“ProJuvenol® is a powerful synergistic blend of 
complex anti-aging ingredients inspired by nature.”

Cardiovascular

Crit Rev Clin Lab Sci. 2013 May-Jun;50(3):65-78. doi: 10.3109/10408363.2013.805182. Epub 2013 Jul 1.

Pterostilbene: Biomedical applications.

Estrela JM1, Ortega A, Mena S, Rodriguez ML, Asensi M.

Author information

Abstract
Resveratrol and its naturally dimethylated analog, pterostilbene, show similar biological activities. However, the higher in vivo bioavailability of pterostilbene represents a fundamental advantage. The main focus of this review is on biomedical applications of pterostilbene. The metabolism and pharmacokinetics of this stilbene in inflammatory dermatoses and photoprotection, cancer prevention and therapy, insulin sensitivity, blood glycemia and lipid levels, cardiovascular diseases, aging, and memory and cognition are addressed. Safety and toxicity, as well as recommendations for future research and biomedical uses, are discussed. This review includes comparisons between pterostilbene and other polyphenols, with particular emphasis on resveratrol. Potential benefits of using combinations of different polyphenols are considered. Based on present evidences we conclude that pterostilbene is an active phytonutrient and also a potential drug with multiple biomedical applications.

PMID: 23808710 DOI: 10.3109/10408363.2013.805182

J Food Sci. 2015 Oct;80(10):H2331-5. doi: 10.1111/1750-3841.13002. Epub 2015 Sep 26.

Pterostilbene Inhibits Vascular Smooth Muscle Cells Migration and Matrix Metalloproteinase-2 through Modulation of MAPK Pathway.

Lin HC1,2,3, Hsieh MJ1,4, Peng CH5, Yang SF1,6, Huang CN1,7.

Author information

Abstract
Smooth muscle cells (SMCs) migration and matrix metalloproteinase-2 (MMP-2) activation are main roles in atherosclerosis. Pterostilbene (trans-3, 5-dimethoxy-4-hydroxystilbene) is known to have various pharmacologic effects such as anti-inflammatory and anticarcinogenic properties. The present study aimed to investigate the anti-atheroscleroic property of pterostilbene in the rat smooth muscle cell (SMC) A7r9 cell lines and the underlying mechanisms. In this study, pterostilbene treatment significantly inhibited migration/invasion capacities of in A7r9 cell. Pterostilbene was also found to significantly decreased MMP-2 activity and expression by gelatin zymography and western blot assay in SMC. In the MAPK signaling pathway, western blot assay also indicated that pterostilbene up-regulated the phosphorylation of extracellular-signal-regulated kinase (Erk)1/2. Moreover, inhibition of Erk1/2 by specific inhibitors significantly abolished the pterostilbene-decreased expression of MMP-2 and migration/invasion capacities. These findings suggest that pterostilbene inhibited SMC migration and that MMP-2 activation could be mediated via Erk1/2 phosphorylation. It is further possible that pterostilbene could play a novel role in the treatment of atherosclerosis.

PRACTICAL APPLICATION:
Pterostilbene is a plant polyphenol compound that is principally found in blueberries. In this study, we found that pterostilbene could inhibit SMCs migration via down-regulation of MMP-2. Particularly, expression of MMP-2 was found to be strongly associated with the phosphorylation of Erk1/2.

© 2015 Institute of Food Technologists®

KEYWORDS:
matrix metalloproteinase-2; migration; pterostilbene; smooth muscle cells

PMID: 26409033 DOI: 10.1111/1750-3841.13002

Pharmacol Biochem Behav. 2015 Aug;135:199-209. doi: 10.1016/j.pbb.2015.06.009. Epub 2015 Jun 15.

Orally administrated pterostilbene attenuates acute cerebral ischemia-reperfusion injury in a dose- and time-dependent manner in mice.

Zhou Y1, Zhang XM1, Ma A1, Zhang YL1, Chen YY1, Zhou H1, Li WJ1, Jin X2.

Author information

Abstract
Pterostilbene (3,5-dimethoxy-4-hydroxystilbene) is a component of blueberry. It has been reported that long-term treatment with blueberry has a neuroprotective effect. However, it has not been reported whether pterostilbene is effective in attenuating cerebral ischemia/reperfusion (I/R) injury. In the present study, focal cerebral ischemia was induced by middle cerebral artery occlusion for 90min followed by reperfusion. To observe the dose-dependent effect, pterostilbene (2.5-80mg/kg, ig) was administered for 3days before ischemia. To determine the time-dependent effect, pterostilbene (10mg/kg, ig) was administered as a single dose at 0, 1, or 3h after reperfusion. Twenty-four hours after I/R, pterostilbene dose-dependently improved neurological function, reduced brain infarct volume, and alleviated brain edema. The most effective dose was 10mg/kg; the therapeutic time window was within 1h after I/R and treatment immediately after reperfusion showed the best protective effect. The protective effect is further confirmed by the results that post-ischemic treatment with pterostilbene (10mg/kg) significantly improved motor function, alleviated blood brain barrier disruption, increased neurons survival and reduced cell apoptosis in cortical penumbra after cerebral I/R. We also found that pterostilbene (10mg/kg) significantly reversed the increased content of malondialdehyde and the decreased activity of superoxide dismutase in the ipsilateral hemisphere. Furthermore, pterostilbene decreased the oxidative stress markers 4-hydroxynonenal and 8-hydroxyguanosine positive cells in the cortical penumbra. All these findings indicate that pterostilbene dose- and time-dependently exerts a neuroprotective effect against acute cerebral I/R injury. This neuroprotective effect of pterostilbene may be associated with its inhibition of oxidative stress and subsequent neuronal apoptosis in the cortical penumbra.

KEYWORDS:
Apoptosis; Cerebral ischemia/reperfusion; Mice; Oxidative stress; Pterostilbene

PMID: 26086685 DOI: 10.1016/j.pbb.2015.06.009

AAPS PharmSciTech. 2014 Aug;15(4):1000-8. doi: 10.1208/s12249-014-0129-4. Epub 2014 May 15.

