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1.
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
2.
PLoS One ; 15(6): e0234386, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32525902

RESUMO

BACKGROUND: Polypharmacy has become a global public health concern particularly in the elderly population. The elderly population is the most susceptible to the negative effects of polypharmacy due to their altered pharmacokinetics and decreased drug clearance. Therefore, polypharmacy can lead to poor health status and higher rates of morbidity and mortality. OBJECTIVE: The objective of this study was to determine the prevalence of polypharmacy (≥ 5 drugs) and its association with non-communicable diseases (NCDs) in elderly (≥65 years) Qatari patients attending Primary Healthcare (PHC) centers in Qatar. METHODS: A retrospective cross-sectional analysis was conducted using the Electronic Medical Record (EMR) database of all PHC centers in Qatar for six months (April-September 2017). RESULTS: Out of 5639 patients screened, 75.5% (95% CI: 74.3-76.6) were exposed to polypharmacy. Females were 1.18 times more likely to have polypharmacy compared to males (95% CI: 1.03-1.34). The multivariate analysis identified having hypertension (AOR 1.71; 95% CI: 1.38-2.13), diabetes (AOR 2.38; 95% CI: 1.97-2.87), dyslipidemia (AOR 1.29; 95% CI: 1.06-1.56), cardiovascular disease (AOR 1.56; 95% CI: 1.25-1.95) and asthma (AOR 1.39; 95% CI: 1.13-1.72) to be independent parameters associated with polypharmacy. Also, the Body Mass Index (BMI) and number of NCDs were found to be significant independent parameters associated with polypharmacy. CONCLUSIONS: The prevalence of polypharmacy among Qatari elderly attending PHC Centers is very high. Our findings confirm the strong relationship between polypharmacy and BMI, and certain NCDs. Healthcare professionals should be educated about the magnitude of polypharmacy, its negative effects, and its associated factors. Best practice guidelines should be developed for improved medical practice in the prescription of medications for such a vulnerable population.


Assuntos
Doenças não Transmissíveis/tratamento farmacológico , Doenças não Transmissíveis/epidemiologia , Polimedicação , Idoso , Idoso de 80 Anos ou mais , Asma/tratamento farmacológico , Asma/epidemiologia , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/epidemiologia , Comorbidade , Estudos Transversais , Registros Eletrônicos de Saúde , Feminino , Humanos , Modelos Logísticos , Masculino , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/epidemiologia , Análise Multivariada , Obesidade/epidemiologia , Prevalência , Atenção Primária à Saúde , Catar/epidemiologia , Estudos Retrospectivos
3.
Cell ; 181(6): 1189-1193, 2020 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-32442404
4.
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
5.
Life Sci ; 247: 117442, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32081663

RESUMO

Transient receptor potential vanilloid type 1 (TRPV1) channels are emerging therapeutic targets for metabolic disorders. Berberine, which is a modulator of TRPV1, has proven antiobesity and antidiabetic potentials. The present study was aimed to investigate the protective effects of berberine in olanzapine-induced alterations in hypothalamic appetite control, inflammation and metabolic aberrations in mice targeting TRPV1 channels. Female BALB/c mice (18-23 g) were treated with olanzapine (6 mg/kg, p.o.) for six weeks to induce metabolic alterations, while berberine (100 and 200 mg/kg, p.o.) and metformin (100 mg/kg, p.o) were used as test and standard interventions respectively. Weekly assessment of feed-water intake, body temperature and body weight was done, while locomotion was measured at the end of week 1 and 6. Serum glucose and lipid profile were assessed by biochemical methods, while other serum biomarkers were assessed by ELISA. qPCR was used to quantify the mRNA expression in the hypothalamus. Olanzapine treatment significantly increased the feed intake, weight gain, adiposity index, while reduced body temperature and locomotor activity which were reversed by berberine treatment. Berberine treatment reduced serum ghrelin and leptin levels as well decrease in hypothalamic mRNA expression of orexigenic neuropeptides, inflammatory markers and ghrelin receptor in olanzapine-treated mice. Olanzapine treatment increased expression of TRPV1/TRPV3 in the hypothalamus which was significantly decreased by berberine treatment. Our results suggest that berberine, by TRPV1/TRPV3 modulation, attenuated the olanzapine-induced metabolic alterations in mice. Hence berberine supplementation in psychiatric patients could be a preventive approach to reduce the metabolic adverse effects of antipsychotics.


