RESUMO
Black soybean contains flavan-3-ols and cyanidin 3-O-glucoside in its seed coat. Polyphenol-rich black soybean seed coat extract (BE) possesses various health benefits, such as antioxidant, anti-obesity, and anti-hyperglycemic effects. However, these functions have been evaluated mainly in the growing stage of animals, and there is no comparison data for different life stages. In this present study, we compared the effect of BE in growing (5-week old) and young adult (22-week old) ICR male mice. These mice were given an AIN 93M diet containing 2.0% BE for 4 weeks. BE did not affect body weight gain in both growing and young adult mice, but it suppressed mesenteric and subcutaneous white adipose tissue weights and decreased the cell size. BE also significantly suppressed plasma free-fatty acid levels. The effect of both BE and life stages were observed in the protein expression of adipogenesis-related transcription factors; in particular, BE suppressed the expression of C/EBPα and PPARγ. No significant change was observed in lipolysis and lipogenesis factors in the white adipose tissue and liver. Alternatively, BE showed low glucose tolerance without affecting plasma insulin levels after glucose loading in young adult mice, as seen from the results of the oral glucose tolerance test. However, plasma glucose and insulin levels remained unchanged at the end of the experimental period. In conclusion, these results strongly suggest that the health-beneficial effects of BE may alter in mice at different life stages.
Assuntos
Glucose , Insulinas , Camundongos , Masculino , Animais , Glucose/metabolismo , Polifenóis/farmacologia , Metabolismo dos Lipídeos , Glycine max , Extratos Vegetais/farmacologia , Camundongos Endogâmicos ICR , Dieta Hiperlipídica , Camundongos Endogâmicos C57BLRESUMO
Black soybean seed coat extract (BE) contains multiple bioactive polyphenols, including flavan-3-ols and anthocyanins. BE improves endothelial function; however, it is unclear whether BE protects endothelial cells from senescence. In this study, we examined the effects of BE on endothelial cell senescence and vascular function in healthy individuals. High concentrations of glucose were used to induce senescence in bovine aortic endothelial cells incubated with BE. Senescence, vascular function, and oxidative stress markers were measured. Incubation with BE remarkably inhibited senescence-associated ß-galactosidase and lactate dehydrogenase activities and dose dependently reduced intracellular reactive oxygen species levels in bovine aortic endothelial cells. BE treatment increased the levels of endothelial nitric oxide synthase (eNOS) mRNA and endothelial nitric oxide (NO) metabolites and increased the mRNA expression of klotho, a gene associated with an antiaging phenotype. To examine the effects of BE in humans, we conducted a clinical study using the second derivative of the fingertip photoplethysmogram to investigate vascular function and aging in 24 healthy volunteers. The participants consumed BE supplements (100 mg/day) or a placebo for 2 weeks. When compared with the placebo group, the BE group showed considerably improved vascular function, NO metabolite levels, and oxidative stress. These results suggest that BE supplementation improves endothelial function, possibly through antioxidant activity and NO production, and may consequently reduce the cardiovascular risk associated with aging. BE supplementation may be an effective and safe approach to reduce the risk of atherosclerosis and cardiovascular disease; however, additional studies investigating chronic vascular inflammation are needed.
Assuntos
Células Endoteliais , Óxido Nítrico , Humanos , Animais , Bovinos , Óxido Nítrico/metabolismo , Glycine max , Antocianinas/metabolismo , Voluntários Saudáveis , Endotélio Vascular , Estresse Oxidativo , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , RNA Mensageiro/metabolismo , Células CultivadasRESUMO
Induction of obesity by dietary fats and oils differs according to the type of fat. Adiponectin is believed to be related to obesity prevention. We hypothesized that flaxseed oil is important for preventing obesity and producing adiponectin. To clarify this hypothesis, we investigated the relationship between obesity and different fat sources in mice fed diets with 6 types of fat and oils. C57BL/6J mice were given a control diet containing 5% corn oil or a high-fat diet containing 20% of either lard, palm oil, rapeseed oil, oleate-rich safflower oil, corn oil, or flaxseed oil for 14 weeks. In another experiment, mice were given a control diet and rosiglitazone (10 mg/kg body weight) by oral gavage for 1 week. At the end of study, plasma adiponectin and expression of fatty acid metabolism-related factors in white and brown adipose tissue and the liver were measured. Dietary flaxseed oil, which is rich in α-linolenic acid, did not induce obesity. Flaxseed oil resulted in increased ß-oxidation-related factors in epididymal white adipose tissue, decreased fatty acid synthesis-related factors in the liver, and thermogenesis-related factor in brown adipose tissue following increase of plasma adiponectin. The results suggested that increase in plasma adiponectin after intake of flaxseed oil may be due to altered expression of AdipoQ and peroxisome proliferator-activated receptor γ in epididymal white adipose tissue. Flaxseed oil increased expression of adiponectin in visceral fat and regulated obesity-controlling fatty acid metabolism-related factors in white adipose tissue and liver, and thermogenesis-related factor in brown adipose tissue.
