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1.
Nutrients ; 13(7)2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-34371983

RESUMO

The worldwide prevalence of metabolic diseases such as obesity, metabolic syndrome and type 2 diabetes shows an upward trend in recent decades. A characteristic feature of these diseases is hyperglycemia which can be associated with hyperphagia. Absorption of glucose in the small intestine physiologically contributes to the regulation of blood glucose levels, and hence, appears as a putative target for treatment of hyperglycemia. In fact, recent progress in understanding the molecular and cellular mechanisms of glucose absorption in the gut and its reabsorption in the kidney helped to develop a new strategy of diabetes treatment. Changes in blood glucose levels are also involved in regulation of appetite, suggesting that glucose absorption may be relevant to hyperphagia in metabolic diseases. In this review we discuss the mechanisms of glucose absorption in the small intestine in physiological conditions and their alterations in metabolic diseases as well as their relevance to the regulation of appetite. The key role of SGLT1 transporter in intestinal glucose absorption in both physiological conditions and in diabetes was clearly established. We conclude that although inhibition of small intestinal glucose absorption represents a valuable target for the treatment of hyperglycemia, it is not always suitable for the treatment of hyperphagia. In fact, independent regulation of glucose absorption and appetite requires a more complex approach for the treatment of metabolic diseases.


Assuntos
Regulação do Apetite , Glucose/metabolismo , Hiperglicemia/metabolismo , Absorção Intestinal/fisiologia , Doenças Metabólicas/metabolismo , Humanos , Hiperglicemia/etiologia , Intestino Delgado/metabolismo , Doenças Metabólicas/complicações , Transportador 1 de Glucose-Sódio/metabolismo
2.
FASEB J ; 35(9): e21810, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34390520

RESUMO

Copper (Cu) is an essential micronutrient required for the activity of redox-active enzymes involved in critical metabolic reactions, signaling pathways, and biological functions. Transporters and chaperones control Cu ion levels and bioavailability to ensure proper subcellular and systemic Cu distribution. Intensive research has focused on understanding how mammalian cells maintain Cu homeostasis, and how molecular signals coordinate Cu acquisition and storage within organs. In humans, mutations of genes that regulate Cu homeostasis or facilitate interactions with Cu ions lead to numerous pathologic conditions. Malfunctions of the Cu+ -transporting ATPases ATP7A and ATP7B cause Menkes disease and Wilson disease, respectively. Additionally, defects in the mitochondrial and cellular distributions and homeostasis of Cu lead to severe neurodegenerative conditions, mitochondrial myopathies, and metabolic diseases. Cu has a dual nature in carcinogenesis as a promotor of tumor growth and an inducer of redox stress in cancer cells. Cu also plays role in cancer treatment as a component of drugs and a regulator of drug sensitivity and uptake. In this review, we provide an overview of the current knowledge of Cu metabolism and transport and its relation to various human pathologies.


Assuntos
Cobre/metabolismo , Homeostase/fisiologia , Animais , Transporte Biológico/fisiologia , ATPases Transportadoras de Cobre/metabolismo , Humanos , Doenças Metabólicas/metabolismo , Doenças Mitocondriais/metabolismo , Doenças Neurodegenerativas/metabolismo
3.
Int J Mol Sci ; 22(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202493

RESUMO

As a newly identified manganese transport protein, ZIP14 is highly expressed in the small intestine and liver, which are the two principal organs involved in regulating systemic manganese homeostasis. Loss of ZIP14 function leads to manganese overload in both humans and mice. Excess manganese in the body primarily affects the central nervous system, resulting in irreversible neurological disorders. Therefore, to prevent the onset of brain manganese accumulation becomes critical. In this study, we used Zip14-/- mice as a model for ZIP14 deficiency and discovered that these mice were born without manganese loading in the brain, but started to hyper-accumulate manganese within 3 weeks after birth. We demonstrated that decreasing manganese intake in Zip14-/- mice was effective in preventing manganese overload that typically occurs in these animals. Our results provide important insight into future studies that are targeted to reduce the onset of manganese accumulation associated with ZIP14 dysfunction in humans.


