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Cancer remains the topmost disorders of the mankind and number of cases is unceasingly growing at unprecedented rates. Although the synthetic anti-cancer compounds still hold the largest market in the modern treatment of cancer, natural agents have always been tried and tested for potential anti-cancer properties. Thymoquinone (TQ), a monoterpene and main ingredient in the essential oil of Nigella sativa L. has got very eminent rankings in the traditional systems of medicine for its anti-cancer pharmacological properties. In this review we summarized the diverse aspects of TQ including its chemistry, biosynthesis, sources and pharmacological properties with a major concern being attributed to its anti-cancer efficacies. The role of TQ in different aspects involved in the pathogenesis of cancer like inflammation, angiogenesis, apoptosis, cell cycle regulation, proliferation, invasion and migration have been described. The mechanism of action of TQ in different cancer types has been briefly accounted. Other safety and toxicological aspects and some combination therapies involving TQ have also been touched. A detailed literature search was carried out using various online search engines like google scholar and pubmed regarding the available research and review accounts on thymoquinone upto may 2019. All the articles reporting significant addition to the activities of thymoquinone were selected. Additional information was acquired from ethno botanical literature focusing on thymoquinone. The compound has been the centre of attention for a long time period and researched regularly in quite considerable numbers for its various physicochemical, medicinal, biological and pharmacological perspectives. Thymoquinone is studied for various chemical and pharmacological activities and demonstrated promising anti-cancer potential. The reviewed reports confirmed the strong anti-cancer efficacy of thymoquinone. Further in-vitro and in-vivo research is strongly warranted regarding the complete exploration of thymoquinone in ethnopharmacological context.
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Benefits of resistant starch (RS) consumption on host physiology encompass microbial activity-derived attenuation of intestinal inflammation. However, little is known about anti-inflammatory properties of RS of type 4. This study compared the effects of transglycosylated starch (TGS) consumption on the jejunal barrier function and expression of genes related to inflammation, barrier function and the mucosal defence in jejunum, ileum, caecum and colon of pigs. Moreover, interactions of TGS-induced alterations in bacterial metabolites and composition with host mucosal responses were assessed using sparse partial least squares regression and relevance network analysis. Intestinal samples were collected after pigs (n 8/diet; 4 months of age) were fed the experimental diets for 10 d. Consumption of TGS did not modify jejunal barrier function and gene expression. By contrast, TGS down-regulated the caecal expression of zonula occludens-1 and mucin 2 and of genes within the toll-like receptor 4 and NF-κB pro-inflammatory signalling cascade. Relevance networks revealed a microbiome signature on ileal, caecal and colonic mucosal signalling as TGS-derived changes in bacterial genera and fermentation acids, such as propionic acid, correlated with the differently expressed genes in ileum, caecum and colon of pigs. In conclusion, the present findings suggest certain anti-inflammatory capabilities of TGS by down-regulating the expression of pro-inflammatory pathways in the caecal mucosa, which seems to be mediated, at least in part, by TGS-induced changes in microbial action in the large intestine.
Assuntos
Imunidade Inata , Imunidade nas Mucosas , Mucosa Intestinal/imunologia , Amido/administração & dosagem , Amido/química , Animais , Regulação para Baixo , Fermentação , Microbioma Gastrointestinal/imunologia , Expressão Gênica , Redes Reguladoras de Genes , Glicosilação , Imunidade Inata/genética , Imunidade nas Mucosas/genética , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Intestino Grosso/imunologia , Intestino Grosso/metabolismo , Intestino Grosso/microbiologia , Masculino , Modelos Animais , Modelos Imunológicos , Sus scrofaRESUMO
Energy restriction (ER) has been widely studied as a novel intervention, and its ability to prolong life has been fully demonstrated. For example, ER can significantly extend the lifespans of model flies, worms, rodents and other mammals. The role of ER in renal protection has also been elucidated. In preclinical studies, adjusting total energy intake or consumption of specific nutrients has prophylactic or therapeutic effects on ageing-related kidney disease and acute and chronic kidney injury. Amino acid restriction has gradually attracted attention. ER mimetics have also been studied in depth. The protective mechanisms of ER and ER mimetics for renal injury include increasing AMP-activated protein kinase and sirtuin type 1 (Sirt1) levels and autophagy and reducing mammalian target of rapamycin, inflammation and oxidative stress. However, the renal protective effect of ER has mostly been investigated in rodent models, and the role of ER in patients cannot be determined due to the lack of large randomised controlled trials. To protect the kidney, the mechanism of ER must be thoroughly researched, and more accurate diet or drug interventions need to be identified.
