Piceatannol and Its Metabolite,Isorhapontigenin, Induce SIRT1 Expression in THP-1 Human Monocytic Cell Line

Piceatannol is a phytochemical that is present in large amounts in passion fruit (Passiflora edulis) seeds, and is an analog of resveratrol. Recently, the absorption and metabolism of piceatannol were investigated in rats, and isorhapontigenin, O-methyl piceatannol, was detected as a piceatannol metabolite in rat plasma. To elucidate the function of piceatannol and its metabolites, we investigated the expression of sirtuin 1 (SIRT1) in THP-1 monocytic cells after treatment with piceatannol and its metabolites, and compared their effects with those of resveratrol and its metabolites. Piceatannol and resveratrol upregulated the expression levels of SIRT1 mRNA and SIRT1 protein. An extract of passion fruit seeds, which contained high levels of piceatannol, also upregulated SIRT1 mRNA expression. As for the metabolites, isorhapontigenin upregulated SIRT1 mRNA expression, whereas resveratrol glucuronides and sulfate did not affect SIRT1 expression. These findings indicate that after intake of piceatannol, not only piceatannol itself, but also its metabolite, isorhapontigenin, contributed to the upregulation of SIRT1 expression.     

白藜芦醇通过上调沉默信息调节因子1调节香烟提取物诱导心肌线粒体产生活性氧簇的机制

目的探讨沉默信息调节因子1（SIRT1）调节香烟提取物（CSE）诱导心肌线粒体产生活性氧簇（ROS）的机制及白藜芦醇（Res）心肌保护作用。方法 H9C2细胞分5组：C组（对照组）、二甲亚砜组（DMSO溶剂对照组）、CSE组（CSE刺激组）、CSE＋Res组、Res组。采用Taqman探针荧光定量PCR检测各组SIRTI的mRNA表达、Weston Blot检测各组细胞SIRTI蛋白表达、荧光分光光度计检测细胞线粒体膜电位、荧光微量平板法检测不同浓度CSE刺激H9C2细胞产生ROS的变化、特异性荧光探针CM-H2DCFDA检测活细胞内ROS变化。结果与C组相比,CSE组SIRT1mRNA及蛋白质表达显著降低,ROS表达显著增强。与CSE组相比,CSE＋Res组SIRT1mRNA及蛋白质表达升高,ROS表达显著减少。随CSE刺激浓度增加,线粒体膜电位降低,ROS产生增加。提前给予Res可使线粒体膜电位升高,ROS产生减少。结论 Res可通过刺激SIRT1的表达而抑制CSE诱导的心肌细胞线粒体功能受损、ROS的释放,这可能是其吸烟相关慢性阻塞性肺疾病诱导的心脏氧化应激损伤中发挥心脏保护作用的机制之一。     

Resveratrol protects intestinal epithelial cells against radiation-induced damage by promoting autophagy and inhibiting apoptosis through SIRT1 activation

Intrinsic autophagy is important for the maintenance of intestinal homeostasis and intestinal regeneration. Ionizing radiation suppresses intrinsic autophagy and reduces damage-induced regeneration in the intestine, resulting in intestinal injury. Resveratrol, a sirtuin 1 (SIRT1) agonist, promotes autophagy and exerts radioprotective effect. In this study, the protective effect of resveratrol against radiation-induced intestinal injury and its potential mechanism were investigated. Intestinal epithelial cells (IEC-6) were exposed to 10 Gy ionizing radiation and resveratrol (0.1–40.0 μM). Cell viability was investigated using Cell Counting Kit 8 (CCK8), apoptosis was observed by Annexin V-fluorescein isothiocyanate/propidium iodide (PI) staining and flow cytometry, and the expression of apoptotic and autophagic proteins was determined by western blotting. Resveratrol exerted a high toxicity against IEC-6 cells, but at low concentrations, it inhibited ionizing radiation-induced apoptosis. Resveratrol increased SIRT1 expression after irradiation and inhibited ionizing radiation-induced p53 acetylation and pro-apoptotic protein, Bax, expression. Furthermore, resveratrol promoted autophagy via the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway, thereby protecting IEC-6 cells against radiation-induced damage. These results suggest that resveratrol reduces radiation-induced IEC-6 cell damage by inhibiting apoptosis and promoting autophagy via the activation of SIRT1, and that the PI3K/AKT/mTOR signaling pathway is involved in the induction of autophagy.     

