RESUMO
BACKGROUND: Generated in intestinal L cells through cleavage of proglucagon (Gcg), glucagon-like peptide 1 (GLP-1) is secreted and rapidly inactivated by dipeptidyl peptidase IV (DPP-IV). GLP-1 regulates insulin secretion and overall glucose homeostasis. The capacity of dietary bioactives to increase GLP-1 circulating levels, and therefore increase insulin secretion and glucose metabolism, has gained significant interest of late. OBJECTIVES: We evaluated the effects of (-)-epicatechin (EC) and different anthocyanins (ACs) and AC metabolites on GLP-1 metabolism in mice and on GLUTag cells. METHODS: We fed 6-week-old C57BL/6J male mice a control diet or a control diet supplemented with either 40 mg AC or 20 mg EC/kg body weight for 14 weeks (AC) or 15 weeks (EC). Intestinal mRNA levels of Gcg and Dpp-iv were measured. In vitro, GLUTag cells were incubated in the presence or absence of different ACs, the AC metabolite protocatechuic acid (PCA), and EC. GLP-1 secretion and the main pathways involved in its release were assessed. RESULTS: Long-term supplementation with EC or AC increased mouse GLP-1 plasma concentrations (55% and 98%, respectively; P < 0.05). In mice, 1) EC and AC increased Gcg mRNA levels in the ileum (91%) and colon (41%), respectively (P < 0.05); and 2) AC lowered ileum Dpp-iv mRNA levels (35%), while EC decreased plasma DPP-IV activity (15%; P < 0.05). In GLUTag cells, 1) cyanidin, delphinidin, PCA, and EC increased GLP-1 secretion (53%, 33%, 53%, and 68%, respectively; P < 0.05); and 2) cyanidin, delphinidin, EC, and PCA increased cyclin adenosine monophosphate levels (25-50%; P < 0.05) and activated protein kinase A (PKA; 100%, 50%, 80%, and 86%, respectively; P < 0.05). CONCLUSIONS: In mice, EC and ACs regulated different steps in GLP-1 regulation, leading to increased plasma GLP-1. Cyanidin, delphinidin, PCA, and EC promoted GLP-1 secretion from GLUTag cells by activating the PKA-dependent pathway. These findings support the beneficial actions of these flavonoids in sustaining intestinal and glucose homeostasis through the modulation of the GLP-1 metabolism.
Assuntos
Antocianinas , Catequina , Peptídeo 1 Semelhante ao Glucagon , Animais , Antocianinas/farmacologia , Catequina/farmacologia , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Glucose/metabolismo , Insulina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/genéticaRESUMO
INTRODUCTION: d-Glucosamine (GlcN) is one of the most widely consumed dietary supplements and complementary medicines in the world and has been traditionally used to attenuate osteoarthritis in humans. GlcN extends life span in different animal models. In humans, its supplementation has been strongly associated with decreased total mortality and improved vascular endothelial function. GlcN acts as a suppressor of inflammation, and by inhibiting glycolysis, it can activate the metabolism of stored fat and mitochondrial respiration. METHODS: The conventional human GlcN dose is 1500 mg·d-1, but extensive evidence indicates that much higher doses are well tolerated. GlcN is one of the supplements that has experienced a greater use in the last years in elite athletes mainly because of its potential chondroprotective effects that may promote cartilage health. However, the possibility of it being an ergogenic aid has not been explored. We aimed to study the potential beneficial effects of GlcN on mitochondrial content, physical performance, and oxidative stress in mice that were aerobically trained and supplemented with three different doses of glucosamine (250, 500, and 1000 mg·kg-1) for 6 wk. We measured exercise performance (grip strength, motor coordination, and running capacity) before and after the training period. Proteins involved in mitochondrial biogenesis (AMPK, PGC-1, NRF-1, SIRT-1, cytochrome c, citrate synthase), markers of oxidative stress (GSSG/GSH) or damage (malondialdehyde, carbonylated proteins), antioxidant enzymes (NRF-2, SOD1, SOD2, catalase, and PRDX6), and MAPKs (p38 and ERK1/2 were also determined in skeletal muscle. RESULTS AND CONCLUSIONS: Our results show that GlcN supplementation in aerobically trained mice, at doses equivalent to those conventionally used in humans, increases the protein levels of mitochondrial biogenesis markers, improves motor coordination, and may have a synergistic effect with exercise training on running distance.
