Resveratrol, pterostilbene and your skin

Antioxidant, anti-inflammatory, lipolytic, anti-ageing, cellulite

Resveratrol, found in black/purple grapes, red wine, blueberries and several other plants is one of the most well-known anti-ageing actives known today, and shares similar properties to its chemical analog, pterostilbene (also found in purple/black grapes, blueberries etc). Both have been found in numerous studies to be powerful antioxidants, anti-inflammatory and lipolytic actives and to reduce pigmentation, but above all they are known for their anti-ageing action, based on sirtuin (SIRT1) enhancement.


Pterostilbene and resveratrol cream

For all those reasons, resveratrol and pterostilbene are of great importance as active ingredients in anti-ageing, anti-cellulite, leg wellness, skin lightening and under-eye creams [the Celluence® creams are the only leg wellness / cellulite creams in the world with high concentrations of 95%+ pure resveratrol and 95%+ pure pterostilbene, plus 38x other natural anti-cellulite actives].


54+ ways resveratrol & pterostilbene...

...boost skin healing and fight free radical damage, inflammation, ageing and cellulite


Resveratrol protects arteries from ageing via modulating the renin-angiotenin system

Resveraterol decreases aortic media thickness, inflammation, fibrosis, and oxidative stress, as well as serum angiotensin II level, the aortic expression of prorenin receptor (PRR) and angiotensin converting enzyme (ACE).

[Source: The protective effect of resveratrol on vascular aging by modulation of the renin-angiotensin system]



Resveratrol alleviates lysophosphatidylcholine-induced damage and inflammation in vascular endothelial cells

Abstract: The role of resveratrol (trans-3,5,4'-trihydroxystilbene; RES) in lysophosphatidylcholine (LPC)‑induced injury and inflammation in endothelial cells (regarded as an early event in arteriosclerosis) is unclear. The present study investigated whether RES reduces lactate dehydrogenase (LDH) activity and secretion of inflammatory cytokines such asinterleukin‑6 and tumor necrosis factor‑α, via the Toll‑like receptor (TLR)‑4/myeloid differentiation primary response gene 88 (MyD88)/nuclear factor (NF)‑κB signal transduction pathway in LPC‑induced damage and inflammation in human umbilical vein endothelial‑12 (HUVE‑12) cells. Using an ELISA and western blotting, the present study investigated the effects of RES on LDH activity and cytokine secretion. The effects of TLR‑4 short hairpin (sh)RNA and TLR‑4 cDNA transfection on NF‑κB activation during LPC‑induced damage and inflammation was also investigated in HUVE‑12 cells. The results demonstrated that RES significantly inhibited the effect of LPC on enzyme activity, pro‑inflammatory cytokine secretion, and expression of TLR‑4, MyD88 and NF‑κBp65 expression. In addition, RES and TLR‑4 shRNA transfection suppressed LPC‑induced injury and inflammation by blocking the TLR‑4/MyD88/NF‑κB signaling pathway Conversely, transfection with TLR‑4 cDNA enhanced LPC‑induced injury and inflammation, which abrogated the protective effects of RES. These data suggested that RES significantly suppressed LPC‑induced damage and inflammation, via suppression of the TLR‑4/MyD88/NF‑κB signaling pathway, which may provide a new mechanistic evidence for the treatment of arteriosclerosis by RES.



Phenolic compounds apigenin, hesperidin and kaempferol reduce in vitro lipid accumulation in human adipocytes.

Abstract: BACKGROUND: Adipocytes derived from human mesenchymal stem cells (MSCs) are widely used to investigate adipogenesis. Taking into account both the novelty of these MSCs and the scarcity of studies focused on the effects of phenolic compounds, the aim of the present study was to analyze the effect of apigenin, hesperidin and kaempferol on pre-adipocyte and mature adipocytes derived from this type of cells. In addition, the expression of genes involved in TG accumulation was also measured. METHODS: Pre-adipocytes were cultured from day 0 to day 8 and mature adipocytes for 48 h with the polyphenols at doses of 1, 10 and 25 µM. RESULTS: Apigenin did not show an anti-adipogenic action. Pre-adipocytes treated with hesperidin and kaempferol showed reduced TG content at the three experimental doses. Apigenin did not modify the expression of the main adipogenic genes (c/ebpβ, c/ebpα, pparγ and srebp1c), hesperidin inhibited genes involved in the three phases of adipogenesis (c/ebpβ, srebp1c and perilipin) and kaempferol reduced c/ebpβ. In mature adipocytes, the three polyphenols reduced TG accumulation at the dose of 25 µM, but not at lower doses. All compounds increased mRNA levels of atgl. Apigenin and hesperidin decreased fasn expression. The present study shows the anti-adipogenic effect and delipidating effects of apigenin, hesperidin and kaempferol in human adipocytes derived from hMSCs. While hesperidin blocks all the stages of adipogenesis, kaempferol only inhibits the early stage. Regarding mature adipocytes, the three compounds reduce TG accumulation by activating, at least in part, lipolysis, and in the case of hesperidin and apigenin, also by reducing lipogenesis. CONCLUSIONS: The present study shows for the first time the anti-adipogenic effect and delipidating effect of apigenin, hesperidin and kaempferol in human adipocytes derived from MSCs for the first time.


Effect of resveratrol and pterostilbene on aging and longevity

Abstract: Over the past years, several studies have found that foods rich in polyphenols protect against age-related disease, such as atherosclerosis, cardiovascular disease, cancer, arthritis, cataracts, osteoporosis, type 2 diabetes (T2D), hypertension and Alzheimer's disease. Resveratrol and pterostilbene, the polyphenol found in grape and blueberries, have beneficial effects as anti-aging compounds through modulating the hallmarks of aging, including oxidative damage, inflammation, telomere attrition and cell senescence. In this review, we discuss the relationship between resveratrol and pterostilbene and possible aging biomarker, including oxidative stress, inflammation, and high-calorie diets. Moreover, we also discuss the positive effect of resveratrol and pterostilbene on lifespan, aged-related disease, and health maintenance. Furthermore, we summarize a variety of important mechanisms modulated by resveratrol and pterostilbene possibly involved in attenuating age-associated disorders. Overall, we describe resveratrol and pterostilbene potential for prevention or treatment of several age-related diseases by modulating age-related mechanisms.



Epigenetic Regulatory Mechanisms Induced by Resveratrol

Abstract: Resveratrol (RVT) is one of the main natural compounds studied worldwide due to its potential therapeutic use in the treatment of many diseases, including cancer, diabetes, cardiovascular diseases, neurodegenerative diseases and metabolic disorders. Nevertheless, the mechanism of action of RVT in all of these conditions is not completely understood, as it can modify not only biochemical pathways but also epigenetic mechanisms. In this paper, we analyze the biological activities exhibited by RVT with a focus on the epigenetic mechanisms, especially those related to DNA methyltransferase (DNMT), histone deacetylase (HDAC) and lysine-specific demethylase-1 (LSD1).



Resveratrol analogues like piceatannol are potent antioxidants as quantitatively demonstrated through the high scavenging ability against reactive oxygen species and methyl radical

Abstract: Resveratrol (RSV) analogues have attracted much attention because of the expected health functions including antioxidant activities. We have carried out a quantitative determination of the scavenging abilities of six trans-RSV analogues against various reactive oxygen species and methyl radical (hydroxyl radical, superoxide, alkoxyl radical, peroxyl radical, methyl radical, and singlet oxygen). RSV analogues are in general more potent scavenger than the parent RSV. Furthermore, piceatannol (PIC) having two OH groups in the ortho position of resveratrol was found to show 11 times higher scavenging ability against peroxyl radical than parent resveratrol. With the aid of previous theoretical studies, the enhanced antioxidant ability was interpreted based on the effects of substituent that modifies the original resveratrol structure and function.



High glucose upregulates endothelin type B receptors in vascular smooth muscle cells via the downregulation of Sirt1

Abstract: Silent information regulator family protein 1 (Sirt1) has recently gained attention for its protective effects against diabetic and cardiovascular diseases (CVDs). Vascular smooth muscle endothelin type B (ETB) receptors are involved in the pathogenesis of CVDs and diabetes. The aim of present study was to explore whether Sirt1 is involved in high glucose (HG)-mediated regulation of ETB receptors in rat superior mesenteric arteries (SMA). The rat SMA segments were cultured in the presence and absence of HG with or without the activator of Sirt1 and specific inhibitor for the extracellular signal-regulated protein kinase 1/2 (ERK1/2) for 24 h. Following organ culture, the contractile responses to sarafotoxin 6c were studied using a sensitive myograph, and the ETB receptor protein expression level was determined using western blotting. The results demonstrated that HG induced upregulation of ETB receptor expression and increased receptor-mediated vasoconstriction in SMA. Resveratrol (Res; a Sirt1 activator) concentration-dependently inhibited the HG-induced upregulation of ETB receptor expression and receptor-mediated vasoconstriction. Additionally, these effects could also be abolished by an inhibitor of the ERK1/2 signaling pathway. Furthermore, upregulation of ERK1/2 phosphorylation induced by HG was inhibited by Res. In conclusion, HG upregulated ETB receptors by downregulating Sirt1 and subsequently activating the ERK1/2 signaling pathways in the organ culture SMA.



Resveratrol Exerts Antioxidant Effects by Activating SIRT2 To Deacetylate Prx1

Abstract: Resveratrol is a promising chemical agent that treats multiple aging-related diseases and improves life span. While reactive oxygen species undoubtedly play ubiquitous roles in the aging process and resveratrol has been shown to be an effective antioxidant, the mechanism through which resveratrol acts against oxidative stress remains unknown. Here we show that resveratrol activates SIRT2 to deacetylate Prx1, leading to an increased H2O2 reduction activity and a decreased cellular H2O2 concentration. Knockdown of SIRT2 or Prx1 by RNA interference abrogates resveratrol's ability to reduce the H2O2 level in HepG2 cells. Using purified SIRT2 and a Prx1 mutant harboring acetyllysine at position 27 (Prx1-27AcK), we show that resveratrol enhances SIRT2's activity to deacetylate Prx1-27AcK, resulting in a significantly increased H2O2 reducing activity. Thus, SIRT2 and Prx1 are targets for modulating intracellular redox status in the therapeutic strategies for the treatment of aging-related disorders.



Pterostilbene, SIRT1 and weight loss

Cocoa, berries and red wine: Sirtuins are a group of body chemicals known for their anti-aging / longevity benefits, and the last few years more and more studies examine their action against fat accumulation / overweight. SIRT1 is the most important sirtuin and its production is stimulated in the body by the plant chemicals resveratrol and pterostilbene, found in grapes, berries, red wine, cocoa and dark chocolate. In this new paper, published recently, it was shown that "SIRT1 acts as a crucial repressor of adipogenesis", i.e. SIRT1 stops the growth of new fat cells (contrary to the urban myth, the body continuously creates new fat cells as old ones die off). By halting the growth of new fat cells, it is possible to reduce adiposity and lose weight, as the excess fat is directed towards oxidation ("fat burning") by the body. Other studies in the past have shown that resveratrol and pterostilbene may also have a direct lipolytic / thermogenic action on fat cells. In fact resveratrol and pterostilbene are also used in quality cellulite creams, due to their direct lipolytic action and their activity against fat cell growth and fat accumulation. Creams with high concentrations of these two chemicals are needed to replicate the amounts of resveratrol and pterostilbene used in studies.

