RESUMO
Although the combination of chemotherapy and radiotherapy has increased the survival rate of patients with nasopharyngeal carcinoma (NPC), certain patients do not respond well to the treatment and have a poor prognosis. Therefore, novel therapeutic drugs and strategies to improve prognosis of patients with NPC are required. As certain plant extracts can suppress the viability of cancer cells, the present study investigated whether oligonol, a polyphenolic compound primarily found in lychee fruit, exerts anticancer activities in NPC cells. MTT, ELISA and immunoblotting were performed to investigate cell survival, cytokeratin-18 fragment release, and the expression of apoptosis and autophagy markers, respectively. Oligonol decreased the viability of NPC-TW01 and NPC/HK1NPC cell lines. Oligonol increased the protein expression of several apoptosis markers, including cleaved caspase-8 and -3, cleaved PARP and cytokeratin 18 fragment. Moreover, it also increased expression of autophagy markers Beclin 1 and LC3-II, as well as LC3-II/LC3-I ratio in both NPC cell lines. Furthermore, treatment with autophagy inhibitors 3-methyladenine or LY294002 significantly increased oligonol-induced viability inhibition in NPC-TW01 cells. Combined treatment of oligonol + LY294002 reduced LC3-II expression and the LC3II/LC3I ratio while increasing cleaved caspase-8 and -3, cleaved PARP and cytokeratin 18 fragment expression in NPC-TW01 cells. These findings indicated autophagy inhibitors could enhance viability inhibition and apoptotic effects induced by oligonol in NPC cells.
RESUMO
Anthocyanin from black rice was reported to have beneficial effects on diabetes, but the molecular mechanisms are still largely unknown. Black rice cultivated from different regions in Taiwan (Hualien and Changhua) were included in this study. Concentrations of anthocyanin were significantly higher using the ethanol extraction method than those using water; therefore, ethanol extracts from Hualien and Changhua black rice (HBRE and CBRE) were used for further investigation. 2-NBDG glucose uptake analysis revealed that both HBRE and CBRE promote glucose uptake in C2C12 myotubes. The membrane expression levels of GLUT4 and phosphorylation of IRS-1 also had been markedly increased by both HBRE and CBRE, which was in accordance with the glucose uptake results. CBRE did not affect the downstream of IRS-1 but significantly enhanced protein levels of p-AMPK/AMPK. In contrast, HBRE was shown to target various signaling participated in GLUT4 glucose uptake, including PI3K/Akt and the p38 MAPK/ERK. Overall, we demonstrated that anthocyanin-rich extracts from black rice stimulate GLUT4 glucose uptake via upregulation of PI3K/Akt and AMPK/p38 MAPK signaling in C2C12 myotubes. Our findings revealed that anthocyanin-rich black rice might be a promising functional food for the prevention and treatment of insulin resistance and diabetic hyperglycemia.
RESUMO
BACKGROUND: Oligonol® is a low-molecular-weight polyphenol that has biological effects on metabolism in animals. However, little is known about its roles in muscle function and muscle quality in middle-aged and older adults. METHODS: 120 participants were enrolled for study based on 1:1 randomization. Participants in the intervention group were provided 200 mg oligonol® prepared as capsules, and 200 mg placebo (dextrin) was provided in control group. RESULTS: Data from 103 participants (52 in the intervention group and 51 in the control group) were available for analysis. The mean age of all participants was 64.0 ± 8.2 years, and two-thirds of the participants were females. Baseline demographic characteristics, functional assessment, laboratory data and muscle parameters were similar between groups. Hip circumference decreased (p = 0.009) during the study period, and the 6-m walking speed increased (p = 0.001) in women in the intervention group. In contrast, 6-m walking speed, 6-min walking distance and handgrip strength were significantly improved in men in the intervention group, but increased total body fat percentage (p = 0.038) and decreased mid-thigh cross-muscle area (CMA) (p = 0.007) were observed in the control group. Compared to the control group, the 12-week interval change in the percentage of mid-thigh CMA was maintained in men in the intervention group but was significantly decreased in the control group (p = 0.03, 95% CI:0.002-0.05). CONCLUSIONS: Oligonol supplementation (200 mg per day) significantly improved physical performance and muscle mass in men. Further studies are needed to confirm the potential favorable effects of oligonol® supplementation.