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Restrição Calórica , Nefropatias/metabolismo , Rim/metabolismo , Sirtuína 1/metabolismo , Envelhecimento , Animais , Autofagia , Dieta , Metabolismo Energético , Feminino , Humanos , Inflamação , Insulina/metabolismo , Masculino , Metformina/química , Modelos Animais , Estresse Oxidativo , Fósforo/metabolismo , Resveratrol/química , Sais/metabolismo , Sirolimo/químicaRESUMO
Hyperlipidaemia is a major cause of atherosclerosis and related CVD and can be prevented with natural substances. Previously, we reported that a novel Bacillus-fermented green tea (FGT) exerts anti-obesity and hypolipidaemic effects. This study further investigated the hypotriglyceridaemic and anti-obesogenic effects of FGT and its underlying mechanisms. FGT effectively inhibited pancreatic lipase activity in vitro (IC50, 0·48 mg/ml) and ameliorated postprandial lipaemia in rats (26 % reduction with 500 mg/kg FGT). In hypertriglyceridaemic hamsters, FGT administration significantly reduced plasma TAG levels. In mice, FGT administration (500 mg/kg) for 2 weeks augmented energy expenditure by 22 % through the induction of plasma serotonin, a neurotransmitter that modulates energy expenditure and mRNA expressions of lipid metabolism genes in peripheral tissues. Analysis of the gut microbiota showed that FGT reduced the proportion of the phylum Firmicutes in hamsters, which could further contribute to its anti-obesity effects. Collectively, these data demonstrate that FGT decreases plasma TAG levels via multiple mechanisms including inhibition of pancreatic lipase, augmentation of energy expenditure, induction of serotonin secretion and alteration of gut microbiota. These results suggest that FGT may be a useful natural agent for preventing hypertriglyceridaemia and obesity.
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Camellia sinensis , Metabolismo Energético/efeitos dos fármacos , Fermentação , Hiperlipidemias/sangue , Hipolipemiantes/farmacologia , Lipase/antagonistas & inibidores , Extratos Vegetais/farmacologia , Animais , Fármacos Antiobesidade/farmacologia , Fármacos Antiobesidade/uso terapêutico , Bacillus , Firmicutes , Microbioma Gastrointestinal/efeitos dos fármacos , Hiperlipidemias/tratamento farmacológico , Hipertrigliceridemia/sangue , Hipertrigliceridemia/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Mesocricetus , Camundongos , Camundongos Endogâmicos C57BL , Pâncreas/enzimologia , Fitoterapia , Extratos Vegetais/metabolismo , Extratos Vegetais/uso terapêutico , RNA Mensageiro/metabolismo , Serotonina/sangue , Chá , Triglicerídeos/sangueRESUMO
Leucine plays an important role in promoting muscle protein synthesis and muscle remodelling. However, what percentage of leucine is appropriate in creep feed and what proteome profile alterations are caused by dietary leucine in the skeletal muscle of piglets remain elusive. In this case, we applied isobaric tags for relative and absolute quantitation to analyse the proteome profile of the longissimus dorsi muscles of weanling piglets fed a normal leucine diet (NL; 1·66 % leucine) and a high-leucine diet (HL; 2·1 % leucine). We identified 157 differentially expressed proteins between these two groups. Bioinformatics analysis of these proteins exhibited the suppression of oxidative phosphorylation and fatty acid ß-oxidation, as well as the activation of glycolysis, in the HL group. For further confirmation, we identified that SDHB, ATP5F1, ACADM and HADHB were significantly down-regulated (P<0·01, except ATP5F1, P<0·05), whereas the glycolytic enzyme pyruvate kinase was significantly up-regulated (P<0·05) in the HL group. We also show that enhanced muscle protein synthesis and the transition from slow-to-fast fibres are altered by leucine. Together, these results indicate that leucine may alter energy metabolism and promote slow-to-fast transitions in the skeletal muscle of weanling piglets.