Assuntos
Antipsicóticos/uso terapêutico , Berberina/uso terapêutico , Doenças Metabólicas/tratamento farmacológico , Olanzapina/metabolismo , Canais de Cátion TRPV/metabolismo , Animais , Antipsicóticos/efeitos adversos , Berberina/efeitos adversos , Temperatura Corporal , Peso Corporal , Citocinas/metabolismo , Ingestão de Líquidos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Grelina/sangue , Grelina/metabolismo , Hipotálamo/metabolismo , Leptina/sangue , Leptina/metabolismo , Metformina/farmacologia , Metformina/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Terapia de Alvo Molecular/métodos , Neuropeptídeos/metabolismo , Obesidade , RNA Mensageiro , Transdução de Sinais , Canais de Cátion TRPV/genética , Resultado do Tratamento
6.
Lancet Diabetes Endocrinol ; 8(4): 278-291, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32109422

RESUMO

BACKGROUND: An urgent need to reduce the metabolic side-effects of glucocorticoid overexposure has been recognised, as glucocorticoid excess can lead to Cushing's syndrome, which is associated with high morbidity. We aimed to evaluate the potential of metformin to reverse such effects while sparing the anti-inflammatory benefits of glucocorticoids. METHODS: We did a randomised, double-blind, placebo-controlled, proof-of-concept, phase 2 trial involving four hospitals in the UK. Patients without diabetes were eligible if they were between the ages of 18 and 75 years with an inflammatory disease treated with continuous prednisolone (≥20 mg/day for ≥4 weeks and remaining on ≥10 mg/day for the subsequent 12 weeks, or its cumulative dose-equivalent). Eligible patients were randomly allocated (1:1) to either the metformin or placebo groups, using a computer-generated randomisation table stratified according to age and BMI. Metformin and placebo were administered orally for 12 weeks in escalating doses: 850 mg/day for the first 5 days, 850 mg twice a day for the next 5 days, and 850 mg three times a day subsequently. The primary outcome was the between-group difference in visceral-to-subcutaneous fat area ratio over 12 weeks, assessed by CT. Secondary outcomes included changes in metabolic, bone, cardiovascular, and inflammatory parameters over 12 weeks. Our analysis followed a modified intention-to-treat principle for the primary outcome. This study is registered with ClinicalTrials.gov, NCT01319994. FINDINGS: Between July 17, 2012, and Jan 14, 2014, 849 patients were assessed for study eligibility, of which 53 were randomly assigned to receive either metformin (n=26) or placebo (n=27) for 12 weeks. 19 patients in the metformin group and 21 in the placebo group were eligible for the primary outcome analysis. Both groups received an equivalent cumulative dose of glucocorticoids (1860 mg prednisolone-equivalent [IQR 1060-2810] in the metformin group vs 1770 mg [1020-2356] in the placebo group); p=0·76). No change in the visceral-to-subcutaneous fat area ratio between the treatment groups was observed (0·11, 95% CI -0·02 to 0·24; p=0·09), but patients in the metformin group lost truncal subcutaneous fat compared with the placebo group (-3835 mm2, 95% CI -6781 to -888; p=0·01). Improvements in markers of carbohydrate, lipid, liver, and bone metabolism were observed in the metformin group compared with the placebo group. Additionally, those in the metformin group had improved fibrinolysis, carotid intima-media thickness, inflammatory parameters, and clinical markers of disease activity. The frequency of pneumonia (one event in the metformin group vs seven in the placebo group; p=0·01), overall rate of moderate-to-severe infections (two vs 11; p=0·001), and all-cause hospital admissions due to adverse events (one vs nine; p=0·001) were lower in the metformin group than in the placebo group. Patients in the metformin group had more events of diarrhoea than the placebo group (18 events vs eight; p=0·01). INTERPRETATION: No significant changes in the visceral-to-subcutaneous fat area ratio between the treatment groups were observed; however, metformin administration did improve some of the metabolic profile and clinical outcomes for glucocorticoid-treated patients with inflammatory disease, which warrants further investigation. FUNDING: Barts Charity and Merck Serono.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Glucocorticoides/uso terapêutico , Hipoglicemiantes/uso terapêutico , Inflamação/tratamento farmacológico , Doenças Metabólicas/tratamento farmacológico , Metformina/uso terapêutico , Adulto , Idoso , Doenças Autoimunes/imunologia , Doenças Autoimunes/fisiopatologia , Método Duplo-Cego , Feminino , Glucocorticoides/efeitos adversos , Humanos , Inflamação/prevenção & controle , Masculino , Doenças Metabólicas/prevenção & controle , Pessoa de Meia-Idade , Estudo de Prova de Conceito , Resultado do Tratamento , Adulto Jovem
7.
J Biomed Sci ; 27(1): 1, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31894001