RESUMO
(-)-Epigallocatechin-3-gallate (EGCG), the most abundant catechin component in green tea, has been reported to attenuate age-associated insulin resistance, lipogenesis and loss of muscle mass through restoring Akt activity in skeletal muscle in our previous and present studies. Accumulated data has suggested that polyphenols regulate signaling pathways involved in aging process such as inflammation and oxidative stress via modulation of miRNA expression. Here we found that miRNA-486-5p was significantly decreased in both aged senescence accelerated mouse-prone 8 (SAMP8) mice and late passage C2C12 cells. Thus, we further investigated the regulatory effect of EGCG on miRNA-486-5p expression in age-regulated muscle loss. SAMP8 mice were fed with chow diet containing without or with 0.32% EGCG from aged 32 weeks for 8 weeks. Early passage (<12 passages) and late passage (>30 passages) of C2C12 cells were treated without or with EGCG at concentrations of 50 µM for 24h. Our data showed that EGCG supplementation increased miRNA-486-5p expression in both aged SAMP8 mice and late passage C2C12 cells. EGCG stimulated AKT phosphorylation and inhibited FoxO1a-mediated MuRF1 and Atrogin-1 transcription via up-regulating the expression of miR-486 in skeletal muscle of 40-wk-old SAMP8 mice as well as late passage C2C12 cells. In addition, myostatin expression was increased in late passage C2C12 cells and anti-myostatin treatment upregulated the expression of miR-486-5p. Our results identify a unique mechanism of a dietary constituent of green tea and suggest that use of EGCG or compounds derived from it attenuates age-associated muscle loss via myostatin/miRNAs/ubiquitin-proteasome signaling.
Assuntos
Envelhecimento/metabolismo , Catequina/análogos & derivados , Regulação da Expressão Gênica/efeitos dos fármacos , MicroRNAs/metabolismo , Proteínas Musculares/biossíntese , Atrofia Muscular/metabolismo , Miostatina/biossíntese , Envelhecimento/efeitos dos fármacos , Envelhecimento/genética , Envelhecimento/patologia , Animais , Catequina/química , Catequina/farmacologia , Linhagem Celular , Camundongos , Camundongos Transgênicos , MicroRNAs/genética , Proteínas Musculares/genética , Atrofia Muscular/genética , Atrofia Muscular/patologia , Miostatina/genética , Chá/químicaRESUMO
The senescence-accelerated mouse (SAM) prone 8 (SAMP8) has been demonstrated for muscular aging research including sarcopenia, but its underlying mechanisms remain scarce. Physiological indices and histology of skeletal muscle were analyzed in SAMP8 mice at different ages. SAMP8 mice exhibited typical features of sarcopenia at 40 weeks of age and were more time-efficient than that at 88 weeks of age in bothSAM resistant 1 (SAMR1) and C57BL/6 mice. Increase in FoxO3a-mediated transcription of Atrogin-1 and MuRF1 and decrease in phosphorylated mTOR/P70s6k were observed at week 40 in SAMP8 mice. High oxidative stress was observed from week 24 and persisted to week 40 in SAMP8 mice evidenced by overexpression of protein carbonyl groups and reduced activities of CAT, SOD, and GPx. Downregulation of genes involved in mitochondrial biogenesis (PGC-1α, Nrf-1, Tfam, Ndufs8, and Cox5b) and in mitochondrial dynamics fission (Mfn2 and Opa1) from week 24 indicated dysregulation of mitochondrial quality control in SAMP8 mice. Impaired autophagic flux was observed in SAMP8 mice evidenced by elevated Atg13 and LC3-II accompanied with the accumulation of P62 and LAMP1. Increases in inflammatory factors (IL-6 and MCP-1), adipokines (leptin and resistin), and myostatin in serum at week 32 and decline in Pax7+ satellite cell resided next to muscle fibers at week 24 implied that muscle microenvironment contributed to the progression of sarcopenia in SAMP8 mice. Our data suggest that early alterations of mitochondrial quality control and autophagic flux worsen muscle microenvironment prior to the onset of sarcopenia.
