Zagreb, Croatia). Complete blood count was performed on Sysmex XN-1000, CRP on Cobas c501, and Fbg on BCS XP analyser. Data were analysed with MedCalc statistical software. Results: Platelet (P = 0.007) and PLR (P = 0.006) were increased, while other platelet indices were decreased in COPD patients compared to controls. Combined model that included PLR, PDW and WBC showed great diagnostic performances, and correctly classified 75% of cases with an AUC of 0.845 (0.788 - 0.892), P < 0.001. Comorbidities (cardiovascular or metabolic diseases) had no effect on investigated parameters, while inhaled corticosteroids/long-acting ß2-agonists (ICS/LABA) therapy increased MPV and PDW values in COPD patients. Conclusion: Platelet indices were altered in COPD patients and they could be valuable as diagnostic markers of COPD development, especially if combined with already known inflammatory markers.


Assuntos
Biomarcadores/sangue , Plaquetas/citologia , Doença Pulmonar Obstrutiva Crônica/patologia , Corticosteroides/uso terapêutico , Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Plaquetas/metabolismo , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/patologia , Estudos de Casos e Controles , Feminino , Volume Expiratório Forçado , Humanos , Leucócitos/citologia , Modelos Logísticos , Linfócitos/citologia , Masculino , Doenças Metabólicas/complicações , Doenças Metabólicas/patologia , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico
2.
Nat Med ; 25(11): 1667-1679, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31700182

RESUMO

Increases in the prevalence of noncommunicable diseases (NCDs), particularly cardiometabolic diseases such as cardiovascular disease, stroke and diabetes, and their major risk factors have not been uniform across settings: for example, cardiovascular disease mortality has declined over recent decades in high-income countries but increased in low- and middle-income countries (LMICs). The factors contributing to this rise are varied and are influenced by environmental, social, political and commercial determinants of health, among other factors. This Review focuses on understanding the rise of cardiometabolic diseases in LMICs, with particular emphasis on obesity and its drivers, together with broader environmental and macro determinants of health, as well as LMIC-based responses to counteract cardiometabolic diseases.


Assuntos
Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus/epidemiologia , Doenças Metabólicas/epidemiologia , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Países em Desenvolvimento , Diabetes Mellitus/metabolismo , Diabetes Mellitus/patologia , Política de Saúde , Humanos , Doenças Metabólicas/metabolismo , Doenças Metabólicas/patologia , Fatores de Risco
4.
Eur J Med Genet ; 62(11): 103562, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31610876

RESUMO

The incidence of inherited metabolic disorders (IMD) in Saudi Arabia is one of the highest in the world. Early diagnosis and advances in the treatment of these diseases have led to improved survival of these patients resulting in a rapidly growing number of adults with IMD. This is the first report from a single tertiary care center, on the experience of managing a large cohort of adult patients with a wide range of IMD. We describe the common IMD seen in adult patients in Saudi Arabia, highlighting the variations from the Caucasian populations, and unique challenges in providing care to these adults. We mention the pitfalls causing the delay in the diagnosis particularly in cases of late-onset IMD in adults. We also discuss some unusual complications seen in adult patients during the course of their disease. We describe the role of genetic prevention services in Saudi Arabia and the importance of research in this field.


Assuntos
Diagnóstico Precoce , Doenças Metabólicas/epidemiologia , Doenças Metabólicas/genética , Adolescente , Adulto , Idade de Início , Feminino , Humanos , Masculino , Doenças Metabólicas/diagnóstico , Doenças Metabólicas/patologia , Pessoa de Meia-Idade , Arábia Saudita , Adulto Jovem
5.
Nat Med ; 25(9): 1390-1395, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31501611