Assuntos
Glucosamina/farmacologia , Biogênese de Organelas , Estresse Oxidativo/efeitos dos fármacos , Substâncias para Melhoria do Desempenho/farmacologia , Condicionamento Físico Animal/métodos , Desempenho Físico Funcional , Animais , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
This study investigated the effects of supplementation with a cyanidin- and delphinidin-rich extract (CDRE) on the postprandial dysmetabolism, inflammation, and redox and insulin signaling, triggered by the consumption of a high fat meal (HFM) in healthy individuals. Participants (n = 25) consumed a 1026-kcal HFM simultaneously with either the CDRE providing 320.4 mg of anthocyanins (90% cyanidin and delphinidin) or placebo. Diets were randomly assigned in a double blind, placebo-controlled crossover design. Blood was collected prior to (fasted, time 0), and for 5 h after meal consumption; plasma, serum, and peripheral blood mononuclear cells (PBMC) were isolated. AC metabolites were detected in serum as early as 30 min after CDRE consumption. The CDRE mitigated HFM-induced endotoxemia, reducing increases in plasma LPS and LPS-binding protein. The CDRE also reduced other events associated with HFM-triggered postprandial dysmetabolism including: i) plasma glucose and triglyceride increases; ii) TNFα and NOX4 upregulation in PBMC; and iii) JNK1/2 activation in PBMC. The CDRE did not significantly affect HFM-mediated increases in plasma insulin, GLP-1, GLP-2, GIP, and LDL- and HDL-cholesterol, and IKK phosphorylation in PBMC. In summary, dietary AC, i.e. cyanidin and delphinidin, exerted beneficial actions against unhealthy diets by modulating the associated postprandial dysmetabolism, endotoxemia, alterations of glycemia and lipidemia, and redox and insulin signaling.
Assuntos
Antocianinas , Endotoxemia , Antocianinas/farmacologia , Antocianinas/uso terapêutico , Glicemia/metabolismo , Estudos Cross-Over , Dieta Hiperlipídica/efeitos adversos , Endotoxemia/metabolismo , Voluntários Saudáveis , Humanos , Insulina , Leucócitos Mononucleares/metabolismoRESUMO
The beneficial effects of moderate red wine consumption on cardiovascular health are well known. The composition of red wine includes several compounds, such as the phytoestrogen resveratrol, that exert these beneficial effects, although not all the mechanisms by which they act are known. Our aim was to study the effect of red wine consumption on longevity-related genes in controlled human populations, such as cloistered nuns. We found that the expression of catalase, manganese-superoxide dismutase, Sirt1, and p53 was increased in peripheral blood mononuclear cells after 14 days of moderate red wine consumption. This increase was accompanied by an enhanced metabolic wellness: fatty acids, cholesterol, branched chain amino acids (isoleucine and leucine), ketone bodies (acetoacetate), bacterial co-metabolites (trimethylamine), and cellular antioxidants (taurine) contributed to a change in metabolic profile after moderate red wine consumption by the nuns. No serious unwanted side effects were observed. Finally, we tested the effect of moderate red wine consumption on longevity in a controlled animal population, such as D. melanogaster, and found that it increased average life span by 7%. In conclusion, moderate red wine consumption increases the expression of key longevity-related genes and improves metabolic health in humans and increases longevity in flies.
RESUMO
(1) Background: The gastrointestinal tract (GI) tract is one of the main organs exposed to particulate matter (PM) directly through ingestion of contaminated food or indirectly through inhalation. Previous studies have investigated the effects of chronic PM exposure on intestinal epithelia in vitro using Caco-2 cells and in vivo using mice. In this study, we hypothesized that chronic PM exposure would increase epithelial permeability and decrease barrier function due to altered redox homeostasis, which alters levels and/or localization of barrier-associated proteins in human three-dimensional (3D) intestinal tissues. (2) Methods: Transepithelial electrical resistance (TEER) in tissues exposed to 50, 100, 150, 250, and 500 µg/cm2 of PM for 1 week and 2 weeks was analyzed. Levels and localization of tight junction proteins zonula occludens protein 1 (ZO-1) and claudin-1 and desmosome-associated desmocollin were analyzed using immunofluorescence. As a marker of oxidative stress, levels of 4-hydroxy-nonenal (4HNE) adducts were measured. (3) Results: No differences in TEER measurements were observed between exposed and un-exposed tissues. However, increased levels of 4HNE adducts in exposed tissues were observed. Additionally, decreased levels of ZO-1, claudin-1, and desmocollin were demonstrated. (4) Conclusion: These data suggest that chronic PM exposure results in an increase of oxidative stress; modified levels of barrier-associated proteins could possibly link to GI tract inflammatory conditions.