Losing weight with resveratrol and pterostilbene: Of course, taking resveratrol or pterostilbene supplements or eating loads of blueberries is not a license to eat anything you fancy and expect to lose or not put on weight. In the end the excess calories will stimulate adipogenic (fattening) chemicals in the body which are much stronger than SIRT1. Between insulin and SIRT1, for example, insulin wins hands-down. But if you follow a healthy diet and you exercise, SIRT1-stimulating foods and supplements, i.e. foods and supplements rich in resveratrol and pterostilbene, will help you make the most of your weight loss effort and and improve your overall health in the process. Furthermore, continuous, lifelong consumption of SIRT1-stimulating foods, or resveratrol and pterostilbene supplements, may also help keep you younger for longer (SIRT1 is more known for its longevity/anti-ageing properties than for its anti-adipogenic action). Of course, getting the majority of your resveratrol and pterostilbene from red wine and dark chocolate is not the same as getting it from blackberries and cocoa powder-enriched shakes and smoothies. So don't get too excited about indulging in wine and chocolate in order to stay young and lose weight - just keep to the berries :)

Paper: SIRT1 suppresses adipogenesis by activating Wnt/β-catenin signaling in vivo and in vitro

Abstract: Sirtuin 1 (SIRT1) regulates adipocyte and osteoblast differentiation. However, the underlying mechanism should be investigated. This study revealed that SIRT1 acts as a crucial repressor of adipogenesis. RNA-interference-mediated SIRT1 knockdown or genetic ablation enhances adipogenic potential, whereas SIRT1 overexpression inhibits adipogenesis in mesenchymal stem cells (MSCs). SIRT1 also deacetylates the histones of sFRP1, sFRP2, and Dact1 promoters; inhibits the mRNA expression of sFRP1, sFRP2, and Dact1; activates Wnt signaling pathways; and suppresses adipogenesis. SIRT1 deacetylates β-catenin to promote its accumulation in the nucleus and thus induces the transcription of genes that block MSC adipogenesis. In mice, the partial absence of SIRT1 promotes the formation of white adipose tissues without affecting the development of the body of mice. Our study described the regulatory role of SIRT1 in Wnt signaling and proposed a regulatory mechanism of adipogenesis.



Anti-adipogenesis mechanism of pterostilbene through the activation of heme oxygenase-1 in 3T3-L1 cells

Abstract: BACKGROUND: Pterostilbene is a stilbenoid and major compound and has diverse biological activities, such as antioxidant, anti-cancer, and anti-inflammatory. However, it has not been shown whether pterostilbene affects the mitotic clonal expansion during adipogenesis in 3T3-L1 cells. PURPOSE: In the present study, we aimed to demonstrate the detailed mechanism of pterostilbene on anti-adipogenesis in 3T3-L1 cells. METHODS: Preadipocytes were converted to adipocytes through treatment with MDI (IBMX; 3-isobutyl-1-methylxanthine, DEX; dexamethasone, insulin) in 3T3-L1 cells. Oil Red O staining was performed to measure intracellular lipid accumulation. Western blot analysis was conducted to analyze protein expressions. RESULTS: Our results showed that pterostilbene decreased the lipid accumulation compared to MDI-induced differentiation, using Oil Red O staining. Next, we found that pterostilbene suppressed the expression of C/EBPα, PPARγ, and aP2 as well as the mitotic clonal expansion-associated proteins CHOP10 and C/EBPβ, by western blot analysis. Our results indicated that pterostilbene may repress adipocyte differentiation through the activation of HO-1 expression prior to entering into the mitotic clonal expansion in 3T3-L1 cells. RNA interference was used to determine whether HO-1 acts as a regulator of CHOP10. CONCLUSION: Our results revealed that pterostilbene induced HO-1 expression which acts as a regulator of CHOP10. Together, we demonstrated that pterostilbene suppresses the initiation of mitotic clonal expansion via up-regulation of HO-1 expression during adipocyte differentiation of 3T3-L1 cells.



Sirt1 decreased adipose inflammation by interacting with Akt2 and inhibiting mTOR/S6K1 pathway in mice

Sirtuin type 1 (Sirt1) and protein kinase B (Akt2) are associated with development of obesity and inflammation, but the molecular mechanisms of Sirt1 and Akt2 interaction on adipose inflammation remain unclear. To explore these mechanisms, a mouse model was used. Mice were fed with a high-fat diet (HFD) for 8 weeks, with interventions of resveratrol (RES) or nicotinamide (NAM) during the last 15 days. The HFD reduced Sirt1 mRNA in adipose tissue and elevated interleukin-6 (IL-6) expression. RES reduced the adipose tissue weight, increased the Sirt1 mRNA level, and reduced both mRNA and protein levels of IL-6, MCP-1, inducible nitric oxide synthase, and TNF-α by inhibiting phosphorylation of Akt2 in adipose tissue. Additionally, macrophage type I marker genes were reduced while macrophage type II marker genes were elevated by RES addition. Moreover, activation of Akt2 signal by using insulin significantly blunted the inhibitory effect of RES on adipose inflammation. Immunoprecipitation assay demonstrated that RES enhances the protein-protein interaction between Sirt1 and Akt2, but NAM inhibits this interaction. Furthermore, Sirt1 significantly reduced the levels of raptor and inactivated mammalian target of rapamycin (mTOR)C1 signal by interacting with Akt2, and confirmed that RES attenuated adipose inflammation by inhibiting the mTOR/S6K1 pathway via rapamycin. 



Biological actions and molecular effects of resveratrol, pterostilbene, and 3'-hydroxypterostilbene

Stilbenes are a class of polyphenolic compounds, naturally found in a wide variety of dietary sources such as grapes, berries, peanuts, red wine, and some medicinal plants. There are several well-known stilbenes including trans-resveratrol, pterostilbene, and 3'-hydroxypterostilbene. The core chemical structure of stilbene compounds is 1,2-diphenylethylene. Recently, stilbenes have attracted extensive attention and interest due to their wide range of health-beneficial effects such as anti-inflammation, -carcinogenic, -diabetes, and -dyslipidemia activities. Moreover, accumulating in vitro and in vivo studies have reported that stilbene compounds act as inducers of multiple cell-death pathways such as apoptosis, cell cycle arrest, and autophagy for chemopreventive and chemotherapeutic agents in several types of cancer cells. The aim of this review is to highlight recent molecular findings and biological actions of trans-resveratrol, pterostilbene, and 3'-hydroxypterostilbene. Recent studies showed that the methoxylation on the free hydroxyl groups of resveratrol could reduce its metabolization and increased its plasma exposure [81,83]. Furthermore, in a pharmacokinetic study, pterostilbene was shown to have 80% oral bioavailability in comparison to only 20% for resveratrol [16]. Thus, the findings of these studies indicated that pterostilbene, dimethyl ether of resveratrol, showed much greater bioavailability than resveratrol.



Resveratrol-Enriched Rice Attenuates UVB-ROS-Induced Skin Aging via Downregulation of Inflammatory Cascades

The skin is the outermost protective barrier between the internal and external environments in humans. Chronic exposure to ultraviolet (UV) radiation is a major cause of skin aging. UVB radiation penetrates the skin and induces ROS production that activates three major skin aging cascades: matrix metalloproteinase- (MMP-) 1-mediated aging; MAPK-AP-1/NF-κB-TNF-α/IL-6, iNOS, and COX-2-mediated inflammation-induced aging; and p53-Bax-cleaved caspase-3-cytochrome C-mediated apoptosis-induced aging. These mechanisms are collectively responsible for the wrinkling and photoaging characteristic of UVB-induced skin aging. There is an urgent requirement for a treatment that not only controls these pathways to prevent skin aging but also avoids the adverse effects often encountered when applying bioactive compounds in concentrated doses. In this study, we investigated the efficacy of genetically modified normal edible rice (NR) that produces the antiaging compound resveratrol (R) as a treatment for skin aging. This resveratrol-enriched rice (RR) overcomes the drawbacks of R and enhances its antiaging potential by controlling the abovementioned three major pathways of skin aging. RR does not exhibit the toxicity of R alone and promisingly downregulates the pathways underlying UVB-ROS-induced skin aging. These findings advocate the use of RR as a nutraceutical for antiaging purposes.



Autophagy-inducing effect of pterostilbene: A prospective therapeutic/preventive option for skin diseases

Pterostilbene is a naturally occurring analog of resveratrol with many health benefits. These health benefits are associated with its antioxidant activity, anti-inflammatory effects, and chemopreventive effects attributed to its unique structure. The skin cancer chemopreventive potential of pterostilbene is supported by a variety of mechanistic studies confirming the anti-inflammatory effects in skin cancer models. Molecular biological studies have identified that pterostilbene targets pleotropic signaling pathways, including those involved in mitogenesis, cell cycle regulation, and apoptosis. Recently, pterostilbene has been reported to induce autophagy in cancer and normal cells. Through autophagy induction, the inflammatory-related skin diseases can be attenuated. This finding suggests the potential use of pterostilbene in the treatment and prevention of skin disorders via alleviating inflammatory responses by autophagy induction. This review summarizes the protective and therapeutic benefits of pterostilbene in skin diseases from the viewpoint of its antioxidant, anti-inflammatory, and autophagy-inducing effects. Novel underlying mechanisms regarding these effects are discussed. We proposed that pterostilbene, a promising natural product, can be used as a preventive and therapeutic agent for inflammation-related skin disorders through induction of autophagy.



Dosis Facit Sanitatem-Concentration-Dependent Effects of Resveratrol on Mitochondria

The naturally occurring polyphenol, resveratrol (RSV), is known for a broad range of actions. These include a positive impact on lifespan and health, but also pro-apoptotic anti-cancer properties. Interestingly, cell culture experiments have revealed a strong impact of RSV on mitochondrial function. The compound was demonstrated to affect mitochondrial respiration, structure and mass of mitochondria as well as mitochondrial membrane potential and, ultimately, mitochondria-associated cell death pathways. Notably, the mitochondrial effects of RSV show a very strict and remarkable concentration dependency: At low concentrations, RSV (<50 μM) fosters cellular antioxidant defense mechanisms, activates AMP-activated protein kinase (AMPK)- and sirtuin 1 (SIRT1)-linked pathways and enhances mitochondrial network formation. These mechanisms crucially contribute to the cytoprotective effects of RSV against toxins and disease-related damage, in vitro and in vivo. However, at higher concentrations, RSV (>50 μM) triggers changes in (sub-)cellular Ca(2+) homeostasis, disruption of mitochondrial membrane potential and activation of caspases selectively yielding apoptotic cancer cell death, in vitro and in vivo. In this review, we discuss the promising therapeutic potential of RSV, which is most probably related to the compound's concentration-dependent manipulation of mitochondrial function and structure.



Depigmenting Effect of Resveratrol Is Dependent on FOXO3a Activation without SIRT1 Activation

Resveratrol exhibits not only anti-melanogenic property by inhibiting microphthalmia-associated transcription factor (MITF), but also anti-aging property by activating sirtuin-1 (SIRT1). In this study, the relationship between depigmenting effect of resveratrol and SIRT1/forkhead box O (FOXO) 3a activation and was investigated. Resveratrol suppressed melanogenesis by the downregulation of MITF and tyrosinase via ERK pathway. Results showed that the expression of both SIRT1 and FOXO3a were increased. It is reported that SIRT1 is critical regulator of FOXO-mediated transcription in response to oxidative stress. However in our study, FOXO3a activation appeared earlier than that of SIRT1. Furthermore, the effect of resveratrol on the levels of MITF and tyrosinase was suppressed when melanocytes were pre-treated with SP600125 (JNK inhibitor). However, pre-treatment with SIRT1 inhibitor (EX527, or sirtinol) did not affect the levels of MITF and tyrosinase. Therefore, resveratrol inhibits melanogenesis through the activation of FOXO3a but not by the activation of SIRT1. Although SIRT1 activation by resveratrol is a well-known mechanism of resveratrol-induced antiaging effects, our study showed that not SIRT1 but FOXO3a activation is involved in depigmenting effects of resveratrol.



A comparative study of anti-aging properties and mechanism: resveratrol and caloric restriction

Resveratrol and caloric restriction (CR) are the powerful therapeutic options for anti-aging. Here, their comparative effect on longevity-associated gene silencing information regulator (SIRT1) were evaluated in vitro and in vivo. IMR-90 cells treated with 2,2'-azobis (2-amidinopropane) dihydrochloride (AAPH) were applied to establish a cellular senescence model, and rats treated with D-galactose (D-gal) were used as an aging animal model. Resveratrol and CR exhibited similar anti-aging activities, evidenced by inhibiting senescence and apoptosis, and restoring cognitive impairment and oxidative damage. Moreover, they could up-regulate telomerase (TE) activity, increase expressions of SIRT1, forkhead box 3a (Foxo3a), active regulator of SIRT1 (AROS) and Hu antigen R (HuR ), but decrease p53 and deleted in breast cancer 1 (DBC1) levels. However, 10 μM resveratrol in vitro and the high dose group in vivo showed relatively stronger activities of anti-aging and stimulating SIRT1 level than CR. In conclusion, resveratrol and CR showed similar anti-aging activities on SIRT1 signaling, implicating the potential of resveratrol as a CR mimetic.