RESUMO

Visceral adipose tissue (VAT)-fat stored around the internal organs-has been suggested as an independent risk factor for cardiovascular and metabolic disease1-3, as well as all-cause, cardiovascular-specific and cancer-specific mortality4,5. Yet, the contribution of genetics to VAT, as well as its disease-related effects, are largely unexplored due to the requirement for advanced imaging technologies to accurately measure VAT. Here, we develop sex-stratified, nonlinear prediction models (coefficient of determination = 0.76; typical 95% confidence interval (CI) = 0.74-0.78) for VAT mass using the UK Biobank cohort. We performed a genome-wide association study for predicted VAT mass and identified 102 novel visceral adiposity loci. Predicted VAT mass was associated with increased risk of hypertension, heart attack/angina, type 2 diabetes and hyperlipidemia, and Mendelian randomization analysis showed visceral fat to be a causal risk factor for all four diseases. In particular, a large difference in causal effect between the sexes was found for type 2 diabetes, with an odds ratio of 7.34 (95% CI = 4.48-12.0) in females and an odds ratio of 2.50 (95% CI = 1.98-3.14) in males. Our findings bolster the role of visceral adiposity as a potentially independent risk factor, in particular for type 2 diabetes in Caucasian females. Independent validation in other cohorts is necessary to determine whether the findings can translate to other ethnicities, or outside the UK.


Assuntos
Adiposidade/genética , Doenças Cardiovasculares/genética , Gordura Intra-Abdominal/metabolismo , Doenças Metabólicas/genética , Adulto , Idoso , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/patologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Hipertensão/genética , Hipertensão/metabolismo , Hipertensão/patologia , Gordura Intra-Abdominal/patologia , Masculino , Análise da Randomização Mendeliana , Doenças Metabólicas/epidemiologia , Doenças Metabólicas/patologia , Pessoa de Meia-Idade , Obesidade/genética , Obesidade/metabolismo , Obesidade/patologia , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Caracteres Sexuais
6.
Biomed Res Int ; 2019: 1365210, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31534953

RESUMO

Interleukin-6 (IL-6) is a unique cytokine that can play both pro- and anti-inflammatory roles depending on the anatomical site and conditions under which it has been induced. Specific neurons of the hypothalamus provide important signals to control food intake and energy expenditure. In individuals with obesity, a microglia-dependent inflammatory response damages the neural circuits responsible for maintaining whole-body energy homeostasis, resulting in a positive energy balance. However, little is known about the role of IL-6 in the regulation of hypothalamic microglia. In this systematic review, we asked what types of conditions and stimuli could modulate microglial IL-6 expression in murine model. We searched the PubMed and Web of Science databases and analyzed 13 articles that evaluated diverse contexts and study models focused on IL-6 expression and microglia activation, including the effects of stress, hypoxia, infection, neonatal overfeeding and nicotine exposure, lipopolysaccharide stimulus, hormones, exercise protocols, and aging. The results presented in this review emphasized the role of "injury-like" stimuli, under which IL-6 acts as a proinflammatory cytokine, concomitant with marked microglial activation, which drive hypothalamic neuroinflammation. Emerging evidence indicates an important correlation of basal IL-6 levels and microglial function with the maintenance of hypothalamic homeostasis. Advances in our understanding of these different contexts will lead to the development of more specific pharmacological approaches for the management of acute and chronic conditions, like obesity and metabolic diseases, without disturbing the homeostatic functions of IL-6 and microglia in the hypothalamus.


Assuntos
Regulação da Expressão Gênica/imunologia , Hipotálamo/imunologia , Interleucina-6/imunologia , Doenças Metabólicas/imunologia , Microglia/imunologia , Obesidade/imunologia , Animais , Humanos , Hipotálamo/patologia , Doenças Metabólicas/patologia , Camundongos , Microglia/patologia , Obesidade/patologia
7.
Hum Genet ; 138(11-12): 1247-1257, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31538237

RESUMO

The reversible oxidation of L-malate to oxaloacetate is catalyzed by NAD(H)-dependent malate dehydrogenase (MDH). MDH plays essential roles in the malate-aspartate shuttle and the tricarboxylic acid cycle. These metabolic processes are important in mitochondrial NADH supply for oxidative phosphorylation. Recently, bi-allelic mutations in mitochondrial MDH2 were identified in patients with global developmental delay, epilepsy and lactic acidosis. We now report two patients from an extended consanguineous family with a deleterious variant in the cytosolic isoenzyme of MDH (MDH1). The homozygous missense variant in the NAD+-binding domain of MDH1 led to severely diminished MDH protein expression. The patients presented with global developmental delay, epilepsy and progressive microcephaly. Both patients had normal concentrations of plasma amino acids, acylcarnitines, lactate, and urine organic acids. To identify the metabolic consequences of MDH1 deficiency, untargeted metabolomics was performed on dried blood spots (DBS) from the patients and in MDH1 knockout HEK293 cells that were generated by Crispr/Cas9. Increased levels of glutamate and glycerol-3-phosphate were found in DBS of both patients. In MDH1 KO HEK293 cells, increased levels of glycerol-3-phosphate were also observed, as well as increased levels of aspartate and decreased levels of fumarate. The consistent finding of increased concentrations of glycerol-3-phosphate may represent a compensatory mechanism to enhance cytosolic oxidation of NADH by the glycerol-P-shuttle. In conclusion, MDH1 deficiency is a new metabolic defect in the malate-aspartate shuttle characterized by a severe neurodevelopmental phenotype with elevated concentrations of glycerol-3-phosphate as a potential biomarker.