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Ração Animal/análise , Dieta/veterinária , Metabolismo Energético/efeitos dos fármacos , Leucina/farmacologia , Músculo Esquelético/fisiologia , Suínos/fisiologia , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Suplementos Nutricionais , Leucina/administração & dosagem , Sistema de Sinalização das MAP Quinases/fisiologia , Proteínas Proto-Oncogênicas c-jun/genética , Proteínas Proto-Oncogênicas c-jun/metabolismoRESUMO
Daytime restricted feeding (2 h of food access from 12.00 to 14.00 hours for 3 weeks) is an experimental protocol that modifies the relationship between metabolic networks and the circadian molecular clock. The precise anatomical locus that controls the biochemical and physiological adaptations to optimise nutrient use is unknown. We explored the changes in liver oxidative lipid handling, such as ß-oxidation and its regulation, as well as adaptations in the lipoprotein profile. It was found that daytime restricted feeding promoted an elevation of circulating ketone bodies before mealtime, an altered hepatic daily rhythmicity of 14CO2 production from radioactive palmitic acid, and an up-regulation of the fatty acid oxidation activators, the α-subunit of AMP-activated protein kinase (AMPK), the deacetylase silent mating type information regulation homolog 1, and the transcriptional factor PPARγ-1α coactivator. An increased localisation of phosphorylated α-subunit of AMPK in the periportal hepatocytes was also observed. Liver hepatic lipase C, important for lipoprotein transformation, showed a change of daily phase with a peak at the time of food access. In serum, there was an increase of LDL, which was responsible for a net elevation of circulating cholesterol. We conclude that our results indicate an enhanced fasting response in the liver during daily synchronisation to food access, which involves altered metabolic and cellular control of fatty acid oxidation as well a significant elevation of serum LDL. These adaptations could be part of the metabolic input that underlies the expression of the food-entrained oscillator.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Relógios Circadianos , Comportamento Alimentar , Hipercolesterolemia/etiologia , Fígado/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Sirtuína 1/metabolismo , Transporte Ativo do Núcleo Celular , Animais , Ácidos Graxos/metabolismo , Hipercolesterolemia/sangue , Hipercolesterolemia/metabolismo , Hipercolesterolemia/patologia , Corpos Cetônicos/sangue , Cetose/sangue , Cetose/etiologia , Cetose/metabolismo , Cetose/patologia , Lipase/metabolismo , Lipoproteínas LDL/sangue , Fígado/enzimologia , Fígado/patologia , Masculino , Oxirredução , Fosforilação , Processamento de Proteína Pós-Traducional , Distribuição Aleatória , Ratos WistarRESUMO
Balance between adipocyte and osteoblast differentiation is the key link of disease progression in obesity and osteoporosis. We have previously reported that formononetin (FNT), an isoflavone extracted from Butea monosperma, stimulates osteoblast formation and protects against postmenopausal bone loss. The inverse relationship between osteoblasts and adipocytes prompted us to analyse the effect of FNT on adipogenesis and in vivo bone loss, triggered by high-fat diet (HFD)-induced obesity. The anti-obesity effect and mechanism of action of FNT was determined in 3T3-L1 cells and HFD-induced obese male mice. Our findings show that FNT suppresses the adipogenic differentiation of 3T3-L1 fibroblasts, through down-regulation of key adipogenic markers such as PPARγ, CCAAT/enhancer-binding protein alpha (C/EBPα) and sterol regulatory element-binding protein (SREBP) and inhibits intracellular TAG accumulation. Increased intracellular reactive oxygen species levels and AMP-activated protein kinase (AMPK) activation accompanied by stabilisation of ß-catenin were attributed to the anti-adipogenic action of FNT. In vivo, 12 weeks of FNT treatment inhibited the development of obesity in mice by attenuating HFD-induced body weight gain and visceral fat accumulation. The anti-obesity effect of FNT results from increased energy expenditure. FNT also protects against HFD-induced dyslipidaemia and rescues deterioration of trabecular bone volume by increasing bone formation and decreasing bone resorbtion caused by HFD. FNT's rescuing action against obesity-induced osteoporosis commenced at the level of progenitors, as bone marrow progenitor cells, obtained from the HFD mice group supplemented with FNT, showed increased osteogenic and decreased adipogenic potentials. Our findings suggest that FNT inhibits adipogenesis through AMPK/ß-catenin signal transduction pathways and protects against HFD-induced obesity and bone loss.