Assuntos
Envelhecimento , Mitocôndrias , Sarcopenia , Animais , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/metabolismo , Sarcopenia/metabolismoRESUMO
The prevalence of cognitive impairments and circadian disturbances increases in the elderly and Alzheimer's disease (AD) patients. This study investigated the effects of a standardized extract of Asparagus officinalis stem, ETAS® on cognitive impairments and circadian rhythm status in senescence-accelerated mice prone 8 (SAMP8). ETAS® consists of two major bioactive constituents: 5-hydroxymethyl-2-furfural (HMF), an abundant constituent, and (S)-asfural, a novel constituent, which is a derivative of HMF. Three-month-old SAMP8 male mice were divided into a control, 200 and 1000 mg/kg BW ETAS® groups, while senescence-accelerated resistant mice (SAMR1) were used as the normal control. After 12-week feeding, ETAS® significantly enhanced cognitive performance by an active avoidance test, inhibited the expressions of amyloid-beta precursor protein (APP) and BACE-1 and lowered the accumulation of amyloid ß (Aß) in the brain. ETAS® also significantly increased neuron number in the suprachiasmatic nucleus (SCN) and normalized the expressions of the melatonin receptor 1 (MT1) and melatonin receptor 2 (MT2). In conclusion, ETAS® enhances the cognitive ability, inhibits Aß deposition and normalizes circadian rhythm signaling, suggesting it is beneficial for preventing cognitive impairments and circadian rhythm disturbances in aging.
Assuntos
Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Asparagus/química , Ácido Aspártico Endopeptidases/metabolismo , Extratos Vegetais/farmacologia , Receptor MT1 de Melatonina/metabolismo , Receptor MT2 de Melatonina/metabolismo , Secretases da Proteína Precursora do Amiloide/genética , Animais , Ácido Aspártico Endopeptidases/genética , Ritmo Circadiano , Cognição/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos , Extratos Vegetais/química , Receptor MT2 de Melatonina/genéticaRESUMO
SCOPE: Oligonol has been shown to moderate mitochondrial biogenesis, protein synthesis, and protein degradation in diabetic mice in a previous study. It is therefore hypothesized that oligonol alleviated sarcopenia by regulating pathways involved in protein turnover and mitochondrial quality. METHODS AND RESULTS: The 32-week-old senescence-accelerated mouse prone 8 (SAMP8) mice are fed with chow diet containing 200 mg kg-1 oligonol for 8 weeks. Oligonol supplementation increased skeletal muscle mass, cross-sectional areas, and grip strength in SAMP8 mice. Oligonol increased phosphorylation of AKT/mTOR/p70sk6, inhibited nuclear localization of FoxO3a and NFκB, and decreased transcription of MuRF-1 and MAFbx in skeletal muscle of SAMP8 mice. Downregulation of mitochondrial biogenesis genes (PGC-1α and Tfam) and mitochondrial fusion genes (Mfn2 and Opa1), loss of PINK1, overexpression of Atg13, LC3-II, and p62, and abundant accumulation of autophagosomes and lysosomes in skeletal muscle of SAMP8 mice are limited by oligonol. Furthermore, oligonol reduced expression of released cytochrome c and cleaved caspase-9 in skeletal muscle of SAMP8 mice. CONCLUSION: Regulating pathways involved in protein synthesis and degradation, mitochondrial biogenesis, mitochondrial fusion/fission, autophagy, and mitochondria-dependent apoptosis by oligonol contribute to positive protein turnover and mitochondrial quality, thus increasing muscle mass and strength in SAMP8 mice.
Assuntos
Catequina/análogos & derivados , Mitocôndrias Musculares/efeitos dos fármacos , Proteínas Musculares/metabolismo , Fenóis/farmacologia , Sarcopenia/tratamento farmacológico , Envelhecimento/fisiologia , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Catequina/farmacologia , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Proteína Forkhead Box O3/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas de Grupo de Alta Mobilidade/genética , Proteínas de Grupo de Alta Mobilidade/metabolismo , Camundongos Endogâmicos , Mitocôndrias Musculares/metabolismo , Dinâmica Mitocondrial/efeitos dos fármacos , Proteínas Musculares/genética , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Ligases SKP Culina F-Box/genética , Proteínas Ligases SKP Culina F-Box/metabolismo , Sarcopenia/metabolismo , Sarcopenia/patologiaRESUMO
Epstein-Barr virus (EBV) infection is associated with B cell lymphomas in humans. The latent membrane protein 1 (LMP-1) of EBV constitutively activates the JAK/STAT signaling pathway and contributes to the proliferation of EBV-infected primary human B lymphocytes. Thus, targeting LMP1-induced JAK/STAT signaling may prove effective in treating B-cell lymphomas. The extract of the fruiting body of Antrodia cinnamomea, has been reported to have cytotoxicity on blood cancer cells. Here, we report that the bioactivity of antcin H, an analog of the JAK2 inhibitor zhankuic acid A (ZAA), inhibits LMP1-induced JAK/STAT related signaling and induces lymphoma cell line apoptosis. Moreover, antcin H enhances low-dose methotrexate (MTX) cytotoxicity against lymphoma cells. Treatment of antcin H with low-dose MTX significantly suppressed tumor growth and prolonged the survival of tumor-bearing mice. Our findings indicate antcin H as a potential therapeutic agent for the treatment of EBV-infected cancer cells.