Assuntos
Ácido Aspártico/metabolismo , Encefalopatias/metabolismo , Encefalopatias/patologia , Malato Desidrogenase/deficiência , Malatos/metabolismo , Doenças Metabólicas/etiologia , Idade de Início , Encefalopatias/complicações , Pré-Escolar , Feminino , Humanos , Masculino , Doenças Metabólicas/metabolismo , Doenças Metabólicas/patologia , Metaboloma , Linhagem
8.
Mini Rev Med Chem ; 19(19): 1611-1626, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31481002

RESUMO

Over the past three decades, the knowledge gained about the mechanisms that underpin the potential use of Rhodiola in stress- and ageing-associated disorders has increased, and provided a universal framework for studies that focused on the use of Rhodiola in preventing or curing metabolic diseases. Of particular interest is the emerging role of Rhodiola in the maintenance of energy homeostasis. Moreover, over the last two decades, great efforts have been undertaken to unravel the underlying mechanisms of action of Rhodiola in the treatment of metabolic disorders. Extracts of Rhodiola and salidroside, the most abundant active compound in Rhodiola, are suggested to provide a beneficial effect in mental, behavioral, and metabolic disorders. Both in vivo and ex vivo studies, Rhodiola extracts and salidroside ameliorate metabolic disorders when administered acutely or prior to experimental injury. The mechanism involved includes multi-target effects by modulating various synergistic pathways that control oxidative stress, inflammation, mitochondria, autophagy, and cell death, as well as AMPK signaling that is associated with possible beneficial effects on metabolic disorders. However, evidence-based data supporting the effectiveness of Rhodiola or salidroside in treating metabolic disorders is limited. Therefore, a comprehensive review of available trials showing putative treatment strategies of metabolic disorders that include both clinical effective perspectives and fundamental molecular mechanisms is warranted. This review highlights studies that focus on the potential role of Rhodiola extracts and salidroside in type 2 diabetes and atherosclerosis, the two most common metabolic diseases.


Assuntos
Glucosídeos/química , Doenças Metabólicas/tratamento farmacológico , Fenóis/química , Extratos Vegetais/química , Rhodiola/química , Proteínas Quinases Ativadas por AMP/metabolismo , Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Antioxidantes/química , Antioxidantes/uso terapêutico , Autofagia/efeitos dos fármacos , Glucosídeos/uso terapêutico , Humanos , Doenças Metabólicas/patologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Fenóis/uso terapêutico , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Rhodiola/metabolismo
9.
Helicobacter ; 24 Suppl 1: e12636, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31486239

RESUMO

In the last year, many studies have demonstrated a potential role of Helicobacter pylori in the pathogenic mechanisms of different extragastric diseases. While the role of H pylori in idiopathic thrombocytopenic purpura, idiopathic iron deficiency anemia, and vitamin B12 deficiency has already been demonstrated, there is growing evidence of other related conditions, especially cardiovascular, metabolic, and neurologic disorders, including neurodegenerative diseases. A summary of the results of the most relevant studies published over the last year on this attractive topic is presented in this review.


Assuntos
Doenças Cardiovasculares/etiologia , Infecções por Helicobacter/patologia , Helicobacter pylori/isolamento & purificação , Doenças Metabólicas/etiologia , Doenças do Sistema Nervoso/etiologia , Doenças Cardiovasculares/patologia , Humanos , Doenças Metabólicas/patologia , Doenças do Sistema Nervoso/patologia
10.
Oxid Med Cell Longev ; 2019: 9372182, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31396308

RESUMO

The transcription factor NRF2 (nuclear factor erythroid 2-related factor 2) triggers the first line of homeostatic responses against a plethora of environmental or endogenous deviations in redox metabolism, proteostasis, inflammation, etc. Therefore, pharmacological activation of NRF2 is a promising therapeutic approach for several chronic diseases that are underlined by oxidative stress and inflammation, such as neurodegenerative, cardiovascular, and metabolic diseases. A particular case is cancer, where NRF2 confers a survival advantage to constituted tumors, and therefore, NRF2 inhibition is desired. This review describes the electrophilic and nonelectrophilic NRF2 activators with clinical projection in various chronic diseases. We also analyze the status of NRF2 inhibitors, which at this time provide proof of concept for blocking NRF2 activity in cancer therapy.