Assuntos
Encéfalo/patologia , Proteínas de Transporte de Cátions/deficiência , Dieta , Suscetibilidade a Doenças , Manganês/metabolismo , Doenças Metabólicas/etiologia , Doenças Metabólicas/metabolismo , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Fígado/metabolismo , Fígado/patologia , Manganês/efeitos adversos , Doenças Metabólicas/patologia , Doenças Metabólicas/prevenção & controle , Camundongos , Especificidade de Órgãos
4.
Int J Mol Sci ; 22(14)2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34299336

RESUMO

The rising prevalence of metabolic diseases related to insulin resistance (IR) have stressed the urgent need of accurate and applicable tools for early diagnosis and treatment. In the last decade, non-coding RNAs (ncRNAs) have gained growing interest because of their potential role in IR modulation. NcRNAs are variable-length transcripts which are not translated into proteins but are involved in gene expression regulation. Thanks to their stability and easy detection in biological fluids, ncRNAs have been investigated as promising diagnostic and therapeutic markers in metabolic diseases, such as type 2 diabetes mellitus (T2D), obesity and non-alcoholic fatty liver disease (NAFLD). Here we review the emerging role of ncRNAs in the development of IR and related diseases such as obesity, T2D and NAFLD, and summarize current evidence concerning their potential clinical application.


Assuntos
Resistência à Insulina/genética , RNA não Traduzido/genética , Animais , Biomarcadores/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Insulina/metabolismo , Fígado/metabolismo , Doenças Metabólicas/genética , Doenças Metabólicas/metabolismo , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/genética , Obesidade/metabolismo , RNA não Traduzido/metabolismo
5.
Nutrients ; 13(6)2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34072678

RESUMO

The incidence of metabolic and chronic diseases including cancer, obesity, inflammation-related diseases sharply increased in the 21st century. Major underlying causes for these diseases are inflammation and oxidative stress. Accordingly, natural products and their bioactive components are obvious therapeutic agents for these diseases, given their antioxidant and anti-inflammatory properties. Research in this area has been significantly expanded to include chemical identification of these compounds using advanced analytical techniques, determining their mechanism of action, food fortification and supplement development, and enhancing their bioavailability and bioactivity using nanotechnology. These timely topics were discussed at the 20th Frontier Scientists Workshop sponsored by the Korean Academy of Science and Technology, held at the University of Hawaii at Manoa on 23 November 2019. Scientists from South Korea and the U.S. shared their recent research under the overarching theme of Bioactive Compounds, Nanoparticles, and Disease Prevention. This review summarizes presentations at the workshop to provide current knowledge of the role of natural products in the prevention and treatment of metabolic diseases.


Assuntos
Anti-Inflamatórios , Antioxidantes , Produtos Biológicos , Doenças Metabólicas , Animais , Suplementos Nutricionais , Humanos , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/metabolismo , Camundongos , Nanopartículas , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos
6.
Nutrients ; 13(5)2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-34063372

RESUMO

Metabolic- (dysfunction) associated fatty liver disease (MAFLD) represents the predominant hepatopathy and one of the most important systemic, metabolic-related disorders all over the world associated with severe medical and socio-economic repercussions due to its growing prevalence, clinical course (steatohepatitis and/or hepatocellular-carcinoma), and related extra-hepatic comorbidities. To date, no specific medications for the treatment of this condition exist, and the most valid recommendation for patients remains lifestyle change. MAFLD has been associated with metabolic syndrome; its development and progression are widely influenced by the interplay between genetic, environmental, and nutritional factors. Nutrigenetics and nutrigenomics findings suggest nutrition's capability, by acting on the individual genetic background and modifying the specific epigenetic expression as well, to influence patients' clinical outcome. Besides, immunity response is emerging as pivotal in this multifactorial scenario, suggesting the interaction between diet, genetics, and immunity as another tangled network that needs to be explored. The present review describes the genetic background contribution to MAFLD onset and worsening, its possibility to be influenced by nutritional habits, and the interplay between nutrients and immunity as one of the most promising research fields of the future in this context.