Assuntos
Antineoplásicos/farmacologia , Infecções por Vírus Epstein-Barr/complicações , Ergosterol/análogos & derivados , Herpesvirus Humano 4/genética , Inibidores de Janus Quinases/farmacologia , Linfoma/etiologia , Triterpenos/farmacologia , Proteínas da Matriz Viral/genética , Animais , Apoptose/efeitos dos fármacos , Antígenos CD40/metabolismo , Linhagem Celular Tumoral , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Infecções por Vírus Epstein-Barr/virologia , Ergosterol/farmacologia , Humanos , Janus Quinases/metabolismo , Camundongos , Fosforilação , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Skeletal muscle, a highly metabolic tissue, is particularly vulnerable to increased levels of saturated free fatty acids (FFAs). The role of autophagy in saturated FFAs-induced cellular senescence and insulin resistance in skeletal muscle remains unclear. Therefore, the present study was aimed to explore autophagic flux in cellular senescence and insulin resistance induced by palmitate in muscle cells, and whether resveratrol limited these responses. Our results showed that palmitate induced cellular senescence in both myoblasts and myotubes. In addition, palmitate delayed differentiation in myoblasts and inhibited expression of insulin-stimulated p-AKTSer473 in myotubes. The accumulations of autophagosome assessed by tandem fluorescent-tagged LC3 demonstrated that autophagic flux was impaired in both palmitate-treated myoblasts and myotubes. Resveratrol protected muscle cells from palmitate-induced cellular senescence, apoptosis during differentiation, and insulin resistance via ameliorating autophagic flux. The direct influence of autophagic flux on development of cellular senescence and insulin resistance was confirmed by blockage of autophagic flux with chloroquine. In conclusion, impairment of autophagic flux is crucial for palmitate-induced cellular senescence and insulin resistance in muscle cells. Restoring autophagic flux by resveratrol could be a promising approach to prevent cellular senescence and ameliorate insulin resistance in muscle.
Assuntos
Autofagia/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Resistência à Insulina , Células Musculares/efeitos dos fármacos , Palmitatos/efeitos adversos , Resveratrol/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Insulina/metabolismo , Camundongos , Células Musculares/citologia , Células Musculares/metabolismo , Fibras Musculares Esqueléticas/citologia , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/citologia , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
The clear mechanism of moderate exercise training (Ex) in attenuating muscle loss remains elusive in diabetes. We investigated the effects of moderate exercise training on diabetes-induced nuclear factor-κB (NF-κB) activation and mitochondrial dysfunction. Skeletal muscle size and atrophy signaling pathways were examined in type 2 diabetic db/db mice with or without moderate exercise training (5.2 m/min, 1 h/day, and 5 days/week for a total of 8 weeks). Exercise training decreased serum leptin, MCP-1, and resistin levels in db/db+Ex mice, but it did not reduce symptoms of insulin resistance including hyperglycemia, hyperinsulinemia, and impaired glucose tolerance. Moderate exercise training prevented the loss of muscle mass of tibialis anterior and gastrocnemius muscles in db/db+Ex mice. The average cross-sectional area of tibialis anterior muscle was increased significantly in db/db+Ex mice compared with untrained mice (830.6 vs. 676.5 µm2). Inhibition of MuRF-1 and K48-linked polyubiquitination was observed in db/db+Ex mice. Exercise training reduced activation of IκBα/NF-κB pathway and lowered IL-6, TNFα, F4/80 (macrophage marker) at mRNA level in db/db+Ex mice compared with untrained mice. Exercise training did not influence FoxO3a phosphorylation and its upstream regulator Akt. Exercise training increased SIRT1 and PGC1α expression and AMPKα and mitochondrial complex IV activities and upregulated genes involved in mitochondrial biogenesis/function including Nrf1, Tfam, and mitochondrial complexes I-V. In conclusion, moderate exercise training inhibits NFκB signaling and activates SIRT1-AMPKα-PGC1α axis, thereby attenuating type 2 diabetes-related muscle atrophy.