RESUMO

It has been more than three decades since the first monoclonal antibody was approved by the United States Food and Drug Administration (US FDA) in 1986, and during this time, antibody engineering has dramatically evolved. Current antibody drugs have increasingly fewer adverse effects due to their high specificity. As a result, therapeutic antibodies have become the predominant class of new drugs developed in recent years. Over the past five years, antibodies have become the best-selling drugs in the pharmaceutical market, and in 2018, eight of the top ten bestselling drugs worldwide were biologics. The global therapeutic monoclonal antibody market was valued at approximately US$115.2 billion in 2018 and is expected to generate revenue of $150 billion by the end of 2019 and $300 billion by 2025. Thus, the market for therapeutic antibody drugs has experienced explosive growth as new drugs have been approved for treating various human diseases, including many cancers, autoimmune, metabolic and infectious diseases. As of December 2019, 79 therapeutic mAbs have been approved by the US FDA, but there is still significant growth potential. This review summarizes the latest market trends and outlines the preeminent antibody engineering technologies used in the development of therapeutic antibody drugs, such as humanization of monoclonal antibodies, phage display, the human antibody mouse, single B cell antibody technology, and affinity maturation. Finally, future applications and perspectives are also discussed.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Doenças Autoimunes/tratamento farmacológico , Doenças Transmissíveis/tratamento farmacológico , Doenças Metabólicas/tratamento farmacológico , Neoplasias/tratamento farmacológico , Humanos , Estados Unidos , United States Food and Drug Administration
8.
Nat Rev Drug Discov ; 19(1): 57-75, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31548636

RESUMO

Fibrosis is the abnormal deposition of extracellular matrix, which can lead to organ dysfunction, morbidity, and death. The disease burden caused by fibrosis is substantial, and there are currently no therapies that can prevent or reverse fibrosis. Metabolic alterations are increasingly recognized as an important pathogenic process that underlies fibrosis across many organ types. As a result, metabolically targeted therapies could become important strategies for fibrosis reduction. Indeed, some of the pathways targeted by antifibrotic drugs in development - such as the activation of transforming growth factor-ß and the deposition of extracellular matrix - have metabolic implications. This Review summarizes the evidence to date and describes novel opportunities for the discovery and development of drugs for metabolic reprogramming, their associated challenges, and their utility in reducing fibrosis. Fibrotic therapies are potentially relevant to numerous common diseases such as cirrhosis, non-alcoholic steatohepatitis, chronic renal disease, heart failure, diabetes, idiopathic pulmonary fibrosis, and scleroderma.


Assuntos
Reprogramação Celular , Proteínas da Matriz Extracelular/metabolismo , Fibrose/tratamento farmacológico , Doenças Metabólicas/tratamento farmacológico , Terapia de Alvo Molecular , Transdução de Sinais/efeitos dos fármacos , Fibrose/metabolismo , Fibrose/patologia , Humanos , Doenças Metabólicas/metabolismo , Doenças Metabólicas/patologia , Fator de Crescimento Transformador beta
9.
Revista Digital de Postgrado ; 9(1): e192, 2020. tab
Artigo em Espanhol | LILACS, LIVECS | ID: biblio-1053027

RESUMO

Objetivo: Evaluar la epidemiología de la sepsis neonatal en los recién nacidos atendidos en emergencia pediátrica del HUC del 1 de enero 2017 al 31 de diciembre del 2017. Métodos: estudio descriptivo, prospectivo, que incluyó a los recién nacidos con diagnóstico de sepsis neonatal. Se recolectaron datos como edad, sexo, lugar de nacimiento, lugar de procedencia, factores de riesgos, manifestaciones clínicas. Resultados: se incluyeron 14 pacientes con diagnóstico de sepsis neonatal. Grupo de edad más afectado: 15-21 días 50% (n=7), género más afectado: masculino 71,42% (n=10), lugar de nacimientos más frecuente Distrito Capital 57,15% (n=8), lugar de procedencia más frecuente estado Miranda 71,43% (n=10), Según tiempo de evolución, la más frecuente fue sepsis neonatal tardía 92,86% (n=13), los principales factores de riesgos identificados fueron: infección materna en el 3er trimestre 36,35% (n=8), prematuridad 29,42% (n=5), bajo peso al nacer 23,54% (n=4), procedimientos invasivos 37,50% (n=3), las manifestaciones clínicas más frecuentes fueron: fiebre, ictericia, palidez o aspecto séptico 7,89% (n=6), la incidencia de sepsis neonatal en el estudio fue 3.92 por 1000 nacidos vivos y 2,6% de casos atendidos con sepsis neonatal. Conclusión: epidemiológicamente la sepsis neonatal, es más frecuente en el grupo de edad de 15-21 días, sexo masculino, lugar de nacimiento Distrito Capital, procedencia estado Miranda, factores de riesgo más frecuentes infección materna en el 3er trimestre, prematuridad, bajo peso al nacer, procedimientos invasivos. Manifestaciones clínicas más frecuente fiebre, ictericia, palidez o aspecto séptico, incidencia de 3.92 por 1000 nacidos vivos y 2,6% de casos atendidos con sepsis neonatal(AU)