Assuntos
Células CACO-2 , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/metabolismo , Mucosa Intestinal/metabolismo , Material Particulado/farmacologia , Junções Íntimas/metabolismo , Animais , Células CACO-2/efeitos dos fármacos , Células CACO-2/fisiologia , Humanos , Intestinos/fisiopatologia , Proteínas de Membrana/metabolismo , Camundongos , Oxirredução , Material Particulado/administração & dosagem , Proteínas de Junções ÍntimasRESUMO
BACKGROUND: Caloric restriction (CR) without micronutrient deficiency has been shown to increase both lifespan and healthspan. In animals, CR has been demonstrated to increase glutathione (GSH), a neuroprotective antioxidant, in the brain and preserve brain mitochondrial function by altering neuroenergetics. In humans it has been associated with improvements in mood states and cognitive function. However, most CR studies have employed a 30-60% reduction in calories which is likely too stringent for most people to adhere to long-term. Thus, there is an unmet need for nutritional supplements which can mimic the biological effects of CR, without the need for calorie limitations. AIM: The purpose of the present randomized, placebo-controlled clinical trial was to use Proton (1H) Magnetic Resonance Spectroscopic (MRS) measurements to determine non-invasively whether a blend of micronutrients, a putative CR mimetic, positively modulates metabolites related to neuroprotection and neuroenergetics in the brain. METHODS: Healthy middle-aged men and women (N = 63 [33 women]; age: 40-60 years) were randomized in a double-blind manner to 6 weeks supplementation with either the putative CR mimetic or placebo. At baseline and 6 weeks, subjects underwent MRS at 3 T to investigate changes in brain chemistry, including the neurometabolites: GSH, Glutamate (Glu), Glutamine (Gln) and N-Acetylaspartate (NAA). RESULTS: GSH, a marker of antioxidant and cellular redox status, increased in the brain of participants in the supplement group. The supplement group also showed an increase in the Glu/Gln ratio, a marker of excitatory neurotransmission and bioenergetics. A trend for an increase in NAA/H2O, a marker of neuronal integrity, was observed in females in the supplement group. CONCLUSIONS: The present study reveals that 6-weeks daily supplementation with a micronutrient blend elicits positive changes in brain neurochemistry. This is the first study to demonstrate that a putative CR mimetic increases brain GSH concentrations and improves neuroprotection and neuroenergetics in the brain of healthy humans. This study was registered at www.clinicaltrials.gov as NCT02439983.
Assuntos
Restrição Calórica , Glutationa , Adulto , Animais , Encéfalo/diagnóstico por imagem , Suplementos Nutricionais , Feminino , Humanos , Masculino , Micronutrientes , Pessoa de Meia-IdadeRESUMO
BACKGROUND: We previously described a novel micronutrient blend that behaves like a putative calorie restriction mimetic. The aim of this paper was to analyze the beneficial effects of our micronutrient blend in mice and C. elegans, and compare them with calorie restriction. METHODS: Whole transcriptomic analysis was performed in the brain cortex, skeletal muscle and heart in three groups of mice: old controls (30 months), old + calorie restriction and old + novel micronutrient blend. Longevity and vitality were tested in C. elegans. RESULTS: The micronutrient blend elicited transcriptomic changes in a manner similar to those in the calorie-restricted group and different from those in the control group. Subgroup analysis revealed that nuclear hormone receptor, proteasome complex and angiotensinogen genes, all of which are known to be directly related to aging, were the most affected. Furthermore, a functional analysis in C. elegans was used. We found that feeding C. elegans the micronutrient blend increased longevity as well as vitality. CONCLUSIONS: We describe a micronutrient supplement that causes similar changes (transcriptomic and promoting longevity and vitality) as a calorie restriction in mice and C. elegans, respectively, but further studies are required to confirm these effects in humans.
