RESUMEN
To examine the safety of Dietary Applephenon® (AP) in feed, Crl: CD (SD) rats of each sex were divided into four groups and given diets containing AP at 0%, 1.25%, 2.5%, or 5.0% for 90 days. All rats survived and toxic changes were not observed throughout the study. Body weight and food efficiency in the 5.0% AP group of both sexes were significantly decreased compared with that in controls. These changes were considered to be caused by the physiological effects of AP (including the inhibitory effects on pancreatic lipase activity). Slight hypertrophy in acinar cells in the parotid and submandibular glands appeared in the 2.5% and 5.0% groups. These were suggested not to be toxicological but physiologic adaptive responses to oral stimuli by the lower pH of AP-containing diets. In conclusion, dietary AP in feed, up to a maximum level of 5.0% for 90 days, given to rats did not induce toxicological effects.
Asunto(s)
Células Acinares/patología , Suplementos Dietéticos , Extractos Vegetales/toxicidad , Polifenoles/toxicidad , Glándulas Salivales/patología , Células Acinares/efectos de los fármacos , Células Acinares/metabolismo , Animales , Peso Corporal/efectos de los fármacos , Dieta , Relación Dosis-Respuesta a Droga , Femenino , Hipertrofia , Masculino , Malus/química , Nivel sin Efectos Adversos Observados , Extractos Vegetales/administración & dosificación , Polifenoles/administración & dosificación , Ratas , Glándulas Salivales/citología , Glándulas Salivales/efectos de los fármacos , Pruebas de Toxicidad SubagudaRESUMEN
We investigated the effects of Cimicifuga racemosa (CR) plant extracts on the changes in levels of the cerebral monoamines norepinephrine (NE), dopamine (DA), and serotonin (5-HT), the respective metabolites 3-methoxy-4-hydroxyphenylglycol (MHPG), 3,4-dihydroxyphenylacetic acid (DOPAC), and 5-hydroxyindoleacetic acid (5-HIAA), and plasma corticosterone in mice subjected to acute immobilization stress. Single oral administration of the CR extract (1,000 mg/kg) significantly attenuated plasma corticosterone levels that had been increased as a result of enforced immobilization. Acute immobilization stress caused significant changes in the corresponding amine-to-metabolite ratios in the hypothalamus, hippocampus, and cortex; however, CR-extract treatment significantly attenuated the MHPG/NE change in the hypothalamus, and the 5-HIAA/5- HT changes in each region of the brain. Our results suggest that the CR extract interacts not only with the hypothalamic-pituitary-adrenal (HPA) axis but also with the sympathetic adrenomedullary (SAM) system under stress conditions. Thus the CR extract can alleviate acute stress responses by suppressing the changes of amine-to-metabolite ratio in brain.
Asunto(s)
Fármacos del Sistema Nervioso Central/administración & dosificación , Cimicifuga/química , Dopamina/metabolismo , Inmovilización , Norepinefrina/metabolismo , Extractos Vegetales/administración & dosificación , Serotonina/metabolismo , Estrés Psicológico/metabolismo , Animales , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Corticosterona/sangre , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Estrés Psicológico/sangre , Estrés Psicológico/tratamiento farmacológicoRESUMEN
Dried rhizomes of Cimicifuga racemosa (CR), known as black cohosh, have been widely used as a herbal dietary supplement in the treatment of menopausal symptoms. Here we used experimental mouse stress models to investigate the role of anti-stress food factors, and found that a CR extract had stress-relieving effects. A single oral administration of CR extract (1,000 mg/kg) significantly attenuated plasma corticosterone and aspartate aminotransferase (AST) levels that had increased as a result of enforced immobilization. Bioassay-guided fractionation of the CR extract resulted in the isolation of 10 triterpenes, among which actein, 23-epi-26-deoxyactein, and cimiracemoside F (100 mg/kg, per os) were shown to contribute to the anti-stress effects. Furthermore, the CR extract significantly prevented the development of water immersion stress-induced gastric mucosal ulcers in rats. We propose that the CR extract might be suitable for the prevention and treatment of stress-related disorders.