Assuntos
Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Nutrigenômica , Dieta , Humanos , Imunidade , Estilo de Vida , Doenças Metabólicas/genética , Doenças Metabólicas/metabolismo , Medicina de Precisão/métodos
7.
Nutrients ; 13(6)2021 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-34072137

RESUMO

Dietary fatty acids (DFAs) play key roles in different metabolic processes in humans and other mammals. DFAs have been considered beneficial for health, particularly polyunsaturated (PUFAs) and monounsaturated fatty acids (MUFAs). Additionally, microRNAs (miRNAs) exert their function on DFA metabolism by modulating gene expression, and have drawn great attention for their potential as biomarkers and therapeutic targets. This review explicitly examined the effects of DFAs on miRNA expression associated with metabolic diseases, such as obesity, non-alcoholic fatty liver disease (NAFLD), and cardiovascular disease (CVD), as well as inflammation, published in the last ten years. DFAs have been shown to induce and repress miRNA expression associated with metabolic disease and inflammation in different cell types and organisms, both in vivo and in vitro, depending on varying combinations of DFAs, doses, and the duration of treatment. However, studies are limited and heterogeneous in methodology. Additionally, recent studies demonstrated that high fat ketogenic diets, many enriched with saturated fats, do not increase serum saturated fat content in humans, and are not associated with increased inflammation. Thus, these findings shed light on the complexity of novel treatment and DFA interventions for metabolic disease and to maintain health. Further studies are needed to advance molecular therapeutic approaches, including miRNA-based strategies in human health and disease.


Assuntos
Gorduras na Dieta/farmacologia , Inflamação/metabolismo , Doenças Metabólicas/metabolismo , MicroRNAs , Animais , Ácidos Graxos/metabolismo , Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Camundongos , MicroRNAs/análise , MicroRNAs/genética , MicroRNAs/metabolismo , Ratos
8.
Int J Mol Sci ; 22(11)2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34072788

RESUMO

The concerning worldwide increase of obesity and chronic metabolic diseases, such as T2D, dyslipidemia, and cardiovascular disease, motivates further investigations into preventive and alternative therapeutic approaches. Over the past decade, there has been growing evidence that the formation and activation of thermogenic adipocytes (brown and beige) may serve as therapy to treat obesity and its associated diseases owing to its capacity to increase energy expenditure and to modulate circulating lipids and glucose levels. Thus, understanding the molecular mechanism of brown and beige adipocytes formation and activation will facilitate the development of strategies to combat metabolic disorders. Here, we provide a comprehensive overview of pathways and players involved in the development of brown and beige fat, as well as the role of thermogenic adipocytes in energy homeostasis and metabolism. Furthermore, we discuss the alterations in brown and beige adipose tissue function during obesity and explore the therapeutic potential of thermogenic activation to treat metabolic syndrome.


Assuntos
Tecido Adiposo/embriologia , Tecido Adiposo/fisiologia , Termogênese , Adipócitos/metabolismo , Adipogenia , Tecido Adiposo Bege/fisiologia , Tecido Adiposo Marrom/fisiologia , Envelhecimento/metabolismo , Animais , Gerenciamento Clínico , Suscetibilidade a Doenças , Metabolismo Energético , Epigênese Genética , Regulação da Expressão Gênica , Humanos , Doenças Metabólicas/etiologia , Doenças Metabólicas/metabolismo , Doenças Metabólicas/terapia , Redes e Vias Metabólicas , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/terapia , Organogênese , Termogênese/efeitos dos fármacos , Termogênese/fisiologia
9.
FEBS J ; 288(12): 3624-3627, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34152675