Assuntos
Fenômenos Fisiológicos da Nutrição Animal , Caenorhabditis elegans/genética , Caenorhabditis elegans/fisiologia , Restrição Calórica , Ingestão de Alimentos/genética , Ingestão de Alimentos/fisiologia , Sequenciamento do Exoma/métodos , Locomoção/genética , Longevidade/genética , Camundongos/genética , Camundongos/fisiologia , Micronutrientes/administração & dosagem , Transcriptoma/genética , Animais , HumanosRESUMO
BACKGROUND: Carotenoids are an important group of phytonutrients that are abundant in fruits and vegetables. Epidemiological and clinical intervention studies have implied the presence of protective qualities of these nutrients against the development of a variety of chronic diseases. Previously, human carotenoid status has been assessed in serum and tissue using high-performance liquid chromatography (HPLC) methodology. Recently, a Raman spectroscopy (RS)-based photonic method has been developed to accurately and noninvasively measure the carotenoid concentration in human skin. OBJECTIVES: (1) To validate skin RS methodology against standard serum carotenoid measurements by HPLC and (2) to establish and compare the reliability of the 2 methods. DESIGN: This study included 372 healthy adults who provided 3 blood samples and 3 RS skin carotenoid measurements within an 8-day period; each day-matched blood sample and RS determination was spaced by >or=48 hours. RESULTS: Consistent positive correlations were observed for each of 3 separate same-day correlation plots of total serum versus RS skin carotenoids. Overall estimate of the line of best fit from analysis of covariance, using all 3 samples (n = 1116), yielded a Pearson correlation of R = 0.81 (r(2) = 0.66; p < 0.001). Based on analysis of variance, RS skin carotenoid methodology exhibited 0.9% less variance over the 3 tests than serum carotenoids by the HPLC method (p < 0.03). CONCLUSIONS: RS accurately measures total carotenoids in human skin with less intra-individual variability than measurement of serum carotenoids by HPLC analysis. RS technology is a valid and reliable noninvasive method to rapidly assess carotenoid nutritional status in humans.
Assuntos
Carotenoides/análise , Carotenoides/metabolismo , Estado Nutricional/fisiologia , Pele/metabolismo , Análise Espectral Raman , Adolescente , Adulto , Idoso , Análise de Variância , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos TestesRESUMO
The gastrointestinal (GI) tract can play a critical role in the development of pathologies associated with overeating, overweight and obesity. We previously observed that supplementation with anthocyanins (AC) (particularly glycosides of cyanidin and delphinidin) mitigated high fat diet (HFD)-induced development of obesity, dyslipidemia, insulin resistance and steatosis in C57BL/6J mice. This paper investigated whether these beneficial effects could be related to AC capacity to sustain intestinal monolayer integrity, prevent endotoxemia, and HFD-associated dysbiosis. The involvement of redox-related mechanisms were further investigated in Caco-2â¯cell monolayers. Consumption of a HFD for 14 weeks caused intestinal permeabilization and endotoxemia, which were associated with a decreased ileum expression of tight junction (TJ) proteins (occludin, ZO-1 and claudin-1), increased expression of NADPH oxidase (NOX1 and NOX4) and NOS2 and oxidative stress, and activation of redox sensitive signals (NF-κB and ERK1/2) that regulate TJ dynamics. AC supplementation mitigated all these events and increased GLP-2 levels, the intestinal hormone that upregulates TJ protein expression. AC also prevented, in vitro, tumor necrosis factor alpha-induced Caco-2 monolayer permeabilization, NOX1/4 upregulation, oxidative stress, and NF-κB and ERK activation. HFD-induced obesity in mice caused dysbiosis and affected the levels and secretion of MUC2, a mucin that participates in intestinal cell barrier protection and immune response. AC supplementation restored microbiota composition and MUC2 levels and distribution in HFD-fed mice. Thus, AC, particularly delphinidin and cyanidin, can preserve GI physiology in HFD-induced obesity in part through redox-regulated mechanisms. This can in part explain AC capacity to mitigate pathologies, i.e. insulin resistance and steatosis, associated with HFD-associated obesity.
