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1.
J Agric Food Chem ; 67(38): 10553-10562, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31490076

RESUMO

Chlorpyrifos (CPF) is a widely used organophosphorus pesticide and detected frequently in fruits, vegetables, as well as in urine and blood in humans. Studies have suggested that CPF can induce metabolic disruption, such as type-2 diabetes mellitus and changed body weight. The main mechanisms are based on oxidative damage, fatty-acid synthesis, and lipid peroxidation. Studies have also shown that CPF can change reproductive hormone (RH) levels. CPF might result in metabolic disorders through altered RH levels. Here, we review the studies showing that CFP causes metabolic disruption. Then, we present the studies showing that CFP changes RH levels. Finally, we discuss a potential pathway of how CPF elicits metabolic disruption.


Assuntos
Clorpirifos/toxicidade , Hormônios Gonadais/metabolismo , Inseticidas/toxicidade , Doenças Metabólicas/metabolismo , Animais , Humanos , Peroxidação de Lipídeos , Doenças Metabólicas/etiologia
2.
Curr Top Med Chem ; 19(16): 1399-1417, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31284862

RESUMO

The pituitary adenylate cyclase-activating polypeptide (PACAP)-selective PAC1 receptor (PAC1R, ADCYAP1R1) is a member of the vasoactive intestinal peptide (VIP)/secretin/glucagon family of G protein-coupled receptors (GPCRs). PAC1R has been shown to play crucial roles in the central and peripheral nervous systems. The activation of PAC1R initiates diverse downstream signal transduction pathways, including adenylyl cyclase, phospholipase C, MEK/ERK, and Akt pathways that regulate a number of physiological systems to maintain functional homeostasis. Accordingly, at times of tissue injury or insult, PACAP/PAC1R activation of these pathways can be trophic to blunt or delay apoptotic events and enhance cell survival. Enhancing PAC1R signaling under these conditions has the potential to mitigate cellular damages associated with cerebrovascular trauma (including stroke), neurodegeneration (such as Parkinson's and Alzheimer's disease), or peripheral organ insults. Conversely, maladaptive PACAP/PAC1R signaling has been implicated in a number of disorders, including stressrelated psychopathologies (i.e., depression, posttraumatic stress disorder, and related abnormalities), chronic pain and migraine, and metabolic diseases; abrogating PAC1R signaling under these pathological conditions represent opportunities for therapeutic intervention. Given the diverse PAC1R-mediated biological activities, the receptor has emerged as a relevant pharmaceutical target. In this review, we first describe the current knowledge regarding the molecular structure, dynamics, and function of PAC1R. Then, we discuss the roles of PACAP and PAC1R in the activation of a variety of signaling cascades related to the physiology and diseases of the nervous system. Lastly, we examine current drug design and development of peptides and small molecules targeting PAC1R based on a number of structure- activity relationship studies and key pharmacophore elements. At present, the rational design of PAC1R-selective peptide or small-molecule therapeutics is largely hindered by the lack of structural information regarding PAC1R activation mechanisms, the PACAP-PAC1R interface, and the core segments involved in receptor activation. Understanding the molecular basis governing the PACAP interactions with its different cognate receptors will undoubtedly provide a basis for the development and/or refinement of receptor-selective therapeutics.


Assuntos
Doenças Metabólicas/tratamento farmacológico , Doenças do Sistema Nervoso/tratamento farmacológico , Peptídeos/farmacologia , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Humanos , Doenças Metabólicas/metabolismo , Modelos Moleculares , Estrutura Molecular , Doenças do Sistema Nervoso/metabolismo , Peptídeos/síntese química , Peptídeos/química , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/química , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/metabolismo , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química
3.
Animal ; 13(S1): s75-s81, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31280745