RESUMO
Phytonutrients may play important roles in human health and yet only recently a few studies have described phytonutrient consumption patterns, using data obtained from daily consumption methods. We aimed to estimate the phytonutrient content in Taiwanese diets and analyzed main food sources of 10 major phytonutrients. In this study, food items and dietary data gathered with the 24-hour dietary recall from 2908 participants in the 2005-2008 Nutrition and Health Survey in Taiwan were used to create a food phytonutrient database with 933 plant-based foods through integrating database, literature search, and chemical analysis and to appraise phytonutrient consumption status of participants. SUDAAN (Survey Data Analysis) was used for generating weighted phytonutrient intake estimates and for statistical testing. In Taiwanese adults, â¼20% met the recommended number of servings for fruits and 30% met that for vegetables from the Taiwan Food-Guide recommendations. However, only 7.4% consumed the recommended numbers for both fruits and vegetables. Those meeting the recommendations tended to be older and with more females compared with those who did not. Phytonutrient intake levels were higher in meeters than nonmeeters. More than 60% of α-carotene, lycopene, hesperetin, epigallocatechin 3-gallate, and isoflavones came from a single phytonutrient-specific food source. In addition, sweet potato leaf, spinach, and water spinach were among the top three sources of multiple phytonutrients. Cross-comparison between this study and two previous studies with similar methodology showed higher mean levels of lycopene and quercetin in the United States, anthocyanidins in Korea, and lutein and zeaxanthin in Taiwan. The Taiwanese phytonutrient pattern is different from that of the Korean and American. It would be interesting to relate phytonutrient patterns to health profiles in the future.
Assuntos
Comportamento Alimentar , Frutas , Compostos Fitoquímicos , Verduras , Adulto , Idoso , Idoso de 80 Anos ou mais , Dieta , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos Nutricionais , Taiwan/epidemiologia , Adulto JovemRESUMO
In this study, a large Clitocybe maxima mycelium biomass was obtained by submerged cultivation under optimal conditions. Three test samples from lyophilized mycelia, including hot water extract (CW) and elutes from solvents with different polarity (CA and CB), were combined and used to explore antioxidant and antihyper-lipidemic activities in vitro and in vivo. The CA group showed the highest DPPH free radical scavenging activity and iron-reducing capability at concentrations of 6.0% and 3.0% (w/v), respectively. Further, the CA group showed the highest glutathione peroxidase and superoxide dismutase activities at a dose of 0.25 mg/kg body weight (CA-0.25 group) in all hyperlipidemic hamsters tested. Serum lipid levels (apart from high-density lipoprotein cholesterol levels) of hamsters in the CA-0.25 group were lower than those of hamsters in the negative control group in antihy-perlipidemic tests. Therefore, we believe that extracts from C. maxima mycelia are rich reservoirs of antioxidant and antihyperlipidemic activities.
Assuntos
Agaricales/crescimento & desenvolvimento , Antioxidantes/isolamento & purificação , Hipolipemiantes/isolamento & purificação , Agaricales/química , Agaricales/metabolismo , Animais , Antioxidantes/farmacologia , Biomassa , Cricetinae , Feminino , Liofilização , Hipolipemiantes/farmacologiaRESUMO
Stimulation of the ubiquitin-proteasome pathway-especially E3 ubiquitin ligases Atrogin-1 and MuRF1-is associated with muscle loss in diabetes. Elevated lipid metabolites impair myogenesis. Oligonol, a low molecular weight polyphenol derived from lychee, exhibited anti-diabetic and anti-obesity properties, suggesting it could be a proper supplement for attenuating muscle loss. Dietary (10 weeks) oligonol supplementation (20 or 200 mg/kg diet) on the skeletal muscle loss was investigated in diabetic db/db mice. Transcription factors NF-κB and FoxO3a involved in regulation of Atrogin-1 and MuRF1 were also investigated. Attenuation of muscle loss by oligonol (both doses) was associated with down-regulation of Atrogin-1 and MuRF1 gene expression. Oligonol supplementation decreased NF-κB expression in the nuclear fraction compared with db/db mice without oligonol supplement. Upregulation of sirtuin1 (SIRT1) expression prevented FoxO3a nuclear localization in db/db mice supplemented with oligonol. Marked increases in AMPKα activity and Ppara mRNA expression leading to lower lipid accumulation by oligonol provided additional benefits for attenuating muscle loss. Oligonol limited palmitate-induced senescent phenotype and cell cycle arrest and suppressed Atrogin-1 and MuRF1 mRNA expression in palmitate-treated C2C12 muscle cells, thus contributing to improving the impaired myotube formation. In conclusion, oligonol-mediated downregulation of Atrogin-1 and MuRF1 gene expression alleviates muscle loss and improves the impaired myotube formation, indicating that oligonol supplementation may be useful for the attenuation of myotube loss.