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Proteínas Quinases Ativadas por AMP/metabolismo , Adipogenia/efeitos dos fármacos , Isoflavonas/farmacologia , Obesidade/prevenção & controle , Osteoporose/prevenção & controle , beta Catenina/metabolismo , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Reabsorção Óssea/tratamento farmacológico , Diferenciação Celular/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Metabolismo Energético/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/etiologia , Osteoporose/etiologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína Desacopladora 1/genética , Regulação para Cima/efeitos dos fármacosRESUMO
1,25-dihydroxyvitamin D3 [1,25(OH)2D3], the bioactive form of vitamin D, has been shown to possess significant anti-tumor potential. While most studies so far have focused on the ability of this molecule to influence the proliferation and apoptosis of cancer cells, more recent data indicate that 1,25(OH)2D3 also impacts energy utilization in tumor cells. In this article, we summarize and review the evidence that demonstrates the targeting of metabolic aberrations in cancers by 1,25(OH)2D3, and highlight potential mechanisms through which these effects may be executed. We shed light on the ability of this molecule to regulate metabolism-related tumor suppressors and oncogenes, energy- and nutrient-sensing pathways, as well as cell death and survival mechanisms such as autophagy.
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Antineoplásicos/farmacologia , Calcitriol/metabolismo , Neoplasias/metabolismo , Vitaminas/farmacologia , Animais , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Calcitriol/farmacologia , Calcitriol/uso terapêutico , Humanos , Neoplasias/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Vitaminas/uso terapêuticoRESUMO
Gestational diabetes mellitus (GDM) is a serious problem growing worldwide that needs to be addressed with urgency in consideration of the resulting severe complications for both mother and fetus. Growing evidence indicates that a healthy diet rich in fruit, vegetables, nuts, extra-virgin olive oil and fish has beneficial effects in both the prevention and management of several human diseases and metabolic disorders. In this review, we discuss the latest data concerning the effects of dietary bioactive compounds such as polyphenols and PUFA on the molecular mechanisms regulating glucose homoeostasis. Several studies, mostly based on in vitro and animal models, indicate that dietary polyphenols, mainly flavonoids, positively modulate the insulin signalling pathway by attenuating hyperglycaemia and insulin resistance, reducing inflammatory adipokines, and modifying microRNA (miRNA) profiles. Very few data about the influence of dietary exposure on GDM outcomes are available, although this approach deserves careful consideration. Further investigation, which includes exploring the 'omics' world, is needed to better understand the complex interaction between dietary compounds and GDM.
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Dieta , Adipocinas/fisiologia , Animais , Glicemia/metabolismo , Diabetes Gestacional/tratamento farmacológico , Ácidos Graxos Insaturados/administração & dosagem , Feminino , Flavonoides/administração & dosagem , Frutas , Homeostase/efeitos dos fármacos , Humanos , Insulina/metabolismo , Resistência à Insulina , MicroRNAs/fisiologia , Polifenóis/administração & dosagem , Gravidez , Transdução de Sinais/efeitos dos fármacos , Resultado do Tratamento , VerdurasRESUMO
Pro-inflammatory cytokines are critical in mechanisms of muscle atrophy. In addition, asparagine (Asn) is necessary for protein synthesis in mammalian cells. We hypothesised that Asn could attenuate lipopolysaccharide (LPS)-induced muscle atrophy in a piglet model. Piglets were allotted to four treatments (non-challenged control, LPS-challenged control, LPS+0·5 % Asn and LPS+1·0 % Asn). On day 21, the piglets were injected with LPS or saline. At 4 h post injection, piglet blood and muscle samples were collected. Asn increased protein and RNA content in muscles, and decreased mRNA expression of muscle atrophy F-box (MAFbx) and muscle RING finger 1 (MuRF1). However, Asn had no effect on the protein abundance of MAFbx and MuRF1. In addition, Asn decreased muscle AMP-activated protein kinase (AMPK) α phosphorylation, but increased muscle protein kinase B (Akt) and Forkhead Box O (FOXO) 1 phosphorylation. Moreover, Asn decreased the concentrations of TNF-α, cortisol and glucagon in plasma, and TNF-α mRNA expression in muscles. Finally, Asn decreased mRNA abundance of muscle toll-like receptor (TLR) 4 and nucleotide-binding oligomerisation domain protein (NOD) signalling-related genes, and regulated their negative regulators. The beneficial effects of Asn on muscle atrophy may be associated with the following: (1) inhibiting muscle protein degradation via activating Akt and inactivating AMPKα and FOXO1; and (2) decreasing the expression of muscle pro-inflammatory cytokines via inhibiting TLR4 and NOD signalling pathways by modulation of their negative regulators.