Nanoemulsion for solubilization, stabilization, and in vitro release of pterostilbene for oral delivery.

Zhang Y1, Shang Z, Gao C, Du M, Xu S, Song H, Liu T.

Author information

Abstract
Pterostilbene, being extracted from many plants, has significant biological activities in preventing cancer, diabetes, and cardiovascular diseases so as to have great potential applications in pharmaceutical fields. But the poor solubility and stability of pterostilbene strictly restrained its applications. As a good protection and oral delivery system, an optimal nanoemulsion for pterostilbene was developed by using low-energy emulsification method. Systematic pseudo-ternary phase diagrams have been studied in optimization of nanoemulsion formulations. The prepared pterostilbene nanoemulsion was characterized by transmission electron microscope, Fourier transform Raman spectrum, and laser droplet size analyzer. Nanoemulsion droplets are circular with smooth margin, and the mean size is 55.8 ± 10.5 nm. The results illustrated that the nanoemulsion as oral delivery system dramatically improved the stability and solubility of pterostilbene, and in vitro release of pterostilbene was significantly improved (96.5% in pH 3.6 buffer; 13.2% in pH 7.4 buffer) in comparison to the pterostilbene suspension (lower than 21.4% in pH 3.6 buffer; 2.6% in pH 7.4 buffer).

PMID: 24831090 PMCID: PMC4113613 DOI: 10.1208/s12249-014-0129-4

Neurochem Int. 2015 Oct;89:227-33. doi: 10.1016/j.neuint.2015.07.017. Epub 2015 Jul 26.

Effects of pterostilbene and resveratrol on brain and behavior.

Poulose SM1, Thangthaeng N1, Miller MG1, Shukitt-Hale B2.

Author information

Abstract
Age is the greatest universal risk factor for neurodegenerative diseases. During aging, these conditions progress from minor loss of function to major disruptions in daily life, loss of independence and ultimately death. Because approximately 25% of the world population is expected to be older than age 65 by 2050, and no treatments exist to halt or reverse ongoing neurodegeneration, the need for effective prevention strategies is more pressing that ever before. A growing body of research supports the role of diet in healthy aging, particularly diets rich in bioactive phytochemical compounds. Recently, stilbenes such as resveratrol (3, 5, 4′-trans-trihydroxystilbene) and its analogue, pterostilbene, have gained a significant amount of attention for their potent antioxidant, anti-inflammatory, and anticarcinogenic properties. However, evidence for the beneficial effects of stilbenes on cerebral function is just beginning to emerge. In this review, we summarize the current knowledge on the role of resveratrol and pterostilbene in improving brain health during aging, with specific focus on antioxidant and anti-inflammatory signaling and behavioral outcomes.

KEYWORDS:
Aging; Brain-signaling; Inflammation; Polyphenols; Pterostilbene; Resveratrol

PMID: 26212523 DOI: 10.1016/j.neuint.2015.07.017

Plant Foods Hum Nutr. 2015 Sep;70(3):263-8. doi: 10.1007/s11130-015-0488-3.

Pterostilbene, an Active Constituent of Blueberries, Stimulates Nitric Oxide Production via Activation of Endothelial Nitric Oxide Synthase in Human Umbilical Vein Endothelial Cells.

Park SH1, Jeong SO, Chung HT, Pae HO.

Author information

Abstract
Endothelial dysfunction, a key process in development of cardiovascular diseases, is largely due to reduced nitric oxide (NO) derived from endothelial NO synthase (eNOS). Resveratrol has been reported to stimulate NO production via estrogen receptor α (ERα) activation in endothelial cells. Here, we investigated whether two natural methylated analogs of resveratrol, pterostilbene (Pts) and trans-3,5,4′-trimethoxystilbene (TMS), similarly to resveratrol, could influence endothelial NO release in human umbilical vein endothelial cells (HUVECs). In HUVECs exposed to Pts or TMS, NO production and phosphorylation of eNOS, protein kinase B (Akt), and ERα were measured by using a fluorimetric NO assay kit and Western blot analysis, respectively. Dimethylated Pts, but not trimethylated TMS, stimulated dose-dependent NO production via eNOS phosphorylation. Pts also stimulated dose-dependent phosphorylation of Akt, but not of ERα. NO production and eNOS phosphorylation in response to Pts were significantly abolished by the phosphoinositide 3-kinase (PI3K)/Akt inhibitor LY294002, but not by the ERα antagonist ICI182780. Our results suggest that Pts, but not TMS, is capable of inducing eNOS phosphorylation and the subsequent NO release, presumably, by activating PI3K/Akt pathway. The potential efficacy of Pts, an active constituent of blueberries, may aid in the prevention of cardiovascular diseases characterized by endothelial dysfunction.

PMID: 26008990 DOI: 10.1007/s11130-015-0488-3

Mol Nutr Food Res. 2016 Feb;60(2):266-77. doi: 10.1002/mnfr.201500466. Epub 2015 Oct 23.

ERK5/HDAC5-mediated, resveratrol-, and pterostilbene-induced expression of MnSOD in human endothelial cells.

Gan W1, Dang Y1, Han X1, Ling S1, Duan J1, Liu J1, Xu JW1.

Author information

Abstract

SCOPE:
Mitochondrial oxidative stress is closely correlated with numerous cardiovascular diseases. Manganese superoxide dismutase (MnSOD) is an important antioxidant enzyme in mitochondria. Although polyphenols can induce the expression of MnSOD, their corresponding mechanisms remains unclear. In this study, we tested the hypothesis that resveratrol and pterostilbene can activate the expression of MnSOD through an AMPK-ERK5/HDAC5-KLF2 pathway.