Metabolism of skin-absorbed resveratrol into its glucuronized form in mouse skin

Resveratrol (RESV) is a plant polyphenol, which is thought to have beneficial metabolic effects in laboratory animals as well as in humans. Following oral administration, RESV is immediately catabolized, resulting in low bioavailability. This study compared RESV metabolites and their tissue distribution after oral uptake and skin absorption. Metabolomic analysis of various mouse tissues revealed that RESV can be absorbed and metabolized through skin. We detected sulfated and glucuronidated RESV metabolites, as well as dihydroresveratrol. These metabolites are thought to have lower pharmacological activity than RESV. Similar quantities of most RESV metabolites were observed 4 h after oral or skin administration, except that glucuronidated RESV metabolites were more abundant in skin after topical RESV application than after oral administration. This result is consistent with our finding of glucuronidated RESV metabolites in cultured skin cells. RESV applied to mouse ears significantly suppressed inflammation in the TPA inflammation model. The skin absorption route could be a complementary, potent way to achieve therapeutic effects with RESV.



Resveratrol: from diet to topical usage    

The stilbene derivative resveratrol (3,5,4′-trihydroxy-stilbene; RESV) has become the subject of interest of many researchers and the pharmaceutical industries due to its well-acclaimed beneficial biological activities. Although earlier research tended to focus on the effects of RESV on cardiovascular disorders, many other studies have described the beneficial effects of RESV in the areas of cancer chemoprevention and inflammation and interest of researchers on this compound is still increasing. It is now well accepted that the effect of RESV is not just due to its so called “antioxidant” activity but mainly (if not only) because of the ability of this compound to trigger cell signaling pathways and gene expression involved in cellular defense systems. Many “in vitro” studies on RESV did not take into account that although its oral absorption is about 75% it undergoes rapid metabolism and the concentration in the blood stream is almost undetectable. For this reason interest in the topical usage of RESV by cosmeceutical skin care brands has exponentially increased in the last decade reporting in general very promising results on its beneficial effect in protecting the skin from outdoor insults, but there is still some controversy on its topical usage mainly surrounding the concentration used. Therefore, more basic research on the topical application of RESV should be performed to better understand the way it prevents cutaneous damage and whether it could be recommended as a preventive skin aging agent for all skin insults.



Protective molecular mechanisms of Resveratrol in UVR induced Skin carcinogenesis.

Abstract: Skin cancer is a major health problem worldwide. It is the most common cancer in the United States and poses a significant healthcare burden. Excessive UVR exposure is the most common cause of skin cancer. Despite various precautionary measures to avoid direct UVR exposure, the incidence of skin cancer and mortality related to it remains high. Furthermore, the current treatment options are expensive and have side effects including toxicity to normal cells. Thus, a safe and effective approach is needed to prevent and treat skin cancer. Chemopreventive strategy by using naturally occurring compounds, such as resveratrol, is a promising approach to reduce the incidence of UVR-induced skin cancer and delay its progression. This review highlights the current body of evidence related to chemopreventive role of resveratrol and its molecular mechanisms in UVR induced skin carcinogenesis. This article is protected by copyright. All rights reserved.



Phytochemicals in regulating fatty acid β-oxidation: Potential underlying mechanisms and their involvement in obesity and weight loss.

Abstract: Excessive accumulation of fat as the result of more energy intake and less energy expenditure is known as obesity. Lipids are essential components in the human body and are vital for maintaining homeostasis and physiological as well as cellular metabolism. Fatty acid synthesis and catabolism (by fatty acid oxidation) are normal part of basic fuel metabolism in animals. Fatty acids are degraded in the mitochondria by a biochemical process called β-oxidation in which two-carbon fragments are produced in each cycle. The increase in fatty acid β-oxidation is negatively correlated with body mass index. Although healthy life style, avoiding Western diet, dieting and strenuous exercise are the commonly used methods to lose weight, they are not considered a permanent solution in addition to risk attenuation of basal metabolic rate (BMR). Pharmacotherapy offers benefits of weight loss by altering the satiety and lowering absorption of fat from the food; however, its side effects may outweigh the benefits of weight loss. Alternatively, dietary phytochemicals and natural health products offer great potential as an efficient weight loss strategy by modulating lipid metabolism and/or increasing BMR and thermogenesis. Specifically, polyphenols such as citrus flavonoids, green tea epigallocatechin gallate, resveratrol, capsaicin and curcumin, have been reported to increase lipolysis and induce fatty acid β-oxidation through modulation of hormone sensitive lipase, acetyl-coA carboxylase, carnitine acyl transferase and peroxisome proliferator-activated receptor gamma coactivator-1. In this review article, we discuss selected phytochemicals in relation to their integrated functionalities and specific mechanisms for weight loss.



SIRT1 Protects Against Systemic Sclerosis-related Pulmonary Fibrosis by Decreasing Pro-inflammatory and Pro-fibrotic Processes.

Abstract: Pulmonary fibrosis is the leading cause of death in systemic sclerosis (SSc). Sirtuin1 (SIRT1) is a deacetylase with known anti-inflammatory and anti-fibrotic activity in the liver, kidney and skin. The role of SIRT1 in SSc-related pulmonary fibrosis is unknown. In the present work, we determined that the expression of SIRT1 in peripheral blood mononuclear cells of SSc patients with pulmonary fibrosis is lower than that in SSc patients without pulmonary fibrosis. In in vivo studies of Bleomycin-induced lung fibrosis in mice, SIRT1 activation with Resveratrol reduced collagen production when it was administered either prophylactically during the inflammatory stage or after the development of fibrosis. Furthermore, SIRT1 activation or overexpression inhibited TNF-α-induced inflammatory responses in vitro in human fetal lung fibroblasts, depletion of SIRT1 in fibroblasts enhanced inflammation, and these effects were related to changes in the acetylation of NF-κB. In addition, SIRT1 activation or exogenous overexpression inhibited collagen production in vitro, and these manipulations also inhibited fibrosis via inactivation of TGF-β/Smad3 and mTOR signaling. Taken together, our results show that a loss of SIRT1 may participate in the pathogenesis of SSc-related pulmonary fibrosis, and that SIRT1 activation is an effective treatment for both the early (inflammatory) and late (fibrotic) stages of pulmonary fibrosis. Thus, SIRT1 may be a promising therapeutic target in the management of SSc-related pulmonary fibrosis.



Antiobesity effects of resveratrol: which tissues are involved?

Abstract: The prevalence of obesity has been increasing in recent decades and is reaching epidemic proportions. The current options for overweight and obesity management are energy restriction and physical activity. However, compliance with these treatments is frequently poor and less successful than expected. Therefore, the scientific community is interested in active biomolecules, which may be useful in body weight management. Among them, resveratrol (3,5,4'-trihydroxy-trans-stilbene) has generated great interest as an antiobesity agent. The focus of this report is the mechanisms of action of resveratrol on several tissues (i.e., white and brown adipose tissues, liver, and skeletal muscle). Resveratrol blunts fat accumulation through decreasing adipogenesis and/or de novo lipogenesis in white adipose tissue. The effects on lipolysis are controversial. Regarding brown adipose tissue, resveratrol increases the capacity for adaptive thermogenesis. As far as liver and skeletal muscle is concerned, resveratrol increases lipid oxidation in both tissues. Therefore, in rodents, there is a general consensus concerning the effect of resveratrol on reducing body fat accumulation. By contrast, in humans, the studies are scarce, and no clear antiobesity action has been revealed so far.



Chronic topical application of resveratrol accelerates wound healing...

...with improved epidermis, collagen deposition and improved vascularization of wound beds in young skin, due to stimulation of the AMPK pathway, the key mediator of wound healing. In aged skin, however, only metformin, a much stronger caloric restriction mimetic than resveratrol, was effective (in aged skin, AMPK pathway is inhibited, correlating with impaired vasculature and reduced healing ability)

[Source: Anti-aging pharmacology in cutaneous wound healing: effects of metformin, resveratrol, and rapamycin by local application]


Resveratrol fights MITOCHONDRIAl-dysfunction related CONDITIONS... protecting mitochondria from oxidative stress, by helping regulate their metabolism and biogenesis and by modulating cell apoptosis due to mitochondrial dysfunction [Source: Dietary Polyphenols and Mitochondrial Function: Role in Health and Disease]




Resveratrol, together with genistein and EGCG, inhibits preadipocyte differentiation... low dosages in an additive manner (but not synergistically). The combination reduces levels of PPAR-gamma and C/EBP-alpha the two key preadipocyte differentiation regulators. The combination also reduced FABP4 and perilipin, two PPAR-γ/C/EBP-α downstream molecules. The individual compounds had no anti-adipogenic effect at low concentrations.

[Source: Antiadipogenic Effects and Mechanisms of Combinations of Genistein, Epigallocatechin-3-Gallate, and/or Resveratrol in Preadipocytes]



Resveratrol decreases lipid accumulation in adipocytes... inhibiting PPAR-gamma, C/EBPs and their target genes (FAS, aP2, SCD-1, and LPL) Resveratrol, the phytochemical found in red wine, berries and other foods and considered responsible for their anti-ageing qualities, is known to trigger fat release from fat cells (lipolysis). Resveratrol exerts both its anti-ageing and its anti-obesity effect by activating a protein called sirtuin (SIRT1). SIRT1 is a major target of anti-ageing strategies and now scientists have found that SIRT1 also stimulates fat release.

Sirtuin, and subsequently resveratrol, does that by: increasing another protein found in fat cells, called ATGL. ATGL (adipocyte triglyceride lipase) is well-known for its stimulation of fat release; inhibiting a protein called PPAR-gamma, one of the most important triggers of fat accumulation

Now that the mechanism of action of resveratrol is clarified, applications of this natural, healthful chemical on anti-cellulite and anti-aging creams is further warranted.

Abstract: To investigate whether sirtuin 1 (Sirt1) could affect the transcriptional expression of the adipose triglyceride lipase (ATGL) gene, we treated porcine adipocytes with the general Sirt1 activator resveratrol (RES) with the Sirt1 inhibitor nicotinamide (NAM) or a knockdown of Sirt1 by Sirt1-specific small interfering RNA (siRNA). The RES (50 μM) activated Sirt1 gene expression and increased ATGL gene expression and glycerol release (P < 0.01). The Sirt1 inhibitor NAM or knockdown with Sirt1 siRNA further proved that the ATGL mRNA abundances were decreased (P < 0.05) after inhibition with Sirt1 in adipocytes. Furthermore, we found the opposite Sirt1 regulation pattern for PPARγ to that of ATGL in adipocytes. In summary, Sirt1 regulates the transcriptional expression of ATGL in adipocytes, and PPARγ appears to have an important role in this process. These results add to our understanding of the role of Sirt1 in adipose mobilization.

[Source: Sirtuin1 affects the transcriptional expression of adipose triglyceride lipase in porcine adipocytes]



Resveratrol fights fat accumulation... inhibiting PPAR-gamma, FAS, LPL and other adipogenic factors.

Resveratrol (3,4,5-trihydroxy-trans-stilbene), a phytoalexin found in grape skin, grape products, and peanuts as well as red wine, has been reported to have various biological and pharmacological properties. The purpose of this study was to investigate the anti-obesity effect of resveratrol-amplified grape skin extracts on adipocytes. The anti-obesity effects of grape skin extracts were investigated by measuring proliferation and differentiation in 3T3-L1 cells. The effect of grape skin ethanol extracts on cell proliferation was detected by the MTS assay. The morphological changes and degree of adipogenesis of preadipocyte 3T3-L1 cells were measured by Oil Red-O staining assay. Treatment with extracts of resveratrol-amplified grape skin decreased lipid accumulation and glycerol-3-phosphate dehydrogenase activity without affecting 3T3-L1 cell viability. Grape skin extract treatment resulted in significantly attenuated expression of key adipogenic transcription factors, including peroxisome proliferator-activated receptor, CCAAT/enhancer-binding proteins, and their target genes (FAS, aP2, SCD-1, and LPL). These results indicate that resveratrol-amplified grape skin extracts may be useful for preventing obesity by regulating lipid metabolism.