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Asparagina/farmacologia , Expressão Gênica/efeitos dos fármacos , Atrofia Muscular/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor 4 Toll-Like/metabolismo , Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Animais , Ativação Enzimática/efeitos dos fármacos , Proteínas F-Box/análise , Proteínas F-Box/genética , Proteína Forkhead Box O1/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Proteínas Musculares/metabolismo , Músculo Esquelético/química , Atrofia Muscular/induzido quimicamente , Proteínas Adaptadoras de Sinalização NOD/antagonistas & inibidores , Fosforilação/efeitos dos fármacos , Complexo Repressor Polycomb 1/análise , Complexo Repressor Polycomb 1/genética , RNA Mensageiro/análise , Transdução de Sinais/efeitos dos fármacos , Sus scrofa , Receptor 4 Toll-Like/genética , DesmameRESUMO
The endothelium, a thin single sheet of endothelial cells, is a metabolically active layer that coats the inner surface of blood vessels and acts as an interface between the circulating blood and the vessel wall. The endothelium through the secretion of vasodilators and vasoconstrictors serves as a critical mediator of vascular homeostasis. During the development of the vascular system, it regulates cellular adhesion and vessel wall inflammation in addition to maintaining vasculogenesis and angiogenesis. A shift in the functions of the endothelium towards vasoconstriction, proinflammatory and prothrombic states characterise improper functioning of these cells, leading to endothelial dysfunction (ED), implicated in the pathogenesis of many diseases including diabetes. Major mechanisms of ED include the down-regulation of endothelial nitric oxide synthase levels, differential expression of vascular endothelial growth factor, endoplasmic reticulum stress, inflammatory pathways and oxidative stress. ED tends to be the initial event in macrovascular complications such as coronary artery disease, peripheral arterial disease, stroke and microvascular complications such as nephropathy, neuropathy and retinopathy. Numerous strategies have been developed to protect endothelial cells against various stimuli, of which the role of polyphenolic compounds in modulating the differentially regulated pathways and thus maintaining vascular homeostasis has been proven to be beneficial. This review addresses the factors stimulating ED in diabetes and the molecular mechanisms of natural polyphenol antioxidants in maintaining vascular homeostasis.
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Antioxidantes/farmacologia , Doenças Cardiovasculares/fisiopatologia , Complicações do Diabetes/fisiopatologia , Diabetes Mellitus/fisiopatologia , Endotélio Vascular/efeitos dos fármacos , Extratos Vegetais/farmacologia , Polifenóis/farmacologia , Animais , Antioxidantes/uso terapêutico , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/prevenção & controle , Complicações do Diabetes/sangue , Complicações do Diabetes/prevenção & controle , Diabetes Mellitus/sangue , Diabetes Mellitus/tratamento farmacológico , Estresse do Retículo Endoplasmático , Endotélio Vascular/patologia , Endotélio Vascular/fisiopatologia , Humanos , Inflamação/etiologia , Óxido Nítrico Sintase/sangue , Estresse Oxidativo , Extratos Vegetais/uso terapêutico , Polifenóis/uso terapêutico , Fator A de Crescimento do Endotélio Vascular/sangueRESUMO
Three areas in the brain continuously generate new neurons throughout life: the subventricular zone lining the lateral ventricles, the dentate gyrus in the hippocampus and the median eminence in the hypothalamus. These areas harbour neural stem cells, which contribute to neural repair by generating daughter cells that then become functional neurons or glia. Impaired neurogenesis leads to detrimental consequences, such as depression, decline of cognitive abilities and obesity. Adult neurogenesis is a versatile process that can be modulated either positively or negatively by many effectors, external or endogenous. Diet can modify neurogenesis both ways, either directly by ways of food-borne molecules, or possibly by the modifications induced on gut microbiota composition. It is therefore critical to define dietary strategies optimal for the maintenance of the stem cell pools.