Asunto(s)
Cimicifuga/química , Fitoterapia , Extractos Vegetales/uso terapéutico , Estrés Psicológico/tratamiento farmacológico , Administración Oral , Animales , Masculino , Ratones , Ratones Endogámicos BALB C , Extractos Vegetales/administración & dosificación , Ratas , Ratas Sprague-Dawley , Restricción FísicaRESUMEN
Studies on metabolisms of alcohol and the metabolites (e.g.:acetaldehyde) after drinking give basic and important information to recognize the physiological influence of drinking to human bodies. The aims of these studies were to clarify the influences of ALDH2 genotype difference, kinds of alcohol beverages, and fasted or prandial state to alcohol metabolisms at moderate drinking. The studies were conducted by a randomized cross-over design. After overnight fast, fifteen of ALDH2*1/*1 (Experiment 1) and twenty of ALDH21/*2 (Experiment 2) in Japanese healthy men aged 40 to 59 years old drank beer or shochu at a dose of 0.32g ethanol / kg body weight with or without test meal (460 kcal). The peak of blood ethanol (C(max)) was higher with shochu than with beer in the fasted condition in both ALDH2 genotypes, however, the difference between two types of alcohol beverages went out in the prandial condition. Simultaneous ingestion of test meal with alcohol beverage significantly decreased blood ethanol concentrations and increased ethanol disappearance rate (EDR) in the both genotypes. EDR values were significantly higher in ALDH2*1/*1 type than in ALDH2*1/*2 type in the both beverages with and without meal, whereas beta values showed no significant difference between two genotypes. The concentrations of blood acetaldehyde in ALDH2*1/*2 type were higher in prandial condition than in fasted condition with shochu. These results indicate that meal modified the differences of alcohol metabolism between beer and shochu and also between ALDH2 genotypes. Thus, alcohol metabolism in daily drinking is shown to be regulated by various combinatorial drinking conditions.
Asunto(s)
Bebidas Alcohólicas , Aldehído Deshidrogenasa/genética , Ingestión de Alimentos/fisiología , Etanol/sangre , Polimorfismo Genético , Acetaldehído/sangre , Adulto , Aldehído Deshidrogenasa Mitocondrial , Cerveza , Estudios Cruzados , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Apple polyphenols (AP) mainly consist of procyanidins (PC), which are composed of (-)-epicatechins and (+)-catechins. In order to investigate the antiageing effects of PC, we measured the lifespan of CAENORHABDITIS ELEGANS worms treated with PC. Treatment with 65 µg/mL PC extended the mean lifespan of wild-type N2 and FEM-1 worms by 12.1 % and 8.4 %, respectively, i.e., to a similar extent as resveratrol. In addition, treatment with 100 µg/mL AP also significantly prolonged the mean lifespan of the same worms by 12.0 % and 5.3 %, respectively, i.e., to a similar extent as PC. In contrast, treatment with (-)-epicatechin did not extend the lifespan of the worms. PC did not modify the growth, food intake, or fecundity of C. elegans. Treatment with PC did not extend the lifespan of MEV-1 worms, which show excessive oxidative stress, indicating that PC had no antioxidant ability in the MEV-1 mutant. Moreover, treatment with PC had no effect on the longevity of SIR-2.1 worms, which lack the activity of SIR-2, a member of the sirtuin family of NAD (+)-dependent protein deacetylases. These results indicated that PC has SIR-2.1-dependent antiageing effects on C. elegans.
Asunto(s)
Caenorhabditis elegans/efectos de los fármacos , Caenorhabditis elegans/fisiología , Longevidad/efectos de los fármacos , Malus/química , Proantocianidinas/farmacología , Animales , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Citocromos b , Mutación , Proantocianidinas/aislamiento & purificación , Resveratrol , Sirtuinas/genética , Estilbenos/farmacología , Succinato Deshidrogenasa/genética , TemperaturaRESUMEN
The gene of a novel O-methyltransferase was isolated from tea cultivars (Camellia sinensis L.). Using the recombinant enzyme, O-methylated (-)-epigallocatechin-3-O-gallate (EGCG) in all cases were synthesized. EGCG and the synthesized O-methylated EGCGs including (-)-epigallocatechin-3-O-(3-O-methyl)-gallate (EGCG3''Me), (-)-epigallocatechin-3-O- (4-O-methyl)-gallate(EGCG4''Me), (-)-epigallocatechin-3-O-(3,5-O-dimethyl)-gallate (EGCG3'',5''diMe), and (-)-3-O-methyl-epigallocatechin-3-O-(3,5-O-dimethyl)-gallate (EGCG3',3'',5''triMe) were assayed using the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging assay and antibacterial activity. EGCG was the most effective of the O-methylated EGCGs. The antiallergic effects of EGCG and the other O-methylated EGCGs were measured by conducting histamine release assays using bone marrow-derived mouse mast cells, and the order of potency was EGCG3',3'',5''triMe = EGCG3'',5''diMe > EGCG3''Me > EGCG. These results indicated that reducing the number of hydroxyl groups decreases the effectiveness of DPPH radical scavenging and antibacterial activity. In contrast, the inhibition of histamine release was potentiated by an increase in the number of methyl groups in EGCG, especially in the galloyl moiety.