RESUMO

The word 'metabolism' is derived from the Greek word µÎµταßολή (metabole), denoting 'change'. True to this definition, it is now appreciated that a cell or tissue cannot change its behaviour without altering its metabolism. Hence, most key cell decision-making processes are tightly coupled to metabolic change. Conversely, perturbations in metabolite abundance or flux can alter cellular (and whole-body) function profoundly, giving rise to disease. This Special Issue on Systemic and Cellular Metabolism and Disease provides an integrative perspective on the importance of metabolism for health and disease alike. Spanning several orders of scale (from metabolites, proteins, organelles, organs/tissues and whole-body physiology), these review articles cover a breadth of topics, including the importance of metabolites as signalling regulators, metabolic disease, immunity, organelle function/dysfunction, ageing and neurodegenerative disease. One of the emergent themes is that just as metabolism is the fulcrum of biology, metabolic perturbances underpin most forms of acute, chronic, infectious and non-infectious human disease; ageing and senescence could be similarly viewed. Arguably most diseases are metabolic diseases; hence, modulating metabolism may help to 'change' disease outcomes.


Assuntos
Envelhecimento/metabolismo , Doenças Metabólicas/metabolismo , Redes e Vias Metabólicas/genética , Mitocôndrias/metabolismo , Neoplasias/metabolismo , Doenças Neurodegenerativas/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Tecido Adiposo Marrom/metabolismo , Envelhecimento/genética , Animais , Regulação da Expressão Gênica , Humanos , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/metabolismo , Doenças Metabólicas/genética , Doenças Metabólicas/patologia , Mitocôndrias/genética , Neoplasias/genética , Neoplasias/patologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia , RNA Circular/genética , RNA Circular/metabolismo , Transdução de Sinais
10.
Nutrients ; 13(5)2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-34062793

RESUMO

Selenium (Se) is an essential element for the maintenance of a healthy physiological state. However, due to environmental and dietary factors and the narrow safety range of Se, diseases caused by Se deficiency or excess have gained considerable traction in recent years. In particular, links have been identified between low Se status, cognitive decline, immune disorders, and increased mortality, whereas excess Se increases metabolic risk. Considerable evidence has suggested microRNAs (miRNAs) regulate interactions between the environment (including the diet) and genes, and play important roles in several diseases, including cancer. MiRNAs target messenger RNAs to induce changes in proteins including selenoprotein expression, ultimately generating disease. While a plethora of data exists on the epigenetic regulation of other dietary factors, nutrient Se epigenetics and especially miRNA regulated mechanisms remain unclear. Thus, this review mainly focuses on Se metabolism, pathogenic mechanisms, and miRNAs as key regulatory factors in Se-related diseases. Finally, we attempt to clarify the regulatory mechanisms underpinning Se, miRNAs, selenoproteins, and Se-related diseases.


Assuntos
Doenças Metabólicas/metabolismo , MicroRNAs/efeitos dos fármacos , Fenômenos Fisiológicos da Nutrição/genética , Selênio/metabolismo , Selenoproteínas/metabolismo , Epigênese Genética/efeitos dos fármacos , Humanos , Doenças Metabólicas/genética
11.
Int J Mol Sci ; 22(10)2021 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-34067931

RESUMO

Consumption of high-calorie foods, such as diets rich in fats, is an important factor leading to the development of steatohepatitis. Several studies have suggested how lipid accumulation creates a lipotoxic microenvironment for cells, leading cells to deregulate their transcriptional and translational activity. This deregulation induces the development of liver diseases such as non-alcoholic fatty liver disease (NAFLD) and subsequently also the appearance of hepatocellular carcinoma (HCC) which is one of the deadliest types of cancers worldwide. Understanding its pathology and studying new biomarkers with better specificity in predicting disease prognosis can help in the personalized treatment of the disease. In this setting, understanding the link between NAFLD and HCC progression, the differentiation of each stage in between as well as the mechanisms underlying this process, are vital for development of new treatments and in exploring new therapeutic targets. Perilipins are a family of five closely related proteins expressed on the surface of lipid droplets (LD) in several tissues acting in several pathways involved in lipid metabolism. Recent studies have shown that Plin5 depletion acts protectively in the pathogenesis of liver injury underpinning the importance of pathways associated with PLIN5. PLIN5 expression is involved in pro-inflammatory cytokine regulation and mitochondrial damage, as well as endoplasmic reticulum (ER) stress, making it critical target of the NAFLD-HCC studies. The aim of this review is to dissect the recent findings and functions of PLIN5 in lipid metabolism, metabolic disorders, and NAFLD as well as the progression of NAFLD to HCC.