RESUMO

The increasing lactational performance of dairy cows over the last few decades is closely related to higher nutritional requirements. The decrease in dry matter intake during the peripartal period results in a considerable mobilisation of body tissues (mainly fat reserves and muscle mass) to compensate for the prevailing lack of energy and nutrients. Despite the activation of adaptive mechanisms to mobilise nutrients from body tissues for maintenance and milk production, the increased metabolic load is still a risk factor for animal health. The prevalence of production diseases, particularly subclinical ketosis is high in the early lactation period. Increased ß-hydroxybutyrate (BHB) concentrations further depress gluconeogenesis, feed intake and the immune system. Despite a variety of adaptation responses to nutrient and energy deficit that exists among dairy cows, an early and non-invasive detection of developing metabolic disorders in milk samples would be useful. The frequent and regular milking process of dairy cows creates the ability to obtain samples at any stage of lactation. Routine identification of biomarkers accurately characterising the physiological status of an animal is crucial for decisive strategies. The present overview recapitulates established markers measured in milk that are associated with metabolic health of dairy cows. Specifically, measurements of milk fat, protein, lactose and urea concentrations are evaluated. Changes in the ratio of milk fat to protein may indicate an increased risk for rumen acidosis and ketosis. The costly determination of individual fatty acids in milk creates barriers for grouping of fatty acids into saturated, mono- and polyunsaturated fatty acids. Novel approaches include the potential of mid-IR (MIR) based predictions of BHB and acetone in milk, although the latter are not directly measured, but only estimated via indirect associations of concomitantly altered milk composition during (sub)clinical ketosis. Although MIR-based ketone body concentrations in milk are not suitable to monitor the metabolic status of the individual cow, they provide an estimate of the overall herd or specific groups of animals earlier in a particular stage of lactation. Management decisions can be made earlier and animal health status improved by adjusting diet composition.


Assuntos
Acidose/veterinária , Doenças dos Bovinos/metabolismo , Cetose/veterinária , Lactação/fisiologia , Doenças Metabólicas/veterinária , Leite/química , Ácido 3-Hidroxibutírico/análise , Acidose/metabolismo , Animais , Biomarcadores/análise , Bovinos , Dieta/veterinária , Ácidos Graxos/análise , Feminino , Cetose/metabolismo , Doenças Metabólicas/metabolismo , Leite/metabolismo , Necessidades Nutricionais , Rúmen/fisiopatologia
5.
J Agric Food Chem ; 67(26): 7315-7324, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31184122

RESUMO

A high-fat diet (HFD) is the main cause of metabolic diseases. However, HFD in previous studies consists of much lard, which contains a large amount of omega-6 (ω-6) polyunsaturated fatty acid (PUFA) and little omega-3 (ω-3) PUFA. The role of ω-6/ω-3 ratio of HFD in the development of metabolic diseases remains incompletely discussed. In this study, rats were fed with either a low or a high ω-6/ω-3 ratio HFD singly or combined with inulin. Metabolism state was valued and metabolomics of cecal content were detected. Results show that HFD with low ω-6/ω-3 ratio promotes the glucose utilization in rats. However, inulin had different effects on metabolism with different diets. Xanthosine and kynurenic acid in cecum were positively related to epididymal white adipose tissues (eWAT) mass. The present study indicates the beneficial effects of low ω-6/ω-3 ratio HFD (LRD) on the metabolic state of rats. Moreover, xanthosine and kynurenic acid were closely related to the development of metabolic diseases.


Assuntos
Ácidos Graxos Ômega-3/metabolismo , Ácidos Graxos Ômega-6/metabolismo , Mucosa Intestinal/metabolismo , Inulina/metabolismo , Doenças Metabólicas/dietoterapia , Purinas/metabolismo , Triptofano/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Dieta Hiperlipídica , Ácidos Graxos Ômega-3/análise , Ácidos Graxos Ômega-6/análise , Glucose/metabolismo , Humanos , Masculino , Doenças Metabólicas/metabolismo , Ratos , Ratos Sprague-Dawley
6.
J Agric Food Chem ; 67(32): 8735-8739, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31244204

RESUMO

The circadian clock is an intrinsic mechanism of biological adaptation to the cyclical changes of the environment. The circadian rhythm disorders affect the life activities of organisms. A variety of phytochemicals (e.g., polyphenols, flavonoids, alkaloids, and melatonin) reportedly can regulate the expression and rhythm of circadian clock genes and stabilize the internal environment. This perspective focuses on the relationship of circadian clock genes with oxidative stress, inflammatory response, and metabolic disorders and emphasizes the regulation of phytochemicals on the circadian clock. Potential mechanisms and applications of supplemental phytochemicals to improve metabolic disorders and circadian rhythm disorders are also discussed.