Asunto(s)
Camellia sinensis/enzimología , Catequina/análogos & derivados , Clonación Molecular , Proteínas de Plantas/genética , Proteína O-Metiltransferasa/genética , Secuencia de Aminoácidos , Animales , Antialérgicos/química , Antialérgicos/farmacología , Antibacterianos/química , Antibacterianos/farmacología , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/inmunología , Camellia sinensis/genética , Catequina/química , Catequina/farmacología , Depuradores de Radicales Libres/química , Depuradores de Radicales Libres/farmacología , Liberación de Histamina/efectos de los fármacos , Ratones , Datos de Secuencia Molecular , Proteínas de Plantas/metabolismo , Proteína O-Metiltransferasa/metabolismo , Alineación de SecuenciaRESUMEN
Recent transcriptomics studies on the effect of long-term or severe energy restriction (ER) have revealed that many genes are dynamically modulated by this condition in rodents. The present study was conducted to define the global gene expression profile in response to mild ER treatment. Growing rats were fed with reduced amount of diet (5-30 % ER) for 1 week or 1 month. Using DNA microarray analysis of the liver, seventy-two genes that were consistently changed through the different ER levels were identified. Many were related to lipid metabolism including genes encoding key enzymes such as carnitine palmitoyltransferase 1 and fatty acid synthase. Interestingly, a number of genes were altered even by 5 % ER for 1 week where no differences in weight gain were observed. The information obtained in the present study can be used as a valuable reference data source in the transcriptomics studies of food and nutrition in which subtle differences in food intake sometimes hinder appropriate interpretation of the data.
Asunto(s)
Restricción Calórica , Ingestión de Energía/fisiología , Expresión Génica , Genes/fisiología , Metabolismo de los Lípidos/genética , Hígado/metabolismo , Animales , Perfilación de la Expresión Génica , Masculino , Nutrigenómica , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Ratas , Ratas Wistar , Valores de ReferenciaRESUMEN
A second class II AP endonuclease, APEX2, possesses strong 3'-5' exonuclease and 3'-phosphodiesterase activities but only very weak AP-endonuclease activity. APEX2 associates with proliferating cell nuclear antigen (PCNA), and the progression of S phase of the cell cycle is accompanied by its expression. APEX2-null mice exhibit severe dyslymphopoiesis in thymus as well as moderate dyshematopoiesis and growth retardation. Comparative gene expression profiling of wild-type and APEX2-null mice using an oligonucleotide microarray revealed that APEX2-null thymus has significantly altered gene expression profiles, reflecting its altered populations of thymocytes. Beyond these altered populations, APEX2-null thymus exhibits significant alterations in expression of genes involved in DNA replication, recombination and repair, including Apex1, Exo1 and Fen1 as well as master genes for the DNA damage response, such as E2f1, Chek1, and proapoptotic genes. We therefore examined the extent of DNA strand breakage, and found that both of single-strand breaks detected as comets and double-strand breaks detected as gammaH2AX foci were significantly higher in frequency in most APEX2-null thymocytes compared to wild-type thymocytes. This higher frequency of DNA breaks was accompanied by increased expression of PCNA and increased phosphorylation of p53 at Ser23 and to a lesser extent, at Ser18. The present study clearly demonstrates that APEX2-null lymphocytes have a higher frequency of DNA breaks, indicating that APEX2 may play an important role(s) during their generation and/or repair.
Asunto(s)
Daño del ADN , Endonucleasas/genética , Perfilación de la Expresión Génica , Sistema Linfático/fisiología , Timo/ultraestructura , Animales , Reparación del ADN , Replicación del ADN , ADN-(Sitio Apurínico o Apirimidínico) Liasa , Masculino , Ratones , Ratones Noqueados , Enzimas Multifuncionales , Análisis de Secuencia por Matrices de OligonucleótidosRESUMEN
Elderly people insidiously manifest the symptoms of heart failure, such as dyspnea and/or physical disabilities in an age-dependent manner. Although previous studies suggested that oxidative stress plays a pathological role in the development of heart failure, no direct evidence has been documented so far. In order to investigate the pathological significance of oxidative stress in the heart, we generated heart/muscle-specific manganese superoxide dismutase-deficient mice. The mutant mice developed progressive congestive heart failure with specific molecular defects in mitochondrial respiration. In this paper, we showed for the first time that the oxidative stress caused specific morphological changes of mitochondria, excess formation of superoxide (O(2)(*)(-)), reduction of ATP, and transcriptional alterations of genes associated with heart failure in respect to cardiac contractility. Accordingly, administration of a superoxide dismutase mimetic significantly ameliorated the symptoms. These results implied that O(2)(*)(-) generated in mitochondria played a pivotal role in the development and progression of heart failure. We here present a bona fide model for human cardiac failure with oxidative stress valuable for therapeutic interventions.