Assuntos
Linho , Óleo de Semente do Linho , Camundongos , Animais , Óleo de Semente do Linho/farmacologia , Adiponectina , Óleo de Milho , Gordura Intra-Abdominal , Camundongos Endogâmicos C57BL , Obesidade/etiologia , Obesidade/prevenção & controle , Dieta Hiperlipídica/efeitos adversos , Ácido alfa-LinolênicoRESUMO
SCOPE: Acetaldehyde is a highly toxic primary metabolite of ethanol, and converts to nontoxic acetic acid by aldehyde dehydrogenase (ALDH). Accumulation of acetaldehyde causes significant damage to human body. Aged garlic extract (AGE) is a functional food material and possesses various health beneficial effects. This study investigates whether AGE contributes to acetaldehyde detoxification through ALDH induction and its underlying mechanism. METHODS AND RESULTS: C57BL/6J mice are orally administrated 10-1000 mg kg-1 body weight (BW) of AGE for 1 week before ethanol administration. AGE suppresses ethanol-caused accumulation of acetaldehyde level in the plasma through inducing mitochondrial ALDH2 but not cytosolic ALDH1A1. AGE also induces antioxidant enzymes, heme oxygenase-1, and NAD(P)H:quinone oxidoreductase 1, resulting in prevention of lipid peroxidation in the liver. In HepG2 cells, AGE prevents ethanol- and acetaldehyde-caused cytotoxicity. AGE induces mitochondrial ALDH2 through activating nuclear factor-erythroid 2-related factor 2 (Nrf2). AGE inhibits protein degradation of Nrf2 and enhances protein degradation of kelch-like ECH-associated protein 1. Furthermore, S-allyl cysteine and S-allyl mercaptocysteine as the bioactive compounds in AGE also induce ALDH2 and Nrf2. CONCLUSION: AGE prevents acetaldehyde-induced hepatotoxicity through enhancing acetaldehyde detoxification through Nrf2-dependent induction of mitochondrial ALDH2.
Assuntos
Alho , Camundongos , Humanos , Animais , Recém-Nascido , Antioxidantes/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Camundongos Endogâmicos C57BL , Etanol/toxicidade , Fígado/metabolismo , Aldeído Desidrogenase/metabolismo , Aldeído Desidrogenase/farmacologia , Acetaldeído/toxicidade , Acetaldeído/metabolismo , Aldeído-Desidrogenase Mitocondrial/metabolismoRESUMO
Nutmeg is the seed of Myristica fragrans or its powder and is used as a spice and a traditional medicine. The antidiabetic effect of nutmeg is not fully understood yet. In this study, we examine the isolation and identification of the active compounds of Myristica fragrans with regards to glucose uptake and elucidate their mechanism in L6 myotubes. Myrisiticin, licarin B, erythro-2-(4-allyl-2,6-dimethoxy-phenoxy)-1-(3,4-dimethoxyphenyl)-propan-1-ol (ADDP) and (7S,8R)-2-(4-allyl-2,6-dimethoxyphenoxy)-1-(3,4,5-trimethoxyphenyl)-propan-1-ol (ADTP) were isolated and identified as the active compounds. Myristicin or a mixture of ADDP and ADTP promoted the translocation of glucose transporter 4 (GLUT4) through phosphorylation of AMP-activated protein kinase in L6 myotubes 15 min after treatment, while licarin B promoted it 240 min after treatment. Oral administration of the fraction from Myristica fragrans containing these active compounds to ICR mice suppressed post-prandial hyperglycemia. Thus, Myristica fragrans is a promising functional food to prevent post-prandial hyperglycemia and type 2 diabetes mellitus by promoting glucose uptake in muscle.