Assuntos
Relógios Circadianos , Doenças Metabólicas/fisiopatologia , Compostos Fitoquímicos/metabolismo , Animais , Humanos , Doenças Metabólicas/genética , Doenças Metabólicas/metabolismo , Estresse Oxidativo , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo
7.
Drugs ; 79(11): 1187-1197, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31243696

RESUMO

Obesity, type 2 diabetes, and the numerous associated metabolic co-morbidities are growing global threats to public health. Despite recent progress in pharmacotherapies for metabolic diseases, the current treatment options have limited efficacy and provide mostly symptomatic relief with little or no impact on disease reversal. Thus, improved therapies are urgently needed. As a result, the scientific community has increasingly invested in leveraging new pathophysiological insights into more efficacious pharmacotherapies for metabolic complications. A heightened understanding of the large, interindividual variation in responsiveness to certain metabolic medicines combined with advances in engineering multi-agonist candidates are important steps towards this goal. Additionally, the emerging pharmacological concept of peptide-mediated targeting of small molecules for tissue-specific delivery holds promise for more powerful treatment solutions in the future. In this review, we summarize recent advances in medicinal chemistry and molecular pharmacology that have enabled the engineering of several, novel, poly-agonist drug candidates for treatment of metabolic diseases, and we discuss the recent results from clinical trials assessing the efficacy and safety of glucagon-like peptide (GLP)-1/glucagon and GLP-1/GIP co-agonists.


Assuntos
Peptídeo 1 Semelhante ao Glucagon/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Glucagon/metabolismo , Doenças Metabólicas/tratamento farmacológico , Receptores dos Hormônios Gastrointestinais/agonistas , Receptores de Glucagon/agonistas , Animais , Ensaios Clínicos como Assunto , Quimioterapia Combinada , Polipeptídeo Inibidor Gástrico/metabolismo , Polipeptídeo Inibidor Gástrico/farmacologia , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Humanos , Doenças Metabólicas/metabolismo , Terapia de Alvo Molecular , Medicina de Precisão , Receptores de Glucagon/metabolismo
8.
Adv Clin Chem ; 90: 25-80, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31122611

RESUMO

Acute-phase reactant serum amyloid A (A-SAA) plays an important role in acute and chronic inflammation and is used in clinical laboratories as an indicator of inflammation. Although both A-SAA and C-reactive protein (CRP) are acute-phase proteins, the detection of A-SAA is more conclusive than the detection of CRP in patients with viral infections, severe acute pancreatitis, and rejection reactions to kidney transplants. A-SAA has greater clinical diagnostic value in patients who are immunosuppressed, patients with cystic fibrosis who are treated with corticoids, and preterm infants with late-onset sepsis. Nevertheless, for the assessment of the inflammation status and identification of viral infection in other pathologies, such as bacterial infections, the combinatorial use of A-SAA and other acute-phase proteins (APPs), such as CRP and procalcitonin (PCT), can provide more information and sensitivity than the use of any of these proteins alone, and the information generated is important in guiding antibiotic therapy. In addition, A-SAA-associated diseases and the diagnostic value of A-SAA are discussed. However, the relationship between different A-SAA isotypes and their human diseases are mostly derived from research laboratories with limited clinical samples. Thus, further clinical evaluations are necessary to confirm the clinical significance of each A-SAA isotype. Furthermore, the currently available A-SAA assays are based on polyclonal antibodies, which lack isotype specificity and are associated with many inflammatory diseases. Therefore, these assays are usually used in combination with other biomarkers in the clinic.


Assuntos
Reação de Fase Aguda , Doença , Inflamação/sangue , Inflamação/diagnóstico , Proteína Amiloide A Sérica/análise , Amiloidose/sangue , Amiloidose/diagnóstico , Amiloidose/metabolismo , Animais , Doenças Autoimunes/sangue , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/metabolismo , Humanos , Inflamação/metabolismo , Hepatopatias/sangue , Hepatopatias/diagnóstico , Hepatopatias/metabolismo , Doenças Metabólicas/sangue , Doenças Metabólicas/diagnóstico , Doenças Metabólicas/metabolismo , Neoplasias/sangue , Neoplasias/diagnóstico , Neoplasias/metabolismo , Proteína Amiloide A Sérica/metabolismo
9.
J Biomed Sci ; 26(1): 34, 2019 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-31078136