Assuntos
Fator 2 Relacionado a NF-E2/metabolismo , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Ensaios Clínicos como Assunto , Curcumina/química , Curcumina/uso terapêutico , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/metabolismo , Doenças Metabólicas/patologia , Fator 2 Relacionado a NF-E2/agonistas , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Estresse Oxidativo , Triterpenos/química , Triterpenos/uso terapêutico
11.
Int J Mol Sci ; 20(16)2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31430977

RESUMO

Metabolic disorders are characterized by an overall state of inflammation and oxidative stress, which highlight the importance of a functional antioxidant system and normal activity of some endogenous enzymes, namely paraoxonase-1 (PON1). PON1 is an antioxidant and anti-inflammatory glycoprotein from the paraoxonases family. It is mainly expressed in the liver and secreted to the bloodstream, where it binds to HDL. Although it was first discovered due to its ability to hydrolyze paraoxon, it is now known to have an antiatherogenic role. Recent studies have shown that PON1 plays a protective role in other diseases that are associated with inflammation and oxidative stress, such as Type 1 and Type 2 Diabetes Mellitus and Non-Alcoholic Fatty Liver Disease. The aim of this review is to elucidate the physiological role of PON1, as well as the impact of altered PON1 levels in metabolic disorders.


Assuntos
Arildialquilfosfatase/metabolismo , Glucose/metabolismo , Metabolismo dos Lipídeos , Doenças Metabólicas/metabolismo , Animais , Progressão da Doença , Homeostase , Humanos , Inflamação/metabolismo , Doenças Metabólicas/patologia , Estresse Oxidativo
12.
EBioMedicine ; 44: 489-501, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31221584

RESUMO

BACKGROUND: A positive energy balance promotes white adipose tissue (WAT) expansion which is characterized by activation of a repertoire of events including hypoxia, inflammation and extracellular matrix remodelling. The transmembrane glycoprotein CD248 has been implicated in all these processes in different malignant and inflammatory diseases but its potential impact in WAT and metabolic disease has not been explored. METHODS: The role of CD248 in adipocyte function and glucose metabolism was evaluated by omics analyses in human WAT, gene knockdowns in human in vitro differentiated adipocytes and by adipocyte-specific and inducible Cd248 gene knockout studies in mice. FINDINGS: CD248 is upregulated in white but not brown adipose tissue of obese and insulin-resistant individuals. Gene ontology analyses showed that CD248 expression associated positively with pro-inflammatory/pro-fibrotic pathways. By combining data from several human cohorts with gene knockdown experiments in human adipocytes, our results indicate that CD248 acts as a microenvironmental sensor which mediates part of the adipose tissue response to hypoxia and is specifically perturbed in white adipocytes in the obese state. Adipocyte-specific and inducible Cd248 knockouts in mice, both before and after diet-induced obesity and insulin resistance/glucose intolerance, resulted in increased microvascular density as well as attenuated hypoxia, inflammation and fibrosis without affecting fat cell volume. This was accompanied by significant improvements in insulin sensitivity and glucose tolerance. INTERPRETATION: CD248 exerts detrimental effects on WAT phenotype and systemic glucose homeostasis which may be reversed by suppression of adipocyte CD248. Therefore, CD248 may constitute a target to treat obesity-associated co-morbidities.