METHODS AND RESULTS:
Our results revealed that two stilbenes reduced mitochondrial superoxide-free radicals, and endothelial cell senescence, and increased the mRNA expression of several genes related to mitochondrial function, including MnSOD. Moreover, two stilbenes upregulated the activation of human MnSOD promoter luciferase reporter gene and protein level in human umbilical vein endothelial cells. Similarly, two stilbenes also stimulated LKB1, AMPKα, extracellular-signal related kinase 5 (ERK5) phosphorylation, and histone acetylase 5 (HDAC5) and Kruppel-like factor 2 (KLF2) expression. The knockdown of AMP-activated protein kinase (AMPK), ERK5, and HDAC5 by using short-hairpin RNA blocked pterostilbene-induced phosphorylation of their downstream signaling proteins and the expression of KLF2. Furthermore, using a chromatin immunoprecipitation-PCR detection method, we found that resveratrol and pterostilbene promoted KLF2 binding to CACCC sites of the human MnSOD promoter.

CONCLUSION:
Resveratrol and pterostilbene can activate MnSOD expression through ERK5/HDAC5 pathway, thus alleviating mitochondrial oxidative stress in endothelial cells that relates to cardiovascular disease.

© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

KEYWORDS:
ERK5; Gene expression; HDAC5; Mitochondrial superoxide dismutase; Stilbenes

PMID: 26443543 DOI: 10.1002/mnfr.201500466

Vascul Pharmacol. 2010 Jul-Aug;53(1-2):61-7. doi: 10.1016/j.vph.2010.04.001. Epub 2010 Apr 14.

Pterostilbene, a natural dimethylated analog of resveratrol, inhibits rat aortic vascular smooth muscle cell proliferation by blocking Akt-dependent pathway.

Park ES1, Lim Y, Hong JT, Yoo HS, Lee CK, Pyo MY, Yun YP.

Author information

Abstract
Vascular smooth muscle cells (VSMCs) are the main cellular component in the arterial wall, and abnormal proliferation of VSMCs plays a central role in the pathogenesis of atherosclerosis and restenosis after angioplasty, and possibly in the development of hypertension. Pterostilbene, a natural dimethylated analog of resveratrol, is known to have diverse pharmacological activities including anti-cancer, anti-inflammation and anti-oxidant activities. The present study was designed to investigate the effects of pterostilbene on platelet-derived growth factor (PDGF)-BB-induced VSMCs proliferation as well as the molecular mechanisms of the antiproliferative effects. The cell growth of VSMCs was determined by cell counting and [(3)H]thymidine incorporation assays. Pterostilbene significantly inhibited the DNA synthesis and proliferation of PDGF-BB-stimulated VSMCs in a concentration-dependent manner. The inhibition percentages of pterostilbene at 1, 3 and 5microM to VSMCs proliferation were 68.5, 80.7 and 94.6%, respectively. The DNA synthesis of pterostilbene at 1, 3 and 5microM in VSMCs was inhibited by 47.4, 76.7 and 100%, respectively. Pterostilbene inhibited the PDGF-BB-stimulated phosphorylation of Akt kinase. However, pterostilbene did not change the expression of extracellular signal-related kinase (ERK) 1/2, PLCgamma1, phosphatidylinositol (PI)3 kinase and PDGF-Rbeta phosphorylation. In addition, pterostilbene down-regulated the cell cycle-related proteins including the expression of cyclin-dependent kinase (CDK) 2, cyclin E, CDK4, cyclin D1, retinoblastoma (Rb) proteins and proliferative cell nuclear antigen (PCNA). These findings suggest that the inhibition of pterostilbene to the cell proliferation and DNA synthesis of PDGF-BB-stimulated VSMCs may be mediated by the suppression of Akt kinase. Furthermore, pterostilbene may be a potential anti-proliferative agent for the treatment of atherosclerosis and angioplasty restenosis.

PMID: 20398797 DOI: 10.1016/j.vph.2010.04.001

Am J Transl Res. 2016 Jul 15;8(7):3049-55. eCollection 2016.

Effects of pterostilbene on treating hyperprolactinemia and related mechanisms.

Zhang H1, Wang C2, Li X3, Zhang Y4.

Author information

Abstract
Hyperprolactinemia (HPRL) frequently causes primary menopause and reproductive disorders. Pterostilbene is known to have anti-inflammation and modulation on cell apoptosis. However, its role in treating HPRL and potential mechanisms remain unclear yet. Healthy female virgin SD rats were randomly assigned into control, HPRL model group, bromocriptine treatment group, and low (20 mg/kg) and high (40 mg/kg) pterostilbene treatment groups. All groups except control ones received metoclopramide hydrochloride injection for generating HPRL model. Uterus and ovarian index in all animals were monitored. Prolactin (PRL), estradiol (E2), follicle stimulating hormone (FSH) and luteinizing hormone (LH) were quantified by ELISA. Caspase 3 activity was assayed, with real time PCR measuring Bcl-2 and Bax mRNA levels. HPRL rats had lower uterus and ovarian index, accompanied with elevated PRL, caspase 3 activity, Bax expression, and decreased FSH, LH, E2 and Bcl-2 expression as compared to control group (p<0.05). Pterostilbene treatment significantly increased uterus and ovarian index, FSH, LH, E2 and Bcl-2 expression, and decreased PRL, caspase 3 activity and Bax expression as compared to control group (p<0.05). 40 mg/kg pterostilbene had similar efficacy as those of bromocriptine. Pterostilbene exerts its function in the treatment of HPRL via modulating apoptosis-anti-apoptosis homeostasis, inhibiting serum PRL level, and regulating secretion of gonadotropin hormones.

KEYWORDS:
Hyperprolactinemia; cell apoptosis; prolactin; pterostilbene

PMID: 27508025 PMCID: PMC4969441

Mol Med Rep. 2015 Jan;11(1):724-8. doi: 10.3892/mmr.2014.2719. Epub 2014 Oct 21.

Pterostilbene attenuates the inflammatory reaction induced by ischemia/reperfusion in rat heart.