Potential of Polyphenols to Restore SIRT1 and NAD+ Metabolism in Renal Disease

SIRT1 is an NAD⁺-dependent class III histone deacetylase that is abundantly expressed in the kidney, where it modulates gene expression, apoptosis, energy homeostasis, autophagy, acute stress responses, and mitochondrial biogenesis. Alterations in SIRT1 activity and NAD⁺ metabolism are frequently observed in acute and chronic kidney diseases of diverse origins, including obesity and diabetes. Nevertheless, in vitro and in vivo studies and clinical trials with humans show that the SIRT1-activating compounds derived from natural sources, such as polyphenols found in fruits, vegetables, and plants, including resveratrol, quercetin, and isoflavones, can prevent disease and be part of treatments for a wide variety of diseases. Here, we summarize the roles of SIRT1 and NAD⁺ metabolism in renal pathophysiology and provide an overview of polyphenols that have the potential to restore SIRT1 and NAD⁺ metabolism in renal diseases.     

Resveratrol increases brown adipose tissue thermogenesis markers by increasing SIRT1 and energy expenditure and decreasing fat accumulation in adipose tissue of mice fed a standard diet

Purpose

Adipose tissue is central to the regulation of energy balance. Two functionally different fat pads are present in mammals: white adipose tissue, the primary site of triglyceride storage, and brown adipose tissue (BAT), which is specialized in heat production. In this context, new strategies capable of modulating the development and function of white and BAT become relevant. In the present study, we analyzed the influence of resveratrol (sirtuin activator) on energy balance and the expression of thermogenesis markers.

Methods

Mice were divided into two groups: standard diet (ST) and standard diet plus resveratrol (ST + RSV).

Results

After 2 months of treatment, ST + RSV mice presented significantly decreased fat accumulation in adipose tissue, with diminished total cholesterol and glucose plasma levels. Additionally, increased oxygen consumption was observed in ST + RSV group. Analyses of mRNA of thermogenesis-related genes showed significant increase in UCP1, SIRT1, PTEN and BMP-7 expression in BAT.

Conclusion

Our data suggest that improved metabolism produced by oral administration of resveratrol is, at least in part, associated with increased thermogenesis followed by high expression of UCP1 and SIRT1, which can mediate higher energy expenditure and decreased fat accumulation in adipose tissue.     

Protective effects of resveratrol against streptozotocin-induced diabetes in rats by modulation of visfatin/sirtuin-1 pathway and glucose transporters

Abstract

This experiment was aimed at elucidating the protective effect of resveratrol against diabetes. Forty male Wistar albino rats were allocated into four groups: the control and streptozotocin (STZ)-induced diabetes groups were treated either with placebo (1?ml/kg, i.p.) or resveratrol (20?mg/kg, i.p.) for 8 weeks. Body weight, blood glucose and serum malondialdehyde (MDA) concentrations were monitored. At the end of the experimental period, expression levels of visfatin, sirtuin-1 (SIRT1) and glucose transporters (GLUTs, 2 and 4) were measured in skeletal muscle and pancreas by Western blotting. The resveratrol treatment partially compensated for body weight loss and alleviated hyperglycaemia and returned serum MDA concentrations to the control group levels. Data suggest that supplementation may reduce the severity of diabetes and its complications through suppressing oxidative stress and increasing potential to internalise glucose by extrahepatic tissues.     