Assuntos
Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/patologia , Antígenos CD/genética , Antígenos de Neoplasias/genética , Metabolismo Energético/genética , Hipóxia/metabolismo , Paniculite/genética , Paniculite/metabolismo , Adulto , Animais , Modelos Animais de Doenças , Matriz Extracelular , Feminino , Fibrose , Expressão Gênica , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Doenças Metabólicas/etiologia , Doenças Metabólicas/metabolismo , Doenças Metabólicas/patologia , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Obesidade/genética , Obesidade/metabolismo , Obesidade/patologia , Paniculite/patologia , Transdução de Sinais
13.
Transl Res ; 210: 26-42, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31121128

RESUMO

Obesity is a major cause of metabolic syndrome and type II diabetes, and it presents with metabolic disorders, such as hyperglycemia, hyperlipidemia, and insulin resistance. Pigment epithelium-derived factor (PEDF), a protein isolated from retinal pigment epithelial cells, has multiple functions, including neuronal protection, antineoplastic effects, and anti-inflammatory activity. The aim of this study is to investigate the antiobesity effects of PEDF. The antiobesity effects of PEDF on fat accumulation, inflammation, energy expenditure, insulin resistance, and obesity-related physiological parameters and protein levels were assessed in high-fat diet (HFD)-induced obese mice in vivo and in 3T3-L1 adipocytes, palmitate (PA)-treated HepG2 cells, and C2C12 myotubes in vitro. In an in vivo assay, PEDF effectively decreased body weight gain, white adipose tissue mass, and inflammation and improved insulin resistance, dyslipidemia, and hyperglycemia in HFD-induced mice. In liver tissue, PEDF decreased lipid accumulation and fibrosis. In an in vitro assay, PEDF diminished the differentiation of 3T3-L1 preadipocytes. We also determined that PEDF promoted lipolysis and prolonged cell cycle progression, through the mTOR-S6K pathway and downstream transcription factors, such as peroxisome proliferator-activated receptor gamma, CCAAT/enhancer-binding protein α (CEBP-α), and CEBP-ß. In addition, PEDF decreased reactive oxygen species production in PA-induced HepG2 cells and improved glucose uptake ability in PA-induced HepG2 cells and C2C12 myotubes. In the present study, PEDF protected against HFD-induced obesity and metabolic disorders in mice, inhibited adipogenesis, and improved insulin resistance. These results provide a new potential treatment for obesity in the future.


Assuntos
Adipócitos/metabolismo , Adipogenia/efeitos dos fármacos , Proteínas do Olho/farmacologia , Doenças Metabólicas/patologia , Fatores de Crescimento Neural/farmacologia , Obesidade/patologia , Obesidade/prevenção & controle , Serpinas/farmacologia , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Tecido Adiposo/patologia , Animais , Proliferação de Células/efeitos dos fármacos , Células Clonais , Dieta Hiperlipídica , Fígado Gorduroso/sangue , Fígado Gorduroso/complicações , Fígado Gorduroso/patologia , Células Hep G2 , Humanos , Inflamação/patologia , Resistência à Insulina , Masculino , Doenças Metabólicas/sangue , Camundongos , Camundongos Endogâmicos C57BL , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Obesidade/sangue , Obesidade/complicações , Estresse Oxidativo/efeitos dos fármacos , Ácido Palmítico , Proteínas Quinases S6 Ribossômicas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
14.
Nutrients ; 11(5)2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-31075850

RESUMO

4-Hydroxy-3-methoxycinnamic acid (HMCA), a hydroxycinnamic acid derivative, is abundant in fruits and vegetables, including oranges, carrots, rice bran, and coffee beans. Several beneficial effects of HMCA have been reported, including improvement of metabolic abnormalities in animal models and human studies. However, its mitigating effects on high-fat diet (HFD)-induced obesity, and the mechanism underlying these effects, remain to be elucidated. In this study, we demonstrated that dietary HMCA was efficacious against HFD-induced weight gain and hepatic steatosis, and that it improved insulin sensitivity. These metabolic benefits of HMCA were ascribable to 3-(4-hydroxy-3-methoxyphenyl)propionic acid (HMPA) produced by gut microbiota. Moreover, conversion of HMCA into HMPA was attributable to a wide variety of microbes belonging to the phylum Bacteroidetes. We further showed that HMPA modulated gut microbes associated with host metabolic homeostasis by increasing the abundance of organisms belonging to the phylum Bacteroidetes and reducing the abundance of the phylum Firmicutes. Collectively, these results suggest that HMPA derived from HMCA is metabolically beneficial, and regulates hepatic lipid metabolism, insulin sensitivity, and the gut microbial community. Our results provide insights for the development of functional foods and preventive medicines, based on the microbiota of the intestinal environment, for the prevention of metabolic disorders.