Assuntos
Diabetes Mellitus Tipo 2 , Lignanas , Myristica , Animais , Glucose , Lignanas/farmacologia , Camundongos , Camundongos Endogâmicos ICR , Fibras Musculares EsqueléticasRESUMO
The adipocytes play an important role in driving the obese-state-white adipose tissue (WAT) stores the excess energy as fat, wherein brown adipose tissue (BAT) is responsible for energy expenditure via the thermoregulatory function of uncoupling protein 1 (UCP1)-the imbalance between these two onsets obesity. Moreover, the anti-obesity effects of brown-like-adipocytes (beige) in WAT are well documented. Browning, the process of transformation of energy-storing into energy-dissipating adipocytes, is a potential preventive strategy against obesity and its related diseases. In the present study, to explore an alternative source of natural products in the regulation of adipocyte transformation, we assessed the potential of theobromine (TB), a bitter alkaloid of the cacao plant, inducing browning in mice (in vivo) and primary adipocytes (in vitro). Dietary supplementation of TB significantly increased skin temperature of the inguinal region in mice and induced the expression of UCP1 protein. It also increased the expression levels of mitochondrial marker proteins in subcutaneous adipose tissues but not in visceral adipose tissues. The microarray analysis showed that TB supplementation upregulated multiple thermogenic and beige adipocyte marker genes in subcutaneous adipose tissue. Furthermore, in mouse-derived primary adipocytes, TB upregulated the expression of the UCP1 protein and mitochondrial mass in a PPARγ ligand-dependent manner. It also increased the phosphorylation levels of PPARγ coactivator 1α without affecting its protein expression. These results indicate that dietary supplementation of TB induces browning in subcutaneous WAT and enhances PPARγ-induced UCP1 expression in vitro, suggesting its potential to treat obesity.
Assuntos
Adipócitos Bege/fisiologia , Adipócitos Brancos/fisiologia , Suplementos Nutricionais , PPAR gama/metabolismo , Teobromina/administração & dosagem , Adipócitos Brancos/efeitos dos fármacos , Tecido Adiposo Branco/citologia , Tecido Adiposo Branco/metabolismo , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Mitofagia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Fosforilação , Prótons , Transdução de Sinais , Temperatura Cutânea , Teobromina/farmacologia , Termogênese , Transcriptoma , Proteína Desacopladora 1/metabolismo , Aumento de PesoRESUMO
Significant efforts have been made to ameliorate diabetic nephropathy (DN) by inhibiting protein kinase C. However, these efforts have not been successful in human trials, suggesting that novel therapeutic strategies are required. Thus far, it has been reported that green tea polyphenol epigallocatechin gallate (EGCg) improved albuminuria in DN in a human trial. Our previous study revealed that activation of diacylglycerol kinase α (DGKα) plays a crucial role in the amelioration of DN and that EGCg activates DGKα. Here, we investigated whether and how DGKα contributes to the amelioration of DN upon stimulation by EGCg by using streptozotocin-induced type 1 diabetic model mice. Our results revealed that EGCg ameliorated albuminuria in DN through DGKα in vivo, and methylated EGCg, which has higher absorption in the plasma improved albuminuria in DN effectively. Additionally, we showed that c-Src mediated EGCg-induced DGKα translocation and colocalized with the 67 kDa laminin receptor, which is an EGCg receptor. Furthermore, EGCg attenuated the loss of podocytes in DN by preventing a decrease in focal adhesion under high glucose conditions. Our results indicate that the DGKα pathway is an attractive therapeutic target and that activating this pathway is a novel strategy for treating DN.
Assuntos
Nefropatias Diabéticas/metabolismo , Diacilglicerol Quinase/metabolismo , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Polifenóis/química , Polifenóis/farmacologia , Chá/química , Animais , Biomarcadores , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/etiologia , Diacilglicerol Quinase/genética , Modelos Animais de Doenças , Imunofluorescência , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Modelos Biológicos , Podócitos/metabolismoRESUMO
Since a decrease in muscle mass leads to an increased risk of mortality, the prevention of muscle wasting contributes to maintaining the quality of life. Recently, we reported that glabridin, a prenylated flavonoid in licorice, prevents dexamethasone-induced muscle loss. In this study, we focused on the other prenylated chalcones 4-hydroxyderricin and xanthoangelol in Ashitaba (Angelica keiskei) and investigated their prevention effect on dexamethasone-induced muscle loss. It was found that 4-hydroxyderricin and xanthoangelol significantly prevented dexamethasone-induced protein degradation in C2C12 myotubes by suppressing the expression of ubiquitin ligases, Cbl-b and MuRF-1. These prenylated chalcones acted as the antagonists of the glucocorticoid receptor and inhibited the binding of dexamethasone to this receptor and its subsequent nuclear translocation. In addition, the chalcones suppressed the phosphorylation of p38 and FoxO3a as the upstream factors for ubiquitin ligases. Dexamethasone-induced protein degradation and upregulation of Cbl-b were attenuated by the knockdown of the glucocorticoid receptor but not by the knockdown of p38. In male C57BL/6J mice, the Ashitaba extract, containing 4-hydroxyderricin and xanthoangelol, suppressed dexamethasone-induced muscle mass wasting accompanied by a decrease in the expression of ubiquitin ligases by inhibiting the nuclear translocation of the glucocorticoid receptor and phosphorylation of FoxO3a. In conclusion, 4-hydroxyderricin and xanthoangelol are effective compounds to inhibit steroid-induced muscle loss.