RESUMO

Nicotinamide adenine dinucleotide (NAD) is an important coenzyme that participates in various energy metabolism pathways, including glycolysis, ß-oxidation, and oxidative phosphorylation. Besides, it is a required cofactor for post-translational modifications such as ADP-ribosylation and deacetylation by poly (ADP-ribose) polymerases (PARPs) and sirtuins, respectively. Thus, NAD regulates energy metabolism, DNA damage repair, gene expression, and stress response through these enzymes. Numerous studies have shown that NAD levels decrease with aging and under disturbed nutrient conditions, such as obesity. Additionally, a decline in NAD levels is closely related to the development of various metabolic disorders, including diabetes and fatty liver disease. In addition, many studies have revealed that administration of NAD precursors, such as nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR), efficiently increase NAD levels in various tissues and prevent such metabolic diseases. These NAD precursors are contained in natural foods, such as cow milk, vegetables, and meats. Therefore, altered NAD metabolism can be a practical target for nutritional intervention. Recently, several human clinical trials using NAD precursors have been conducted to investigate the safety, pharmacokinetics, and efficacy against metabolic disorders such as glucose intolerance. In this review, we summarize current knowledge on the implications of NAD metabolism in metabolic diseases and discuss the outcomes of recent human clinical trials.


Assuntos
Dieta , Doenças Metabólicas/fisiopatologia , NAD/metabolismo , Humanos , Doenças Metabólicas/metabolismo
10.
J Med Food ; 22(5): 469-478, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31084539

RESUMO

Aging and lifestyle factors, including high-sugar and high-fat diets, promote a systemic metabolic imbalance that promotes neurodegeneration. Hericium erinaceus has long been used in traditional Chinese medicine. Recently, its functional activities, such as antimetabolic dysfunction, antineuroinflammatory activities, and stimulation of nerve growth factor (NGF) synthesis, have been revealed. This study demonstrated that Hericium erinaceus mycelium (HEM) and an isolated diterpenoid derivative, erinacine A (EA), may reverse spatial learning disabilities in aging mice (15 months old) fed with a high-fat and high-sucrose diet (HFSD). Aging mice were randomly assigned to one of four treatment groups: (1) a chow diet (control), (2) an HFSD, and an HFSD supplemented with either (3) HEM or (4) EA for 18 weeks. The Morris water maze (MWM) and Y-maze were used for behavioral assessments. Both HEM- and EA-treated mice had shorter mean daily escape latencies than HFSD-treated mice in the MWM. In addition, HEM-treated mice had a slightly increased exploratory time and frequency in the novel arm in the Y-maze. Quantitative PCR revealed that both HEM- and EA-treated mice exhibited reduced messenger RNA (mRNA) expression of tumor necrosis factor-α, interleukin-1ß, and HEM-treated mice exhibited increased mRNA expression of NGF and NeuN in the hippocampus. Moreover, HEM and EA also decreased body weight, abdominal fat, plasma glucose, serum and liver total cholesterol, and liver triacylglycerol. Thus, HEM may be a potential health-promoting supplement for minimizing the progression of aging and obesity-induced neurodegeneration by reducing metabolic abnormalities and neuroinflammatory cytokines and increasing neurogenesis factors.


Assuntos
Envelhecimento/efeitos dos fármacos , Basidiomycota/química , Dieta Hiperlipídica/efeitos adversos , Diterpenos/administração & dosagem , Doenças Metabólicas/tratamento farmacológico , Sacarose/efeitos adversos , Envelhecimento/metabolismo , Envelhecimento/psicologia , Animais , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Humanos , Masculino , Aprendizagem em Labirinto , Doenças Metabólicas/etiologia , Doenças Metabólicas/metabolismo , Doenças Metabólicas/psicologia , Camundongos , Camundongos Endogâmicos C57BL , Micélio/química , Fator de Crescimento Neural/genética , Fator de Crescimento Neural/metabolismo , Aprendizagem Espacial/efeitos dos fármacos
11.
Ecotoxicol Environ Saf ; 178: 94-104, 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-30999185