Assuntos
Antocianinas/farmacologia , Dieta Hiperlipídica/efeitos adversos , Microbioma Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/metabolismo , Oxirredução , Substâncias Protetoras/farmacologia , Células CACO-2 , Disbiose , Endotoxemia/tratamento farmacológico , Endotoxemia/etiologia , Endotoxemia/metabolismo , Células Caliciformes/metabolismo , Humanos , Mucina-2/genética , Mucina-2/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Permeabilidade/efeitos dos fármacos , Transdução de SinaisRESUMO
BACKGROUND: Anthocyanins and prebiotics impact overall health and wellness, likely through modulation of the microbiota and the intestinal ecosystem. OBJECTIVES: An 8-week open-label study in male and female volunteers with uncomplicated obesity was designed to study the efficacy of an anthocyanin and prebiotic blend in modulating intestinal microbiota and intestinal inflammation. RESULTS: After 8 weeks of daily supplementation, participants had a significant decrease in Firmicutes (p < 0.001) and Actinobacteria (p < 0.001) and a significant increase in Bacteroidetes (p < 0.001). Bowel habits were improved as evidenced by reductions in the severity of bloating (p < 0.05), gas (p=0.035), and abdominal pain (p=0.015) as well as significant improvements in stool consistency (p < 0.05). Finally, a nonsignificant decrease in the inflammatory marker fecal calprotectin was seen (p=0.107). The supplement was safe and well tolerated. CONCLUSIONS: The results suggest that regular consumption of the anthocyanin-prebiotic blend positively modulated the intestinal ecosystem and provided insights into the mechanisms of action and its impact on health benefits.
RESUMO
Consumption of diets high in fat and/or fructose content promotes tissue inflammation, oxidative stress, and insulin resistance, activating signals (e.g. NF-κB/JNK) that downregulate the insulin cascade. Current evidence supports the concept that select flavonoids can mitigate obesity and type 2 diabetes (T2D). This work investigated if supplementation with the anthocyanidins (AC) cyanidin and delphinidin could attenuate the adverse consequences of consuming a high fat diet (HFD) in mice. Consumption of an AC-rich blend mitigated HFD-induced obesity, dyslipidemia and insulin resistance (impaired responses to insulin and glucose). HFD-fed mice were characterized by increased liver lipid deposition and inflammation, which were also attenuated upon AC supplementation. HFD caused liver oxidative stress showing an increased expression of NADPH oxidases, generators of superoxide and H2O2, and high levels of oxidized lipid-protein adducts. This was associated with the activation of the redox sensitive signals IKK/NF-κB and JNK1/2, and increased expression of the NF-κB-regulated PTP1B phosphatase, all known inhibitors of the insulin pathway. In agreement with an improved insulin sensitivity, AC supplementation inhibited oxidative stress, NF-κB and JNK activation, and PTP1B overexpression. Thus, cyanidin and delphinidin consumption either through diet or by supplementation could be a positive strategy to control the adverse effects of Western style diets, including overweight, obesity, and T2D. Modulation of inflammation, oxidative stress, and NF-κB/JNK activation emerge as relevant targets of AC beneficial actions.
Assuntos
Antocianinas/uso terapêutico , Dieta Hiperlipídica/efeitos adversos , Inflamação/tratamento farmacológico , Resistência à Insulina , Obesidade/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Animais , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/etiologia , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos Endogâmicos C57BL , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/patologia , Oxirredução/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: The human body relies on several aging defense mechanisms (ADMs) to limit damage induced from pro-aging stressors (aging aggressors). However, such protective mechanisms can be compromised, leading to accelerated aging. The skin provides a model to probe the effects of an oral nutritional intervention on ADMs in response to ultraviolet radiation (UVR)-induced damage. OBJECTIVE: To determine whether supplementation with a novel nutritional and phytonutrient blend could protect against UVR-induced skin damage and positively influence facial skin attributes and characteristics by bolstering ADMs. METHODS: Thirty-six healthy, nonsmoking women (40-75 years) with Fitzpatrick skin types I and II were recruited. UVR-induced erythema and the number of apoptotic cells were determined before (pre-) and after 8-week (post-) supplementation. Other clinical variables included skin carotenoid concentrations, facial skin attributes and characteristics. RESULTS: Eight-week supplementation led to protection against UVR-induced skin damage as evidenced by reductions in erythema at all three minimal erythema doses (MEDs) (9.1 to 7.4 [P = 0.10]; 15.8 to 13.6 [P = 0.02]; and 19.6 to 17.3 [P = 0.01] for one, two, and three MEDs and a reduction in the average number of apoptotic cells [11.3 to 5.3, P < 0.0001] pre- and post-supplementation, respectively). Skin carotenoid concentrations increased from 28 111 Raman intensity units to 38 472 (P < 0.0001) along with noticeable improvements in facial skin attributes and characteristics: elasticity, transepidermal water loss, radiance, texture, and overall appearance (all P < 0.05) following supplementation. CONCLUSION: Eight weeks of oral supplementation positively impacted ADMs resulting in protection against UVR-induced skin damage and improvements in facial skin attributes and characteristics.