Objective: To evaluate the epidemiology of neonatal sepsis in newborns attended in pediatric emergency of the HUC from January 1, 2017 to December 31, 2017. Methods: a prospective, descriptive study that included newborns with a diagnosis of neonatal sepsis. Data were collected as age, sex, place of birth, place of origin, risk factors, clinical manifestations. Results: 14 patients with diagnosis of neonatal sepsis were included. Most affected age group: 15-21 days 50% (n = 7), most affected gender: male 71.42% (n = 10), most frequent place of births Capital District 57.15% (n = 8), Most frequent place of origin Miranda state 71.43% (n = 10), According to time of evolution, the most frequent was late neonatal sepsis 92.86% (n = 13), the main risk factors identified were: maternal infection in 3rd trimester 36.35% (n = 8), prematurity 29.42% (n = 5), low birth weight 23.54% (n = 4), invasive procedures 37.50% (n = 3), the most frequent clinical manifestations were: fever, jaundice, pallor or septic appearance 7.89% (n = 6), the incidence of neonatal sepsis in the study was 3.92 per 1000 live births and 2.6% of cases attended with neonatal sepsis. Conclusion: neonatal sepsis is epidemiologically more frequent in the age group of 15-21 days, male sex, place of birth, Capital District, Miranda state origin, most frequent risk factors maternal infection in the 3rd trimester, prematurity, low weight at birth, invasive procedures. Clinical manifestations more frequent fever, jaundice, pallor or septic appearance, incidence of 3.92 per 1000 live births and 2.6% of cases treated with neonatal sepsis(AU)


Assuntos
Humanos , Recém-Nascido , Infecções Bacterianas/tratamento farmacológico , Aleitamento Materno , Sepse Neonatal/diagnóstico , Sepse Neonatal/epidemiologia , Recém-Nascido , Recém-Nascido Prematuro/crescimento & desenvolvimento , Estudos Prospectivos , Cardiopatias Congênitas , Doenças Metabólicas/tratamento farmacológico
10.
Heart Fail Clin ; 16(1): 11-21, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31735309

RESUMO

"Chronic heart failure (CHF) is a complex syndrome characterized by symptoms and signs supported by different forms of cardiac impairment. The link between multiple hormonal and metabolic derangements and the development of CHF and the beneficial effects seen with hormonal replacement therapy suggest that a reduction of anabolic pathways might contribute to the onset of CHF. Therefore, an imbalance between anabolic and catabolic forces could be responsible for the development of CHF. There are sufficient evidence to support the screening in patients with CHF of hormonal deficiencies and their correction with replacement therapy."


Assuntos
Hormônio do Crescimento/sangue , Insuficiência Cardíaca/metabolismo , Resistência à Insulina , Doenças Metabólicas/etiologia , Testosterona/sangue , Hormônios Tireóideos/sangue , Biomarcadores/sangue , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/tratamento farmacológico , Terapia de Reposição Hormonal/métodos , Humanos , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/metabolismo
11.
Life Sci ; 242: 117212, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31884092

RESUMO

AIMS: Oxidative stress is an important risk factor in development and progression of type 2 diabetes. Resveratrol (RSV), as a natural antioxidant, reduces intracellular reactive oxygen species (ROS) and oxidative stress. MATERIALS AND METHODS: The study investigated the effects of RSV treatment on high-fat diet (HFD)-fed mice and muscle, adipose, and hepatic cells of insulin resistance. HFD-fed mice were treated with RSV for 10 weeks. Blood glucose, plasma triglyceride (TG), body weight and glucose-lipid metabolism of skeletal muscle, fat and liver were examined. We further assessed the metabolic regulation of RSV in C2C12 myotubes, 3T3-L1 adipocytes and HepG2 cells of insulin resistance. KEY FINDINGS: We found that RSV reduced blood glucose, plasma TG and body weight, ameliorated insulin resistance in HFD-fed mice. RSV reduced lipid accumulation and increased glycogen storage in muscle and hepatic cells, promoted lipolysis in adipocytes. We further found RSV reduced ROS levels in muscle, adipose, and hepatic cells of insulin resistance, contributing to improvement of metabolic abnormalities in HFD-fed mice. SIGNIFICANCE: The study reveals that RSV ameliorates metabolic disorders and insulin resistance in HFD-fed mice, which provides further demonstration in RSV-treated type 2 diabetes.