RESUMO

Light is involved in many critical physiological or biochemical processes of human beings, such as visual sensing and the production of vitamin D. Recent studies have showed that the lights of different wavelengths have a profound influence in life activities. For example, blue light promotes alertness, whereas green light (GL) induces sleep in mice. On the other hand, metabolic homeostasis is regulated by a variety of factors, including dietary habits and light exposure. Our study aims to study whether certain wavelength of light would affect metabolic status of mice. Mice were divided into normal diet-fed group and high-fat diet (HFD)-fed group, and then exposed to various colors of the light. Physiological parameters, such as body weight, food intake and water drinking were regularly measured. Glucose tolerance test and pyruvate tolerance test were simultaneously performed. After mice were humanely sacrificed, liver histology and serologic analysis were performed for detecting lipid levels. We found that GL group showed obvious glucose intolerance and increased levels of serum and liver lipid contents compared to white light group. Meanwhile, the expression levels of lipid metabolism-related genes were almost down-regulated in liver. Furthermore, melatonin receptor-1b and thyroid hormone receptor-ß expression levels were significantly lowered in liver of GL-treated obese mice, suggesting that these hormone pathways may mediate the changes of lipid metabolism. Our data indicate that GL has a detrimental effect on the energy metabolism and aggravates HFD-induced obesity in mice. In addition to malnutrition, the colors of the lights also have a profound influence in the metabolic homeostasis and should be taken into consideration in the therapy of metabolic disorders.


Assuntos
Dieta Hiperlipídica , Metabolismo Energético/efeitos da radiação , Luz , Metabolismo dos Lipídeos/efeitos da radiação , Doenças Metabólicas/metabolismo , Obesidade/metabolismo , Animais , Peso Corporal/efeitos da radiação , Ingestão de Alimentos/efeitos da radiação , Homeostase/efeitos da radiação , Fígado/efeitos da radiação , Masculino , Doenças Metabólicas/sangue , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/sangue
12.
Int J Mol Sci ; 20(7)2019 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-30935034

RESUMO

Circadian timekeeping allows appropriate temporal regulation of an organism's internal metabolism to anticipate and respond to recurrent daily changes in the environment. Evidence from animal genetic models and from humans under circadian misalignment (such as shift work or jet lag) shows that disruption of circadian rhythms contributes to the development of obesity and metabolic disease. Inappropriate timing of food intake and high-fat feeding also lead to disruptions of the temporal coordination of metabolism and physiology and subsequently promote its pathogenesis. This review illustrates the impact of genetically or environmentally induced molecular clock disruption (at the level of the brain and peripheral tissues) and the interplay between the circadian system and metabolic processes. Here, we discuss some mechanisms responsible for diet-induced circadian desynchrony and consider the impact of nutritional cues in inter-organ communication, with a particular focus on the communication between peripheral organs and brain. Finally, we discuss the relay of environmental information by signal-dependent transcription factors to adjust the timing of gene oscillations. Collectively, a better knowledge of the mechanisms by which the circadian clock function can be compromised will lead to novel preventive and therapeutic strategies for obesity and other metabolic disorders arising from circadian desynchrony.


Assuntos
Relógios Circadianos , Doenças Metabólicas/metabolismo , Animais , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/genética , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/metabolismo , Metabolismo Energético , Humanos , Doenças Metabólicas/fisiopatologia
13.
Genomics Proteomics Bioinformatics ; 17(1): 64-75, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-31026583

RESUMO

Inulin has been used as a prebiotic to alleviate glucose and lipid metabolism disorders in mice and humans by modulating the gut microbiota. However, the mechanism underlying the alleviation of metabolic disorders by inulin through interactions between the gut microbiota and host cells is unclear. We use ob/ob mice as a model to study the effect of inulin on the cecal microbiota by 16S rRNA gene amplicon sequencing and its interaction with host cells by transcriptomics. The inulin-supplemented diet improved glucose and lipid metabolism disorder parameters in ob/ob mice, alleviating fat accumulation and glucose intolerance. The α diversity of gut microbial community of ob/ob mice was reduced after inulin treatment, while the ß diversity tended to return to the level of wild type mice. Interestingly, Prevotellaceae UCG 001 (family Prevotellaceae) was obviously enriched after inulin treatment. A comparative analysis of the gene expression profile showed that the cecal transcriptome was changed in leptin gene deficiency mice, whereas the inulin-supplemented diet partially reversed the changes in leptin gene-related signaling pathways, especially AMPK signaling pathway, where the levels of gene expression became comparable to those in wild type mice. Further analysis indicated that Prevotellaceae UCG 001 was positively correlated with the AMPK signaling pathway, which was negatively correlated with markers of glycolipid metabolism disorders. Our results suggest that the inulin-supplemented diet alleviates glucose and lipid metabolism disorders by partially restoring leptin related pathways mediated by gut microbiota.