[Source: Anti-obesity effect of resveratrol-amplified grape skin extracts on 3T3-L1 adipocytes differentiation]



Resveratrol fights ageing by boosting the activity of SIRT1

Resveratrol is a well-known anti-ageing and slimming natural compound and is one of the molecules associated with the anti-ageing effects of red wine (the "French paradox").

Now scientists in Hong Kong have found that resveratrol reduces stem cell decline and significantly extends life span in mice suffering from premature ageing (progeria), by helping bind a protein called Lamin A onto SIRT1, the "longevity" gene. By boosting the activity of the longevity gene, resveratrol helps fight ageing.

Resveratrol is an ideal anti-ageing and anti-cellulite cream active ingredient. It is more and more widely used as an anti-ageing supplement and is an ideal ingredient in anti-ageing creams. In addition, resveratrol has been shown to halt the growth of new fat cells (adipogenesis), on its own and when combined with other natural substances, such as the phytoestrogen genistein.

Abnormal splicing of LMNA gene or aberrant processing of prelamin A results in progeroid syndrome. Here we show that lamin A interacts with and activates SIRT1. SIRT1 exhibits reduced association with nuclear matrix (NM) and decreased deacetylase activity in the presence of progerin or prelamin A, leading to rapid depletion of adult stem cells (ASCs) in Zmpste24(-/-) mice. Resveratrol enhances the binding between SIRT1 and A-type lamins to increases its deacetylase activity. Resveratrol treatment rescues ASC decline, slows down body weight loss, improves trabecular bone structure and mineral density, and significantly extends the life span in Zmpste24(-/-) mice. Our data demonstrate lamin A as an activator of SIRT1 and provide a mechanistic explanation for the activation of SIRT1 by resveratrol. The link between conserved SIRT1 longevity pathway and progeria suggests a stem cell-based and SIRT1 pathway-dependent therapeutic strategy for progeria.

[Source: Resveratrol rescues SIRT1-dependent adult stem cell decline and alleviates progeroid features in laminopathy-based progeria]


resveratrol protects fat cells from inflammation, helps fight cellulite

Dietary phytochemicals called polyphenols are known potent antioxidants that protect body tissues from free radical damage and consequent inflammation. Inflammation and oxidative damage are key components of cellulite, as well as diabetes and several other so-called civilisation diseases, such as heart disease and arthritis.

Recent research has now looked into 28 polyphenols (such as hesperidin, resveratrol, epigallocatechin gallate and curcumin) and concluded that those polyphenols protect fat cells from both oxidative damage and inflammation, by reducing inflammatory hormones, such as IL-6.

This practically means that orally taken polyphenols (either as foods or as supplements) can be used in the fight against fat tissue inflammation for the prevention of diabetes and cellulite. Polyphenols may also be used with local application in the fight against cellulite as active ingredients in an anti-cellulite cream. Naturally, the more of those polyphenols are present in the cream the better results are to be expected, due to a synergistic effect of using multiple ingredients.

Abstract: "Obesity has been associated with a marked risk of metabolic diseases and requires therapeutic strategies. Changes in redox status with increased oxidative stress in adipose tissue have been linked with obesity-related disorders. Thus, the biological effect of antioxidants such as polyphenols is of high interest. We aimed to measure antioxidant capacities of 28 polyphenols representative of main dietary phenolic acids, flavonoids, stilbenes and curcuminoids. Then, 14 molecules were selected for the evaluation of their effect on 3T3-L1 preadipocytes and human red blood cells exposed to oxidative stress. Analysis of reducing and free radical-scavenging capacities of compounds revealed antioxidant properties related to their structure, with higher activities for flavonoids such as quercetin and epicatechin. Their effects on preadipocytes' viability also depended on their structure, dose and time of exposure. Interestingly, most of the compounds exhibited a protective effect on preadipocytes exposed to oxidative stress, by reversing H₂O₂-induced anti-proliferative action and reactive oxygen species production. Polyphenols also exerted an anti-inflammatory effect on preadipocytes exposed to H₂O₂ by reducing IL-6 secretion. Importantly, such antioxidant and anti-inflammatory effects were observed in co-exposition (polyphenol and prooxidant during 24 h) or pretreatment (polyphenol during 24 h, then prooxidant for 24 h) conditions. Moreover, compounds protected erythrocytes from AAPH radical-induced lysis. Finally, these results led to demonstrate that antioxidant and anti-inflammatory properties of polyphenols may depend on structure, dose, time of exposure and cell conditioning with oxidative stress. Such findings should be considered for a better understanding of polyphenols' benefits in strategies aiming to prevent obesity-related diseases."

[Source: Evaluation of antioxidant properties of major dietary polyphenols and their protective effect on 3T3-L1 preadipocytes and red blood cells exposed to oxidative stress]



Resveratrol boosts thermogenic activity in brown fat cells, helps burn fat

Resveratrol, found in grapes, berries and red wine, is one of the most important anti-ageing natural chemicals available, and also possesses lipolytic capacity. In a new study published recently it was found that resveratrol boosts mitochondrial activity in brown fat cells under a high fat diet. Brown fat cells differ from normal white fat cells in that they burn fat in the mitochondria, thereby reducing obesity and its effects. This is in contrast to white fat cells, which accumulate fat, leading to obesity. Resveratrol was also found to improve insulin sensitivity, a hallmark of diabetes type II. This, and many other studies, point to the potential of resveratrol (and its more bioavailable form, pterostilbene) to help reduce body fat accumulation and its complications.

Source: The Effects of High Fat Diet and Resveratrol on Mitochondrial Activity of Brown Adipocytes.

Abstract: BACKGROUND: Resveratrol (RSV) is a polyphenolic phytoalexin that has many effects on metabolic diseases such as diabetes and obesity. Given the importance of brown adipose tissue (BAT) for energy expenditure, we investigated the effects of RSV on brown adipocytes. METHODS: For the in vitro study, interscapular BAT was isolated from 7-week-old male Sprague Dawley rats. For the in vivo study, 7-week-old male Otsuka Long Evans Tokushima Fatty (OLETF) rats were divided into four groups and treated for 27 weeks with: standard diet (SD); SD+RSV (10 mg/kg body weight, daily); high fat diet (HFD); HFD+RSV. RSV was provided via oral gavage once daily during the in vivo experiments. RESULTS: RSV treatment of primary cultured brown preadipocytes promoted mitochondrial activity, along with over-expression of estrogen receptor α (ER-α). In OLETF rats, both HFD and RSV treatment increased the weight of BAT and the differentiation of BAT. However, only RSV increased the mitochondrial activity and ER-α expression of BAT in the HFD-fed group. Finally, RSV improved the insulin sensitivity of OLETF rats by increasing the mitochondrial activity of BAT, despite having no effects on white adipocytes and muscles in either diet group. CONCLUSION: RSV could improve insulin resistance, which might be associated with mitochondrial activity of brown adipocyte. Further studies evaluating the activity of RSV for both the differentiation and mitochondrial activity of BAT could be helpful in investigating the effects of RSV on metabolic parameters.



The sirtuin SIRT1 (and consequently resveratrol and pterostilbene) improves metabolic health, may prevent ageing

SIRT1 and other sirtuins in metabolism. Study highlights: Sirtuins respond to energy level changes and execute salutary effects resembling calorie restriction (CR). Sirtuins mediate CR effects in various cellular compartments and are crucial metabolic regulators in multiple tissues. Small molecules that enhance sirtuin activities, including CR mimetics and NAD+ precursors, are promising strategies to ameliorate age-related diseases. Abstract: Sirloins such as SIRT1 are conserved protein NAD+-dependent deacylases and thus their function is intrinsically linked to cellular metabolism. Over the past two decades, accumulating evidence has indicated that sirtuins are not only important energy status sensors but also protect cells against metabolic stresses. Sirtuins regulate the aging process and are themselves regulated by diet and environmental stress. The versatile functions of sirtuins including, more specifically, SIRT1 are supported by their diverse cellular location allowing cells to sense changes in energy levels in the nucleus, cytoplasm, and mitochondrion. SIRT1 plays a critical role in metabolic health by deacetylating many target proteins in numerous tissues, including liver, muscle, adipose tissue, heart, and endothelium. This sirtuin also exerts important systemic effects via the hypothalamus. This review will cover these topics and suggest that strategies to maintain sirtuin activity may be on the horizon to forestall diseases of aging.



Resveratrol reduces fat and cholesterol and improves metabolism, especially when combined with a high protein diet

Source: Distinct metabolic effects of resveratrol on lipogenesis markers in mice adipose tissue treated with high-polyunsaturated fat and high-protein diets

Abstract: OBJECTIVE: A healthy diet is essential for the prevention of metabolic syndrome. The present study evaluated the effect of resveratrol associated with high-polyunsaturated fat and high-protein diets on expression of adipogenic and lipogenic genes. RESEARCH METHODS & PROCEDURES: FVB/N mice were divided into 6 groups (n=7 each) and fed with experimental diets for 60days: standard (ST), high-fat diet (HFD), and high-protein diet (HPD), with and without resveratrol (RSV) (4g/kg diet). The body weight, food intake, energy intake (kcal), and blood parameters (HDL-C, total cholesterol, glucose, and triglyceride levels) were assessed. Real-time PCR was performed to analyze the expression of adipogenesis and lipogenesis markers: PPARγ, SREBP-1c, ACC and FAS in samples from perigonadal adipose tissue. RESULTS: In the HPD+RSV group, resveratrol decreased body weight, body adiposity, adipose tissue weight, adipocyte area, total cholesterol, ACC and FAS expression, and increased HDL-cholesterol in comparison to HPD. In the HPD group there was a decrease in adipocyte area, as well as PPARγ, SREBP-1c and ACC expression in comparison to ST. While in HFD+RSV, resveratrol decreased levels of total cholesterol in comparison to HFD. In the HFD group there was decrease in body weight, and PPARγ, SREBP-1c and ACC expression in comparison to ST. CONCLUSIONS: The obtained results show that resveratrol decreases lipogenesis markers and metabolic parameters in the setting of a high-protein diet. Moreover, resveratrol decreased total cholesterol in both diets. These results point to the increased potential of resveratrol use in prevention of metabolic syndrome, acting on different dietary compositions.



Resveratrol and pterostilbene can inhibit low grade adipocyte inflammation via sirtuin activation

SIRT1 activation can inhibit NF-κB, and thereby inflammation, in adipose tissue, via multiple pathways. Low grade inflammation is a major component of the metabolic syndrome, diabetes, and of course cellulite. Pterostilbene and resveratrol activate SIRT1 expression in adipose tissue, which in turn inhibits inflammation, and thereby can help treat cellulite, via either oral or local application, as components of a cellulite cream.

Source: Molecular Mechanisms of Latent Inflammation in Metabolic Syndrome. Possible Role of Sirtuins and Peroxisome Proliferator-Activated Receptor Type γ.

Abstract: The problem of metabolic syndrome is one of the most important in medicine today. The main hazard of metabolic syndrome is development of latent inflammation in adipose tissue, which promotes atherosclerosis, non-alcoholic fatty liver disease, myocarditis, and a number of other illnesses. Therefore, understanding of molecular mechanisms of latent inflammation in adipose tissue is very important for treatment of metabolic syndrome. Three main components that arise during hypertrophy and hyperplasia of adipocytes underlie such inflammation: endoplasmic reticulum stress, oxidative stress, and hypoxia. Each of these components mediates activation in different ways of the key factor of inflammation - NF-κB. For metabolic syndrome therapy, it is suggested to influence a number of inflammatory signaling components by activating other cell factors to suppress development of inflammation. Such potential factors are peroxisome proliferator-activated receptors type γ that suppress transcription factor NF-κB through direct contact or via kinase of a NF-κB inhibitor (IKK), and also the antiinflammatory transcription factor AP-1. Other possible targets are type 3 NAD+-dependent histone deacetylases (sirtuins). There are mutually antagonistic relationships between NF-κB and sirtuin type 1 that prevent development of inflammation in metabolic syndrome. Moreover, sirtuin type 1 inhibits the antiinflammatory transcription factor AP-1. Study of the influence of these factors on the relationship between macrophages and adipocytes, macrophages, and adipose tissue-derived stromal cells can help to understand mechanisms of signaling and development of latent inflammation in metabolic syndrome.



