Piceatannol,a Dietary Polyphenol,Alleviates Adipose Tissue Loss in Pre-Clinical Model of Cancer-Associated Cachexia via Lipolysis Inhibition

Cancer-associated cachexia (CAC) is the nutrition-independent loss of lean muscle and adipose tissues, and results in reduced chemotherapy effectiveness and increased mortality. Preventing adipose loss is considered a key target in the early stages of cachexia. Lipolysis is considered the central driver of adipose loss in CAC. We recently found that piceatannol, but not its analogue resveratrol, exhibits an inhibitory effect on lipolysis. The objective of this study was to investigate the role of piceatannol in cancer-associated lipolysis and cachexia-induced weight loss. Cancer cell-induced lipolysis in adipocytes was stimulated using cancer-conditioned media (CCM) or co-culture with human pancreatic cancer cells and the cachexia-associated cytokines TNF-α and interleukin-6 in 3T3-L1 adipocytes. C26 colon carcinoma-bearing mice were modeled using CAC in vivo. Piceatannol reduced cancer-associated lipolysis by at least 50% in both CCM and cytokine-induced lipolysis in vitro. Further gene and protein analysis confirmed that piceatannol modulated the stability of lipolytic proteins. Moreover, piceatannol protected tumor-bearing mice against weight-loss in early stages of CAC largely through preserving adipose tissue, with no effect on survival. This study demonstrates the use of a dietary compound to preserve adipose in models of early stage CAC and provides groundwork for further investigation of piceatannol or piceatannol-rich foods as alternative medicine in the preservation of body fat mass and future CAC therapy.     

Resveratrol is rapidly metabolized in athymic (nu/nu) mice and does not inhibit human melanoma xenograft tumor growth

Resveratrol has been shown to have anticarcinogenic activity. We previously found that resveratrol inhibited growth and induced apoptosis in 2 human melanoma cell lines. In this study we determined whether resveratrol would inhibit human melanoma xenograft growth. Athymic mice received control diets or diets containing 110 micromol/L or 263 micromol/L resveratrol, 2 wk prior to subcutaneous injection of the tumor cells. Tumor growth was measured during a 3-wk period. Metabolism of resveratrol was assayed by bolus gavage of 75 mg/kg resveratrol in tumor-bearing and nontumor-bearing mice. Pellets containing 10-100 mg resveratrol were implanted into the mice, next to newly palpated tumors, and tumor growth determined. We also determined the effect of a major resveratrol metabolite, piceatannol, on experimental lung metastasis. Resveratrol, at any concentration tested, did not have a statistically significant effect on tumor growth. The higher levels of resveratrol tested (0.006% in food or 100 mg in slow-release pellets) tended to stimulate tumor growth (P = 0.08-0.09). Resveratrol and its major metabolites, resveratrol glucuronide and piceatannol, were found in serum, liver, skin, and tumor tissue. Piceatannol did not affect the in vitro growth of a murine melanoma cell line, but significantly stimulated the number of lung metastases when these melanoma cells were directly injected into the tail vein of the mouse. These results suggest that resveratrol is not likely to be useful in the treatment of melanoma and that the effects of phytochemicals on cell cultures may not translate to the whole animal system.     

Oligonol promotes anti-aging pathways via modulation of SIRT1-AMPK-Autophagy Pathway

BACKGROUND/OBJECTIVESOligonol, mainly found in lychee fruit, is an antioxidant polyphenolic compound which has been shown to have anti-inflammatory and anti-cancer properties. The detailed mechanisms by which oligonol may act as an anti-aging molecule have not been determined.MATERIALS/METHODSIn this study, we evaluated the ability of oligonol to modulate sirtuin (SIRT) expression in human lung epithelial (A549) cells. Oligonol was added to A549 cells and reactive oxygen species production, mitochondrial superoxide formation, and p21 protein levels were measured. Signaling pathways activated upon oligonol treatment were also determined by western blotting. Furthermore, the anti-aging effect of oligonol was evaluated ex vivo in mouse splenocytes and in vivo in Caenorhabditis elegans.RESULTSOligonol specifically induced the expression of SIRT1, whose activity is linked to gene expression, metabolic control, and healthy aging. In response to influenza virus infection of A549 cells, oligonol treatment significantly up-regulated SIRT1 expression and down-regulated viral hemagglutinin expression. Oligonol treatment also resulted in the activation of autophagy pathways and the phosphorylation of AMP-activated protein kinase (AMPK). Furthermore, oligonol-treated spleen lymphocytes from old mice showed increased cell proliferation, and mRNA levels of SIRT1 in the lungs of old mice were significantly lower than those in the lungs of young mice. Additionally, in vivo lethality assay revealed that oligonol extended the lifespan of C. elegans infected with lethal Vibrio cholerae.CONCLUSIONSThese data demonstrated that oligonol may act as an anti-aging molecule by modulating SIRT1/autophagy/AMPK pathways.     