Formyl Peptide Receptor (FPR)1 Modulation by Resveratrol in an LPS-Induced Neuroinflammatory Animal Model

Among therapeutic approaches that have been investigated, targeting of receptors implicated in managing neuroinflammation has been described. One such family of receptors comprises the formyl peptide receptors (FPRs) whose ligands could play a role in host defense. The murine FPR gene family includes at least six members while in humans there are only three. The two most important members are the Fpr1 and Fpr2. Fpr1encodes murine FPR1, which is considered the murine orthologue of human FPR. Resveratrol, a non-flavonoid polyphenol rich in red wine and grapes, apart from its beneficial health effects and anti-inflammatory properties, has been reported to reduce neuroinflammation in different neurodegenerative disease models. Resveratrol anti-inflammatory responses involve the activation of the protein deacetylase sirtuin 1 (SIRT1) gene. In this work we have investigated in an LPS-based murine model of neuroinflammation the role of FPR1, examining not only if this receptor undergoes a reduction of its expression during neuroinflammation, but also whether treatment with resveratrol was able to modulate its expression leading to an amelioration of neuroinflammatory picture in a murine model of neuroinflammation. Results of this work showed that FPR1 together with SIRT1 resulted upregulated by resveratrol treatment and that this increase is associated with an amelioration of the neuroinflammatory picture, as demonstrated by the induction of IL-10 and IL1-RA expression and the downregulation of proinflammatory mediators, such as TNF-α and IL-1β. The expression and the modulation of FPR1 by resveratrol may be evaluated in order to propose a novel anti-inflammatory and pro-resolving therapeutic approach for the reduction of the detrimental effects associated with neuro-inflammation based neurodegenerative diseases and also as a promising strategy to promote human health by a diet rich in antioxidative bioactive compounds.     

Korean mistletoe (Viscum album coloratum) extract improves endurance capacity in mice by stimulating mitochondrial activity

The beneficial effects of exercise on overall health make it desirable to identify the orally active agents that enhance the effects of exercise in an effort to cure metabolic diseases. Natural compounds such as resveratrol (RSV) are known to increase endurance by potentiating mitochondrial function. Korean mistletoe (Viscum album coloratum) extract (KME) has characteristics similar to those of RSV. In the present study, we determined whether KME could increase mitochondrial activity and exert an anti-fatigue effect. We found that KME treatment significantly increased the mitochondrial oxygen consumption rate (OCR) in L6 cells and increased the expression of peroxisome proliferator-activated receptor γ coactivator (PGC)-1α and silent mating type information regulation 2 homolog 1 (SIRT1), two major regulators of mitochondria function, in C2C12 cells. In the treadmill test, KME-treated mice could run 2.5-times longer than chow-fed control mice. Additionally, plasma lactate levels of exhausted mice were significantly lower in the KME-treated group. In addition, the swimming time to exhaustion of mice treated with KME was prolonged by as much as 212% in the forced-swim test. Liver and kidney histology was similar between the KME-treated and phosphate-buffered saline-treated animals, indicating that KME was nontoxic. Taken together, our data show that KME induces mitochondrial activity, possibly by activating PGC-1α and SIRT1, and improves the endurance of mice, strongly suggesting that KME has great potential as a novel mitochondria-activating agent.     

Blood SIRT1 Shows a Coherent Association with Leptin and Adiponectin in Relation to the Degree and Distribution of Adiposity: A Study in Obesity,Normal Weight and Anorexia Nervosa

Sirtuin 1 (SIRT1) is a sensor of cell energy availability, and with leptin and adiponectin, it regulates metabolic homeostasis. Widely studied in tissues, SIRT1 is under evaluation as a plasmatic marker. We aimed at assessing whether circulating SIRT1 behaves consistently with leptin and adiponectin in conditions of deficiency, excess or normal fat content. Eighty subjects were evaluated: 27 with anorexia nervosa (AN), 26 normal-weight and 27 with obesity. Bloodstream SIRT1, leptin and adiponectin (ELISA), total and trunk fat mass (FM) %, abdominal visceral adipose tissue, liver steatosis and epicardial fat thickness (EFT) were assessed. For each fat store, the coefficient of determination (R²) was used to evaluate the prediction capability of SIRT1, leptin and adiponectin. Plasma SIRT1 and adiponectin coherently decreased with the increase of FM, while the opposite occurred with leptin. Mean levels of each analyte were different between groups (p < 0.005). A significant association between plasma variables and FM depots was observed. SIRT1 showed a good predictive strength for FM, particularly in the obesity group, where the best R² was recorded for EFT (R² = 0.7). Blood SIRT1, adiponectin and leptin behave coherently with FM and there is synchrony between them. The association of SIRT1 with FM is substantially superimposable to that of adiponectin and leptin. Given its homeostatic roles, SIRT1 may deserve to be considered as a plasma clinical/biochemical parameter of adiposity and metabolic health.     