Lv M1, Liu K2, Fu S1, Li Z1, Yu X3.

Author information

Abstract
The role of pterostilbene (Pte) in inflammation induced by ischemia/reperfusion is not well understood. The aim of this study was to investigate whether Pte modulates neutrophil accumulation and the induction of tumor necrosis factor-α (TNF-α) in an ischemia/reperfusion (I/R)-injured rat heart model. Rats were randomly exposed to a sham operation, myocardial ischemia/reperfusion (MI/R) alone, MI/R+Pte, MI/R+Pte+L-NAME and MI/R+Pte+ (methylene blue) MB. The results demonstrated that compared with MI/R, Pte reduced the area of myocardial infarction, the levels of myocardial myeloperoxidase, serum creatinine kinase and lactate dehydrogenase, and the production of serum and myocardial TNF-α. These Pte-induced effects were eliminated by the administration of L-NAME, a nitric oxide (NO) synthase inhibitor, and MB, a cyclic guanosine monophosphate (cGMP) inhibitor. In conclusion, Pte produces cardioprotective and anti-inflammatory effects. These effects may be associated with an increase in NO production, the inhibition of neutrophil accumulation, and induction of TNF-α and cGMP signaling pathways in myocardium subjected to MI/R.

PMID: 25333895 DOI: 10.3892/mmr.2014.2719

Eur J Pharmacol. 2016 Oct 15;789:229-243. doi: 10.1016/j.ejphar.2016.07.046. Epub 2016 Jul 27.

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

Kosuru R1, Rai U1, Prakash S1, Singh A2, Singh S3.

Author information

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.

KEYWORDS:
AMPK; Cardiovascular disease; HO-1; NF-κB; Nrf2; Pterostilbene

PMID: 27475678 DOI: 10.1016/j.ejphar.2016.07.046

Eur J Pharmacol. 2016 Apr 5;776:26-33. doi: 10.1016/j.ejphar.2016.02.052. Epub 2016 Feb 24.

Restoration of sirt1 function by pterostilbene attenuates hypoxia-reoxygenation injury in cardiomyocytes.

Guo Y1, Zhang L2, Li F2, Hu CP3, Zhang Z4.

Author information

Abstract
Restoration of blood supply to ischemic myocardium causes cardiomyocyte damage, a process known as ischemia-reperfusion injury. Excess reactive oxygen species and intracellular calcium contribute to cell damage but the involvement of sirt1, a versatile protein deacetylase in reperfusion-induced cell damage remains unknown. Here, we found that hypoxia-reoxygenation, an in vitro model of ischemia-reperfusion injury, induced H9c2 cardiomyocyte apoptosis as revealed by caspase-3 assay, Hoechst 33258 staining, flow cytometric analysis and JC-1 staining. Molecular docking analysis showed that, pterostilbene, a natural dimethyl ether derivative of resveratrol, binds to the enzymatic active pocket of sirt1. Importantly, application of pterostilbene at low concentrations of 0.1-3.0 μM rescued H9c2 cells from apoptosis, an effect comparable with resveratrol at 20 μM. Mechanistically, pterostilbene exerted its cardioprotective effects via 1) stimulation of sirt1 activity, since pretreatment of H9c2 cells with splitomicin, an antagonist of sirt1, removed the effects of pterostilbene, and 2) enhancement of sirt1 expression. Therefore, the present study demonstrates that activation of sitr1 during ischemia-reperfusion is cardioprotective and that the natural compound-pterostilbene-could be used therapeutically to alleviate ischemia-reperfusion injury.

KEYWORDS:
Cardiomyocyte apoptosis; Ischemia-reperfusion injury; Pterostilbene; Sirt1

PMID: 26921129 DOI: 10.1016/j.ejphar.2016.02.052

J Clin Exp Cardiolog. 2012 Jun 7;S5:8.

Suppression of Nitric Oxide Production and Cardiovascular Risk Factors in Healthy Seniors and Hypercholesterolemic Subjects by a Combination of Polyphenols and Vitamins.

Qureshi AA1, Khan DA, Mahjabeen W, Papasian CJ, Qureshi N.

Author information

Abstract

BACKGROUND:
Dysregulated immune function associated with ageing has been implicated in a variety of human diseases. We have demonstrated the anti-inflammatory properties of resveratrol, pterostilbene, morin hydrate, quercetin, δ-tocotrienol, riboflavinin a variety of experimental animal models, and determined that these compounds act by inhibiting proteasome activity.

AIMS:
To determine whether serum nitric oxide (NO) levels increase with age in humans, and whether the combined cholesterol-lowering and inflammation-reducing properties of resveratrol, pterostilbene, Morin hydrate, quercetin, δ-tocotrienol, riboflavin, and nicotinic acid would reduce cardiovascular risk factors in humans when used as nutritional supplements with, or without, other dietary changes.

METHODS:
Elderly human subjects were stratified into two groups based on total serum cholesterol levels. Initial total serum cholesterol levels were normal and elevated in Group 1 and 2 subjects, respectively. Baseline serum NO, C-reactive protein (CRP), γ-glutamyltransferase (γ-GT) activity, uric acid, total antioxidant status (TAS), total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides levels were established over a four week period. Group 1 subjects subsequently received nutritional supplementation with one of two different combinations (NS-7 = 25 mg of each, resveratrol, pterostilbene, quercetin, δ-tocotrienol, nicotinic acid, morin hydrate or NS-6 = morin hydrate replaced with quercetin, 50 mg/capsule). Group 2 subjects also received these nutritional supplements (two capsules/d), but an AHA Step-1 diet was also implemented. After these interventions were administered for four weeks, the above parameters were re-measured and changes from baseline levels determined. Nitric acid (NO) levels in children, young adults, and seniors were also compared.