Assuntos
Carcinoma Hepatocelular/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Perilipina-5/metabolismo , Biomarcadores/metabolismo , Estresse do Retículo Endoplasmático/fisiologia , Humanos , Gotículas Lipídicas/metabolismo , Metabolismo dos Lipídeos/genética , Metabolismo dos Lipídeos/fisiologia , Fígado/metabolismo , Fígado/patologia , Neoplasias Hepáticas/metabolismo , Doenças Metabólicas/metabolismo , Perilipina-5/fisiologia , Microambiente Tumoral/fisiologia
12.
Int J Mol Sci ; 22(10)2021 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-34069293

RESUMO

The gonadal steroids, including androgens, estrogens and progestogens, are involved in the control of body fat distribution in humans. Nevertheless, not only the size and localization of the fat depots depend on the sex steroids levels, but they can also highly affect the functioning of adipose tissue. Namely, the gonadocorticoids can directly influence insulin signaling, lipid metabolism, fatty acid uptake and adipokine production. They may also alter energy balance and glucose homeostasis in adipocytes in an indirect way, e.g., by changing the expression level of aquaglyceroporins. This work presents the recent advances in understanding the molecular mechanism of how the gonadal steroids influence the functioning of adipose tissue leading to a set of detrimental metabolic consequences. Special attention is given here to highlighting the sexual dimorphism of adipocyte functioning in terms of health and disease. Particularly, we discuss the molecular background of metabolic disturbances occurring in consequence of hormonal imbalance which is characteristic of some common endocrinopathies such as the polycystic ovary syndrome. From this perspective, we highlight the potential drug targets and the active substances which can be used in personalized sex-specific management of metabolic diseases, in accord with the patient's hormonal status.


Assuntos
Tecido Adiposo/fisiologia , Doenças Metabólicas/metabolismo , Esteroides/metabolismo , Adipócitos/metabolismo , Animais , Aquaporinas/metabolismo , Distribuição da Gordura Corporal , Feminino , Hormônios Esteroides Gonadais/fisiologia , Humanos , Resistência à Insulina/fisiologia , Lipogênese/fisiologia , Masculino , MicroRNAs/metabolismo , Síndrome do Ovário Policístico/metabolismo , Fatores Sexuais , Esteroides/fisiologia
13.
Mutat Res Rev Mutat Res ; 787: 108367, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34083034

RESUMO

Chronic diseases such as cardiovascular diseases, type 2 diabetes or cancer are the global leading cause of mortality. Lifestyle interventions are most effective in reducing metabolic risk factors, disease progression or even side effects of a disease. They are also contributing to decelerate the aging process. Genome instability is very often associated with aging or the above-mentioned diseases, and triggered by inflammation and oxidative stress. An established method to measure chromosomal damage is the cytokinesis block micronucleus (CBMN) cytome assay. The aim of this review and meta-analysis is to collect and analyse the current literature regarding the effects of a lifestyle based (dietary) intervention on changes of micronuclei (MNi), nucleoplasmic bridges (NPBs) and nuclear buds (NBUDs) in elderly subjects or people diagnosed with diabetes, metabolic disorders, cardiovascular disease, cancer or micronutrient deficiency. Although the main important diseases were considered as well as the large topic of aging, the number and methodological quality in terms of samples size, duration and rationale of the intervention or an inclusion of a control group of available intervention studies with these backgrounds was low. Most of the studies used antioxidant vitamins or folate, few investigated the whole diet. Only one study showed a physical activity intervention approach. The interventions did not lead to decreased genomic marker despite a few cancer related studies, where particularly MN frequency in mucosa lesions and leukoplakia was reduced by green tea and antioxidants. The performed meta-analysis of the available RCTs did not show a significant reduction of MNi, NBUDs or NPBs of most of the interventions performed, except for green tea. Data show in general a lack of an appropriate number of sound lifestyle based intervention studies linking cytogenetic damage and chronic diseases.