白藜芦醇抑制NLRP3炎性小体介导的细胞焦亡信号通路改善肥胖小鼠认知功能

目的 观察白藜芦醇(RES)对肥胖小鼠认知功能的保护作用,并探讨其海马组织核苷酸结合寡聚化结构域样受体蛋白3(NLRP3)炎性小体—细胞焦亡信号通路机制。方法 50只小鼠随机均分为：正常对照组、模型组和白藜芦醇高(100 mg/kg)、中(50 mg/kg)、低(25 mg/kg)剂量组,喂养6个月后,检测小鼠认知功能,海马组织细胞焦亡水平,海马组织沉默信息调节因子1(SIRT1)、NLRP3、半胱氨酸天冬氨酸蛋白酶1(Caspase-1)、白细胞介素-1β(IL-1β)、IL-18和肿瘤坏死因子-α(TNF-α)等蛋白表达情况。采用单因素方差分析或重复测量方差分析进行结果分析。结果 与模型组比较,白藜芦醇高剂量组小鼠终体质量降低(t=-14.453,P=0.021),海马组织细胞焦亡水平降低(t=-17.328,P=0.011),学习记忆能力改善,海马组织SIRT1蛋白表达升高(t=32.812,P<0.001),NLRP3、Caspase-1、IL-1β、IL-18和TNF-α蛋白表达均下降(t=-28.462,P=0.003;t=-38.148,P<0.001;t=-...     

Circulating SIRT1 and Sclerostin Correlates with Bone Status in Young Women with Different Degrees of Adiposity

Sirtuin1 (SIRT1) and sclerostin play important roles in adipose tissue and bone metabolism. We evaluated the circulating SIRT1 and sclerostin relationship with mass and quality of bone while considering the degree of adiposity. Sixty-six premenopausal women (16 underweight, 25 normal weight and 25 with obesity), aged <50 years, were enrolled. Plasma SIRT1, sclerostin and DXA body composition (total fat mass (FM), abdominal visceral adipose tissue, lean mass, trabecular bone score (TBS) and lumbar spine and femoral neck (FN) bone mineral density (BMD)) were assessed. The patients with obesity showed the lowest SIRT1 and TBS values and the highest sclerostin concentrations; BMD increased with FM and BMI and had an inverse association with SIRT1. Sclerostin was negatively correlated with SIRT1 (ρ = −0.37, p = 0.002). When spine BMD, FN BMD and TBS were standardized for BMI, a positive correlation with SIRT1 and a negative correlation with sclerostin were seen (p < 0.005). In the regression analysis, sclerostin was the best independent, negative predictor for BMD and TBS, while SIRT1 directly predicted TBS (p < 0.05). In conclusion, blood measurement of SIRT1 and sclerostin could represent a snapshot of the bone status that, taking into account the degree of adiposity, may reduce the interference of confounding factors in the interpretation of bone health parameters.     

Sirtuin1功能及调控研究进展

Sirtuin1(SIRT1)是依赖于烟酰胺腺嘌呤二核苷酸辅酶(nicotinamide adenine dinucleotide,NAD+)的去乙酰化酶(Sirtuins,SIRTs)家族7个成员中最大的一个,是近年来研究最为广泛的长寿因子。SIRT1除了对组蛋白赖氨酸残基去乙酰化修饰调节表观遗传外,SIRT1还可以调节细胞其他关键蛋白活性,控制细胞增殖、分化和细胞凋亡等生理功能。最近研究发现,SIRT1调控细胞功能除了与其酶活性水平有关,也可能与其在细胞中的定位有关。SIRT1在细胞核质之间穿梭和SIRT1活性水平及其相对应的生理功能仍需深入研究.     