Assuntos
Microbioma Gastrointestinal/efeitos dos fármacos , Inulina/uso terapêutico , Leptina/genética , Doenças Metabólicas/tratamento farmacológico , Prebióticos , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Ceco/enzimologia , Ceco/metabolismo , Ceco/microbiologia , Masculino , Doenças Metabólicas/enzimologia , Doenças Metabólicas/metabolismo , Doenças Metabólicas/microbiologia , Camundongos , Camundongos Obesos , Transdução de Sinais/efeitos dos fármacos , Transcriptoma
14.
Nat Commun ; 10(1): 1209, 2019 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-30872577

RESUMO

Sparse profiling of CpG methylation in blood by microarrays has identified epigenetic links to common diseases. Here we apply methylC-capture sequencing (MCC-Seq) in a clinical population of ~200 adipose tissue and matched blood samples (Ntotal~400), providing high-resolution methylation profiling (>1.3 M CpGs) at regulatory elements. We link methylation to cardiometabolic risk through associations to circulating plasma lipid levels and identify lipid-associated CpGs with unique localization patterns in regulatory elements. We show distinct features of tissue-specific versus tissue-independent lipid-linked regulatory regions by contrasting with parallel assessments in ~800 independent adipose tissue and blood samples from the general population. We follow-up on adipose-specific regulatory regions under (1) genetic and (2) epigenetic (environmental) regulation via integrational studies. Overall, the comprehensive sequencing of regulatory element methylomes reveals a rich landscape of functional variants linked genetically as well as epigenetically to plasma lipid traits.


Assuntos
Doenças Cardiovasculares/genética , Ilhas de CpG/genética , Epigênese Genética , Doenças Metabólicas/genética , Sequências Reguladoras de Ácido Nucleico/genética , Tecido Adiposo/metabolismo , Adulto , Idoso , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/metabolismo , Metilação de DNA , Epigenômica/métodos , Feminino , Perfilação da Expressão Gênica , Genoma Humano , Estudo de Associação Genômica Ampla , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Lipídeos/sangue , Masculino , Doenças Metabólicas/sangue , Doenças Metabólicas/metabolismo , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA/métodos
15.
Mar Drugs ; 17(3)2019 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-30857204

RESUMO

Phlorotannins are phloroglucinol-based phenolic compounds, occurring particularly in brown macroalgae, that have been recognized for their promising bioactive properties. In this study, the extraction of phlorotannins from Fucus vesiculosus was evaluated with particular emphasis on the influential parameters, including the solvent concentration, solvent-solid ratio, extraction temperature and extraction time, using a single-factor design followed by a Box-Behnken design. The maximum total phlorotannin content, determined using the 2,4-dimethoxybenzaldehyde (DMBA) method, corresponded to 2.92 ± 0.05 mg of phloroglucinol equivalents/g dry seaweed (mg PGE/g DS), and was achieved for extracts carried out with acetone 67% (v/v), a solvent-solid ratio of 70 mL/g and temperature at 25 °C. This crude extract, together with a semi-purified phlorotannin fraction, were further evaluated for their anti-enzymatic capacity against α-glucosidase, α-amylase and pancreatic lipase, both showing promising inhibitory effects, particularly against α-glucosidase for which a greater inhibitory effect was observed compared to the pharmaceutical drug acarbose (IC50 = 4.5 ± 0.8 and 0.82 ± 0.3 µg/mL, respectively, against 206.6 ± 25.1 µg/mL). Additionally, the ultra-high-pressure liquid chromatography coupled to mass spectrometry (UHPLC-MS) analysis carried out on the ethyl acetate fraction revealed the presence of fucols, fucophlorethols, fuhalols and several other phlorotannin derivatives. Moreover, possible new phlorotannin compounds, including fucofurodiphlorethol, fucofurotriphlorethol and fucofuropentaphlorethol, have been tentatively identified in this extract. Overall, this study provides evidence that F. vesiculosus phlorotannin-rich extracts hold potential for the management of the activity of α-glucosidase, α-amylase and pancreatic lipase, which are well known to be linked to metabolic disorders such as diabetes and obesity.