Assuntos
Doenças Cardiovasculares/metabolismo , Diabetes Mellitus/metabolismo , Doenças Metabólicas/metabolismo , Doenças Cardiovasculares/genética , Dano ao DNA/genética , Dano ao DNA/fisiologia , Diabetes Mellitus/genética , Humanos , Doenças Metabólicas/genética , Testes para Micronúcleos , Neoplasias/genética , Neoplasias/metabolismo
14.
Int J Mol Sci ; 22(10)2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34065168

RESUMO

Increasing evidence links metabolic disorders with neurodegenerative processes including Alzheimer's disease (AD). Late AD is associated with amyloid (Aß) plaque accumulation, neuroinflammation, and central insulin resistance. Here, a humanized AD model, the 5xFAD mouse model, was used to further explore food intake, energy expenditure, neuroinflammation, and neuroendocrine signaling in the hypothalamus. Experiments were performed on 6-month-old male and female full transgenic (Tg5xFAD/5xFAD), heterozygous (Tg5xFAD/-), and non-transgenic (Non-Tg) littermates. Although histological analysis showed absence of Aß plaques in the hypothalamus of 5xFAD mice, this brain region displayed increased protein levels of GFAP and IBA1 in both Tg5xFAD/- and Tg5xFAD/5xFAD mice and increased expression of IL-1ß in Tg5xFAD/5xFAD mice, suggesting neuroinflammation. This condition was accompanied by decreased body weight, food intake, and energy expenditure in both Tg5xFAD/- and Tg5xFAD/5xFAD mice. Negative energy balance was associated with altered circulating levels of insulin, GLP-1, GIP, ghrelin, and resistin; decreased insulin and leptin hypothalamic signaling; dysregulation in main metabolic sensors (phosphorylated IRS1, STAT5, AMPK, mTOR, ERK2); and neuropeptides controlling energy balance (NPY, AgRP, orexin, MCH). These results suggest that glial activation and metabolic dysfunctions in the hypothalamus of a mouse model of AD likely result in negative energy balance, which may contribute to AD pathogenesis development.


Assuntos
Doença de Alzheimer/metabolismo , Metabolismo Energético/fisiologia , Hipotálamo/metabolismo , Doenças Metabólicas/metabolismo , Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Proteínas Amiloidogênicas/metabolismo , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Feminino , Polipeptídeo Inibidor Gástrico/metabolismo , Grelina/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Insulina/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Placa Amiloide/metabolismo , Resistina/metabolismo
15.
Int J Mol Sci ; 22(11)2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34070384

RESUMO

Over the last decades, the study of cancer metabolism has returned to the forefront of cancer research and challenged the role of genetics in the understanding of cancer development. One of the major impulses of this new trend came from the discovery of oncometabolites, metabolic intermediates whose abnormal cellular accumulation triggers oncogenic signalling and tumorigenesis. These findings have led to reconsideration and support for the long-forgotten hypothesis of Warburg of altered metabolism as oncogenic driver of cancer and started a novel paradigm whereby mitochondrial metabolites play a pivotal role in malignant transformation. In this review, we describe the evolution of the cancer metabolism research from a historical perspective up to the oncometabolites discovery that spawned the new vision of cancer as a metabolic disease. The oncometabolites' mechanisms of cellular transformation and their contribution to the development of new targeted cancer therapies together with their drawbacks are further reviewed and discussed.