沉默信息调节因子 1 与急性肺损伤/急性呼吸窘迫综合征

沉默信息调节因子1(Sirtuin1,silent information regulator 1,SIRT1)是与酿酒酵母沉默信息调节器2(Sir2)同源的去乙酰化酶家族。SIRT1通过介导多条细胞信号通路,在细胞生物学功能和疾病发生机制中发挥关键作用,调节各种疾病的病理进展。在急性肺损伤(acute lung injury,ALI)/急性呼吸窘迫综合征(acute respiratory distress syndrome,ARDS)的动物模型中,SIRT1表达异常,且表达水平与模型的疾病严重程度密切相关,可能成为早期诊治ALI/ARDS新的生物学指标。本文简要综述了SIRT1通过抗炎、抗氧化应激、调节细胞凋亡及自噬、改变血管内皮细胞通透性等途径发挥其减轻ALI/ARDS的作用,探讨SIRT1在ALI/ARDS防治中的潜在价值。     

Resveratrol blunts tumor necrosis factor-��-induced monocyte adhesion and transmigration

The leukocyte recruitment and transmigration across the endothelial barrier into the vessel wall are crucial steps in atherosclerosis. Leukocyte trafficking on the endothelium is elicited by induction of endothelial adhesion molecules, and its transmigration is mediated by degradation of basement membrane proteins through enzymatic activity of matrix metalloproteinases (MMP). The current study investigated whether resveratrol, a polyphenol present in grapes and red wine, was capable of inhibiting leukocyte adhesion to tumor necrosis factor (TNF)-α-activated endothelium. It was found that resveratrol inhibited the TNF-α-activated endothelial expression of vascular cell adhesion molecule-1 in a dose-dependent manner. In addition, resveratrol hampered THP-1 monocyte adhesion to activated endothelial cells. This study further examined whether resveratrol interfered with transendothelial migration of leukocytes. The MMP-2 gelatinolytic activity of endothelial cells was enhanced by TNF-α, which was attenuated by an addition of ≥25 µM resveratrol. In addition, 25 µM resveratrol mitigated the MMP-9 activity of THP-1 cells, followed by a marked inhibition of transendothelial migration. These results demonstrated that resveratrol suppressed monocyte adhesion and migration induced by TNF-α through modulating expression of adhesion molecules and gelatinolytic activity of MMP. These findings suggest that dietary resveratrol may be therapeutic agent for inhibiting leukocyte recruitment into the subendothelium during inflammatory atherosclerosis.     

Ketogenesis and SIRT1 as a tool in managing obesity

Obesity is a serious chronic disease and a public health concern in both developing and developed countries. Managing obesity has been a great challenge for both health care professionals and patients alike. Among the various diet programs aimed at promoting weight loss, the ketogenic diet, a diet high in fat and low in carbohydrates, has been at the forefront recently and its mechanism in weight loss is much debated. Activation of Sirtuin 1 or SIRT1 is able to circumvent various diseases, including metabolic syndrome and obesity and is thought to be a potentially reliable treatment target for both of them. Augmentation of SIRT1 may be carried out using dietary means such as nicotinamide adenine dinucleotide (NAD) supplementation and/or ketogenic diet. Although ketogenic diet may augment SIRT1 activation in people affected by obesity, recent studies have indicated that the relationship between SIRT1 and ketogenesis is unpredictable. The exact circumstances and mechanisms of SIRT1, NAD and ketogenesis in the clinical setting as an intervention tool in managing obesity remained uncertain. Although several recent literatures have documented significant weight-loss following ketogenic diet interventions, there were limitations with regards to duration of trial, choice and the number of trial subjects. Studies investigating the safety of ketogenic diet in the long term, beyond 46 weeks and related mechanism and pathways are still lacking and the sustainability of this diet remains to be determined. This review explores the recent progress on ketogenic diet and its relationships with SIRT1 as a tool in managing obesity and relevant clinical implications.     