RESULTS:
The key results of the current study were: 1) that serum NO levels were significantly increased in seniors compared to both children (~80%) and young adults (~65%); 2) that the intake of two capsules/d of NS-7 or NS-6 for four weeks significantly (P < 0.05) decreased serum NO (39%, 24%), CRP (19%, 21%), uric acid (6%, 12%) levels, and γ-GT activity (8%, 6%), respectively in free-living healthy seniors; 3) that serum NO (36%, 29%), CRP (29%, 20%), uric acid (6%, 9%) γ-GT activity (9%, 18%), total cholesterol (8%, 11%), LDL-cholesterol (10%, 13%), and triglycerides (16%, 23%) levels were significantly (P < 0.02) decreased in hypercholesterolemic subjects restricted to AHA Step-1 diet plus intake of SN-7 or SN-6 (two capsules/d), respectively; 4) that TAS was increased (3%, 9%; P < 0.05) in free-living healthy seniors receiving NS-7 or NS-6 alone, and in hypercholesterolemic subjects plus AHA Step-1 diet (20%, 12%; P < 0.02) with either of the combinations tested.

CONCLUSIONS:
Serum NO levels are elevated in elderly humans compared to children or young adults. Diet supplementation with combinations of resveratrol, pterostilbene, morin hydrate, quercetin, δ-tocotrienol, riboflavin, and nicotinic acid reduce cardiovascular risk factors in humans when used as nutritional supplements with, or without, other dietary changes.

PMID: 23125945 PMCID: PMC3486425 DOI: 10.4172/2155-9880.S5-008

PLoS One. 2013 May 3;8(5):e62652. doi: 10.1371/journal.pone.0062652. Print 2013.

Pterostilbene exerts antitumor activity via the Notch1 signaling pathway in human lung adenocarcinoma cells.

Yang Y1, Yan X, Duan W, Yan J, Yi W, Liang Z, Wang N, Li Y, Chen W, Yu S, Jin Z, Yi D.

Author information

Abstract
Although pterostilbene (PTE) has been shown to have potent antitumor activities against various cancer types, the molecular mechanisms of these activities remain unclear. In this study, we investigated the antitumor activity of PTE against human lung adenocarcinoma in vitro and in vivo and explored the role of the Notch1 signaling pathway in this process. PTE treatment resulted in a dose- and time-dependent decrease in the viability of A549 cells. Additionally, PTE exhibited strong antitumor activity, as evidenced not only by a reduced mitochondrial membrane potential (MMP) and a decreased intracellular glutathione content but also by increases in the apoptotic index and the level of reactive oxygen species (ROS). Furthermore, PTE treatment induced the activation of the Notch1 Intracellular Domain (NICD) protein and activated Hes1. DAPT (a gamma secretase inhibitor) and Notch1 siRNA prevented the induction of NICD and Hes1 activation by PTE treatment and sensitized the cells to PTE treatment. The down-regulation of Notch signaling also prevented the activation of pro-survival pathways (most notably the PI3K/Akt pathway) after PTE treatment. In summary, lung adenocarcinoma cells may enhance Notch1 activation as a protective mechanism in response to PTE treatment. Combining a gamma secretase inhibitor with PTE treatment may represent a novel approach for treating lung adenocarcinoma by inhibiting the survival pathways of cancer cells.

PMID: 23671619 PMCID: PMC3643961 DOI: 10.1371/journal.pone.0062652

Biomed Pharmacother. 2016 Jul;81:345-55. doi: 10.1016/j.biopha.2016.04.031. Epub 2016 Apr 26.

Pterostilbene, a novel natural plant conduct, inhibits high fat-induced atherosclerosis inflammation via NF-κB signaling pathway in Toll-like receptor 5 (TLR5) deficient mice.

Zhang Y1, Zhang Y2.

Author information

Abstract
Atherosclerosis is a specific form of an artery wall thickens, a syndrome affecting arterial blood vessels due to a chronic inflammatory response in the walls of arteries, which is promoted by fat accumulation. Toll-like receptors (TLRs) play prominent roles in inflammatory responses. And TLR5 is overexpressed in several diseases. Here in our study, we investigated the effect of TLR5 in high fat-induced atherosclerosis via NF-κB signaling pathway modulating pro-inflammatory cytokines releasing. Our results found that high fat induced atherosclerosis in wild type mice with fat accumulation and inflammatory response through NF-κB activation. Contrastly, TLR5 knockout mice displayed lower fat accumulation and ameliorated inflammation after high fat feeding with NF-κB inactivation. In addition, pterostilbene, as a natural dimethyl ether derivative of resveratrol mainly from blueberries, has diverse pharmacological activities, especially anti-inflammation. Our study also found that pterostilbene displayed inhibited role in suppressing inflammatory response through inactivating NF-κB signaling pathway regulated by TLR5 down-regulation in high fat-induced mice. Moreover, in vitro experiments of vascular smooth muscle cells (VSMCs) challenged with LPS or TNF-α, further indicated that NF-κB was involved in atherosclerosis progression, leading to high secretion of pro-inflammatory cytokines. However, VSMCs from TLR5 deficient mice inhibited phosphorylated levels of NF-κB signalilng pathway, finally resulting in down-regulation of inflammatory cytokines. Notably, pterostilbene also displayed suppressed role in inflammatory response via NF-κB inactivity in LPS or TNF-α-induced VSMCs by decreasing TLR5 expression. The results above indicated a novel therapeutic strategy of pterostilbene to protect against atherosclerosis via TLR5 regulation for clinic treatment in the future.

KEYWORDS:
Atherosclerosis; Inflammation; NF-κB; Pterostilbene; TLR5

PMID: 27261612 DOI: 10.1016/j.biopha.2016.04.031

Fitoterapia. 2015 Sep;105:228-33. doi: 10.1016/j.fitote.2015.07.009. Epub 2015 Jul 18.

Effect of substituted stilbenes on platelet function.

Messina F1, Guglielmini G2, Curini M1, Orsini S2, Gresele P3, Marcotullio MC1.