Assuntos
Transformação Celular Neoplásica/metabolismo , Doenças Metabólicas/metabolismo , Mitocôndrias/metabolismo , Neoplasias/metabolismo , Transdução de Sinais , Transformação Celular Neoplásica/patologia , Humanos , Doenças Metabólicas/patologia , Mitocôndrias/patologia , Neoplasias/patologia
16.
Int J Mol Sci ; 22(11)2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-34073381

RESUMO

Isoflavones are phytoestrogens of plant origin, mostly found in the members of the Fabaceae family, that exert beneficial effects in various degenerative disorders. Having high similarity to 17-ß-estradiol, isoflavones can bind estrogen receptors, scavenge reactive oxygen species, activate various cellular signal transduction pathways and modulate growth and transcription factors, activities of enzymes, cytokines, and genes regulating cell proliferation and apoptosis. Due to their pleiotropic activities isoflavones might be considered as a natural alternative for the treatment of estrogen decrease-related conditions during menopause. This review will focus on the effects of isoflavones on inflammation and chronic degenerative diseases including cancer, metabolic, cardiovascular, neurodegenerative diseases, rheumatoid arthritis and adverse postmenopausal symptoms.


Assuntos
Sequestradores de Radicais Livres/uso terapêutico , Isoflavonas/uso terapêutico , Doenças Metabólicas/tratamento farmacológico , Neoplasias/tratamento farmacológico , Doenças Neurodegenerativas/tratamento farmacológico , Pós-Menopausa , Feminino , Humanos , Masculino , Doenças Metabólicas/metabolismo , Neoplasias/metabolismo , Doenças Neurodegenerativas/metabolismo
17.
Nat Commun ; 12(1): 2598, 2021 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-33972511

RESUMO

The intestinal immune system is an important modulator of glucose homeostasis and obesity-associated insulin resistance. Dietary factors, the intestinal microbiota and their metabolites shape intestinal immunity during obesity. The intestinal immune system in turn affects processes such as intestinal permeability, immune cell trafficking, and intestinal hormone availability, impacting systemic insulin resistance. Understanding these pathways might identify mechanisms underlying treatments for insulin resistance, such as metformin and bariatric surgery, or aid in developing new therapies and vaccination approaches. Here, we highlight evolving concepts centered on intestinal immunity, diet, and the microbiota to provide a working model of obesity-related metabolic disease.


Assuntos
Microbioma Gastrointestinal/imunologia , Doenças Metabólicas/imunologia , Doenças Metabólicas/metabolismo , Obesidade/metabolismo , Animais , Linfócitos B/imunologia , Citocinas/metabolismo , Dietoterapia , Humanos , Sistema Imunitário/citologia , Sistema Imunitário/metabolismo , Inflamação/imunologia , Inflamação/metabolismo , Resistência à Insulina/imunologia , Doenças Metabólicas/microbiologia , Doenças Metabólicas/terapia , Obesidade/dietoterapia , Obesidade/imunologia , Obesidade/terapia , Linfócitos T/imunologia
18.
Nat Commun ; 12(1): 2887, 2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-34001905

RESUMO

Obesity is a major risk factor underlying the development of metabolic disease and a growing public health concern globally. Strategies to promote skeletal muscle metabolism can be effective to limit the progression of metabolic disease. Here, we demonstrate that the levels of the Hippo pathway transcriptional co-activator YAP are decreased in muscle biopsies from obese, insulin-resistant humans and mice. Targeted disruption of Yap in adult skeletal muscle resulted in incomplete oxidation of fatty acids and lipotoxicity. Integrated 'omics analysis from isolated adult muscle nuclei revealed that Yap regulates a transcriptional profile associated with metabolic substrate utilisation. In line with these findings, increasing Yap abundance in the striated muscle of obese (db/db) mice enhanced energy expenditure and attenuated adiposity. Our results demonstrate a vital role for Yap as a mediator of skeletal muscle metabolism. Strategies to enhance Yap activity in skeletal muscle warrant consideration as part of comprehensive approaches to treat metabolic disease.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Adiposidade/genética , Ácidos Graxos/metabolismo , Doenças Metabólicas/genética , Músculo Esquelético/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Regulação da Expressão Gênica , Resistência à Insulina/genética , Masculino , Doenças Metabólicas/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/genética , Obesidade/metabolismo , Oxirredução , Interferência de RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos
19.
Biochim Biophys Acta Gen Subj ; 1865(8): 129898, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33878388