Assuntos
Catequina/análogos & derivados , Diabetes Mellitus Experimental/fisiopatologia , Litchi/química , Proteínas Musculares/antagonistas & inibidores , Fenóis/farmacologia , Proteínas Ligases SKP Culina F-Box/antagonistas & inibidores , Sarcopenia/tratamento farmacológico , Proteínas com Motivo Tripartido/antagonistas & inibidores , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Animais , Catequina/farmacologia , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Proteína Forkhead Box O3/genética , Proteína Forkhead Box O3/metabolismo , Frutas/química , Regulação da Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Peso Molecular , Proteínas Musculares/genética , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Polifenóis/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Ligases SKP Culina F-Box/genética , Sirtuína 1/genética , Sirtuína 1/metabolismo , Proteínas com Motivo Tripartido/genética , Ubiquitina-Proteína Ligases/genéticaRESUMO
Rodent animal models take at least 18months to develop aging phenotypes for researchers to investigate the mechanism of age-related metabolic complications. Senescence-accelerated mouse prone 8 (SAMP8) shortens the process of aging and may facilitate an alternative model for studying age-related insulin resistance. The short-lived strain SAMP8 and two long-lived strains SAM resistant 1 (SAMR1) mice and C57BL/6 mice at 12 (young) and 40weeks old (old) were used in the present study. Glucose tolerance test, histology and signaling pathways involved in lipid metabolism in adipose tissue and liver and key components of insulin signaling pathway in the skeletal muscle were determined in these three strains. We found that short-lived SAMP8 mice developed symptoms of insulin resistance including hyperglycemia, hyperinsulinemia, and impaired glucose tolerance in association with adipocyte hypertrophy and ectopic lipid accumulation in liver and muscle at 40-wk.-old. Significantly increased serum IL-6, leptin, and resistin levels and adipogenic transcription factor PPARγ and macrophage marker F4/80 mRNA expression in adipose tissues were observed in old SAMP8 mice, compared with that in young SAMP8 mice. Marked increases in SREBP1 and PPARγ and a decrease in PPARα at mRNA level in accordance with activation of mTOR/Akt pathway were contributed to hepatic lipid accumulation in old SAMP8 mice. Down-regulation of insulin signaling pathway including IRß, IRS1, and AS160 at protein level in skeletal muscle was observed in old SAMP8 mice. At 40-wk.-old, both long-lived SAMR1 and C57BL/6 mice have not been fully developed age-related metabolic disorders including insulin resistance and visceral fat expansion in line with fewer defects in lipid metabolism and skeletal muscle insulin signaling pathway. In conclusion, our data suggest the suitability of the SAMP8 mice as a model for studying age-related metabolic complications.