Assuntos
Apoptose/efeitos dos fármacos , Suplementos Nutricionais , Eritema/prevenção & controle , Dermatoses Faciais/prevenção & controle , Compostos Fitoquímicos/uso terapêutico , Envelhecimento da Pele/efeitos dos fármacos , Adulto , Idoso , Apoptose/efeitos da radiação , Carotenoides/metabolismo , Elasticidade/efeitos dos fármacos , Eritema/etiologia , Dermatoses Faciais/etiologia , Feminino , Humanos , Pessoa de Meia-Idade , Compostos Fitoquímicos/farmacologia , Fatores de Proteção , Pele/metabolismo , Fenômenos Fisiológicos da Pele/efeitos dos fármacos , Raios Ultravioleta/efeitos adversos , Perda Insensível de Água/efeitos dos fármacosRESUMO
An increased permeability of the intestinal barrier is proposed as a major event in the pathophysiology of conditions characterized by chronic gut inflammation. This study investigated the capacity of pure anthocyanins (AC), and berry and rice extracts containing different types and amounts of AC, to inhibit tumor necrosis alpha (TNFα)-induced permeabilization of Caco-2 cell monolayers. Caco-2 cells differentiated into intestinal epithelial cell monolayers were incubated in the absence/presence of TNFα, with or without the addition of AC or AC-rich plant extracts (ACRE). AC and ACRE inhibited TNFα-induced loss of monolayer permeability as assessed by changes in transepithelial electrical resistance (TEER) and paracellular transport of FITC-dextran. In the range of concentrations tested (0.25-1 µM), O-glucosides of cyanidin, and delphinidin, but not those of malvidin, peonidin and petunidin protected the monolayer from TNFα-induced decrease of TEER and increase of FITC-dextran permeability. Cyanidin and delphinidin acted by mitigating TNFα-triggered activation of transcription factor NF-κB, and downstream phosphorylation of myosin light chain (MLC). The protective actions of the ACRE on TNFα-induced TEER increase was positively correlated with the sum of cyanidins and delphinidins (r2 = 0.83) content in the ACRE. However, no correlation was observed between TEER and ACRE total AC, malvidin, or peonidin content. Results support a particular capacity of cyanidins and delphinidins in the protection of the intestinal barrier against inflammation-induced permeabilization, in part through the inhibition of the NF-κB pathway.
Assuntos
Antocianinas/farmacologia , Substâncias Protetoras/farmacologia , Junções Íntimas/efeitos dos fármacos , Fator de Necrose Tumoral alfa/imunologia , Células CACO-2 , Permeabilidade da Membrana Celular/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/imunologia , Humanos , Cadeias Leves de Miosina/genética , Cadeias Leves de Miosina/imunologia , NF-kappa B/genética , NF-kappa B/imunologia , Junções Íntimas/imunologia , Fator de Necrose Tumoral alfa/genéticaRESUMO
Caloric restriction (CR) without malnutrition has been shown to retard several aspects of the aging process and to extend lifespan in different species. There is strong interest in the identification of CR mimetics (CRMs), compounds that mimic the beneficial effects of CR on lifespan and healthspan without restriction of energy intake. Identification of CRMs in mammals is currently inefficient due to the lack of screening tools. We have performed whole-genome transcriptional profiling of CR in seven mouse strains (C3H/HeJ, CBA/J, DBA/2J, B6C3F1/J, 129S1/SvImJ, C57BL/6J, and BALB/cJ) in white adipose tissue (WAT), gastrocnemius muscle, heart, and brain neocortex. This analysis has identified tissue-specific panels of genes that change in expression in multiple mouse strains with CR. We validated a subset of genes with qPCR and used these to evaluate the potential CRMs bezafibrate, pioglitazone, metformin, resveratrol, quercetin, 2,4-dinitrophenol, and L-carnitine when fed to C57BL/6J 2-month-old mice for 3 months. Compounds were also evaluated for their ability to modulate previously characterized biomarkers of CR, including mitochondrial enzymes citrate synthase and SIRT3, plasma inflammatory cytokines TNF-α and IFN-γ, glycated hemoglobin (HbA1c) levels and adipocyte size. Pioglitazone, a PPAR-γ agonist, and L-carnitine, an amino acid involved in lipid metabolism, displayed the strongest effects on both the novel transcriptional markers of CR and the additional CR biomarkers tested. Our findings provide panels of tissue-specific transcriptional markers of CR that can be used to identify novel CRMs, and also represent the first comparative molecular analysis of several potential CRMs in multiple tissues in mammals.