Assuntos
Antioxidantes/farmacologia , Dieta Hiperlipídica/efeitos adversos , Resistência à Insulina , Doenças Metabólicas/tratamento farmacológico , Resveratrol/farmacologia , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Glicemia/análise , Células Hep G2/efeitos dos fármacos , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Doenças Metabólicas/etiologia , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Triglicerídeos/sangue
12.
An Real Acad Farm ; 85(4): 288-300, oct.-dic. 2019. ilus, graf
Artigo em Espanhol | IBECS | ID: ibc-188788

RESUMO

El estrés oxidativo, alteración de la homeostasis REDOX en células y tejidos con un incremento de los niveles de especies reactivas de oxígeno (ROS), es un mecanismo patogénico común a múltiples patologías como las enfermedades cardiovasculares, los desórdenes neurodegenerativos, la inflamación y el cáncer, razón por la cual ha existido una investigación intensa en las últimas décadas sobre los posibles efectos protectores de las terapias antioxidantes en estas enfermedades. No obstante, la señalización REDOX juega, por otra parte, un papel crítico en la homeostasis y supervivencia celular, y las ROS son producidas en pequeñas cantidades durante la función celular normal. Las investigaciones llevadas a cabo en nuestro grupo han estado enfocadas al estudio del estrés oxidativo como factor patogénico clave en la disfunción endotelial en la obesidad y en otros estados de resistencia a la insulina. La disfunción endotelial subyace a las complicaciones vasculares de la diabetes y la obesidad, y representa un fenotipo endotelial mal adaptado con alteración de la función vasodilatadora, angiogénica y de barrera del endotelio, lo que conduce a un estado vasoconstrictor, proinflamatorio y protrombótico de la pared vascular. Debido a su capacidad de inhabilitar el óxido nítrico (NO), las ROS son en parte responsables de la disfunción endotelial. Por otra parte, nuestros estudios durante estos años han permitido caracterizar el papel clave de ROS como el H2O2 en la función endotelial de arterias de resistencia renales y coronarias, y su participación en la función vascular mediante la modulación de canales iónicos y enzimas implicados en vías de señalización de la pared arterial. Estas investigaciones sugieren la necesidad de valorar el papel de las ROS en los procesos fisiológicos de los distintos lechos vasculares y de revisar los esfuerzos en la búsqueda de terapias antioxidantes para las complicaciones vasculares de estados de resistencia a la insulina teniendo en cuenta la implicación de las ROS en la función endotelial normal. Palabras clave: especies reactivas de oxígeno (ROS), endotelio vascular, hiperpolarización derivada del endotelio (EDH), estrés oxidativo, obesidad, disfunción endotelial


Oxidative stress, impairment of REDOX homeostasis in cells and tissues leading to increased levels of reactive oxygen species (ROS), is a pathogenic mechanism underlying numerous pathologies including cardiovascular diseases, cancer, neurodegenerative disorders and inflammation. Therefore, there has been an intensive investigation during the last decades on the potential protective effects of antioxidant therapies on these disorders. Nevertheless, REDOX signaling plays a critical role in homeostasis and cell survival, and ROS are produced in small amount during normal cell function. Investigations carried out in our group during the last decade have been focused on the study of oxidative stress as a key pathogenic factor in endothelial and vascular dysfunction of resistance arteries in obesity and other insulin resistant states. Endothelial dysfunction underlies vascular complications of diabetes and obesity, and represents a maladapted endothelial phenotype consisting of impaired vasodilatation, angiogenesis and barrier function leading to a vasoconstrictor, pro-inflammatory and pro-thrombotic state of the vascular wall. ROS are involvedin endothelial dysfunction since they reduce bioavailability of nitric oxide (NO). On the other hand, our investigations have provided evidence for a key role of ROS such as hydrogen peroxide (H2O2) in the endothelial function of healthy coronary and renal resistance arteries, and its involvement in vascular function through modulation of ion channels and enzymes involved in signalling pathways of the arterial wall.These investigations suggest the need to assess the functional role of ROS in the different vascular beds and to revise the efforts in the search of antioxidant therapies for vascular complications of metabolic diseases by taking into account ROS involvement in endothelial function