Assuntos
Angelica/química , Chalcona/análogos & derivados , Chalcona/isolamento & purificação , Dexametasona/efeitos adversos , Músculos/efeitos dos fármacos , Atrofia Muscular/prevenção & controle , Extratos Vegetais/farmacologia , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Chalconas/antagonistas & inibidores , Chalconas/isolamento & purificação , Isoflavonas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atrofia Muscular/induzido quimicamente , Fenóis , Fosforilação , Qualidade de VidaRESUMO
A flavone luteolin has various health-promoting activities. Several studies reported that high dose of luteolin activates the Nrf2/ARE pathway in the liver. However, the effect of the low dose of luteolin that can be taken from a dietary meal on the Nrf2 activation remain unclear. It is expected that the flavonoid metabolism possesses a circadian rhythm, since nutritional metabolism processes daily cycle. In this study we investigated whether an administration affects the Nrf2 activation. ICR mice were orally administered 0.01-10 mg/kg body weight of luteolin once a day for 7 days at two time-points: at the start of active phase (ZT12) or at that of inactive phase (ZT0). Luteolin increased the nuclear translocation of Nrf2, resulting in the increases in its target gene products HO-1 and NQO1 at ZT12 but not at ZT0. The expression level of Nrf2 was lower at ZT12 than at ZT0 in the liver. We also found that the level of luteolin aglycon in the plasma is higher at ZT12 than at ZT0. These results suggest that the low dose of luteolin can activate Nrf2 pathway and the aglycon form of luteolin may mainly contribute to activate the Nrf2 pathway at ZT12 in the liver.
Assuntos
Fígado/efeitos dos fármacos , Luteolina/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Animais , Relógios Biológicos/genética , Núcleo Celular/metabolismo , Heme Oxigenase-1/metabolismo , Fígado/metabolismo , Luteolina/sangue , Masculino , Camundongos , Camundongos Endogâmicos ICR , NAD(P)H Desidrogenase (Quinona)/metabolismo , Regulação para Cima/efeitos dos fármacosRESUMO
Black soybean seed coat polyphenols were reported to possess various bioregulatory functions. However, the effects of black soybean seed coat polyphenols on vascular functions are unknown. Vascular dysfunction caused by aging and vascular stiffness is associated with a risk of cardiovascular disease (CVD), and a reduction in nitric oxide (NO) levels can trigger the onset of CVD. In the present study, we investigated the effect of polyphenol-rich black soybean seed coat extract (BE) on vascular functions and the underlying mechanisms involved. The oral administration of BE at 50 mg per kg body weight to Wistar rats increased NO levels as determined by eNOS phosphorylation. The administration of BE also increased GLP-1 and cAMP levels. Furthermore, the effects of BE were inhibited in the presence of a GLP-1 receptor antagonist. This suggests that GLP-1 is strongly involved in the underlying mechanism of NO production in vivo. In conclusion, BE contributes to the improvement of vascular functions by promoting NO production. Regarding the putative underlying mechanism, GLP-1 secreted from intestinal cells by the polyphenols in BE activates eNOS in vascular endothelial cells.