Pterostilbene reduces lipogenesis (fat accumulation in fat tissue), even when on a high calorie diet

Pterostilbene, a dimethyl ether derivative of resveratrol, reduces fat accumulation in rats fed an obesogenic diet

The current study aimed to demonstrate the effects of pterostilbene in rats fed an obesogenic  diet. For this purpose, pterostilbene was administered at doses of 15 mg/kg body weight/day (PT15 group) or 30 mg/kg body weight/day (PT30 group) for 6 weeks. Pterostilbenereduced adipose tissue mass -15.1% (PT15) and -22.9% (PT30). In this tissue, it decreased malic enzyme (-39.4 and -49.5% for PT15 and PT30 groups, respectively) and fatty acid synthase (-45 and -53.4% for PT15 and PT30) activities. Acetyl-CoA carboxylase activity was reduced and AMPK activity was increased only in the PT30 group. In the liver, pterostilbene (PT30) reduced malic enzyme (-29.5%) and glucose-6-P dehydrogenase (-43.2%) activities and increased carnitine palmitoyltransferase-1a (37.5%) and acyl-coenzyme A oxidase (42.5%) activities. This increased oxidative capacity was not associated with increased mitochondriogenesis. Among biochemical serum parameters, only insulin was modified by pterostilbene (-31.6%) in the PT15 group. The amounts of pterostilbene in serum and tissues from rats in the PT30 group were in all cases 2-fold greater than those found in the PT15 group. In conclusion, pterostilbene shows antiobesity properties due, at least in part, to reduced lipogenesis in adipose tissue and increased fatty acid oxidation in liver.



Pterostilbene displays better anti-inflammatory activity than resveratrol!

Source: Pterostilbene surpassed resveratrol for anti-inflammatory application: Potency consideration and pharmacokinetics perspective

Abstract: This study aimed to evaluate the suitability of pterostilbene for anti-inflammatory application. The in vitro anti-inflammatory activities of pterostilbene were assessed using resveratrol, piceatannol and resveratrol trimethyl ether as comparators while its pharmacokinetics was examined in rats. All tested compounds displayed concentration-dependent anti-proliferative effect in E11 human rheumatoid arthritic synovial fibroblasts. They also suppressed LPS-induced NF-κB p65 nuclear translocation, down-regulated the secretions of IL-6, IL-18, VEGF, nitric oxide, MMP-2 and MMP-9 in E11 cells and attenuated E11-driven migration of THP-1 and U937 monocytes. Similarly, they inhibited LPS-induced pro-inflammatory cytokines in THP-1 cells. Interestingly, pterostilbene usually displayed in vitro anti-inflammatory potencies stronger than resveratrol. In vivo studies revealed that pterostilbene was extensively distributed to major drug target organs like liver, kidney, heart, lung as well as brain and repeated oral dosing did not significantly alter its pharmacokinetics. In conclusion, pterostilbene appears to be a promising candidate for further development.



Pterostilbene inhibits fat accumulation in adipocytes by blocking PPAR-gamma and FAS

Pterostilbene inhibits lipid accumulation through cell cycle delay in 3T3-L1 adipocyte

Obesity is caused abnormal or excessive fat accumulation that presents a risk to health such as high blood pressure, type 2 diabetes and atherosclerosis. However, recent studies have reported that resveratrol has numerous beneficial effect on cardio-protective, anti-cancer and obesity. Pterostilbene is a stilbenoid and structurally related to resveratrol. Pterostilbene have reported that anti-oxidant, anti-inflammatory, and anti-carcinogenic properties more than resveratrol. Objective: In this study, we examined that pterostilbene inhibits lipid accumulation by cell cycle delay. ABSTRACT: Methods: We investigated Cell viability of pterostilbene through XTT assay. Lipid accumulation of 3T3-L1 checked by using Oil-Red O staining. We experimented western blot to check down regulating obesity-related genes in protein level. Results: Pterostilbene delayed cell cycle in the S phage which is related with delay of cell differentiation. Pterostilbene decreased the accumulation of lipid droplets. The expression of Peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT-enhancer-binding proteins (C/EBPα), and adipocyte protein 2 was decreased by pterostilbene. In addition, pterostilbene reduced lipogenesis (LPAATθ, lipin1, and DGAT1) and fatty acid synthesis (FASN, SREBP) factor in protein level dose dependent manner. Conclusion: Our findings show that pterostilbene inhibits lipid accumulation by regulating adipogenic factors and delaying cell cycle.



The berry phytochemicals quercetin, kaempferol and pterostilbene boost antioxidant defences by activating NrF2

Source: The berry constituents quercetin, kaempferol, and pterostilbene synergistically attenuate reactive oxygen species: involvement of the Nrf2-ARE singling pathway,

Abstract: Quercetin, kaempferol, and pterostilbene are abundant in berries. The anti-oxidative properties of these constituents may contribute to cancer chemoprevention. However, their precise mechanisms of action and their combinatorial effects are not completely understood. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) regulates anti-oxidative stress enzymes and Phase II drug metabolizing/detoxifying enzymes by binding to antioxidant response element (ARE). This study aimed to investigate the anti-oxidative stress activities of quercetin, kaempferol, and pterostilbene individually and in combination, as well as the involvement of the Nrf2-ARE signaling pathway. Quercetin, kaempferol, and pterostilbene all exhibited strong free-radical scavenging activity in the DPPH assay. The MTS assay revealed that low concentration combinations we tested were relatively non-toxic to HepG2-C8 cells. The results of the DCFH-DA assay and combination index (CI) indicated that quercetin, kaempferol, and pterostilbene attenuated intracellular reactive oxygen species (ROS) levels when pretreated individually and had synergistic effects when used in combination. In addition, the combination treatment significantly induced ARE and increased the mRNA and protein expression of Nrf2-regulated genes. Collectively, our study demonstrated that the berry constituents quercetin, kaempferol, and pterostilbene activated the Nrf2-ARE signaling pathway and exhibited synergistic anti-oxidative stress activity at appropriate concentrations.



Pterostilbene protects from UV-B skin damage (wrinkles, ageing and redness) and skin cancer, by boosting the skin's antioxidant defences

Source: Topical treatment with pterostilbene, a natural phytoalexin, effectively protects hairless mice against UVB radiation-induced skin damage and carcinogenesis,

Abstract: The aim of our study was to investigate in the SKH-1 hairless mouse model the effect of pterostilbene (Pter), a natural dimethoxy analog of resveratrol (Resv), against procarcinogenic ultraviolet B radiation (UVB)-induced skin damage. Pter prevented acute UVB (360 mJ/cm(2))-induced increase in skin fold, thickness, and redness, as well as photoaging-associated skin wrinkling and hyperplasia. Pter, but not Resv, effectively prevented chronic UVB (180 mJ/cm(2), three doses/week for 6 months)-induced skin carcinogenesis (90% of Pter-treated mice did not develop skin carcinomas, whereas a large number of tumors were observed in all controls). This anticarcinogenic effect was associated with (a) maintenance of skin antioxidant defenses (i.e., glutathione (GSH) levels, catalase, superoxide, and GSH peroxidase activities) close to control values (untreated mice) and (b) an inhibition of UVB-induced oxidative damage (using as biomarkers 8-hydroxy-2'-deoxyguanosine, protein carbonyls, and isoprostanes). The molecular mechanism underlying the photoprotective effect elicited by Pter was further evaluated using HaCaT immortalized human keratinocytes and was shown to involve potential modulation of the Nrf2-dependent antioxidant response.



Pterostilbene more effective than resveratrol due to increased bioavailability 

Source: Promising therapeutic potential of pterostilbene and its mechanistic insight based on preclinical evidence.

Abstract: Pterostilbene (PS) is a well-recognized antioxidant that primarily exists in blueberries, grapevines and heartwood of red sandalwood. Interest in this compound has been renewed in recent years, and studies have found that PS possesses an array of pharmacological properties, including chemopreventive, antiinflammatory, antidiabetic, antidyslipidemic, antiatherosclerotic and neuroprotective effects. However, the greater in vivo bioavailability of PS, as compared to resveratrol, is an added advantage for its efficacy. This review provides a summary regarding the sources, pharmacokinetic aspects and pharmacodynamics of PS, with a focus on the molecular mechanisms underlying its protective effects against cancer, brain injuries and heart disease. Studies regarding the safety profile of PS have also been included. Based on the presently available evidence, we conclude that PS represents an active phytonutrient and a potential drug with pleiotropic health applications.



Pterostilbene may fight cellulite by reducing inflammation in fat cells 


Broad-spectrum protection against fight tissue inflammation - and cellulite

Pterostilbene, is an anti-ageing phytochemical primarily found in berries and grapes. It is closely related to another well-known anti-ageing chemical, resveratrol (the secret behind the so-called "French paradox"). Based on animal studies, both resveratrol and pterostilbene are thought to exhibit anti-cancer, anti-inflammatory and anti-ageing properties.

In this study it was discovered that pterostilbene (and the phytochemical garcinol) has a specific anti-inflammatory action on adipocytes (fat cells), reducing almost all important inflammatory markers: COX-2, iNOS, IL-6, and IL-1β and IL-6!

This is important news for cellulite reduction, as fat tissue inflammation is an important aspect of cellulite, and pterostilbene may be used in the fight against cellulite as an anti-cellulite cream ingredient, or to a lesser extent as a nutritional supplement ingredient.

Paper: The inhibitory effect of pterostilbene on inflammatory responses during the interaction of 3T3-L1 adipocytes and RAW 264.7 macrophages,

Abstract: Chronic inflammation is characterized by the upregulation of proinflammatory cytokines in obese adipose tissue. Accumulations of adipose tissue macrophages enhance a chronic inflammatory state in adipose tissues. Many studies have indicated that the adipocyte-related inflammatory response in obesity is characterized by an enhanced infiltration of macrophages. The aim of this work was to study the inhibitory effects of garcinol and pterostilbene on the change in inflammatory response due to the interaction between 3T3-L1 adipocytes and RAW 264.7 macrophages. In the TNF-α-induced 3T3-L1 adipocyte model, garcinol and pterostilbene significantly decreased the mRNA expression of COX-2, iNOS, IL-6, and IL-1β and IL-6 secretion by suppressing phosphorylation of p-IκBα and p-p65. In a coculture model of 3T3-L1 adipocytes and RAW 264.7 macrophages, pterostilbene suppressed IL-6 and TNF-α secretion and proinflammatory mRNA expression and also reduced the migration of macrophages toward adipocytes. In the RAW 264.7 macrophage-derived conditioned medium (RAW-CM)-induced 3T3-L1 adipocyte and 3T3-CM-induced RAW 264.7 macrophage models, pterostilbene significantly decreased IL-6 and TNF-α secretion and proinflammatory mRNA expression (COX-2, iNOS, IL-6, TNF-α, PAI-1, CRP, MCP-1, resistin, and leptin). Our findings suggest that garcinol and pterostilbene may provide novel and useful applications to reduce the chronic inflammatory properties of adipocytes. We also found that pterostilbene inhibits proinflammatory responses during the interaction between 3T3-L1 adipocytes and RAW 264.7 macrophages.