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Giro Denteado , Dieta , Hipocampo , Neurogênese , Adulto , Humanos , Células-Tronco Neurais , NeurôniosRESUMO
n-3 Long-chain PUFA up-regulate intestinal lipid metabolism. However, whether these metabolic effects of PUFA on intestine are mediated by AMP-activated protein kinase (AMPK) remains to be elucidated. To determine the effects of α-linolenic acid (ALA) on intestinal fatty acid (FA) metabolism and whether these effects were affected by AMPK deletion, mice deficient in the catalytic subunit of AMPKα1 or AMPKα2 and wild-type (WT) mice were fed either a high-fat diet (HF) or HF supplemented with ALA (HF-A). The results showed that ALA supplementation decreased serum TAG content in WT mice. ALA also increased mRNA expression of genes (carnitine palmitoyltransferase 1a, acyl-CoA oxidase 1, medium-chain acyl-CoA dehydrogenase, cytochrome P450 4A10 and pyruvate dehydrogenase kinase isoenzyme 4a) involved in intestinal lipid oxidation and mRNA expression of TAG synthesis-related genes (monoacylglycerol O-acyltransferase 2, diacylglycerol O-acyltransferases 1 and 2) in WT mice. Consistent with these, expression levels of phosphorylated AMPKα1 and AMPKα2 were also increased in WT mice after ALA addition. However, in the absence of either AMPKα1 or AMPKα2, ALA supplementation failed to increase intestinal lipid oxidation. In addition, no significant effects of either diet (HF and HF-A) or genotype (WT, AMPKα1(-/-) and AMPKα2(-/-)) on FA uptake in the intestine and faecal TAG output were observed. Our results suggest that AMPK is indispensable for the effects of ALA on intestinal lipid oxidation.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Indução Enzimática , Mucosa Intestinal/metabolismo , Metabolismo dos Lipídeos , Regulação para Cima , Ácido alfa-Linolênico/uso terapêutico , Proteínas Quinases Ativadas por AMP/genética , Animais , Dieta Hiperlipídica/efeitos adversos , Suplementos Nutricionais , Fezes/química , Hipertrigliceridemia/sangue , Hipertrigliceridemia/etiologia , Hipertrigliceridemia/metabolismo , Hipertrigliceridemia/prevenção & controle , Íleo/enzimologia , Íleo/metabolismo , Mucosa Intestinal/enzimologia , Jejuno/enzimologia , Jejuno/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação , Processamento de Proteína Pós-Traducional , Triglicerídeos/efeitos adversos , Triglicerídeos/análise , Triglicerídeos/sangue , Triglicerídeos/metabolismoRESUMO
n-3 PUFA such as EPA and DHA as well as oestrogen have been reported to decrease blood levels of cholesterol, but their underlying mechanism is unclear. The purpose of this study was to determine the effects of the combination of n-3 PUFA supplementation and oestrogen injection on hepatic cholesterol metabolism. Rats were fed a modified AIN-93G diet with 0, 1 or 2 % n-3 PUFA (EPA+DHA) relative to the total energy intake for 12 weeks. Rats were surgically ovariectomised at week 8, and, after 1-week recovery, rats were injected with 17ß-oestradiol-3-benzoate (E2) or maize oil for the last 3 weeks. Supplementation with n-3 PUFA and E2 injection significantly increased the ratio of the hepatic expression of phosphorylated AMP activated protein kinase (p-AMPK):AMP activated protein kinase (AMPK) and decreased sterol regulatory element-binding protein-2, 3-hydroxy-3-methylglutaryl coenzyme A reductase and proprotein convertase subtilisin/kexin type 9. Supplementation with n-3 PUFA increased hepatic expression of cholesterol 7α-hydroxylase (CYP7A1), sterol 12α-hydroxylase (CYP8B1) and sterol 27-hydroxylase (CYP27A1); however, E2 injection decreased CYP7A1 and CYP8B1 but not CYP27A1. Additionally, E2 injection increased hepatic expression of oestrogen receptor-α and ß. In conclusion, n-3 PUFA supplementation and E2 injection had synergic hypocholesterolaemic effects by down-regulating hepatic cholesterol synthesis (n-3 PUFA and oestrogen) and up-regulating bile acid synthesis (n-3 PUFA) in ovariectomised rats.