RESUMO

Galactose is an essential carbohydrate for cellular metabolism, as it contributes to energy production and storage in several human tissues while also being a precursor for glycosylation. Galactosylated glycoconjugates, such as glycoproteins, keratan sulfate-containing proteoglycans and glycolipids, exert a plethora of biological functions, including structural support, cellular adhesion, intracellular signaling and many more. The biological relevance of galactose is further entailed by the number of pathogenic conditions consequent to defects in galactosylation and galactose homeostasis. The growing number of rare congenital disorders involving galactose along with its recent therapeutical applications are drawing increasing attention to galactose metabolism. In this review, we aim to draw a comprehensive overview of the biological functions of galactose in human cells, including its metabolism and its role in glycosylation, and to provide a systematic description of all known congenital metabolic disorders resulting from alterations of its homeostasis.


Assuntos
Defeitos Congênitos da Glicosilação/patologia , Galactose/metabolismo , Homeostase , Doenças Metabólicas/patologia , Defeitos Congênitos da Glicosilação/metabolismo , Glicosilação , Humanos , Doenças Metabólicas/metabolismo
20.
J Biol Chem ; 296: 100667, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33864813

RESUMO

The epoxyeicosatrienoic acid (EET) exerts beneficial effects on insulin resistance and/or hypertension. EETs could be readily converted to less biological active diols by soluble epoxide hydrolase (sEH). However, whether sEH inhibition can ameliorate the comorbidities of insulin resistance and hypertension and the underlying mechanisms of this relationship are unclear. In this study, C57BL/6 mice were rendered hypertensive and insulin resistant through a high-fat and high-salt (HF-HS) diet. The sEH inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), was used to treat mice (1 mg/kg/day) for 8 weeks, followed by analysis of metabolic parameters. The expression of sEH and the sodium-glucose cotransporter 2 (SGLT2) was markedly upregulated in the kidneys of mice fed an HF-HS diet. We found that TPPU administration increased kidney EET levels, improved insulin resistance, and reduced hypertension. Furthermore, TPPU treatment prevented upregulation of SGLT2 and the associated increased urine volume and the excretion of urine glucose and urine sodium. Importantly, TPPU alleviated renal inflammation. In vitro, human renal proximal tubule epithelial cells (HK-2 cells) were used to further investigate the underlying mechanism. We observed that 14,15-EET or sEH knockdown or inhibition prevented the upregulation of SGLT2 upon treatment with palmitic acid or NaCl by inhibiting the inhibitory kappa B kinase α/ß/NF-κB signaling pathway. In conclusion, sEH inhibition by TPPU alleviated insulin resistance and hypertension induced by an HF-HS diet in mice. The increased urine excretion of glucose and sodium was mediated by decreased renal SGLT2 expression because of inactivation of the inhibitory kappa B kinase α/ß/NF-κB-induced inflammatory response.


Assuntos
Epóxido Hidrolases/antagonistas & inibidores , Regulação da Expressão Gênica , Hipertensão/prevenção & controle , Resistência à Insulina , Rim/metabolismo , Doenças Metabólicas/prevenção & controle , Transportador 2 de Glucose-Sódio/metabolismo , Animais , Regulação para Baixo , Hipertensão/etiologia , Hipertensão/metabolismo , Hipertensão/patologia , Proteínas I-kappa B/genética , Proteínas I-kappa B/metabolismo , Rim/efeitos dos fármacos , Rim/patologia , Masculino , Doenças Metabólicas/etiologia , Doenças Metabólicas/metabolismo , Doenças Metabólicas/patologia , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/genética , Transportador 2 de Glucose-Sódio/genética
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