Assuntos
Espécies Reativas de Oxigênio/química , Doenças Metabólicas/tratamento farmacológico , Receptores de Fatores de Crescimento do Endotélio Vascular/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Espécies Reativas de Oxigênio/farmacologia , Oxirredução/efeitos dos fármacos , NADPH Oxidases/metabolismo
13.
Mar Drugs ; 17(11)2019 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-31717879

RESUMO

Metabolic disorders such as diabetes and obesity are serious global health issues. These diseases are accelerated by mineral deficiencies, emphasizing the importance of addressing these deficiencies in disease management plans. Lactate metabolism is fundamentally linked to glucose metabolism, and several clinical studies have reported that blood lactate levels are higher in obese and diabetic patients than in healthy subjects. Balanced deep-sea water contains various minerals and exhibits antiobesity and antidiabetic activities in mice; however, the impact of balanced deep-sea water on lactate metabolism is unclear. Thus, we evaluated the effects of balanced deep-sea water on lactate metabolism in C2C12 myotubes, and found that balanced deep-sea water mediated lactate metabolism by regulating the gene expression levels of lactate dehydrogenases A and B, a monocarboxylate transporter, and a mitochondrial pyruvate carrier. The activities of peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) and signaling molecules involved in PGC-1α activation were also upregulated by treatment with balanced deep-sea water. These results suggest that balanced deep-sea water, which can mediate lactate metabolism, may be used to prevent or treat obesity and diabetes mellitus.


Assuntos
Lactatos/metabolismo , Minerais/administração & dosagem , Fibras Musculares Esqueléticas/efeitos dos fármacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Animais , Linhagem Celular , Regulação da Expressão Gênica/efeitos dos fármacos , Isoenzimas/genética , L-Lactato Desidrogenase/genética , Lactato Desidrogenase 5/genética , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/fisiopatologia , Camundongos , Minerais/farmacologia , Fibras Musculares Esqueléticas/metabolismo , Obesidade/tratamento farmacológico , Obesidade/fisiopatologia , Água do Mar/química , Transdução de Sinais/efeitos dos fármacos
14.
Int J Mol Sci ; 20(20)2019 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-31614705

RESUMO

Adipose tissue is traditionally categorized into white and brown relating to their function and morphology. The classical white adipose tissue builds up energy in the form of triglycerides and is useful for preventing fatigue during periods of low caloric intake and the brown adipose tissue more energetically active, with a greater number of mitochondria and energy production in the form of heat. Since adult humans possess significant amounts of active brown fat depots and its mass inversely correlates with adiposity, brown fat might play an important role in human obesity and energy homeostasis. New evidence suggests two types of thermogenic adipocytes with distinct developmental and anatomical features: classical brown adipocytes and beige adipocytes. Beige adipocyte has recently attracted special interest because of its ability to dissipate energy and the possible ability to differentiate themselves from white adipocytes. The presence of brown and beige adipocyte in human adults has acquired attention as a possible therapeutic intervention for metabolic diseases. Importantly, adult human brown appears to be mainly composed of beige-like adipocytes, making this cell type an attractive therapeutic target for obesity and obesity-related diseases, such as atherosclerosis, arterial hypertension and diabetes mellitus type 2. Because many epigenetics changes can affect beige adipocyte differentiation from adipose progenitor cells, the knowledge of the circumstances that affect the development of beige adipocyte cells may be important to new pathways in the treatment of metabolic diseases. New molecules have emerged as possible therapeutic targets, which through the impulse to develop beige adipocytes can be useful for clinical studies. In this review will discuss some recent observations arising from the unique physiological capacity of these cells and their possible role as ways to treat obesity and diabetes mellitus type 2.