Assuntos
Ácidos Cumáricos/farmacologia , Dieta , Microbioma Gastrointestinal/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Obesidade/metabolismo , Propionatos/farmacologia , Animais , Bacteroidetes/efeitos dos fármacos , Bacteroidetes/crescimento & desenvolvimento , Bacteroidetes/metabolismo , Citrus sinensis/química , Coffea/química , Ácidos Cumáricos/metabolismo , Daucus carota/química , Dieta Hiperlipídica/efeitos adversos , Fígado Gorduroso/etiologia , Fígado Gorduroso/prevenção & controle , Firmicutes/crescimento & desenvolvimento , Firmicutes/metabolismo , Trato Gastrointestinal/metabolismo , Trato Gastrointestinal/microbiologia , Resistência à Insulina , Fígado/metabolismo , Fígado/patologia , Masculino , Doenças Metabólicas/etiologia , Doenças Metabólicas/metabolismo , Doenças Metabólicas/patologia , Doenças Metabólicas/prevenção & controle , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/complicações , Obesidade/etiologia , Oryza/química , Plantas Comestíveis/química , Propionatos/metabolismo , Ganho de Peso/efeitos dos fármacos
15.
Nutrients ; 11(5)2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-31075905

RESUMO

The improvement of the social and economic conditions of society has eliminated the threat of death from the majority of infectious diseases. However, the rapid progress of civilization has created new possibilities for the appearance of factors with adverse effects for the health of society. This has led to increased morbidity from certain diseases, the presence of which had not been observed several centuries ago. Chronic noncommunicable diseases (e.g., cancers, cardio-vascular disorders, diabetes, obesity, neurodegenerative diseases) result from an inappropriate relationship between people and their environment. The common characteristic for all chronic diseases is a "new" form of inflammation, very often called metaflammation, which is considered as a subclinical, permanent inflammation. As a result, metabolic cascade, including cellular oxidative stress, atherosclerotic process, and insulin resistance, occurs, which slowly generates significant deterioration in the organism. Polyphenols are the major group of non-nutrients, considering their diversity, food occurrence, and biological properties. The current review aims to present a wide spectrum of literature data, including the molecular mechanism of their activity and experimental model used, and summarize the recent findings on the multitude of physiological effects of dietary polyphenols towards the prevention of several chronic diseases. However, despite several studies, the estimation of their dietary intake is troublesome and inconclusive, which will be also discussed.


Assuntos
Dieta , Doenças não Transmissíveis/prevenção & controle , Fitoterapia , Extratos Vegetais/uso terapêutico , Polifenóis/uso terapêutico , Doenças Cardiovasculares/patologia , Doenças Cardiovasculares/prevenção & controle , Doença Crônica , Humanos , Inflamação/prevenção & controle , Doenças Metabólicas/patologia , Doenças Metabólicas/prevenção & controle , Neoplasias/patologia , Neoplasias/prevenção & controle , Doenças Neurodegenerativas/patologia , Doenças Neurodegenerativas/prevenção & controle
16.
Hamostaseologie ; 39(2): 164-172, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31132800

RESUMO

Nutrient excess in obesity drives metabolic reprogramming in multiple tissues involving extensive interorgan and intercellular crosstalk. Experimental and clinical studies show that prolonged nutrient excess often compromises metabolic adaptation propagating proobesogenic and proinflammatory responses. Chronic inflammation further promotes insulin resistance and associated comorbidities. Obesity and type 2 diabetes are characterized by a hypercoagulable state and clinical studies show a strong correlation of markers of coagulation activation in metabolic disorders. Coagulation protease-dependent signalling via protease-activated receptors is intimately associated with inflammation. The experimental evidence supports roles of tissue factor and G protein coupled protease-activated receptor-2 signalling in the regulation of insulin resistance and metabolic inflammation in diet-induced obesity. Likewise, increases in plasminogen activator inhibitor-1 levels and fibrin-driven inflammation promote insulin resistance in obesity. Additionally, impaired thrombomodulin-dependent protein C activation is mechanistically linked to diabetic kidney disease. Given the increased usage of direct oral anticoagulants, understanding the role of specific coagulation proteases in regulation of metabolic inflammation is highly relevant and might provide insights into the design of novel treatment regimens for patients suffering from thromboinflammatory and cardiometabolic disorders.