Assuntos
Envelhecimento/efeitos dos fármacos , Restrição Calórica , Carnitina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Tiazolidinedionas/farmacologia , 2,4-Dinitrofenol/farmacologia , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Envelhecimento/metabolismo , Animais , Bezafibrato/farmacologia , Citrato (si)-Sintase/genética , Citrato (si)-Sintase/metabolismo , Perfilação da Expressão Gênica , Hemoglobinas Glicadas/genética , Hemoglobinas Glicadas/metabolismo , Interferon gama/genética , Interferon gama/metabolismo , Masculino , Metformina/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Endogâmicos DBA , Camundongos Endogâmicos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Miocárdio/metabolismo , Neocórtex/efeitos dos fármacos , Neocórtex/metabolismo , Pioglitazona , Quercetina/farmacologia , Resveratrol , Sirtuína 3/genética , Sirtuína 3/metabolismo , Estilbenos/farmacologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
PURPOSE: This study was conducted to determine if 6 wk of supplementation with vitamins E and C could alleviate exercise-induced muscle damage. We studied 22 runners during a 50-km ultramarathon. METHODS: Subjects were randomly assigned to one of two groups: (a) placebos (PL) or (b) antioxidants (AO) (1000 mg vitamin C and 300 mg RRR-alpha-tocopheryl acetate). Blood samples were obtained before supplementation (baseline), 24 h pre-, 12 h pre-, and 1 h prerace; midrace, postrace, 2 h postrace, and for 6 d postrace. Plasma alpha-tocopherol (alpha-TOH), ascorbic acid (AA), and muscle damage markers (creatine kinase (CK) and lactate dehydrogenase (LDH)), as well as maximal voluntary contraction (MVC) of the hamstring and quadriceps were assessed. RESULTS: With supplementation, plasma alpha-TOH and AA increased in the AO but not the PL group. LDH and CK increased in response to the race; LDH peaked at postrace and CK reached maximal values 2 h and 1 d postrace; neither was affected by treatment. Adjusting for between-subject differences in baseline CK values revealed that men had higher levels of CK than did women throughout the study. Correcting CK values for lean body mass (kg) eliminated sex differences, but not changes over time. CK was significantly correlated (R = 0.52, P < 0.0001) with C-reactive protein, an acute phase response marker. MVC decreased 14-26% in all groups in response to the run. Eccentric hamstring (EH) torque and concentric quadriceps (CQ) power exhibited the largest deficits, 26 and 24%, respectively, with no effect of treatment. CQ recovered at a faster rate in women than in men. CONCLUSION: Antioxidants appeared to have no effect on exercise-induced increases in muscle damage or recovery, but important sex differences were observed.