Author information

Abstract
Stilbenes, including resveratrol, are polyphenols provided with protective actions on the cardiovascular system. Some natural derivatives of resveratrol, like pterostilbene, have a better bioavailability than the parent compound. The aim of the present study was to prepare different substituted stilbenes (dimethylallyloxy-stilbene, dimethylallyloxy-pterostilbene) and compare them with resveratrol, p-hydroxy-stilbene and pterostilbene for their biologic activities on platelet aggregation, platelet radical oxygen species (ROS) production, and platelet nitric oxide (NO) synthesis. The results show that the increase of stilbene derivative lipophilicity enhances their biologic activities.

KEYWORDS:
Dimethylallyloxy-stilbene; Platelet NOx production; Platelet ROS production; Platelet aggregation; Resveratrol

PMID: 26197385 DOI: 10.1016/j.fitote.2015.07.009

Cytokine. 2016 Jan;77:88-97. doi: 10.1016/j.cyto.2015.11.006. Epub 2015 Nov 7.

Pterostilbene exerts an anti-inflammatory effect via regulating endoplasmic reticulum stress in endothelial cells.

Liu J1, Fan C2, Yu L1, Yang Y3, Jiang S4, Ma Z2, Hu W3, Li T3, Yang Z3, Tian T5, Duan W6, Yu S7.

Author information

Abstract
Pterostilbene (PT), an analog of resveratrol, exerts a potent anti-inflammatory effect. However, the protective effects of PT against inflammation in endothelial cells have not been elucidated. Previous studies have confirmed that endoplasmic reticulum stress (ERS) plays an important role in regulating the pathological process of endothelial cell inflammation. In this study, we explored the effect of PT on the tumor necrosis factor-α (TNF-α)-induced inflammatory response in human umbilical vein endothelial cells (HUVECs) and elaborated the role of ERS in this process. TNF-α treatment significantly upregulated the levels of inflammation-related molecules in cell culture media, increased the adhesion of monocytes to HUVECs, and enhanced the expression of the MMP9 and ICAM proteins in HUVECs. Additionally, TNF-α potently increased ERS-related protein levels, such as GRP78 and p-eIF2α. However, PT treatment reversed the increased production of inflammatory cytokines and the adhesion of monocytes to HUVECs, as well as reduced the TNF-α-induced effects exerted by ERS-related molecules. Furthermore, thapsigargin (THA), an ERS inducer, attenuated the protective effect of PT against TNF-α-induced inflammation and ERS in HUVECs. Additionally, the downregulation of ERS signaling using siRNA targeting eIF2α and IRE1 not only inhibited ERS-related molecules but also simulated the therapeutic effects of PT on TNF-α-induced inflammation. In summary, PT treatment potently attenuates inflammation in vascular endothelial cells, which at least partly depends on the reduction of ERS.

KEYWORDS:
Anti-inflammatory; Endoplasmic reticulum stress; Endothelial cells; Pterostilbene

PMID: 26551859 DOI: 10.1016/j.cyto.2015.11.006

Lipids Health Dis. 2012 Jul 10;11:76. doi: 10.1186/1476-511X-11-76.

Inhibition of nitric oxide and inflammatory cytokines in LPS-stimulated murine macrophages by resveratrol, a potent proteasome inhibitor.

Qureshi AA1, Guan XQ, Reis JC, Papasian CJ, Jabre S, Morrison DC, Qureshi N.

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Abstract

BACKGROUND:
Altered immune function during ageing results in increased production of nitric oxide (NO) and other inflammatory mediators. Recently, we have reported that NO production was inhibited by naturally-occurring proteasome inhibitors (quercetin, δ-tocotrienol, and riboflavin) in lipopolysaccharide (LPS)-stimulated RAW264.7 cells, and thioglycolate-elicited peritoneal macrophages from C57BL/6 mice. In a continuous effort to find more potent, non-toxic, commercially available, naturally-occurring proteasome inhibitors that suppress inflammation, the present study was carried out to describe the inhibition of NF-κB activation and NO, TNF-α, IL-6, IL-1β, and iNOS expression by trans-resveratrol, trans-pterostilbene, morin hydrate, and nicotinic acid in LPS-induced RAW 264.7 cells and thioglycolate-elicited peritoneal macrophages from C57BL/6 and BALB/c mice.

RESULTS:
The present results indicate that resveratrol, pterostilbene, and morin hydrate caused significant inhibition (>70% to 90%; P < 0.02) in the activities of chymotrypsin-like, trypsin-like, and post-acidic (post-glutamase) proteasome sites in RAW 264.7 cells at a dose of only 20 μM. These compounds also inhibited the production of NO by RAW-264.7 cells stimulated with LPS alone (>40%; P < 0.05), or LPS + interferon-γ (IFN-γ; >60%; P < 0.02). Furthermore, resveratrol, pterostilbene, morin hydrate, and quercetin suppressed secretion of TNF-α (>40%; P < 0.05) in LPS-stimulated RAW 264.7 cells, and suppressed NF-κB activation (22% to 45%; P < 0.05) in LPS-stimulated HEK293T cells. These compounds also significantly suppressed LPS-induced expression of TNF-α, IL-1β, IL-6, and iNOS genes in RAW 264.7 cells, and also in thioglycolate-elicited peritoneal macrophages from C57BL/6 and BALB/c mice.

CONCLUSIONS:
The present results clearly demonstrate that resveratrol and pterostilbene are particularly potent proteasome inhibitors that suppress expression of genes, and production of inflammatory products in LPS-stimulated RAW 264.7 cells, and macrophages from C57BL/6 and BALB/c mice. Resveratrol and pterostilbene which are present in grapes, blueberries, and red wine, have been implicated as contributing factors to the lower incidence of cardiovascular disease in the French population, despite their relatively high dietary fat intake. Consequently, it appears likely that the beneficial nutritional effects of resveratrol and pterostilbene are due at least in part, to their ability to inhibit NF-κB activation by the proteasome, thereby suppressing activation of pro-inflammatory cytokines and iNOS genes, resulting in decreased secretion of TNF-α, IL-1β, IL-6, and NO levels, in response to inflammatory stimuli. This is the first report demonstrating that resveratrol and pterostilbene act as proteasome inhibitors, thus providing a mechanism for their anti-inflammatory effects.