Assuntos
Aorta/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Glycine max/química , Óxido Nítrico/metabolismo , Extratos Vegetais/administração & dosagem , Polifenóis/farmacologia , Animais , Aorta/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Mucosa Intestinal/metabolismo , Masculino , Óxido Nítrico Sintase Tipo III/metabolismo , Ratos , Ratos WistarRESUMO
Procyanidins have been reported to possess potential for the prevention of hyperglycaemia. However, there are very few data for procyanidins about the difference the degree of polymerisation (DP) has on anti-hyperglycaemic effects. Moreover, the underlying molecular mechanisms by which procyanidins suppress hyperglycaemia are not yet fully understood. In the present study, we prepared procyanidin fractions with different DP, namely low-DP (DP≤3) and high-DP (DP≥4) fractions, from a cacao liquor procyanidin-rich extract (CLPr). These fractions were administered orally to Institute of Cancer Research (ICR) mice and their anti-hyperglycaemic effects were examined. We found that CLPr and its fractions prevent postprandial hyperglycaemia accompanied by an increase in the plasma glucagon-like peptide-1 (GLP-1) level with or without glucose load. In the absence of glucose load, both fractions increased the plasma insulin level and activated its downstream signalling pathway in skeletal muscle, resulting in promotion of the translocation of GLUT4. Phosphorylation of AMP-activated protein kinase (AMPK) was also involved in the promotion of GLUT4 translocation. High- and low-DP fractions showed a similar activation of insulin and AMPK pathways. In conclusion, cacao liquor procyanidins prevent hyperglycaemia by promoting GLUT4 translocation in skeletal muscle, and both the GLP-1-activated insulin pathway and the AMPK pathway are involved in the underlying molecular mechanism.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Cacau/química , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Hiperglicemia/prevenção & controle , Proantocianidinas/farmacologia , Animais , Modelos Animais de Doenças , Glucose/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Insulina/sangue , Masculino , Camundongos , Camundongos Endogâmicos ICR , Músculo Esquelético/metabolismo , Fosforilação , Extratos Vegetais/farmacologia , Polifenóis/farmacologia , Transdução de Sinais/efeitos dos fármacosRESUMO
For over 4000 years, liquorice has been one of the most frequently employed botanicals as a traditional herbal medicine. Although previous reports have found that liquorice flavonoids possess various health beneficial effects, the underlying mechanism responsible for the anti-diabetic effect of liquorice flavonoids remains unclear. The present study demonstrates that liquorice flavonoid oil (LFO) improves type 2 diabetes mellitus through GLUT4 translocation to the plasma membrane by activating both the adenosine monophosphate-activated protein kinase (AMPK) pathway and Akt pathway in muscle of KK-Ay mice. Furthermore, LFO lowered postprandial hyperglycaemia in a human study. These results indicate that LFO may exert a therapeutic effect on metabolic disorders, such as diabetes and hyperglycaemia, by modulating glucose metabolism through AMPK- and insulin-dependent pathways in skeletal muscle.
Assuntos
Flavonoides/farmacologia , Transportador de Glucose Tipo 4/metabolismo , Glycyrrhiza/química , Hiperglicemia/prevenção & controle , Hipoglicemiantes/farmacologia , Músculo Esquelético/metabolismo , Óleos de Plantas/farmacologia , Adenilato Quinase/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Membrana Celular/metabolismo , Diabetes Mellitus Tipo 2/prevenção & controle , Dieta Hiperlipídica , Humanos , Insulina/sangue , Masculino , Camundongos , Músculo Esquelético/enzimologia , Tamanho do Órgão/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
We investigated the absorption, metabolism, distribution and faecal excretion of 3 B-type procyanidin oligomers, including procyanidin B2, procyanidin C1 and cinnamtannin A2, and their monomeric unit (-)-epicatechin after a single oral administration of black soybean seed coat extract (BE) to male ICR mice at 250 mg per kg body weight. Plasma, tissues and faeces samples were collected within 24 h for the determination of (-)-epicatechin, procyandidin B2, procyanidin C1 and cinnamtannin A2 with or without ß-glucuronidase and sulfatase treatment by the high-performance liquid chromatography method. A portion of the B-type procyanidin oligomers and (-)-epicatechin in BE was absorbed from the small intestine after the oral administration of BE. In the plasma, absorbed procyanidins and (-)-epicatechin existed mainly as conjugates. In the tissues, procyanidin B2, procyandin C1 and cinnamtannin A2, in addition to (-)-epicatechin distributed widely, primarily in their free forms. Their conjugation occurred mainly in the small intestine, rather than in the liver. Monomeric unit (-)-epicatechin had the highest bioavailability, followed by procyanidin B2, procyanidin C1 and cinnamtannin A2.