Assuntos
Envelhecimento , Anticolesterolemiantes/uso terapêutico , Suplementos Nutricionais , Estrogênios/uso terapêutico , Ácidos Graxos Ômega-3/uso terapêutico , Hipercolesterolemia/prevenção & controle , Fígado/efeitos dos fármacos , Animais , Anticolesterolemiantes/administração & dosagem , Colestanotriol 26-Mono-Oxigenase/química , Colestanotriol 26-Mono-Oxigenase/metabolismo , Colesterol 7-alfa-Hidroxilase/química , Colesterol 7-alfa-Hidroxilase/metabolismo , Terapia Combinada , Dieta com Restrição de Gorduras , Estradiol/administração & dosagem , Estradiol/análogos & derivados , Estradiol/uso terapêutico , Estrogênios/administração & dosagem , Ácidos Graxos Ômega-3/administração & dosagem , Feminino , Hidroximetilglutaril-CoA Redutases/química , Hidroximetilglutaril-CoA Redutases/metabolismo , Hipercolesterolemia/enzimologia , Hipercolesterolemia/metabolismo , Fígado/enzimologia , Fígado/metabolismo , Ovariectomia , Pró-Proteína Convertase 9 , Distribuição Aleatória , Ratos Wistar , Serina Endopeptidases/química , Serina Endopeptidases/metabolismo , Esteroide 12-alfa-Hidroxilase/química , Esteroide 12-alfa-Hidroxilase/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 2/antagonistas & inibidores , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismoRESUMO
Energy restriction (ER; also known as caloric restriction) is the only nutritional intervention that has repeatedly been shown to increase lifespan in model organisms and may delay ageing in humans. In the present review we discuss current scientific literature on ER and its molecular, metabolic and hormonal effects. Moreover, criteria for the classification of substances that might induce positive ER-like changes without having to reduce energy intake are summarised. Additionally, the putative ER mimetics (ERM) 2-deoxy-d-glucose, metformin, rapamycin, resveratrol, spermidine and lipoic acid and their suggested molecular targets are discussed. While there are reports on these ERM candidates that describe lifespan extension in model organisms, data on longevity-inducing effects in higher organisms such as mice remain controversial or are missing. Furthermore, some of these candidates produce detrimental side effects such as immunosuppression or lactic acidosis, or have not been tested for safety in long-term studies. Up to now, there are no known ERM that could be recommended without limitations for use in humans.
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Obesity is a global health concern owing to its association with numerous degenerative diseases and the fact that it may lead to early aging. Various markers of aging, including telomere attrition, epigenetic alterations, altered protein homeostasis, mitochondrial dysfunction, cellular senescence, stem cell disorders, and intercellular communication, are influenced by obesity. Consequently, there is a critical need for safe and effective approaches to prevent obesity and mitigate the onset of premature aging. In recent years, intermittent fasting (IF), a dietary strategy that alternates between periods of fasting and feeding, has emerged as a promising dietary strategy that holds potential in counteracting the aging process associated with obesity. This article explores the molecular and cellular mechanisms through which IF affects obesity-related early aging. IF regulates various physiological processes and organ systems, including the liver, brain, muscles, intestines, blood, adipose tissues, endocrine system, and cardiovascular system. Moreover, IF modulates key signaling pathways such as AMP-activated protein kinase (AMPK), sirtuins, phosphatidylinositol 3-kinase (PI3K)/Akt, mammalian target of rapamycin (mTOR), and fork head box O (FOXO). By targeting these pathways, IF has the potential to attenuate aging phenotypes associated with obesity-related early aging. Overall, IF offers promising avenues for promoting healthier lifestyles and mitigating the premature aging process in individuals affected by obesity.
Assuntos
Senilidade Prematura , Jejum Intermitente , Obesidade , Animais , Humanos , Envelhecimento , Senilidade Prematura/prevenção & controle , Senescência Celular , Obesidade/prevenção & controle , Transdução de SinaisRESUMO
Introduction: Gut microbiota has been implicated in the pharmacological activities of many natural products. As an effective hypolipidemic agent, berberine (BBR)'s clinical application is greatly impeded by the obvious inter-individual response variation. To date, little evidence exists on the causality between gut microbes and its therapeutic effects, and the linkage of bacteria alterations to the inter-individual response variation. Objectives: This study aims to confirm the causal role of the gut microbiota in BBR's anti-hyperlipidemic effect and identify key bacteria that can predict its effectiveness. Methods: The correlation between gut microbiota and BBR's inter-individual response variation was studied in hyperlipidemic patients. The causal role of gut microbes in BBR's anti-hyperlipidemic effects was subsequently assessed by altered administration routes, co-treatment with antibiotics, fecal microbiota transplantation, and metagenomic analysis. Results: Three-month clinical study showed that BBR was effectively to decrease serum lipids but displayed an obvious response variation. The cholesterol-lowering but not triglyceride-decreasing effect of BBR was closely related to its modulation on gut microbiota. Interestingly, the baseline levels of Alistipes and Blautia could accurately predict its anti-hypercholesterolemic efficiency in the following treatment. Causality experiments in mice further confirmed that the gut microbiome is both necessary and sufficient to mediate the lipid-lowering effect of BBR. The absence of Blautia substantially abolished BBR's cholesterol-decreasing efficacy. Conclusion: The gut microbiota is necessary and sufficient for BBR's hyperlipidemia-ameliorating effect. The baseline composition of gut microbes can be an effective predictor for its pharmacotherapeutic efficacy, providing a novel way to achieve personalized therapy.