PMID: 22698256 PMCID: PMC3393619 DOI: 10.1186/1476-511X-11-76

J Clin Exp Cardiolog. 2013 Mar 2;4(3). pii: 238.

Nutritional Supplement-5 with a Combination of Proteasome Inhibitors (Resveratrol, Quercetin, δ-Tocotrienol) Modulate Age-Associated Biomarkers and Cardiovascular Lipid Parameters in Human Subjects.

Qureshi AA1, Khan DA, Mahjabeen W, Papasian CJ, Qureshi N.

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Abstract

BACKGROUND:
Age-associated altered redox imbalances and dysregulated immune function, contribute to the development of a variety of age associated diseases. Inflammatory markers and lipid profiles are useful prognostic indicators of a variety of age-associated and cardiovascular diseases. We have previously studied the impact of several proteasome inhibitors on several markers of inflammation and lipid profiles in vitro, in vivo, in cell lines, animal models, and in human subjects. The current study represents an extension of this work. Our main hypothesis is that a combination of various naturally-occurring proteasome inhibitors, which inhibits nitric oxide (NO), and C-reactive protein (CRP) mediated inflammation, will have better efficacy in the prevention and treatment of age-associated disorders including cardiovascular disease.

METHODS:
Two double blind, randomized, placebo-controlled cross-over trials were conducted to determine the impact of a mixture of NS-5 (resveratrol, pterostilbene, quercetin, δ-tocotrienol, nicotinic acid) on serum NO, CRP, γ-glutamyl-transferase (γ-GT) activity, total antioxidant status (TAS), total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides levels. Healthy seniors (Group-1; n = 32) free-living (A, B; 16/group), and hypercholesterolemic (Group-2; n = 64) subjects on AHA-Step-1-diet were divided into two groups (C, D; 32/group). Baseline levels were established for parameters as mentioned above. Groups A, C were administered 4-capsules/d of NS-5 and groups B, D, placebo (starch) for 6-weeks. Groups were crossed-over, followed by a 2-week wash-out period. Groups A, C were given 4-capsules/d of placebo and groups B, D, 4-capsules/d of NS-5 for 6-weeks. Groups C, D were continued on AHA-Step-1-diet.

RESULTS:
All the subjects completed each phase in both studies without any complaints. There were significant ( P < 0.01 – 0.05) decreases in the serum levels of NO (30%, 26%), CRP (29%, 21%), γ-GT activity (14%, 17%), and blood pressure (systolic/diastolic, 3/6%, 3/3%) of Groups A and B, respectively, of free-living healthy seniors without affecting the total, HDL-, LDL-cholesterol or triglycerides compared to their respective baseline values. However, serum levels of NO (36%, 43%), CRP (31%, 48%), γ-GT (17%, 20%), total cholesterol (19%, 15%), LDL-cholesterol (28%, 20%), triglycerides (11%, 18%) of Groups C and D were significantly ( P < 0.01-0.05) decreased with NS-5 treatment of hypercholesterolemic subjects compared to baseline values, without affecting the serum HDL-cholesterol levels. The serum levels of total antioxidant status (TAS) were increased (10%, 14%; P < 0.05) in Groups A and B, increased (19%, 24%; P < 0.02), and blood pressure (systolic/diastolic, 5/6%, 3/5%) in Groups C and D with NS-5 treatment, compared to respective baseline values.

CONCLUSIONS:
The consumption of NS-5 mixture decreased significantly serum NO, CRP and γ-GT levels, improved TAS and lipid profiles at risk cardiovascular and hold promise for delaying onset of age-associated diseases.

KEYWORDS:
Anti-inflammatory and anti-ageing agents; C-reactive protein (CRP); Nitric oxide (NO); Quercetin; Resveratrol; Total antioxidant status (TAS); γ-glutamyl-transferase (γ-GT); δ-tocotrienol

PMID: 24319627 PMCID: PMC3851026 DOI: 10.4172/2155-9880.1000238

Neoplasia. 2005 Jan;7(1):37-47.

Association between pterostilbene and quercetin inhibits metastatic activity of B16 melanoma.

Ferrer P1, Asensi M, Segarra R, Ortega A, Benlloch M, Obrador E, Varea MT, Asensio G, Jordá L, Estrela JM.

Author information

Abstract
Inhibition of cancer growth by resveratrol (trans-3,5,4′-trihydroxystilbene; RESV), a phytoalexin present in many plant species, is limited by its low bioavailability. Pterostilbene (3,5-dimethoxy-4′-hydroxystilbene; PTER) and quercetin (3,3′,4′,5,6-pentahydroxyflavone; QUER), two structurally related and naturally occurring small polyphenols, show longer half-life in vivo. In vitro growth of highly malignant B16 melanoma F10 cells (B16M-F10) is inhibited (56%) by short-time exposure (60 min/day) to PTER (40 microm) and QUER (20 microm) (approximate mean values of plasma concentrations measured within the first hour after intravenous administration of 20 mg/kg each polyphenol). Intravenous administration of PTER and QUER (20 mg/kg per day) to mice inhibits (73%) metastatic growth of B16M-F10 cell in the liver, a common site for metastasis development. The anti-metastatic mechanism involves: 1) a PTER-induced inhibition of vascular adhesion molecule 1 expression in the hepatic sinusoidal endothelium, which consequently decreases B16M-F10 cell adhesion to the endothelium through very late activation antigen 4; and 2) a QUER- and PTER-induced inhibition of Bcl-2 expression in metastatic cells, which sensitizes them to vascular endothelium-induced cytotoxicity. Our findings demonstrate that the association of PTER and QUER inhibits metastatic melanoma growth and extends host survival.