Assuntos
Biflavonoides/metabolismo , Catequina/metabolismo , Fezes/química , Glycine max/metabolismo , Extratos Vegetais/metabolismo , Proantocianidinas/metabolismo , Animais , Biflavonoides/química , Transporte Biológico , Catequina/química , Intestino Delgado/metabolismo , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Extratos Vegetais/química , Proantocianidinas/química , Sementes/química , Sementes/metabolismo , Glycine max/química , Distribuição TecidualRESUMO
Malignant melanoma is an aggressive tumor of the skin and still lacks effective preventive and therapeutic treatments. In melanoma, both the BRAF/MEK/ERK and PI3-K/AKT signaling pathways are constitutively activated through multiple mechanisms, which result in cell-cycle progression and prevention of apoptosis. Therefore, the development of novel strategies for targeting BRAF and PI3K are of utmost importance. In this study, we found that Ashitaba (Angelica keiskei) chalcones, 4-hydroxyderricin (4HD) and xanthoangelol (XAG), suppressed melanoma development by directly targeting both BRAFV600E and PI3K, which blocked the activation of downstream signaling. This led to the induction of G1 phase cell-cycle arrest and apoptosis in melanoma cells. Importantly, 4HD or XAG dramatically attenuated tumor incidence and volume in the BRAF-activated Pten-deficient melanoma mouse model. Our findings suggest that 4HD and XAG are promising chemopreventive or potential therapeutic agents against melanomagenesis that act by targeting both BRAF and PI3K, providing hope for rapid clinical translation. Cancer Prev Res; 11(10); 607-20. ©2018 AACR.
Assuntos
Carcinogênese/efeitos dos fármacos , Chalcona/análogos & derivados , Melanoma Experimental/prevenção & controle , Extratos Vegetais/farmacologia , Neoplasias Cutâneas/prevenção & controle , Angelica/química , Animais , Carcinogênese/patologia , Linhagem Celular Tumoral , Chalcona/farmacologia , Chalcona/uso terapêutico , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Melanoma Experimental/induzido quimicamente , Melanoma Experimental/genética , Melanoma Experimental/patologia , Camundongos , Camundongos Knockout , Mutação , PTEN Fosfo-Hidrolase/genética , Fosfatidilinositol 3-Quinases/metabolismo , Extratos Vegetais/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Transdução de Sinais/efeitos dos fármacos , Neoplasias Cutâneas/induzido quimicamente , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Resultado do TratamentoRESUMO
Lycii Fructus is the dried ripe fruits of Lycium chinense and L. barbarum, which has long been used as a traditional food material in East Asia. The purpose of this study was to investigate the role of the indirect antioxidative action in the Lycii fructus extract (LFE)-induced cytoprotective effect in vitro. LFE significantly enhanced the expression of the drug-metabolizing enzyme genes and intracellular glutathione level in mouse hepatoma Hepa1c1c7 cells. LFE stimulated the nuclear translocation of aryl hydrocarbon receptor as well as nuclear factor (erythroid-derived 2)-like 2. The pretreatment of LFE for 24 h, but not for 30 min, completely inhibited the cytotoxic effect of hydrogen peroxide. Furthermore, chlorogenic acid, one of the main constituents of LFE, showed cytoprotection against hydrogen peroxide with the enhanced phase 2 enzyme gene expression. These results suggested that LFE exhibits a cytoprotective effect, possibly through the enhancement of the antioxidant gene expression. ABBREVIATIONS: LFE: Lycii Fructus extract; GSH: glutathione; NQO1: NAD(P)H:quinone oxidoreductase 1; HO-1: heme oxygenase-1; GCLC: glutamate-cysteine ligase, catalytic subunit; xCT: a component of cysteine/glutamate antiporter (cystine/glutamate exchanger); CYP1A1: cytochrome P450 1A1; GSH: glutathione; AhR: aryl hydrocarbon receptor; Nrf2: nuclear factor (erythroid-derived 2)-like 2; CGA: chlorogenic acid; RT-PCR: reverse transcription-polymerase chain reaction; DTT: dithiothreitol; PMSF: phenylmethylsulfonyl fluoride; ARE: antioxidant response element; XRE: xenobiotic responsive element.