Resveratrol inhibits the growth of adipose tissue

The natural anti-aging chemical resveratrol was shown in this study to inhibit the growth of new fat tissue - and consequently the growth of cellulite - by activating a protein called Wnt/β-catenin. Pterostilbene, which also activates SIRT1 and is more bioavailable should exert the same effect too. In combination with other anti-cellulite actives, resveratrol and pterostilbene can be a valuable component of anti-cellulite creams. On the other hand, nicotinamide  / vitamin B3, which is erroneously used in anti-cellulite creams, was shown in the same study (and multiple studies in the past) to actually stimulate the growth of fat tissue

Technical summary: Resveratrol and SIRT1 inhibit adipogenesis by upregulating Wnt/β-catenin

Source:  SIRT1 inhibits adipogenesis and promotes myogenic differentiation in C3H10T1/2 pluripotent cells by regulating Wnt signaling

Abstract: BACKGROUND: The directed differentiation of mesenchymal stem cells (MSCs) is tightly controlled by a complex network. Wnt signaling pathways have an important function in controlling the fate of MSCs. However, the mechanism through which Wnt/β-catenin signaling is regulated in differentiation of MSCs remains unknown. SIRT1 plays an important role in the regulation of MSCs differentiation. RESULTS: This study aimed to determine the effect of sirtuin 1 (SIRT1) on adipogenesis and myogenic differentiation of C3H10T1/2 cells. First, the MSC commitment and differentiation model was established by using 5-azacytidine. Using the established model, C3H10T1/2 cells were treated with SIRT1 activator/inhibitor during differentiation. The results showed that resveratrol inhibits adipogenic differentiation and improves myogenic differentiation, whereas nicotinamide promotes adipogenic differentiation. Notably, during commitment, resveratrol blocked adipocyte formation and promoted myotubes differentiation, whereas nicotinamide enhanced adipogenic potential of C3H10T1/2 cells. Furthermore, resveratrol elevated the expression of Cyclin D1 and β-catenin in the early stages. The luciferase assay showed that knockdown SIRT1 inhibits Wnt/β-catenin signaling, while resveratrol treatment or overexpression SIRT1 activates Wnt/β-catenin signaling. SIRT1 suppressed the expression of Wnt signaling antagonists sFRP2 and DACT1. Knockdown SIRT1 promoted adipogenic potential of C3H10T1/2 cells, whereas overexpression SIRT1 inhibited adipogenic differentiation and promoted myogenic differentiation. CONCLUSIONS: Together, our results suggested that SIRT1 inhibits adipogenesis and stimulates myogenic differentiation by activating Wnt signaling.



Resveratrol stimulates the body to use its own antioxidant defences

Resveratrol is a mild pro-oxidant, not an anti-oxidant, which in turn stimulates the cells' antioxidant defences. Most people think that resveratrol, the active ingredient in blueberries and red wine, is an antioxidant itself. This paper suggests that resveratrol is a mild pro-oxidant instead, which stimulates the cell's Nrf-2 antioxidant capacity. This triggers cells to produce glutathione, the body's most potent detoxification and antioxidant chemical, which in turns fights oxidation and DNA damage. However, all the latest research agrees with this finding: polyphenols and carotenoids do not act as antioxidant themselves inside the body, they instead act either as anti-inflammatory or they trigger the Nrf-2 system which then boosts detoxification and antioxidant capacity.

Resveratrol is not an "antioxidant": Resveratrol is a well-known anti-ageing plant molecule, contained in grapes, berries and red wine, among other foods. Resveratrol works by increasing a protein called SIRT1, which improves lifespan and overall health and fights fat accumulation. But most importantly, resveratrol was thought to work as an "antioxidant".

However, this new study published this week shows that resveratrol does not act as an antioxidant. Instead it acts in quite the opposite way, as a pro-oxidant. The researchers have found that by being slightly poor-oxidant, resveratrol stimulates the body to boost its antioxidant defences and produce more glutathione, one of the body's own powerful antioxidants.

Resveratrol is "hormetic": Resveratrol achieves this effect by stimulating a protein called Nrf2, which is known to stimulate the body's own antioxidant defences. In fact, more and more papers, published the last few months, show that previously thought antioxidant molecules actually act as pro oxidants, by stimulating the same process, mediated by the protein Nrf2. nudge

The process by which a little bit of negative stimulation leads to positive changes in the body is called hormesis, a Greek work which means "gaining momentum". So by getting a bit of negative stimulation (mild free radical damage) that body is gently nudged, it gains momentum, to get much more efficient in fighting free radical damage.

Paper: Hormetic shifting of redox environment by pro-oxidative resveratrol protects cells against stress.

Abstract: Resveratrol has gained tremendous interest owing to multiple reported health-beneficial effects. However, the underlying key mechanism of action of this natural product remained largely controversial. Here, we demonstrate that under physiologically relevant conditions major biological effects of resveratrol can be attributed to its generation of oxidation products such as reactive oxygen species (ROS). At low nontoxic concentrations (in general <50µM), treatment with resveratrol increased viability in a set of representative cell models, whereas application of quenchers of ROS completely truncated these beneficial effects. Notably, resveratrol treatment led to mild, Nrf2-specific gene expression reprogramming. For example, in primary epidermal keratinocytes derived from human skin this coordinated process resulted in a 1.3-fold increase of endogenously generated glutathione (GSH) and subsequently in a quantitative reduction of the cellular redox environment by 2.61mVmmol GSH per g protein. After induction of oxidative stress by using 0.78% (v/v) ethanol, endogenous generation of ROS was consequently reduced by 24% in resveratrol pre-treated cells. In contrast to the common perception that resveratrol acts mainly as a chemical antioxidant or as a target protein-specific ligand, we propose that the cellular response to resveratrol treatment is essentially based on oxidative triggering. In physiological microenvironments this molecular training can lead to hormetic shifting of cellular defense towards a more reductive state to improve physiological resilience to oxidative stress.



Resveratrol and curcumin hybrids provide strong anti-inflammatory action

Resveratrol, found in black grapes, berries and red wine) and curcumin (found in turmeric) are proven anti-inflammatory, antioxidant and anti-ageing natural molecules, but their absorption and instability limit their clinical use. Liposomal and other enhanced absorption and stability forms are already sued in supplements and cosmetics with the combination of the two natural chemicals providing synergistic results. Now scientists have created hybrids of curcumin and resveratrol which possess increased anti-inflammatory activity and proved their efficacy on acute lung injury, hoping that these compounds can lead to the development of new drugs against inflammatory conditions. In the meantime, the stabilised forms of high purity resveratrol and curcumin already provide valuable anti-ageing, anti-inflammatory and antioxidant benefits in a group of select skin care products, if used in high concentrations.

Source: Development of resveratrol-curcumin hybrids as potential therapeutic agents for inflammatory lung diseases.

Abstract: Acute lung injury (ALI) is a major cause of acute respiratory failure in critically-ill patients. Resveratrol and curcumin are proven to have potent anti-inflammatory efficacy, but their clinical application is limited by their metabolic instability. Here, a series of resveratrol and the Mono-carbonyl analogs of curcumin (MCAs) hybrids were designed and synthesized by efficient aldol construction strategy, and then screened for anti-inflammatory activities in vitro and in vivo. The results showed that the majority of analogs effectively inhibited the LPS-induced production of IL-6 and TNF-α. Five analogs, a9, a18, a19, a20 and a24 exhibited excellent anti-inflammatory activity in a dose-dependent manner along with low toxicity in vitro. Structure activity relationship study revealed that the electron-withdrawing groups at meta-position and methoxyl group (OCH3) at the para position of the phenyl ring were important for anti-inflammatory activities. The most promising compound a18 decreased LPS induced TNF-α, IL-6, IL-12, and IL-33 mRNA expression. Additionally, a18 significantly protected against LPS-induced acute lung injury in the in vivo mouse model. The research of resveratrol and MCAs hybrids could bring insight into the treatment of inflammatory diseases and compound a18 may serve as a lead compound for the development of anti-ALI agents.




Resveratrol reduces conversion of glucose into fat in fat cells, boosts the lipolytic effect of adrenaline / exercise and inhibits the anti-lipolytic effect of insulin

Source: Resveratrol directly affects in vitro lipolysis and glucose transport in human fat cells.

Abstract: Resveratrol is a naturally occurring polyphenol found in many dietary sources and red wine. Recognized as a cancer chemoprevention agent, an anti-inflammatory factor and an antioxidant molecule, resveratrol has been proposed as a potential anti-obesity compound and to be beneficial in diabetes. Most of the studies demonstrating the anti-adipogenic action of resveratrol were performed as long-term treatments on cultured preadipocytes. The aim of this study was to analyse the acute effects of resveratrol on glucose uptake and lipolysis in human mature adipocytes. Samples of subcutaneous abdominal adipose tissue were obtained from overweight humans and immediately digested by liberase. Fat cells were incubated (from 45 min to 4 h) with resveratrol 1 μM-1 mM. Then, glycerol release or hexose uptake was determined. Regarding lipolysis, the significant effects of resveratrol were found at 100 μM, consisting in a facilitation of isoprenaline stimulation and an impairment of insulin antilipolytic action. At 1 and 10 μM, resveratrol only tended to limit glucose uptake. Resveratrol 100 μM did not change basal glucose uptake but impaired its activation by insulin or by benzylamine. This inhibition was not found with other antioxidants. Such impairment of glucose uptake activation in fat cells may led to a reduced availability of glycerol phosphate and then to a decreased triacylglycerol assembly. Therefore, resveratrol increased triacylglycerol breakdown triggered by β-adrenergic activation and impaired lipogenesis. Consequently, our data indicate that resveratrol can be considered as limiting fat accumulation in human fat cells and further support its use for the mitigation of obesity.



Resveratrol has antioxidant, anti-ageing and anti-inflammatory action (ideal for leg/anti-cellulite/anti-ageing creams)

Resveratrol is well-known and widely researched for its anti-ageing, anti-inflammatory and antioxidant action, and for these reasons is an ideal ingredient of anti-ageing, leg wellness and anti-cellulite creams  