Assuntos
Berberina , Microbioma Gastrointestinal , Hiperlipidemias , Animais , Bactérias , Berberina/farmacologia , Berberina/uso terapêutico , Colesterol/farmacologia , Humanos , Hiperlipidemias/tratamento farmacológico , CamundongosRESUMO
Cardiovascular disease is the most common disease in the world and the first among the causes of human death. Its morbidity and mortality increase annually, but no effective treatment is available. Therefore, new drugs should be developed to treat cardiovascular disease. Gentianella acuta (Michx.) Hulten (G. acuta) is an important Mongolian medicine in China and elicits protective effects on cardiovascular health. In this study, liquid chromatography-mass spectrometry (LC-MS) combined with network pharmacology was used to screen the main active ingredients and confirm that bellidifolin was one of the main components for the treatment of ischemic heart disease. Then, rat myocardial (H9c2) cells injury model induced by hydrogen peroxide (H2O2) in vitro was established to verify the effect of bellidifolin on oxidative stress stimulation, including determination of antioxidant enzyme activity and apoptosis. Transcriptome sequencing, qRT-PCR, and western blot were performed to further verify the antioxidant stress mechanism of bellidifolin. Results showed that bellidifolin pretreatment decreased the rate of apoptosis and the levels of lactate dehydrogenase (LDH), creatine kinase (CK), and alanine aminotransferase (ALT). Conversely, it increased the contents of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in a dose-dependent manner, indicating that bellidifolin caused a protective effect on cardiomyocyte injury. Bellidifolin minimized the H2O2-induced cell injury by activating the PI3K-Akt signal pathway and downregulating glycogen synthase kinase-3ß (GSK-3ß) and p-Akt1/Akt1. Therefore, this work revealed that G. acuta has a good development prospect as an edible medicinal plant in cardiovascular disease. Its bellidifolin component is a potential therapeutic agent for cardiovascular disease induced by oxidative stress damage.
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Diabetes mellitus, a group of metabolic disorders characterized by persistent hyperglycemia, affects millions of people worldwide and is on the rise. Dietary proteins, from a wide range of food sources, are rich in bioactive peptides with antidiabetic properties. Notable examples include AGFAGDDAPR, a black tea-derived peptide, VRIRLLQRFNKRS, a ß-conglycinin-derived peptide, and milk-derived peptide VPP, which have shown antidiabetic effects in diabetic rodent models through variety of pathways including improving beta-cells function, suppression of alpha-cells proliferation, inhibiting food intake, increasing portal cholecystokinin concentration, enhancing insulin signaling and glucose uptake, and ameliorating adipose tissue inflammation. Despite the immense research on glucoregulatory properties of bioactive peptides, incorporation of these bioactive peptides in functional foods or nutraceuticals is widely limited due to the existence of several challenges in the field of peptide research and commercialization. Ongoing research in this field, however, is fundamental to pave the road for this purpose.
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Alzheimer's disease (AD), the most prominent form of dementia in the elderly, has no cure. Strategies focused on the reduction of amyloid beta or hyperphosphorylated Tau protein have largely failed in clinical trials. Novel therapeutic targets and strategies are urgently needed. Emerging data suggest that in response to environmental stress, mitochondria initiate an integrated stress response (ISR) shown to be beneficial for healthy aging and neuroprotection. Here, we review data that implicate mitochondrial electron transport complexes involved in oxidative phosphorylation as a hub for small molecule-targeted therapeutics that could induce beneficial mitochondrial ISR. Specifically, partial inhibition of mitochondrial complex I has been exploited as a novel strategy for multiple human conditions, including AD, with several small molecules being tested in clinical trials. We discuss current understanding of the molecular mechanisms involved in this counterintuitive approach. Since this strategy has also been shown to enhance health and life span, the development of safe and efficacious complex I inhibitors could promote healthy aging, delaying the onset of age-related neurodegenerative diseases.