Assuntos
Antioxidantes/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Peróxido de Hidrogênio/toxicidade , Lycium/química , Extratos Vegetais/farmacologia , Animais , Western Blotting , Linhagem Celular Tumoral , Expressão Gênica/efeitos dos fármacos , Glutationa/metabolismo , Camundongos , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Cacao extract (CE) consumption has beneficial effects on human health, such as lowering the risk of obesity. However, the underlying molecular mechanism for the anti-obesity effect of CE remains incompletely understood. Here, we used a 50% aqueous alcohol extract of cacao mass, which is rich in methylxanthine derivatives (about 11%) and poor in flavan-3-ols (less than 1%), and assessed the suppression effects of this extract on adipocyte differentiation to investigate the anti-obesity mechanism. CE dose-dependently decreased fat accumulation in 3T3-L1 cells without affecting cell viability. CE also dose-dependently decreased the protein and gene expression levels of two adipogenesis-related transcription factors, peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer-binding proteins (C/EBPs). Moreover, CE decreased protein expression levels of sterol regulatory element-binding protein 1 (SREBP1) and its downstream fatty acid synthase (FAS), which was accompanied by the retained localization of SREBP1 in the cytoplasm of 3T3-L1 cells. After ICR mice were fed a diet containing 1% CE for 1 wk, their white adipose tissue weight was lower, whereas their brown adipose tissue weight was higher compared with those of control animals. Additionally, the protein expression levels of PPARγ, C/EBPs, SREBP1, and FAS in the white adipose tissue of these mice were also lower than those in control animals. In contrast, diet supplementation with CE induced higher levels of phosphorylated AMP-activated protein kinase (AMPK) and its downstream acetyl-CoA carboxylase. In conclusion, methylxanthine derivative-rich CE decreases fat accumulation in adipocytes by downregulating the expression of the adipocyte differentiation master regulators through the activation of AMPK.
Assuntos
Adipogenia/efeitos dos fármacos , Tecido Adiposo/efeitos dos fármacos , Proteína alfa Estimuladora de Ligação a CCAAT/metabolismo , Cacau/química , Obesidade/metabolismo , PPAR gama/metabolismo , Xantinas/farmacologia , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Tecido Adiposo/citologia , Tecido Adiposo/metabolismo , Animais , Fármacos Antiobesidade/farmacologia , Fármacos Antiobesidade/uso terapêutico , Chocolate , Regulação para Baixo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Obesidade/prevenção & controle , Fitoterapia , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Xantinas/uso terapêuticoRESUMO
AIMS: Muscle mass is regulated by the balance between the synthesis and degradation of muscle proteins. Loss of skeletal muscle mass is associated with an increased risk of developing metabolic diseases such as obesity and type 2 diabetes mellitus. The aim of this study was to clarify the effects of licorice flavonoid oil on muscle mass in KK-Ay/Ta mice. MAIN METHODS: Male genetically type II diabetic KK-Ay/Ta mice received 0, 1, or 1.5â¯g/kg BW of licorice flavonoid oil by mouth once daily for 4â¯weeks. After 4â¯weeks, the femoral and soleus muscles were collected for western blotting for evaluation of the mTOR/p70 S6K, p38/FoxO3a, and Akt/FoxO3a signaling pathways. KEY FINDINGS: Ingestion of licorice flavonoid oil significantly enhanced femoral muscle mass without affecting body weight in KK-Ay/Ta mice. Licorice flavonoid oil also decreased expression of MuRF1 and atrogin-1, which are both markers of muscle atrophy. The mechanisms by which licorice flavonoid oil enhances muscle mass include activation of mTOR and p70 S6K, and regulation of phosphorylation of FoxO3a. SIGNIFICANCE: Ingestion of licorice flavonoids may help to prevent muscle atrophy.
Assuntos
Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Flavonoides/farmacologia , Glycyrrhiza/química , Músculo Esquelético/efeitos dos fármacos , Óleos de Plantas/farmacologia , Animais , Proteínas de Transporte/antagonistas & inibidores , Proteínas de Transporte/biossíntese , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Proteína Forkhead Box O3/biossíntese , Proteína Forkhead Box O3/genética , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Camundongos , Proteínas Musculares/antagonistas & inibidores , Proteínas Musculares/biossíntese , Proteínas Musculares/genética , Músculo Esquelético/crescimento & desenvolvimento , Músculo Esquelético/patologia , Tamanho do Órgão/efeitos dos fármacos , Proteínas Ligases SKP Culina F-Box/antagonistas & inibidores , Proteínas Ligases SKP Culina F-Box/biossíntese , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/biossíntese , Proteínas com Motivo Tripartido , Proteínas Quinases p38 Ativadas por Mitógeno/biossínteseRESUMO
The potential health benefits of phenolic acids found in food and beverages has been suggested from a number of large population studies. However, the mechanism of how these compounds may exert biological effects is less well established. It is also now recognised that many complex polyphenols in the diet are metabolised to simple phenolic acids which can be taken up in the circulation. In this paper a number of selected phenolic compounds have been tested for their bioactivity in two cell culture models. The expression and activity of endothelial nitric oxide synthase (eNOS) in human aortic endothelial cells and the uptake of glucose in muscle cells. Our data indicate that while none of the compounds tested had a significant effect on eNOS expression or activation in endothelial cells, several of the compounds increased glucose uptake in muscle cells. These compounds also enhanced the translocation of the glucose transporter GLUT4 to the plasma membrane, which may explain the observed increase in cellular glucose uptake. These results indicate that simple cell culture models may be useful to help understand the bioactivity of phenolic compounds in relation to cardiovascular protection.