Source: Well-Known Antioxidants and Newcomers in Sport Nutrition: Resveratrol

Abstract: Resveratrol (3,5,4´-trihydroxystilbene) is a natural polyphenolic flavonoid (Baur and Sinclair 2006). It is freely available in food supplements and is found in the seeds and skins of grapes, red wine, mulberries, peanuts and rhubarb (Baur and Sinclair 2006, Nieman et al. 2012). Many in vivo and in vitro studies (Brisdelli et al. 2009, Ventura-Clapier 2012) have provided evidence for neuroprotective, anti-atherogenic, antithrombotic, antihypercholesterolemic, anti-inflammatory, antioxidant, proangiogenic, vasorelaxing and anticancer effects of resveratrol. Interestingly, it has also been shown that resveratrol increases skeletal muscle mitochondrial biogenesis and fatty acid oxidation in many tissues as well as exercise performance in mice (Dolinsky et al. 2012). Pharmacokinetic studies indicate that resveratrol has a poor bioavailability. Resveratrol, even at the high dosage of 750 mg (kg·body weight–1) per day for 13 weeks by the oral route, has been shown to have no adverse effects (Edwards et al. 2011). Pharmacological studies also suggest that therapeutic doses of resveratrol are non-toxic, easily absorbed and well tolerated by humans. A dose of 150 mg·kg–1·day–1 has been used in the study of Dolinsky et al. (2012), while other studies have shown that lower doses of 20––1 proved to be efficient in preventing cardiac dysfunction (Rimbaud et al. 2011) and pulmonary hypertension (Csiszar et al. 2009) and also in vasoprotection (Ungvari et al. 2007). Interest in resveratrol in sport medicine arose after animal studies assessed endurance performance of mice and found a dose-dependent increase in exercise tolerance, improved motor skills and increased number and activity of mitochondria in muscle cells. Both exercise and resveratrol are thought to trigger biochemical cascades, leading to improved mitochondrial function and energy metabolism. Indeed, it has been shown that resveratrol enhances mitochondrial biogenesis and induces adenosine 5´ monophosphate-activated protein kinase (AMPK) in the skeletal muscle of mice (Baur and Sinclair 2006, Lagouge et al. 2006). However, when SIRT1 was knocked out, these effects were absent (Price et al. 2012). Resveratrol as a food supplement in sport medicine has not received much attention especially in human studies, despite some basic scientific evidence that this substance could have multiple indications related to high-performance sport (Nieman et al. 2012). Resveratrol has been also touted as an exercise mimetic effect through its activation of SIRT1 and AMPK (Hart et al. 2013). To support this hypothesis, it has been demonstrated that resveratrol supplementation increases the exercise performance in aged mice (Murase et al. 2009) and mice fed by a Western diet (Lagouge et al. 2006) in the absence of exercise training, suggesting that resveratrol can stimulate pathways similar to exercise. Ryan et al. (2010)demonstrated that 10 days of resveratrol supplementation also diminishes the basal levels of oxidative stress associated with ageing. Functional measurements of maximal isometric force and rate of fatigue were unaffected by resveratrol supplementation in aged animals. Mice treated with resveratrol demonstrated elevations in AMPK activation and PGC-1α expression, along with increases in mitochondria in animals fed by a high fat diet (Baur and Sinclair 2006). Additionally, enhanced SIRT1 activity like exercise training decreases plasma glucose levels, improves insulin sensitivity, increases mitochondrial number and function, decreases adiposity, improves exercise tolerance and potentially lowers body weight (Elliott and Jirousek 2008). The induction of PGC-1α and activation of AMPK are commonly observed following both exercise and resveratrol administration (Ruderman and Prentki 2004,Baur and Sinclair 2006, Lagouge et al. 2006, Zang et al. 2006). Menzies et al. (2013) demonstrated that SIRT1 protein is responsible for the partial maintenance of basal mitochondrial content and function, in addition to lowering mitochondrial ROS generation and improving fatigue in skeletal muscle. They also showed that resveratrol can activate both AMPK and p38 in temporally distinct stages, which could promote post-translational changes in PGC-1α, thereby altering its activity (Jäger and Nguyen-Duong 1999). These studies (Jäger and Nguyen-Duong 2007, Menzies et al. 2013) also demonstrated that high doses of resveratrol were necessary for AMPK-mediated activation of SIRT1. The resveratrol-induced improvement in energy metabolism is at least partly mediated by specific signal transduction pathways and resveratrol seems mediated by enhanced mitochondrial biogenesis with the activation of the AMPK-SIRT1-PGC-1α pathway (Ventura-Clapier 2012). Resveratrol administration seems to induce a higher aerobic capacity in mice, as shown by the increased running time and oxygen consumption in muscle fibres (Menzies et al. 2013). Similarly, Hart et al. (2013) suggested that resveratrol supplementation enhanced the effects of exercise on endurance capacity, and this was shown in rats which already had a high level of aerobic endurance. These findings suggest that resveratrol could be used as a performance enhancer (Baur and Sinclair 2006, Lagouge et al. 2006). Dolinsky et al. (2012) demonstrated that a combination of resveratrol and exercise training increased time to exhaustion compared to exercise training. The authors suggested that resveratrol optimises fatty acid metabolism, which may contribute to the increased contractile force response of skeletal muscles. 



Resveratrol leads to fat reduction and weight loss in animals and humans

Yet another study, published today, which shows that resveratrol boosts fat reduction - and is therefore ideal in the fight against cellulite. This study shows that resveratrol inhibits the growth of new fat cells (preadipocyte differentiation) and reduces the growth of mitochondria and fat storage in fat cells, leading to weight loss in animals and humans

Source: Resveratrol inhibits lipogenesis of 3T3-L1 and SGBS cells by inhibition of insulin signalling and mitochondrial mass increase

Abstract: Resveratrol is attracting much interest because of its potential to decrease body weight and increase life span, influencing liver and muscle function by increasing mitochondrial mass and energy expenditure. Even though resveratrol was already shown to reduce the adipose tissue mass in animal models, its effects on mitochondrial mass and network structure in adipocytes has not yet been studied. For this purpose, we investigated the effect of resveratrol on mitochondrial mass increase and remodelling during adipogenic differentiation of two in vitro models of adipocyte biology, the murine 3 T3-L1 cell line and the human SGBS cell strain. We confirm that resveratrol inhibits lipogenesis in differentiating adipocytes, both mouse and human. We further show that this is linked to inhibition of the normally observed mitochondrial mass increase and mitochondrial remodelling. At the molecular level, the anti-lipogenic effect of resveratrol seems to be mediated by a blunted expression increase and an inhibition of acetyl-CoA carboxylase (ACC). This is one of the consequences of an inhibited insulin-induced signalling via Akt, and maintained signalling via AMP-activated protein kinase. The anti-lipogenic effect of resveratrol is further modulated by expression levels of mitochondrial ATAD3, consistent with the emerging role of this protein as an important regulator of mitochondrial biogenesis and lipogenesis. Our data suggest that resveratrol acts on differentiating preadipocytes by inhibiting insulin signalling, mitochondrial biogenesis, and lipogenesis, and that resveratrol-induced reduction of mitochondrial biogenesis and lipid storage contribute to adipose tissue weight loss in animals and humans.



Natural slimming compounds: dandelion induces early fat cell death/apoptosis, while caffeine, resveratrol from red wine and berries and DHA from fish oil, boost lipolysis and inhibit fat cell growth

In a new study published yesterday it was found that the humble dandelion (taraxacum official) is very effective in causing apoptosis in human visceral pre-adipocytes (abdominal "baby" fat cells). On the other hand DHA, on the the two main omega-3 fatty acids in fish oil, caffeine and the berry extract resveratrol, we more effective in reducing fat accumulation in fat cells. Caffeine, DHA and the olive leaf extract oleuropein were more effective in boosting fat reduction (lipolysis) in pre-adipocytes ("baby" fat cells). On the other hand, oleuropein, bitter orange and dandelion were more effective lipolytic agents in mature fat cells. Finally caffeine inhibited adipogenesis in pre-adipocytes, i.e. it inhibited the growth of baby fat cells. In summary, the most effective overall natural slimming chemicals that were assessed in this study were dandelion, caffeine and DHA, with resveratrol, oleuropein and bitter orange, also contributing to fat reduction. This limited study only assessed 8 natural chemicals, out of hundreds with proven activities in lipolysis, adipogenesis, apoptosis etc, so a much more broad comparative study of natural slimming agents is warranted

Source: Different anti-adipogenic effects of bio-compounds on primary visceral pre-adipocytes and adipocytes.

Abstract: Several natural compounds exhibit strong capacity for decreasing triglyceride accumulation, enhancing lipolysis and inducing apoptosis. The present study reports the anti-adipogenic effects of Silybum marianum (SL), Citrus aurantium (CA), Taraxacum officinale (TO), resveratrol (RE), Curcuma longa (CU), caffeine (CF), oleuropein (OL) and docosahexaenoic acid (DHA) in reducing differentiation and increasing lipolysis and apoptosis. Analyses were performed on human primary visceral pre-adipocytes after 10 (P10) and 20 (P20) days of treatment during differentiation and on mature adipocytes after 7 days of treatment (A7). The percentage of apoptosis induced by TO extract in P10 and P20 cells was significantly higher than that induced by all other compounds and in CTRL cells. Triglyceride accumulation was significantly lower in cells treated with DHA, CF, RE in comparison to cells treated with OL and in CTRL cells. Treatments with CF, DHA and OL significantly incremented lipolysis in P20 cells in comparison to other compounds and in CTRL cells. On the contrary, the treatment of A7 cells with OL, CA and TO compounds significantly increased cell lipolysis. The addition of CF in differentiating P20 pre-adipocytes significantly increased the expression of genes involved in inhibition of adipogenesis, such as GATA2, GATA3, WNT1, WNT3A, SFRP5, and DLK1. Genes involved in promoting adipogenesis such as CCND1, CEBPB and SREBF1 were significantly down-regulated by the treatment. The screening of bioactive compounds for anti-adipogenic effects showed that in differentiating cells TO extract was the most effective in inducing apoptosis and CF and DHA extracts were more efficient in inhibition of differentiation and in induction of cell lipolysis.



Study on mood and longevity gene identifies  quercetin, resveratrol, fish oil & vitamin D as potential longevity promoting compounds

Source: Mood, stress and longevity: convergence on ANK3.

Abstract: Antidepressants have been shown to improve longevity in C. elegans. It is plausible that orthologs of genes involved in mood regulation and stress response are involved in such an effect. We sought to understand the underlying biology. First, we analyzed the transcriptome from worms treated with the antidepressant mianserin, previously identified in a large-scale unbiased drug screen as promoting increased lifespan in worms. We identified the most robust treatment-related changes in gene expression, and identified the corresponding human orthologs. Our analysis uncovered a series of genes and biological pathways that may be at the interface between antidepressant effects and longevity, notably pathways involved in drug metabolism/degradation (nicotine and melatonin). Second, we examined which of these genes overlap with genes which may be involved in depressive symptoms in an aging non-psychiatric human population (n=3577), discovered using a genome-wide association study (GWAS) approach in a design with extremes of distribution of phenotype. Third, we used a convergent functional genomics (CFG) approach to prioritize these genes for relevance to mood disorders and stress. The top gene identified was ANK3. To validate our findings, we conducted genetic and gene-expression studies, in C. elegans and in humans. We studied C. elegans inactivating mutants for ANK3/unc-44, and show that they survive longer than wild-type, particularly in older worms, independently of mianserin treatment. We also show that some ANK3/unc-44 expression is necessary for the effects of mianserin on prolonging lifespan and survival in the face of oxidative stress, particularly in younger worms. Wild-type ANK3/unc-44 increases in expression with age in C. elegans, and is maintained at lower youthful levels by mianserin treatment. These lower levels may be optimal in terms of longevity, offering a favorable balance between sufficient oxidative stress resistance in younger worms and survival effects in older worms. Thus, ANK3/unc-44 may represent an example of antagonistic pleiotropy, in which low-expression level in young animals are beneficial, but the age-associated increase becomes detrimental. Inactivating mutations in ANK3/unc-44 reverse this effect and cause detrimental effects in young animals (sensitivity to oxidative stress) and beneficial effect in old animals (increased survival). In humans, we studied if the most significant single nucleotide polymorphism (SNP) for depressive symptoms in ANK3 from our GWAS has a relationship to lifespan, and show a trend towards longer lifespan in individuals with the risk allele for depressive symptoms in men (odds ratio (OR) 1.41, P=0.031) but not in women (OR 1.08, P=0.33). We also examined whether ANK3, by itself or in a panel with other top CFG-prioritized genes, acts as a blood gene-expression biomarker for biological age, in two independent cohorts, one of live psychiatric patients (n=737), and one of suicide completers from the coroner's office (n=45). We show significantly lower levels of ANK3 expression in chronologically younger individuals than in middle age individuals, with a diminution of that effect in suicide completers, who presumably have been exposed to more severe and acute negative mood and stress. Of note, ANK3 was previously reported to be overexpressed in fibroblasts from patients with Hutchinson-Gilford progeria syndrome, a form of accelerated aging. Taken together, these studies uncover ANK3 and other genes in our dataset as biological links between mood, stress and longevity/aging, that may be biomarkers as well as targets for preventive or therapeutic interventions. Drug repurposing bioinformatics analyses identified the relatively innocuous omega-3 fatty acid DHA (docosahexaenoic acid), piracetam, quercetin, vitamin D and resveratrol as potential longevity promoting compounds, along with a series of existing drugs, such as estrogen-like compounds, antidiabetics and sirolimus/rapamycin. Intriguingly, some of our top candidate genes for mood and stress-modulated longevity were changed in expression in opposite direction in previous studies in the Alzheimer disease. Additionally, a whole series of others were changed in expression in opposite direction in our previous studies on suicide, suggesting the possibility of a "life switch" actively controlled by mood and stress.



Citrus flavonoids, EGCG, resveratrol and curcumin increase lipolysis and fat burning, can help fight obesity, cellulite

Source: Phytochemicals in regulating fatty acid β-oxidation: Potential underlying mechanisms and their involvement in obesity and weight loss.