Assuntos
Antioxidantes/farmacologia , Músculo Esquelético/lesões , Corrida/fisiologia , Adolescente , Adulto , Antioxidantes/administração & dosagem , Ácido Ascórbico/administração & dosagem , Feminino , Humanos , Perna (Membro) , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/efeitos dos fármacos , Oregon , Vitamina E/administração & dosagemRESUMO
To determine if 6 weeks of supplementation with vitamins E and C could alleviate exercise-induced lipid peroxidation and inflammation, we studied 22 runners during a 50 km ultramarathon. Subjects were randomly assigned to one of two groups: (1) placebos (PL) or (2) antioxidants (AO: 1000 mg vitamin C and 300 mg RRR-alpha-tocopheryl acetate). Blood samples were obtained prior to supplementation (baseline), after 3 weeks of supplementation, 1 h pre-, mid-, and postrace, 2 h postrace and for 6 days postrace. Plasma levels of alpha-tocopherol (alpha-TOH), ascorbic acid (AA), uric acid (UA), F2-isoprostanes (F2-IsoPs), tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and C-reactive protein (CRP) were measured. With supplementation, plasma alpha-TOH and AA increased in the AO but not the PL group. Although F2-IsoP levels were similar between groups at baseline, 28 +/- 2 (PL) and 27 +/- 3 pg/ml (AO), F2-IsoPs increased during the run only in the PL group (41 +/- 3 pg/ml). In PL women, F2-IsoPs were elevated postrace (p <.01), but returned to prerace concentrations by 2 h postrace. In PL men, F2-IsoP concentrations were higher postrace, 2 h postrace, and 1, 2, 3, 4, and 6 days postrace (PL vs. AO group, each p <.03). Markers of inflammation were increased dramatically in response to the run regardless of treatment group. Thus, AO supplementation prevented endurance exercise-induced lipid peroxidation but had no effect on inflammatory markers.
Assuntos
Antioxidantes/farmacologia , Suplementos Nutricionais , Exercício Físico , Inflamação/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Corrida , Adolescente , Adulto , Antioxidantes/administração & dosagem , Ácido Ascórbico/administração & dosagem , Ácido Ascórbico/sangue , Ácido Ascórbico/farmacologia , Proteína C-Reativa/metabolismo , F2-Isoprostanos/sangue , Feminino , Humanos , Inflamação/metabolismo , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/metabolismo , Ácido Úrico/sangue , Vitamina E/administração & dosagem , Vitamina E/farmacologia , alfa-Tocoferol/sangueRESUMO
To determine if 6 weeks of supplementation with antioxidants could alleviate exercise-induced DNA damage, we studied 21 runners during a 50 km ultramarathon. Subjects were randomly assigned to one of two groups: (1) placebos (PL) or (2) antioxidants (AO) (1000 mg vitamin C and 400 IU RRR-alpha-tocopheryl acetate). The comet assay was used to assess DNA damage in circulating leukocytes at selected time points: pre-, mid-, and 2 h postrace and daily for 6 days postrace. All subjects completed the race: run time 7.1 +/- 0.1 h, energy expenditure 5008 +/- 80 kcal for women (n = 10) and 6932 +/- 206 kcal for men (n = 11). Overall, the percentage DNA damage increased at midrace (p <.02), but returned to baseline by 2 h postrace, indicating that the exercise bout induced nonpersistent DNA damage. There was a gender x treatment x time interaction (p <.01). One day postrace, women taking AO had 62% less DNA damage than women taking PL (p <.0008). In contrast, there were no statistically significant differences between the two treatment groups of men at any time point. Thus, endurance exercise resulted in DNA damage as shown by the comet assay and AO seemed to enhance recovery in women but not in men.
Assuntos
Dano ao DNA , Exercício Físico , Anti-Inflamatórios não Esteroides/uso terapêutico , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Peso Corporal , Ensaio Cometa , Dieta , Suplementos Nutricionais , Feminino , Radicais Livres/metabolismo , Humanos , Leucócitos/patologia , Masculino , Placebos , Distribuição Aleatória , Corrida , Fatores Sexuais , Fatores de Tempo , alfa-Tocoferol/metabolismoRESUMO
Oxidative injury and inflammation are intimately involved in the aging process and the development of age-related diseases. To date, most nutritional antiaging strategies have focused solely on the delivery of exogenous antioxidants to combat the negative effects of aging. A promising new strategy is to identify nutrients and phytochemicals that can directly target intrinsic cytoprotective mechanisms, including modulation of the expression of (1) genes involved in the detoxification of xenobiotics, (2) genes involved in the synthesis and regulation of intrinsic antioxidants and antioxidant enzymes, (3) genes involved in the regulation of inflammation, and (4) vitagenes. The purpose of this review is to provide an overview of the age-related changes in gene expression related to oxidative stress, detoxification, and inflammatory processes, and to discuss natural compounds with the potential to oppose age-related changes in gene expression related to these processes, which therefore may be suitable for use in human antiaging research.