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 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.     

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。     

Netrin-1 Promotes Visceral Adipose Tissue Inflammation in Obesity and Is Associated with Insulin Resistance

Netrin (NTN)-1 exhibits pro- and anti-inflammatory roles in different settings, playing important roles in the obesity-associated low-grade chronic inflammation. We aimed to determine the impact of NTN-1 on obesity and obesity-associated type 2 diabetes, as well as its role in visceral adipose tissue (VAT) inflammation. A total of 91 subjects were enrolled in this case-control study. Circulating levels of NTN-1 and its receptor neogenin (NEO)-1 were determined before and after weight loss achieved by caloric restriction and bariatric surgery. mRNA levels of NTN1 and NEO1 were assessed in human VAT, liver, and peripheral blood mononuclear cells. In vitro studies in human visceral adipocytes and human monocytic leukemia cells (THP-1)-derived macrophages were performed to analyze the impact of inflammation-related mediators on the gene expression levels of NTN1 and its receptor NEO1 as well as the effect of NTN-1 on inflammation. Increased (p < 0.001) circulating concentrations of NTN-1 in obesity decreased (p < 0.05) after diet-induced weight loss being also associated with a reduction in glucose (p < 0.01) and insulin levels (p < 0.05). Gene expression levels of NTN1 and NEO1 were upregulated (p < 0.05) in the VAT from patients with obesity with the highest expression in the stromovascular fraction cells compared with mature adipocytes (p < 0.01). NTN1 expression levels were enhanced (p < 0.01) under hypoxia and by inflammatory factors in both adipocytes and macrophages. Adipocyte-conditioned media strongly upregulated (p < 0.001) the mRNA levels of NTN1 in macrophages. The treatment of adipocytes with NTN-1 promoted the upregulation (p < 0.05) of pro-inflammatory and chemotactic molecules as well as its receptor NEO1. Collectively, these findings suggest that NTN-1 regulates VAT chronic inflammation and insulin resistance in obesity.     

Piceatannol, a natural analog of resveratrol, inhibits progression through the S phase of the cell cycle in colorectal cancer cell lines

Piceatannol, a naturally occurring analog of resveratrol, was previously identified as the active ingredient in herbal preparations in folk medicine and as an inhibitor of p72(Syk). We studied the effects of piceatannol on growth, proliferation, differentiation and cell cycle distribution profile of the human colon carcinoma cell line Caco-2. Growth of Caco-2 and HCT-116 cells was analyzed by crystal violet assay, which demonstrated dose- and time-dependent decreases in cell numbers. Treatment of Caco-2 cells with piceatannol reduced proliferation rate. No effect on differentiation was observed. Determination of cell cycle distribution by flow cytometry revealed an accumulation of cells in the S phase. Immunoblotting demonstrated that cyclin-dependent kinases (cdk) 2 and 6, as well as cdc2 were expressed at steady-state levels, whereas cyclin D1, cyclin B1 and cdk 4 were downregulated. The abundance of p27(Kip1) was also reduced, whereas the protein level of cyclin E was enhanced. Cyclin A levels were enhanced only at concentrations up to 100 micromol/L. These changes also were observed in studies with HCT-116 cells. On the basis of our findings, piceatannol can be considered to be a promising chemopreventive or anticancer agent.     

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.     

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.     

Suffruticosol C-Mediated Autophagy and Cell Cycle Arrest via Inhibition of mTORC1 Signaling

Paeonia species are well-known ornamental plants that are used in traditional Chinese medicines. The seeds of these species are rich in stilbenes, which have wide-ranging health-promoting effects. In particular, resveratrol, which is a common stilbene, is widely known for its anticancer properties. Suffruticosol C, which is a trimer of resveratrol, is the most dominant stilbene found in peony seeds. However, it is not clear whether suffruticosol C has cancer regulating properties. Therefore, in the present study, we aimed to determine the effect of suffruticosol C against various cancer cell lines. Our findings showed that suffruticosol C induces autophagy and cell cycle arrest instead of cell apoptosis and ferroptosis. Mechanistically, suffruticosol C regulates autophagy and cell cycle via inhibiting the mechanistic target of rapamycin complex 1 (mTORC1) signaling. Thus, our findings imply that suffruticosol C regulates cancer cell viability by inducing autophagy and cell cycle arrest via the inhibition of mTORC1 signaling.     