Assuntos
Adipócitos Bege/metabolismo , Doenças Metabólicas/metabolismo , Adipócitos Bege/efeitos dos fármacos , Adipócitos Bege/fisiologia , Animais , Fármacos Antiobesidade/farmacologia , Fármacos Antiobesidade/uso terapêutico , Exercício Físico , Humanos , Doenças Metabólicas/tratamento farmacológico , Termogênese
15.
EBioMedicine ; 48: 462-477, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31631034

RESUMO

BACKGROUND: The development of a clinically useful fibroblast growth factor 21 (FGF21) hormone has been impeded by its inherent instability and weak FGF receptor (FGFR) binding affinity. There is an urgent need for innovative approaches to overcome these limitations. METHODS: We devised a structure-based chimerisation strategy in which we substituted the thermally labile and low receptor affinity core of FGF21 with an HS binding deficient endocrinised core derived from a stable and high receptor affinity paracrine FGF1 (FGF1ΔHBS). The thermal stability, receptor binding ability, heparan sulfate and ßKlotho coreceptor dependency of the chimera were measured using a thermal shift assay, SPR, SEC-MALS and cell-based studies. The half-life, tissue distribution, glucose lowering activity and adipose tissue remodeling were analyzed in normal and diabetic mice and monkeys. FINDINGS: The melting temperature of the engineered chimera (FGF1ΔHBS-FGF21C-tail) increased by ∼22 °C relative to wild-type FGF21 (FGF21WT), and resulted in a ∼5-fold increase in half-life in vivo. The chimera also acquired an ability to bind the FGFR1c isoform - the principal receptor that mediates the metabolic actions of FGF21 - and consequently was dramatically more effective than FGF21WT in correcting hyperglycemia and in ameliorating insulin resistance in db/db mice. Our chimeric FGF21 also exerted a significant beneficial effect on glycemic control in spontaneous diabetic cynomolgus monkeys. INTERPRETATION: Our study describes a structure-based chimerisation approach that effectively mitigates both the intrinsically weak receptor binding affinities and short half-lives of endocrine FGFs, and advance the development of the FGF21 hormone into a potentially useful drug for Type 2 diabetes.


Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Doenças Metabólicas/metabolismo , Comunicação Parácrina , Adipócitos/metabolismo , Animais , Biomarcadores , Cromatografia Líquida de Alta Pressão , Modelos Animais de Doenças , Fatores de Crescimento de Fibroblastos/química , Fatores de Crescimento de Fibroblastos/genética , Expressão Gênica , Humanos , Insulina/metabolismo , Masculino , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/etiologia , Camundongos , Modelos Moleculares , Comunicação Parácrina/efeitos dos fármacos , Ligação Proteica , Conformação Proteica , Domínios e Motivos de Interação entre Proteínas , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/química , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Proteínas Recombinantes , Relação Estrutura-Atividade
16.
Int J Mol Sci ; 20(19)2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31597283

RESUMO

A balanced metabolic profile is essential for normal human physiological activities. Disproportions in nutrition give rise to imbalances in metabolism that are associated with aberrant immune function and an elevated risk for inflammatory-associated disorders. Inflammation is a complex process, and numerous mediators affect inflammation-mediated disorders. The available clinical modalities do not effectively address the underlying diseases but rather relieve the symptoms. Therefore, novel targeted agents have the potential to normalize the metabolic system and, thus, provide meaningful therapy to the underlying disorder. In this connection, polyphenols, the well-known and extensively studied phytochemical moieties, were evaluated for their effective role in the restoration of metabolism via various mechanistic signaling pathways. The various flavonoids that we observed in this comprehensive review interfere with the metabolic events that induce inflammation. The mechanisms via which the polyphenols, in particular flavonoids, act provide a promising treatment option for inflammatory disorders. However, detailed clinical studies of such molecules are required to decide their clinical fate.


Assuntos
Anti-Inflamatórios/farmacologia , Flavonoides/farmacologia , Inflamação/metabolismo , Doenças Metabólicas/metabolismo , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Biomarcadores , Ensaios Clínicos como Assunto , Suscetibilidade a Doenças , Avaliação Pré-Clínica de Medicamentos , Flavonoides/química , Flavonoides/uso terapêutico , Humanos , Inflamação/complicações , Inflamação/diagnóstico , Mediadores da Inflamação/metabolismo , Doenças Metabólicas/diagnóstico , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/etiologia , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Resultado do Tratamento
17.
Int J Mol Sci ; 20(19)2019 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-31590292

RESUMO

: Mitochondria play a key role in maintaining energy homeostasis in metabolic tissues, including adipose tissues. The two main types of adipose tissues are the white adipose tissue (WAT) and the brown adipose tissue (BAT). WAT primarily stores excess energy, whereas BAT is predominantly responsible for energy expenditure by non-shivering thermogenesis through the mitochondria. WAT in response to appropriate stimuli such as cold exposure and ß-adrenergic agonist undergoes browning wherein it acts as BAT, which is characterized by the presence of a higher number of mitochondria. Mitochondrial dysfunction in adipocytes has been reported to have strong correlation with metabolic diseases, including obesity and type 2 diabetes. Dysfunction of mitochondria results in detrimental effects on adipocyte differentiation, lipid metabolism, insulin sensitivity, oxidative capacity, and thermogenesis, which consequently lead to metabolic diseases. Recent studies have shown that mitochondrial function can be improved by using thiazolidinedione, mitochondria-targeted antioxidants, and dietary natural compounds; by performing exercise; and by controlling caloric restriction, thereby maintaining the metabolic homeostasis by inducing adaptive thermogenesis of BAT and browning of WAT. In this review, we focus on and summarize the molecular regulation involved in the improvement of mitochondrial function in adipose tissues so that strategies can be developed to treat metabolic diseases.