Assuntos
Coagulação Sanguínea , Doenças Metabólicas/patologia , Doenças Metabólicas/fisiopatologia , Transdução de Sinais , Animais , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/fisiopatologia , Modelos Animais de Doenças , Humanos , Obesidade/patologia , Obesidade/fisiopatologia
17.
J Pediatr Endocrinol Metab ; 32(5): 537-541, 2019 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-31075084

RESUMO

Hematopoietic stem cell transplantation (HSCT) has been newly identified as an etiology underlying acquired lipodystrophy (ALD). We report about two children with leukemia who underwent HSCT and later manifested aberrant fat distributions consistent with acquired partial lipodystrophy (APL). Both patients manifested graft-versus-host disease (GVHD), suggesting that GVHD may trigger lipodystrophy. The patients exhibited diabetic blood glucose patterns in the oral glucose tolerance test (OGTT) with high homeostasis model assessment ratios (HOMA-Rs), hypertriglyceridemia, fatty liver, and decreased serum leptin and adiponectin levels. Both patients were diagnosed with APL with metabolic disease. A review of the data of patients with ALD after HSCT revealed common clinical features, including aberrant fat distribution, impaired glucose tolerance (IGT) or diabetes and dyslipidemia. Based on previous reports and our two cases, we speculate that GVHD in the adipose tissue supports the development of ALD after HSCT. In conclusion, children may develop APL after HSCT. Therefore, evaluations of fat distribution and metabolic disease may be important during the long-term follow-up of these patients.


Assuntos
Fígado Gorduroso/etiologia , Intolerância à Glucose/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hipertrigliceridemia/etiologia , Leucemia Mieloide Aguda/terapia , Lipodistrofia/etiologia , Doenças Metabólicas/etiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Criança , Fígado Gorduroso/patologia , Feminino , Intolerância à Glucose/patologia , Humanos , Hipertrigliceridemia/patologia , Lactente , Leucemia Mieloide Aguda/patologia , Lipodistrofia/patologia , Doenças Metabólicas/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Prognóstico
18.
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
19.
J Atheroscler Thromb ; 26(5): 389-402, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30930344

RESUMO

Fasting and postprandial hypertriglyceridemia is a risk factor for atherosclerotic cardiovascular diseases (ASCVD). Fibrates have been used to treat dyslipidemia, particularly hypertriglyceridemia, and low HDL-cholesterol (HDL-C). However, conventional fibrates have low selectivity for peroxisome proliferator-activated receptor (PPAR)α. Fibrates' clinical use causes side effects such as worsening liver function and elevating the creatinine level. Large-scale clinical trials of fibrates have shown negative results for prevention of ASCVD. To overcome these issues, the concept of the selective PPARα modulator (SPPARMα), with a superior balance of efficacy and safety, has been proposed. A SPPARMα, pemafibrate (K-877), was synthesized by Kowa Company, Ltd. for better efficacy and safety. Clinical trials conducted in Japan confirmed the superior effects of pemafibrate on triglyceride reduction and HDL-C elevation.Conventional fibrates showed elevated liver function test values and worsened kidney function test values, while pemafibrate demonstrated improved liver function test values and was less likely to increase serum creatinine or decrease the estimated glomerular filtration rate. There were extremely few drug interactions even when it was used concomitantly with various statins. Furthermore, unlike many of the conventional fibrates that are renal excretory-type drugs, pemafibrate is excreted into the bile, so it can be safely used even in patients with impaired renal function and there is no increase in its blood concentration.This novel SPPARMα, pemafibrate, has superior benefit-risk balance compared to conventional fibrates and can be used for patients for whom it was difficult to use existing fibrates, including those who are taking statins and those with renal dysfunction. A large-scale trial PROMINENT using pemafibrate for patients with type 2 diabetes is in progress. In the current review, the latest data on pemafibrate will be summarized.


Assuntos
Benzoxazóis/uso terapêutico , Butiratos/uso terapêutico , Dislipidemias/tratamento farmacológico , Doenças Metabólicas/tratamento farmacológico , PPAR alfa/antagonistas & inibidores , Animais , Dislipidemias/metabolismo , Dislipidemias/patologia , Humanos , Doenças Metabólicas/metabolismo , Doenças Metabólicas/patologia , PPAR alfa/metabolismo
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