Combined Phyllostachys pubescens and Scutellaria baicalensis Prevent High-Fat Diet-Induced Obesity via Upregulating Thermogenesis and Energy Expenditure by UCP1 in Male C57BL/6J Mice

This study examined the anti-obesity effects of a Phyllostachys pubescens (leaf) and Scutellaria baicalensis root mixture (BS21), and its underlying mechanisms of action, in high-fat diet (HFD)-induced obese mice. Mice were fed a HFD with BS21 (100, 200, or 400 mg/kg) for 9 weeks. BS21 reduced body weight, white adipose tissue (WAT) and liver weights, liver lipid accumulation, and adipocyte size. Additionally, BS21 reduced serum concentrations of non-esterified fatty acid, triglyceride, glucose, lactate dehydrogenase, low-density lipoprotein cholesterol, total cholesterol, leptin, and insulin growth factor 1, but elevated the adiponectin concentrations. Furthermore, BS21 suppressed the mRNA levels of lipogenesis-related proteins, such as peroxisome proliferator–activated receptor (PPAR) γ, SREBP-1c, C/EBP-α, fatty acid synthase, and leptin, but increased the mRNA gene expression of lipolysis-related proteins, such as PPAR-α, uncoupling protein (UCP) 2, adiponectin, and CPT1b, in WAT. In addition, BS21 increased the cold-stimulated adaptive thermogenesis and UCP1 protein expression with AMPK activation in adipose tissue. Furthermore, BS21 increased the WAT and mRNA expression of energy metabolism-related proteins SIRT1, PGC-1α, and FNDC5/irisin in the quadriceps femoris muscle. These results suggest that BS21 exerts anti-obesity and antihyperlipidemic activities in HFD-induced obese mice by increasing the thermogenesis and energy expenditure, and regulating lipid metabolism. Therefore, BS21 could be useful for preventing and treating obesity and its related metabolic diseases.     

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.     

Antioxidant Supplementation Hinders the Role of Exercise Training as a Natural Activator of SIRT1

Exercise training (ET) is a natural activator of silent mating type information regulation 2 homolog 1 (SIRT1), a stress-sensor able to increase the endogenous antioxidant system. SIRT1 activators include polyphenols and vitamins, the antioxidant properties of which are well-known. Antioxidant supplements are used to improve athletic performance. However, they might blunt ET-related benefits. Middle-distance runners (MDR) taking (MDR-S) or not taking antioxidant supplements (MDR-NoS) were compared with each other and with sedentary subjects (CTR) to evaluate the ET effects on SIRT1 levels and oxidative stress, and to investigate whether an exogenous source of antioxidants could interfere with such effects. Thirty-two MDR and 14 CTR were enrolled. MDR-S took 240 mg vitamin C and 15 mg vitamin E together with mineral salts. SIRT1 mRNA and activity were measured in PBMCs. Total oxidative status (TOS) and total antioxidant capacity (TEAC) were determined in plasma. MDR showed higher levels of SIRT1 mRNA (p = 0.0387) and activity (p = 0.0055) than did CTR. MDR-NoS also showed higher levels than did MDR-S without reaching statistical significance. SIRT1 activity was higher (p = 0.0012) in MDR-NoS (1909 ± 626) than in MDR-S (1276 ± 474). TOS did not differ among the groups, while MDR showed higher TEAC levels than did CTR (2866 ± 581 vs. 2082 ± 560, p = 0.0001) as did MDR-S (2784 ± 643) and MDR-NoS (2919 ± 551) (MDR-S vs. CTR, p = 0.0007 and MDR-NoS vs. CTR, p = 0.003). TEAC (β = 0.4488356, 95% CI 0.2074645 0.6902067; p < 0.0001) and the MDR-NoS group (β = 744.6433, 95% CI 169.9954 1319.291; p= 0.012) predicted SIRT1 activity levels. Antioxidant supplementation seems to hinder the role of ET as a natural activator of SIRT1.     

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.     

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.