Assuntos
Células Endoteliais/efeitos dos fármacos , Hidroxibenzoatos/farmacologia , Óxido Nítrico Sintase Tipo III/metabolismo , Polifenóis/farmacologia , Animais , Doenças Cardiovasculares , Células Cultivadas , Dieta , Células Endoteliais/metabolismo , Glucose/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Humanos , Estrutura Molecular , Células Musculares/efeitos dos fármacos , Células Musculares/metabolismo , RatosRESUMO
BACKGROUND: Glucose transporter 4 (GLUT4) is firmly established to play a pivotal role in glucose metabolism and in particular in modulating the insulin-stimulated glucose transport in several tissues, such as skeletal muscle and adipose tissue. Stimulation of GLUT4 by insulin results in its translocation to the plasma membrane, activation of several kinases, and finally in a large glucose influx into cells. PURPOSE: In this study we investigated the modulating properties of four biologically active oxyprenylated ferulic acid and umbelliferone derivatives and of their unprenylated parent compounds on GLUT-4 mediated glucose uptake and translocation. METHODS: Oxyprenylated phenylpropanoids have been synthesized in high yields and purity by already reported methodologies. All the synthesized chemicals were tested for their capacity to modulate GLUT4 mediated glucose uptake and GLUT4 translocation in L6 rat skeletal myoblasts in the concentration range 0.1 - 10 µM. Insulin (0.1 µM) was used as positive control. Western blot analysis was employed to assess if GLUT4 translocation occurred prior to increase of glucose uptake. Statistical analyses were carried out by the Dunnett multiple comparison test. RESULTS: 4'-Geranyloxyferulic acid (GOFA), 7-isopentenyloxycoumarin, and auraptene (7-geranyloxycoumarin) increased glucose uptake in a concentration-dependent manner, and significant increases were observed at 0.1 µM for GOFA, and 10 µM for 7-isopentenyloxycoumarin, and auraptene. These products also were able to significantly promote the translocation of GLUT4 to the plasma membrane of L6 myotubes. After treatment with compounds for 15â¯min, the incorporated amounts of GOFA, 7-isopentenyloxucoumarin, and auraptene were 0.15, 0.32, and 1.77 nmols/60-mm culture dish, respectively. A sample of raw Italian propolis, found to be rich in GOFA and auraptene, was also seen to mimic insulin-effect in the concentration range 0.01 - 1.0â¯mg/ml. CONCLUSIONS: Among the compounds assayed, auraptene showed to possess potentialities to be a potent activator of both translocation of GLUT4 and glucose influx into skeletal muscle cells with the highest bioavailability among effective compounds. Its capacity to modulate sugar metabolism, coupled to its presence in edible Citrus fruits, can be regarded as an additional reason to account for the already known stimulating properties of some vegetable (e.g. bitter orange).
Assuntos
Cumarínicos/farmacocinética , Transportador de Glucose Tipo 4/metabolismo , Glucose/metabolismo , Fibras Musculares Esqueléticas/efeitos dos fármacos , Animais , Disponibilidade Biológica , Linhagem Celular , Ácidos Cumáricos/farmacocinética , Insulina/farmacologia , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/citologia , Músculo Esquelético/efeitos dos fármacos , Própole/química , Transporte Proteico/efeitos dos fármacos , Ratos , Umbeliferonas/farmacocinéticaRESUMO
Polycyclic aromatic hydrocarbons (PAHs) and halogenated aromatic hydrocarbons (HAHs) develop various adverse effects through activation of an aryl hydrocarbon receptor (AhR). The suppressive effects of brewed green tea and black tea on 3-methylcholanthrene (MC)-induced AhR activation and its downstream events were examined in the liver of rats. Ad-libitum drinking of green tea and black tea suppressed MC-induced AhR activation and elevation of ethoxyresorufin O-deethylase activity in the liver, whereas the teas themselves did not induce them. Tea showed a suppressive fashion on the expression of cytochrome P450 1A1 (CYP1A1). Tea suppressed the AhR activation induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) ex vivo. A part of catechins and theaflavins was present in plasma and liver as conjugated and intact forms. The results of this study suggested that active component(s) of tea are incorporated in the liver and suppress the activity of CYP1As through the AhR activation pathway.