Assuntos
Inibidores Enzimáticos/farmacologia , Fucus/química , Extratos Vegetais/farmacologia , Alga Marinha/química , Taninos/farmacologia , Cromatografia Líquida de Alta Pressão/métodos , Ensaios Enzimáticos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Inibidores Enzimáticos/uso terapêutico , Lipase/antagonistas & inibidores , Lipase/metabolismo , Espectrometria de Massas , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/metabolismo , Floroglucinol/química , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/uso terapêutico , Taninos/química , Taninos/isolamento & purificação , Taninos/uso terapêutico , alfa-Amilases/antagonistas & inibidores , alfa-Amilases/metabolismo , alfa-Glucosidases/metabolismo
16.
Environ Pollut ; 247: 935-943, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30823348

RESUMO

Bisphenols (BPs) are common environmental pollutants that are ubiquitous in the natural environment and can affect human health. In this study, we explored the effects of perinatal exposure to BPA, BPF and BPAF on liver function involving in oxidative damage and metabolic disorders in male mouse offspring. We found that BPA exposure impairs the antioxidant defense system, increases lipid peroxidation, and causes oxidative damage in the liver. Furthermore, the levels of 13 metabolites were significantly altered following BPA exposure. We found that BPF exposure significantly increased the expression and activity of CAT, suggesting disturbances in the antioxidant defense system. Moreover, BPF exposure led to metabolic disorders in the liver due to changes in the levels of 8 key metabolites. Exposure to BPAF caused no negative effects on oxidative damage, but altered the levels of ß-glucose and glycogen. In summary, perinatal exposure to BPA, BPF and BPAF differentially influence oxidative damage and metabolic disorders in the livers of male mouse offspring. The impact of early life exposure to BPs now warrants future investigations.


Assuntos
Compostos Benzidrílicos/toxicidade , Poluentes Ambientais/toxicidade , Fígado/efeitos dos fármacos , Troca Materno-Fetal , Fenóis/toxicidade , Animais , Feminino , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Masculino , Doenças Metabólicas/induzido quimicamente , Doenças Metabólicas/metabolismo , Camundongos Endogâmicos ICR , Estresse Oxidativo/efeitos dos fármacos , Gravidez
17.
Medicina (Kaunas) ; 55(3)2019 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-30866568

RESUMO

Background: Epidemiological studies suggest a possible relationship between metabolic alterations, cardiovascular disease and aggressive prostate cancer, however, no clear consensus has been reached. Objective: The aim of the study was to analyze the recent literature and summarize our experience on the association between metabolic disorders, aggressive hormone-naïve prostate cancer and cardiovascular disease. Method: We identified relevant papers by searching in electronic databases such as Scopus, Life Science Journals, and Index Medicus/Medline. Moreover, we showed our experience on the reciprocal relationship between metabolic alterations and aggressive prostate cancer, without the influence of hormone therapy, as well the role of coronary and carotid vasculopathy in advanced prostate carcinoma. Results: Prostate cancer cells have an altered metabolic homeostatic control linked to an increased aggressivity and cancer mortality. The absence of discrimination of risk factors as obesity, systemic arterial hypertension, diabetes mellitus, dyslipidemia and inaccurate selection of vascular diseases as coronary and carotid damage at initial diagnosis of prostate cancer could explain the opposite results in the literature. Systemic inflammation and oxidative stress associated with metabolic alterations and cardiovascular disease can also contribute to prostate cancer progression and increased tumor aggressivity. Conclusions: Metabolic alterations and cardiovascular disease influence aggressive and metastatic prostate cancer. Therefore, a careful evaluation of obesity, diabetes mellitus, dyslipidemia, systemic arterial hypertension, together with a careful evaluation of cardiovascular status, in particular coronary and carotid vascular disease, should be carried out after an initial diagnosis of prostatic carcinoma.


Assuntos
Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/metabolismo , Doenças Metabólicas/epidemiologia , Doenças Metabólicas/metabolismo , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/metabolismo , Animais , Comorbidade , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/metabolismo , Dislipidemias/epidemiologia , Dislipidemias/metabolismo , Humanos , Hipertensão/epidemiologia , Hipertensão/metabolismo , MEDLINE , Masculino , Camundongos , Obesidade/epidemiologia , Obesidade/metabolismo , Fatores de Risco
18.
BMJ Case Rep ; 12(3)2019 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-30904888