Assuntos
Envelhecimento/sangue , Envelhecimento/metabolismo , Senescência Celular , Dislipidemias/metabolismo , Metabolismo Energético , Resistência à Insulina , Adipócitos/metabolismo , Adipócitos/patologia , Adipocinas/sangue , Fatores Etários , Envelhecimento/genética , Animais , Biomarcadores/sangue , Glicemia/metabolismo , Senescência Celular/genética , Modelos Animais de Doenças , Dislipidemias/sangue , Dislipidemias/genética , Dislipidemias/patologia , Metabolismo Energético/genética , Regulação da Expressão Gênica , Genótipo , Mediadores da Inflamação/sangue , Insulina/sangue , Gordura Intra-Abdominal/metabolismo , Gordura Intra-Abdominal/patologia , Lipídeos/sangue , Fígado/metabolismo , Camundongos Endogâmicos AKR , Camundongos Endogâmicos C57BL , Músculo Esquelético/metabolismo , Fenótipo , Transdução de Sinais , Fatores de TempoRESUMO
Herein, we report the oncolytic activity of cationic, one-dimensional (1D) fibril assemblies formed from coil-sheet poly(L-lysine)-block-poly(L-threonine) (PLL-b-PLT) block copolypeptides for cancer therapy. The 1D fibril assemblies can efficiently interact with negatively charged cellular and mitochondrial membranes via electrostatic interactions, leading to necrosis via membrane lysis and apoptosis via the mitochondria-lytic effect. The concept is analogous to that of 1D drug carriers that exhibit enhanced cell penetration. In comparison to free PLL chains, PLL-b-PLT fibril assemblies exhibit selective cytotoxicity toward cancer cells, low hemolysis activity, enhanced membranolytic activity, and a different apoptosis pathway, which may be due to differences in the peptide-membrane interactions. Antitumor studies using a metastatic LL2 lung carcinoma model indicate that the fibril assemblies significantly inhibited tumor growth, improved survival in tumor-bearing mice and suppressed lung metastasis without obvious body weight loss. An additive efficacy was also observed for treatment with both PLL-b-PLT and cisplatin. These results support the feasibility of using 1D fibril assemblies as potential apoptotic anticancer therapeutics. STATEMENT OF SIGNIFICANCE: We report that cationic, one-dimensional (1D) fibril assemblies formed by coil-sheet poly(L-lysine)-block-poly(L-threonine) (PLL-b-PLT) block copolypeptides exhibited potent anticancer activity by enhancing membranolysis. The 1D fibril assemblies can efficiently interact with negatively charged cellular and mitochondrial membranes via electrostatic interactions, leading to necrosis via membrane lysis and apoptosis via mitochondria-lytic effect. Moreover, the fibril assemblies exhibited low hemolytic activity and selective cytotoxicity toward cancer cell, which is advantageous as compared to PLL and most antimicrobial/anticancerous peptides. This study provides a new concept of using cationic, 1D fibril assemblies for cancer therapy.
Assuntos
Antineoplásicos , Peptídeos Penetradores de Células , Cisplatino , Neoplasias Pulmonares/tratamento farmacológico , Membranas Mitocondriais/metabolismo , Neoplasias Experimentais/tratamento farmacológico , Polilisina , Células A549 , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Peptídeos Penetradores de Células/química , Peptídeos Penetradores de Células/farmacocinética , Peptídeos Penetradores de Células/farmacologia , Cisplatino/química , Cisplatino/farmacocinética , Cisplatino/farmacologia , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Membranas Mitocondriais/patologia , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Polilisina/química , Polilisina/farmacocinética , Polilisina/farmacologiaRESUMO
AIM: To compare a dipeptide- and tripeptide-based enteral formula with a standard enteral formula for tolerance and nutritional outcomes in abdominal surgery patients. METHODS: A retrospective study was performed to assess the differences between a whole-protein formula (WPF) and a dipeptide- and tripeptide-based formula (PEF) in clinical outcomes. Seventy-two adult intensive care unit (ICU) patients with serum albumin concentrations less than 3.0 g/dL were enrolled in this study. Patients were divided into two groups (WPF group = 40 patients, PEF group = 32 patients). The study patients were fed for at least 7 d, with ≥ 1000 mL of enteral formula infused on at least 3 of the days. RESULTS: The mean serum albumin level on postoperative day (POD) 10, prealbumin levels on POD-5 and POD-10, and total lymphocyte count on POD-5 were significantly higher in the PEF group compared to those in the WPF group (P < 0.05). The average maximum gastric residual volume of the PEF patients during their ICU stays was significantly lower than that for WPF patients. CONCLUSION: Dipeptide- and tripeptide-based enteral formulas are more efficacious and better tolerated than whole-protein formulas.