Assuntos
Tecido Adiposo/metabolismo , Doenças Metabólicas/metabolismo , Mitocôndrias/metabolismo , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Restrição Calórica , Metabolismo Energético , Humanos , Doenças Metabólicas/dietoterapia , Doenças Metabólicas/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos
18.
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
19.
Expert Opin Drug Metab Toxicol ; 15(10): 787-802, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31512529

RESUMO

Introduction: Drug-drug interactions (DDI) between antiretroviral drugs and drugs for the treatment of metabolic disturbances in people living with human immunodeficiency virus (HIV) (PLWH) have represented a problem of paramount importance in the recent times. The problem has been mainly driven by sharing common metabolizing pathways. This problem has classically been worsened by the frequent use of pharmacokinetic boosters to enhance protease inhibitors and some integrase inhibitors plasma levels. Areas covered: This article focuses on the interactions between antiretroviral drugs and those drugs used to treat metabolic disturbances which frequently appear in PLWH. These include dyslipidemia, diabetes mellitus, hyperuricemia, and finally, drugs for the treatment of overweight and clinical obesity. References from PubMed, Embase, or Web of Science, among others, were reviewed. Expert opinion: The advent of safer drugs, in terms of DDI, in the antiretroviral and the metabolic field,such as non-boosted antiretrovirals and drugs with divergent metabolizing paths. Besides, learning by the caregivers on how to decrease and manage DDI, together with the extensive use of online updated DDI databases, has undoubtedly minimized the problem. The foreseeable increase in the burden of HIV-associated comorbidities and their associated treatments anticipates further complexities in the management of DDI in PLWH.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Infecções por HIV/tratamento farmacológico , Doenças Metabólicas/tratamento farmacológico , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/farmacocinética , Interações Medicamentosas , Infecções por HIV/complicações , Inibidores da Protease de HIV/administração & dosagem , Inibidores da Protease de HIV/efeitos adversos , Inibidores da Protease de HIV/farmacocinética , Humanos , Doenças Metabólicas/etiologia , Doenças Metabólicas/fisiopatologia
20.
Expert Opin Investig Drugs ; 28(10): 917-930, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31430206

RESUMO

Introduction: Acetyl-CoA Carboxylase (ACC) is an essential rate-limiting enzyme in fatty acid metabolism. For many years, ACC inhibitors have gained great attention for developing therapeutics for various human diseases including microbial infections, metabolic syndrome, obesity, diabetes, and cancer. Areas covered: We present a comprehensive review and update of ACC inhibitors. We look at the current advance of ACC inhibitors in clinical studies and the implications in drug discovery. We searched ScienceDirect ( https://www.sciencedirect.com/ ), ACS ( https://pubs.acs.org/ ), Wiley ( https://onlinelibrary.wiley.com/ ), NCBI ( https://www.ncbi.nlm.nih.gov/ ) and World Health Organization ( https://www.who.int/ ). The keywords used were Acetyl-CoA Carboxylase, lipid, inhibitors and metabolic syndrome. All documents were published before June 2019. Expert opinion: The key regulatory role of ACC in fatty acid synthesis and oxidation pathways makes it an attractive target for various metabolic diseases. In particular, the combination of ACC inhibitors with other drugs is a new strategy for the treatment of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Expanding the clinical indications for ACC inhibitors will be one of the hot directions in the future. It is also worth looking forward to exploring safe and efficient inhibitors that act on the BC domain of ACC.


Assuntos
Acetil-CoA Carboxilase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Síndrome Metabólica/tratamento farmacológico , Acetil-CoA Carboxilase/metabolismo , Animais , Desenvolvimento de Medicamentos/métodos , Descoberta de Drogas/métodos , Inibidores Enzimáticos/efeitos adversos , Ácidos Graxos/metabolismo , Humanos , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/fisiopatologia , Síndrome Metabólica/fisiopatologia
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