Abstract: Excessive accumulation of fat as the result of more energy intake and less energy expenditure is known as obesity. Lipids are essential components in the human body and are vital for maintaining homeostasis and physiological as well as cellular metabolism. Fatty acid synthesis and catabolism (by fatty acid oxidation) are normal part of basic fuel metabolism in animals. Fatty acids are degraded in the mitochondria by a biochemical process called β-oxidation in which two-carbon fragments are produced in each cycle. The increase in fatty acid oxidation is positively correlated with body mass index. Although healthy life style, avoiding Western diet, dieting and strenuous exercise are the commonly used methods to lose weight, they are not considered a permanent solution in addition to risk attenuation of in basal metabolic rate (BMR). Pharmacotherapy offers benefits of weight loss by altering the satiety and lowering absorption of fat from the food; however, its side effects may outweigh the benefits of weight loss. Alternatively, dietary phytochemicals and natural health products offer great potential as an efficient weight loss strategy by modulating lipid metabolism and/or increasing BMR and thermogenesis. Specifically, polyphenols such as citrus flavonoids, green tea epigallocatechin gallate, resveratrol, capsaicin and curcumin, have been reported to increase lipolysis and induce fatty acid β-oxidation through modulation of hormone sensitive lipase, acetyl-coA carboxylase, carnitine acyl transferase and peroxisome proliferator-activated receptor gamma coactivator-1. In this review article, we discuss selected phytochemicals in relation to their integrated functionalities and specific mechanisms for weight loss.



Metformin and resveratrol inhibit fat tissue hypoxia and inflammation - potential for cellulite reduction

Metformin and resveratrol ameliorate muscle insulin resistance through preventing lipolysis and inflammation in hypoxic adipose tissue.

Abstract: This study aims to investigate the effects of metformin and resveratrol on muscle insulin resistance with emphasis on the regulation of lipolysis in hypoxic adipose tissue. ICR mice were fed with high fat diet (HFD) for 10days with administration of metformin, resveratrol, or intraperitoneal injection of digoxin. Adipose hypoxia, inflammation and cAMP/PKA-dependent lipolysis were investigated. Moreover, lipid deposition and insulin resistance were examined in the muscle. Metformin and resveratrol attenuated adipose hypoxia, inhibited HIF-1α expression and inflammation in the adipose tissue of HFD-fed mice. Metformin and resveratrol inhibited lipolysis through prevention of PKA/HSL activation by decreasing the accumulation of cAMP via preserving PDE3B. Metformin and resveratrol reduced FFAs influx and DAG accumulation, and thus improved insulin signaling in the muscle by inhibiting PKCθ translocation. This study presents a new view of regulating lipid metabolism to ameliorate insulin resistance and provides the clinical guiding significance for obesity and type 2 diabetes with metformin and resveratrol treatment.



Resveratrol fights inflammation in obesity and overweight

Source: The Effects of Resveratrol Supplementation in Overweight and Obese Humans: A Systematic Review of Randomized Trials.

Abstract: BACKGROUND: Obesity and metabolic syndrome are significant global health issues, with current public health messages predominately focused on altering dietary and physical activity behaviors. Resveratrol is a polyphenol (stilbenoid) commonly found in grapes, and human trials to date have shown conflicting and limited beneficial effects with respect to health. The aim of this study was to determine the effect of resveratrol supplementation on reducing body weight and modifying associated inflammatory markers. METHODS: A systematic review was undertaken following the PRISMA guidelines and using five indexed databases (OVID MEDLINE, Cochrane Library, Web of Science, SCOPUS, and CINAHL). A search strategy was formulated to select randomized, double-blind, placebo-controlled human trials investigating the effects of resveratrol supplementation on obesity or overweight, including body weight, metabolic and inflammatory markers. RESULTS: Five thousand five hundred sixty-nine studies published from 1990 to November 2015 were identified, with only nine papers meeting the inclusion criteria. The studies involved 208 participants (aged 49.2 ± 8.3 years) and utilized a substantial range of resveratrol doses (75-3000 mg/day). Study durations were a minimum of 2 weeks (14-90 days). Seven studies indicated no significant change in body mass index or body weight (P > 0.05), and three studies showed no improvements in fat mass, fat volume, or abdominal fat distribution (P > 0.05). Four studies included measurements of inflammatory markers, with three of these finding resveratrol supplementation to have a significant positive effect (P > 0.05). CONCLUSION: Based on the included studies, there is currently insufficient evidence to support the recommendation of resveratrol supplements in management of obesity. However, there were significant but not entirely consistent anti-inflammatory effects after resveratrol supplementation in overweight and obese individuals.



Retinol, niacinamide, resveratrol and hexylresorcinol cream provides anti-ageing, skin brightening results

Source: Efficacy and Tolerability of a Skin Brightening/Anti-Aging Cosmeceutical Containing Retinol 0.5%, Niacinamide, Hexylresorcinol, and Resveratrol.

Abstract: Consumers are increasingly interested in over-the-counter skin care products that can improve the appearance of photodamaged and aging skin. This 10-week, open-label, single- center study enrolled 25 subjects with mild to moderate hyperpigmentation and other clinical stigmata of cutaneous aging including fine lines, sallowness, lack of clarity, and wrinkling. Their mean age was 53.4±7.7 years. The test product contained retinol 0.5% in combination with niacinamide 4.4%, resveratrol 1%, and hexylresorcinol 1.1% in a moisturizing base. Subjects were provided a skin care regimen including a cleanser, hydrating serum, moisturizer, and an SPF 30 sunscreen for daily use. The test product was applied only at night. The use of this skin brightening/anti-aging cosmeceutical was found to provide statistically significant improvements in all efficacy endpoints by study end. Fine lines, radiance, and smoothness were significantly improved as early as week 2. By week 4, hyperpigmentation, overall skin clarity, evenness of skin tone, and wrinkles showed statistically significant improvement compared to baseline. Mild retinoid dermatitis including flaking and redness occurred early in the study as reflected by tolerability scores. By week 10, subjects reported no stinging, itching, dryness, or tingling. The results of this open-label clinical study suggest that a topical cream containing retinol 0.5% in combination with niacinamide, resveratrol, and hexylresorcinol is efficacious and tolerable for skin brightening/anti-aging when used with a complementary skin care regimen including SPF 30 sun protection.



How polyphenols ("antioxidants"), such as resveratrol, curcumin and EGCG, fight fat and obesity

Dietary polyphenols are beneficial plant chemicals found in fruit, herbs and vegetables, which are known primarily from their antioxidant action. Most importantly, however, different polyphenols also exert anti-inflammatory, anti-cancer, metabolic and anti-obesity action on the human body. In fact, scientists now know that it is not the antioxidant action that is important in polyphenols but the action on inflammation and metabolism. EGCG (from green tea), resveratrol (found in berries), quercetin (found in onions), curcumin (from turmeric), catechins (in cocoa), epicatechins (in pine bark and grape seeds), proanthocyanidins (e.g. in cranberries), and myricetin (found in fruit) are some of the most "famous" polyphenols. A review published in 2014 reports that thousands of cell, tissue, animal and human studies in the last few years have shown the beneficial effects of polyphenols on health, and specifically in metabolic disorders and obesity. Cell studies show that dietary polyphenols fight fat in multiple ways. They:

  • Reduce the life span of adipocytes (fat cells)
  • Reduce fat cell growth
  • Inhibit the capacity of fat cells to accumulate fat
  • Reduce fat cell proliferation
  • Stimulate lipolysis (fat breakdown and release from fat cells)
  • Boost energy expenditure / fat oxidation ("fat burning") outside fat cells
  • Stimulate thermogenesis (fat burning inside fat cells)
  • Inhibit adipose tissue inflammation within and outside adipose tissue
  • Fight oxidative damage within and outside fat tissue
  • Fight metabolic dysfunction within and outside adipose tissue
  • Reduce high glucose levels, triglycerides, cholesterol and glycation

"Animal studies strongly suggest that commonly consumed polyphenols have a pronounced effect on obesity as shown by lower body weight, fat mass and triglycerides through enhancing energy expenditure and fat utilization, and modulating glucose homeostasis". "On the other hand, human studies are more limited and are more inconsistent about the anti-obesity impact of dietary polyphenols probably due to the various study designs and lengths, variation among subjects (age, gender, ethnicity), chemical forms of the dietary polyphenols used and confounding factors such as other weight-reducing agents", the study authors state. However, our experience of reviewing such studies in the last decade shows that polyphenols are more effective on cell cultures, tissues and animals are more effective simply because of the much higher dosage than used on humans, which is quite often one or two orders of magnitude greater. Nevertheless, the general trend with the use of polyphenols in human trials is towards a healthier metabolic profile and reduced fat accumulation, obesity and its complications, even with normal, dietary intakes or with reasonably increased intakes in the form of supplements etc. However, polyphenols could be much more beneficial at local level, i.e. for spot fat / cellulite reduction than it is for whole body level. This is because whole body weight loss depends too much on food intake and exercise and because very high intake of polyphenols at whole body level is practically impossible and possibly unhealthy. Clearly, high-concentration topical application, similar to that seen in cell, tissue and animal studies makes much more sense, and is a trend seen in quality cosmeceuticals recently, including anti-ageing and cellulite creams. In all cases, more "randomised controlled trials are warranted to reconcile the discrepancies between preclinical efficacies and inconclusive clinic outcomes of these polyphenols", as the study authors report.

Source: Novel insights of dietary polyphenols and obesity.

Abstract: The prevalence of obesity has steadily increased over the past three decades both in the United States and worldwide. Recent studies have shown the role of dietary polyphenols in the prevention of obesity and obesity-related chronic diseases. Here, we evaluated the impact of commonly consumed polyphenols, including green tea catechins, especially epigallocatechin gallates, resveratrol and curcumin, on obesity and obesity-related inflammation. Cellular studies demonstrated that these dietary polyphenols reduce viability of adipocytes and proliferation of preadipocytes, suppress adipocyte differentiation and triglyceride accumulation, stimulate lipolysis and fatty acid β-oxidation, and reduce inflammation. Concomitantly, the polyphenols modulate signaling pathways including the adenosine-monophosphate-activated protein kinase, peroxisome proliferator activated receptor γ, CCAAT/enhancer binding protein α, peroxisome proliferator activator receptor gamma activator 1-alpha, sirtuin 1, sterol regulatory element binding protein-1c, uncoupling proteins 1 and 2, and nuclear factor-κB that regulate adipogenesis, antioxidant and anti-inflammatory responses. Animal studies strongly suggest that commonly consumed polyphenols described in this review have a pronounced effect on obesity as shown by lower body weight, fat mass and triglycerides through enhancing energy expenditure and fat utilization, and modulating glucose homeostasis. Limited human studies have been conducted in this area and are inconsistent about the antiobesity impact of dietary polyphenols probably due to the various study designs and lengths, variation among subjects (age, gender, ethnicity), chemical forms of the dietary polyphenols used and confounding factors such as other weight-reducing agents. Future randomized controlled trials are warranted to reconcile the discrepancies between preclinical efficacies and inconclusive clinic outcomes of these polyphenols.



Resveratrol reduces fat by inhibiting lipogenesis, maximising adrenergic lipolysis and boosting thermogenesis

Source: Resveratrol: anti-obesity mechanisms of action

Abstract: Resveratrol is a non-flavonoid polyphenol which belongs to the stilbenes group and is produced naturally in several plants in response to injury or fungal attack. Resveratrol has been recently reported as preventing obesity. The present review aims to compile the evidence concerning the potential mechanisms of action which underlie the anti-obesity effects of resveratrol, obtained either in cultured cells lines and animal models. Published studies demonstrate that resveratrol has an anti-adipogenic effect. A good consensus concerning the involvement of a down-regulation of C/EBPα and PPARγ in this effect has been reached. Also, in vitro studies have demonstrated that resveratrol can increase apoptosis in mature adipocytes. Furthermore, different metabolic pathways involved in triacylglycerol metabolism in white adipose tissue have been shown to be targets for resveratrol. Both the inhibition of de novo lipogenesis and adipose tissue fatty acid uptake mediated by lipoprotein lipase play a role in explaining the reduction in body fat which resveratrol induces. As far as lipolysis is concerned, although this compound per se seems to be unable to induce lipolysis, it increases lipid mobilization stimulated by β-adrenergic agents. The increase in brown adipose tissue thermogenesis, and consequently the associated energy dissipation, can contribute to explaining the body-fat lowering effect of resveratrol. In addition to its effects on adipose tissue, resveratrol can also acts on other organs and tissues. Thus, it increases mitochondriogenesis and consequently fatty acid oxidation in skeletal muscle and liver. This effect can also contribute to the body-fat lowering effect of this molecule.