Asunto(s)
Cardiopatías/metabolismo , Cardiopatías/patología , Mitocondrias Cardíacas/metabolismo , Estrés Oxidativo , Animales , Apoptosis , Progresión de la Enfermedad , Regulación de la Expresión Génica , Cardiopatías/genética , Peroxidación de Lípido , Ratones , Ratones Noqueados , Microscopía Electrónica de Transmisión , Músculo Esquelético/citología , Músculo Esquelético/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Superóxido Dismutasa/deficiencia , Superóxido Dismutasa/genética , Superóxido Dismutasa/metabolismo , Transcripción Genética/genéticaRESUMEN
The dose-dependent hypocholesterolemic and antiatherogenic effects of dietary apple polyphenol (AP) from unripe apple, which contains approximately 85% catechin oligomers (procyanidins), were examined in male Sprague-Dawley rats (4 wk of age) given a purified diet containing 0.5% cholesterol. Dietary AP at 0.5 and 1.0% levels significantly decreased the liver cholesterol level compared with that in the control (AP-free diet-fed) group. Dietary AP also significantly lowered the serum cholesterol level compared with that in the control group. However, the HDL cholesterol level was significantly higher in the 1.0% AP-fed group than in the control group. Accordingly, the ratio of HDL-cholesterol/total cholesterol was significantly higher in the 0.5% AP-fed group and 1.0% AP-fed group than in the control group. Moreover, the atherogenic indices in the 0.5 and 1.0% AP-fed groups were significantly lower than those in the control group. The activity of hepatic cholesterol 7alpha-hydroxylase tended to be increased by dietary AP in a dose-dependent manner. In accord with this observation, dietary AP increased the excretion of acidic steroids in feces. Dietary AP also significantly promoted the fecal excretion of neutral steroids in a dose-dependent manner. These observations suggest that dietary AP at a 0.5 or 1.0% level exerts hypocholesterolemic and antiatherogenic effects through the promotion of cholesterol catabolism and inhibition of intestinal absorption of cholesterol.
Asunto(s)
Anticolesterolemiantes/administración & dosificación , Colesterol en la Dieta , Flavonoides/administración & dosificación , Malus/química , Fenoles/administración & dosificación , Animales , Anticolesterolemiantes/uso terapéutico , Peso Corporal/efectos de los fármacos , Colesterol 7-alfa-Hidroxilasa/metabolismo , Heces/química , Flavonoides/uso terapéutico , Metabolismo de los Lípidos/efectos de los fármacos , Lípidos/sangre , Hígado/efectos de los fármacos , Masculino , Tamaño de los Órganos/efectos de los fármacos , Fenoles/uso terapéutico , Polifenoles , Ratas , Ratas Sprague-Dawley , Esteroides/metabolismoRESUMEN
We isolated a strain from hop-resistant Lactobacillus hrevis ABBC45, which had lost a plasmid (pRH45) harboring a putative hop resistance gene, horA. The hop resistance level of this horA-deficient strain, named ABBC45(C), was initially low but gradually induced by repeated growth in media containing progressively increasing levels of hop compounds. Although the hop resistance level was substantially lower than that of the hop-adapted wild type strain, hop-adapted ABBC45(C) (ABBC45(CR)) was still capable of growing in beer, suggesting ABBC45 possesses at least two hop resistance mechanisms. Hop resistance acquired by ABBC45(CR) gradually diminished to the pre-adapted level, when the strain was grown repeatedly in the absence of hop compounds. ABBC45(CR) was found to be cross-resistant to several structurally unrelated drugs, including ethidium bromide, daunomycin and nisin. In addition, ABBC45(CR) was shown to extrude ethidium in an energy-dependent manner, while ABBC45(C) did not show such activity. This indicates that the efflux pump was induced by adaptation to hop compounds. The efflux activity of ethidium was reduced by the addition of hop compounds, suggesting hop compounds are also the substrate of the efflux pump. It was also shown that the efflux activity was completely dissipated with the abolition of proton motive force (PMF). These results, taken together, suggest the hop resistance mechanism of ABBC45(C) is mediated by PMF-dependent multidrug efflux pump.