RESUMO
SCOPE: An elevated intracellular lipid contents resulted from lipid oversupply links obesity to insulin resistance. Flavanol-rich lychee fruit extract, oligonol, exhibited anti-obesity property in vitro and in vivo; however, the effects of oligonol on peripheral lipid metabolism and insulin sensitivity have not been fully investigated. We hypothesized that oligonol alleviated insulin resistance via decreasing intracellular lipid contents in peripheral tissues. METHODS AND RESULTS: Dietary oligonol supplementation (20 or 200 mg/kg bw) reduced glucose and insulin levels, improved oral glucose tolerance, and suppressed inflammatory markers, MCP-1 and IL-6, in High-Fat diet (HFD) induced obese mice. Marked decreases in subcutaneous and visceral fat area, adipocyte size, and adipocyte released hormones including leptin and resistin by high-dose oligonol treatment were associated with downregulation of PPARγ gene expression. Significantly reduced intrahepatocellular lipid contents and hepatic triglyceride levels by oligonol (both doses) were associated with downregulation of mTOR/SREBP-1-mediated de novo lipogenesis. In skeletal muscle, oligonol enhanced Sirtuin1 protein expression and AMPKα activation, consequently resulted in reductions of intramuscular lipid contents and triglyceride levels and restoration of IRS-1 and AS160 phosphorylation. CONCLUSION: Oligonol reduced intracellular lipid contents in liver and skeletal muscle and suppressed inflammatory markers, thereby alleviating HFD-induced insulin resistance.
Assuntos
Catequina/análogos & derivados , Resistência à Insulina , Litchi/química , Fígado/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Fenóis/farmacologia , Animais , Catequina/farmacologia , Dieta Hiperlipídica/efeitos adversos , Frutas/química , Insulina/metabolismo , Lipogênese/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Músculo Esquelético/metabolismo , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Serina-Treonina Quinases TOR/metabolismoRESUMO
BACKGROUND AND OBJECTIVES: Certain patients who undergo proximal jejunum resection are unable to undergo primary anastomosis and require exteriorization of the proximal jejunum. These patients usually have major problems with short bowel due to the high output of the stoma. The output of a proximal jejunostomy contains abundant amounts of enzymes and electrolytes. Therefore, it is a feasible approach to re-infuse jejunostomy output to regain homeostasis. To evaluate the effects of proximal jejunostomy output reinfusion into the distal small bowel for patients with short bowel syndrome, and to determine whether reinfusion could avoid long-term parenteral nutrition (PN). METHODS AND STUDY DESIGN: PN was initiated immediately after surgery. When patients started enteral nutrition, we started the proximal jejunostomy output reinfusion protocol. Proximal jejunostomy output reinfusion was performed by the patients, and continued by them after discharge. When proximal jejunostomy output reinfusion could be performed stably, PN was stopped. RESULTS: The median length of the proximal jejunum was 20 cm and of the distal small bowel was 77.5 cm in patients who could stably receive proximal jejunostomy output reinfusion alone. Three patients did not require home PN; they only required PN during hospitalization. Four patients successfully underwent stoma takedown with intestinal anastomosis after 6-7 months without any nutritional or metabolic complications. CONCLUSION: Short bowel syndrome patients with an adequate length of small bowel and functional colon could avoid long-term PN by receiving reinfusion of proximal jejunostomy output into the distal small bowel.
Assuntos
Intestino Delgado/cirurgia , Jejunostomia , Estado Nutricional , Nutrição Parenteral/estatística & dados numéricos , Síndrome do Intestino Curto/cirurgia , Idoso , Idoso de 80 Anos ou mais , Anastomose Cirúrgica , Feminino , Humanos , Jejuno/cirurgia , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Hyperglycemia, increased inflammatory responses, and dysregulation of mitochondrial function accompanied by type 2 diabetes may eventually lead to kidney damage. We examined the protective effects of oligonol, a low-molecular-weight polyphenol derived from lychee fruit and green tea, on kidney damage in diabetic db/db mice. Dietary oligonol supplementation lowered glucose and insulin levels and improved oral glucose tolerance. Oligonol attenuated serum resistin and IL-6 levels and reduced glomerular hypertrophy and mesangial matrix expansion caused by diabetes. Oligonol reduced activation of nuclear factor-kappa B (NF-κB) and p38 mitogen-activated protein kinase. Suppressed renal oxidative stress by oligonol was associated with stimulated sirtuin1 expression and restored AMP-activated kinase protein α activity, mitochondrial DNA copy number, and mitochondrial biogenesis associated genes including nuclear respiratory factor 1 and mitochondrial transcription factor A. In conclusion, oligonol reduced fasting glucose level, improved insulin sensitivity, suppressed inflammatory responses, and upregulated metabolic regulators involved in mitochondrial biogenesis, thereby leading to protection against diabetes-induced kidney damage.