Apo-10'-lycopenoic acid, a lycopene metabolite, increases sirtuin 1 mRNA and protein levels and decreases hepatic fat accumulation in ob/ob mice

Lycopene has been shown to be beneficial in protecting against high-fat diet-induced fatty liver. The recent demonstration that lycopene can be converted by carotene 9',10'-oxygenase into a biologically active metabolite, ALA, led us to propose that the function of lycopene can be mediated by ALA. In the present study, male ob/ob mice were fed a liquid high-fat diet (60% energy from fat) with ALA supplementation (ALA group, 240 μg?·?kg body weight(-1)?·?d(-1)) or without ALA supplementation as the control (C group) for 16 wk. Steatosis, SIRT1 expression and activity, genes involved in lipid metabolism, and ALA concentrations in the livers of mice were examined. The results showed that ALA supplementation resulted in a significant accumulation of ALA in the liver and markedly decreased the steatosis in the ALA group without altering body and liver weights compared to the C group. The mRNA and protein levels of hepatic SIRT1 were higher in the ALA group compared to the C group. SIRT1 activity also was higher in the ALA group, as indicated by the lower levels of acetylated forkhead box class O1 protein levels. In addition, the mRNA level of acetyl CoA carboxylase 1 was significantly lower in the ALA group than in the C group. Because SIRT1 plays a key role in lipid homeostasis, the present study suggests that the lycopene metabolite, ALA, protects against the development of steatosis in ob/ob mice by upregulating SIRT1 gene expression and activity.     

Resveratrol role in cardiovascular and metabolic health and potential mechanisms of action

Resveratrol is a polyphenolic flavonoid found in a diversity of plants, especially berry fruits and is a popular nutritional supplement. It is known to have antioxidant, anti-inflammatory, and anticarcinogenic properties. Recently, additional evidence has been found that resveratrol is beneficial to metabolic and cardiovascular health and may increase the life expectancy of various organisms. These biological effects are widely believed to be due to the ability of resveratrol to activate silent mating-type information regulation 2 homolog 1, a nicotinamide adenine dinucleotide-dependent deacetylase. However, other research has shown that 5′-adenosine monophosphate–activated kinase and not silent mating-type information regulation 2 homolog 1 may be the target of resveratrol. A recent study reported that resveratrol directly inhibits cyclic adenosine monophosphate–specific phosphodiesterases and then activates 5′-adenosine monophosphate–activated kinase. Therefore, the mechanism underlying the diverse nutritional and therapeutic activities of resveratrol needs to be further explored. Furthermore, the optimal dose and possible adverse effects of resveratrol in humans are completely clear. The purpose of this review is to present some of the newly discovered biological effects of resveratrol, including autophagy and stem cell regulation, and research opportunities for the application of resveratrol in cardiovascular and metabolic health. Described herein is the recent understanding of the mechanism of action of resveratrol and future research directions to ascertain the potential of this flavonoid that is present in food.     

SIRT1通过抑制卵母细胞衰老改善卵巢储备功能的研究进展

卵母细胞衰老及卵巢储备功能降低所造成的生育力下降是生殖领域的瓶颈问题,改善卵巢储备功能是提高不孕女性自然妊娠率及辅助生殖技术(ART)成功率的重要因素。沉默信息调节因子2相关酶类1(SIRT1)是调节卵子发生和细胞应激反应关键过程的重要参与者,可通过调控卵母细胞数量、改善卵母细胞质量、抑制氧化应激、调节线粒体功能等途径抑制卵母细胞衰老,提高卵巢储备功能,延长卵巢寿命,进而增加ART过程中的获卵数、成胚率及临床妊娠率。综述SIRT1通过抑制卵母细胞衰老改善卵巢储备功能的相关机制研究进展。