RESUMO

An 8-month-old boy presented to hospital with a fever, irritability and 'back arching'. On examination, he demonstrated profound opisthotonic posturing and had tonsillitis. He had a full septic screen and was treated with broad spectrum antibiotics. Blood tests showed a transaminitis, raised alpha fetoprotein and deranged clotting. The clotting abnormalities and raised alpha fetoprotein persisted post discharge and an abdominal ultrasound showed steatosis, splenomegaly and bilateral increased renal cortical reflectivity. A full metabolic screen revealed type 1 tyrosinaemia. The opisthotonic posturing, a major part of this child's presentation, has not been reported as a presenting feature of tyrosinaemia. It was part of a 'neurological crisis' caused by tyrosinaemia and exacerbated by the intercurrent infection. These are known to occur in tyrosinaemia but not commonly as the first presentation. This represents an unusual presentation of a metabolic condition which, without intervention, can lead to severe hepatic, renal and neurodevelopmental complications.


Assuntos
Doenças Metabólicas/diagnóstico , Esplenomegalia/diagnóstico , Tonsilite/diagnóstico , Cicloexanonas/administração & dosagem , Cicloexanonas/uso terapêutico , Dieta com Restrição de Proteínas , Gerenciamento Clínico , Febre/etiologia , Humanos , Lactente , Masculino , Doenças Metabólicas/complicações , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/metabolismo , Nitrobenzoatos/administração & dosagem , Nitrobenzoatos/uso terapêutico , Esplenomegalia/etiologia , Tonsilite/etiologia
19.
Int J Mol Sci ; 20(5)2019 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-30845751

RESUMO

Lysophosphatidylcholine (LPC) is increasingly recognized as a key marker/factor positively associated with cardiovascular and neurodegenerative diseases. However, findings from recent clinical lipidomic studies of LPC have been controversial. A key issue is the complexity of the enzymatic cascade involved in LPC metabolism. Here, we address the coordination of these enzymes and the derangement that may disrupt LPC homeostasis, leading to metabolic disorders. LPC is mainly derived from the turnover of phosphatidylcholine (PC) in the circulation by phospholipase A2 (PLA2). In the presence of Acyl-CoA, lysophosphatidylcholine acyltransferase (LPCAT) converts LPC to PC, which rapidly gets recycled by the Lands cycle. However, overexpression or enhanced activity of PLA2 increases the LPC content in modified low-density lipoprotein (LDL) and oxidized LDL, which play significant roles in the development of atherosclerotic plaques and endothelial dysfunction. The intracellular enzyme LPCAT cannot directly remove LPC from circulation. Hydrolysis of LPC by autotaxin, an enzyme with lysophospholipase D activity, generates lysophosphatidic acid, which is highly associated with cancers. Although enzymes with lysophospholipase A1 activity could theoretically degrade LPC into harmless metabolites, they have not been found in the circulation. In conclusion, understanding enzyme kinetics and LPC metabolism may help identify novel therapeutic targets in LPC-associated diseases.


Assuntos
1-Acilglicerofosfocolina O-Aciltransferase/metabolismo , Lisofosfatidilcolinas/metabolismo , Doenças Metabólicas/metabolismo , Fosfolipases A2/metabolismo , Homeostase , Humanos , Hidrólise , Lipoproteínas LDL/metabolismo , Doenças Metabólicas/enzimologia , Fosfatidilcolinas/metabolismo , Diester Fosfórico Hidrolases/metabolismo
20.
Molecules ; 24(6)2019 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-30884797

RESUMO

As a cellular bile acid sensor, farnesoid X receptor (FXR) and the membrane G-coupled receptor (GPBAR1) participate in maintaining bile acid, lipid, and glucose homeostasis. To date, several selective and dual agonists have been developed as promising pharmacological approach to metabolic disorders, with most of them possessing an acidic conjugable function that might compromise their pharmacokinetic distribution. Here, guided by docking calculations, nonacidic 6-ethyl cholane derivatives have been prepared. In vitro pharmacological characterization resulted in the identification of bile acid receptor modulators with improved pharmacokinetic properties.


Assuntos
Colanos/química , Doenças Metabólicas/tratamento farmacológico , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Acoplados a Proteínas-G/agonistas , Ácidos e Sais Biliares/metabolismo , Colanos/síntese química , Colanos/farmacocinética , Glucose/metabolismo , Células HEK293 , Células Hep G2 , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Doenças Metabólicas/metabolismo , Doenças Metabólicas/patologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Conformação Proteica/efeitos dos fármacos , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Relação Estrutura-Atividade
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