PMID: 15736313 PMCID: PMC1490314

Yao Xue Xue Bao. 2010 Apr;45(4):422-9.

[Chemical principles and bioactivities of blueberry].

[Article in Chinese]

Chen CF1, Li YD, Xu Z.

Author information

Abstract
The bioactive principles contained in blueberries (Vaccinium) are various kind of anthocyanins (anthocyanidins, or phenolic aglycone, conjugated with sugar), chlorogenic acid, flavonids, alpha-linolenic acid, pterostilbene, resveratrol, and vitamins. After oral administration, anthocyanins can pass through blood-brain barrier and thus appear in various organs and brain. Improve visual function by increasing rhodopsin regeneration and ocular health is the earliest reported bioactivities of anthocyanin. Recent studies demonstrated the benefit of blueberries to prevent the age-related chronic diseases such as cancer, diabeties, hyperlipidemia, hypertension, neurodegeneration, obesity, and osteoporosis through its apoptosis, antioxidant, antiinflammation, and antiangiogenesis effects. Blueberries can eradicate microorganisms for the prevention of symptomatic urinary tract infections in women. Thus, blueberries are recognized as one of the most nutritious foods and cultivated worldwide. However, how to prolong the shelving time of fresh fruit, well utilize the leaf and stem to isolate the bioactive chemicals, improve quality consistency of juicy and dry products, all should be further concerned.

PMID: 21355205

Eur J Pharmacol. 2016 Jul 5;782:120. doi: 10.1016/j.ejphar.2016.05.002.

Corrigendum to “Restoration of sirt1 function by pterostilbene attenuates hypoxia-reoxygenation injury in cardiomyocytes” [Eur. J. Pharmacol. 776 (2016) 26-33].

Guo Y1, Zhang L2, Li F2, Hu CP3, Zhang Z4.

Author information

PMID: 27180043 DOI: 10.1016/j.ejphar.2016.05.002

Biofactors. 2017 Dec 8. doi: 10.1002/biof.1401. [Epub ahead of print]

Chemoprevention by resveratrol and pterostilbene: Targeting on epigenetic regulation.

Lee PS1, Chiou YS1, Ho CT2, Pan MH1,3,4.

Author information

Abstract
Epigenetic mechanisms are essential in regulating normal cellular functions and play an important role during the disease developmental stages. However, aberrant epigenetic mechanisms may lead to pathological consequences such as cancer, neurological disorders, bone and skeletal diseases, cardiovascular dysfunction, and metabolic syndrome. The molecular mechanisms of epigenetic modification include DNA methylation, histone modification (acetylation, methylation and phosphorylation), and microRNAs (miRNAs). Unlike genetic modifications, epigenetic states of genes are reversible and can be altered by certain intrinsic and extrinsic factors. In the past few decades, accumulated evidence shows that dietary phytochemicals with chemopreventive effects are also potent epigenetic regulators. Resveratrol and pterostilbene are stilbenoids, which have been reported to have anti-cancer, anti-inflammatory, anti-lipid, and anti-diabetic properties. Stilbenoids are also reported to improve cardiovascular disease. By altering DNA methylation and histone modification or by modulating miRNA expression, resveratrol, and pterostilbene become potent epigenetic modifiers. In this review, we summarize these studies and underlying mechanisms of resveratrol and pterostilbene and their influence on epigenetic mechanisms.

© 2017 BioFactors, 2017.

KEYWORDS:
chemoprevention; epigenetic; pterostilbene; resveratrol

PMID: 29220106 DOI: 10.1002/biof.1401

Vascul Pharmacol. 2016 Jul;82:51-9. doi: 10.1016/j.vph.2016.04.006. Epub 2016 May 14.

Multiple pathway assessment to predict anti-atherogenic efficacy of drugs targeting macrophages in atherosclerotic plaques.

Alaarg A1, Zheng KH2, van der Valk FM3, da Silva AE4, Versloot M5, van Ufford LC6, Schulte DM7, Storm G8, Metselaar JM9, Stroes ES10, Hamers AA11.

Author information

Abstract

BACKGROUND:
Macrophages play a central role in atherosclerosis development and progression, hence, targeting macrophage activity is considered an attractive therapeutic. Recently, we documented nanomedicinal delivery of the anti-inflammatory compound prednisolone to atherosclerotic plaque macrophages in patients, which did however not translate into therapeutic efficacy. This unanticipated finding calls for in-depth screening of drugs intended for targeting plaque macrophages.

METHODS AND RESULTS:
We evaluated the effect of several candidate drugs on macrophage activity, rating overall performance with respect to changes in cytokine release, oxidative stress, lipid handling, endoplasmic reticulum (ER) stress, and proliferation of macrophages. Using this in vitro approach, we observed that the anti-inflammatory effect of prednisolone was counterbalanced by multiple adverse effects on other key pathways. Conversely, pterostilbene, T0901317 and simvastatin had an overall anti-atherogenic effect on multiple pathways, suggesting their potential for liposomal delivery.

CONCLUSION:
This dedicated assay setup provides a framework for high-throughput assessment. Further in vivo studies are warranted to determine the predictive value of this macrophage-based screening approach and its potential value in nanomedicinal drug development for cardiovascular patients.

Copyright © 2016 Elsevier Inc. All rights reserved.

KEYWORDS:

Atherosclerosis; Drug screening; Inflammation; Macrophages; Nanomedicine

PMID: 27189780 DOI: 10.1016/j.vph.2016.04.006

Biofactors. 2017 Dec 6. doi: 10.1002/biof.1400. [Epub ahead of print]

Effect of resveratrol and pterostilbene on aging and longevity.

Li YR1,2, Li S3, Lin CC2,4,5.

Author information

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.

© 2017 BioFactors, 2017.

KEYWORDS:
aging; healthspan; lifespan; pterostilbene; resveratrol

PMID: 29210129 DOI: 10.1002/biof.1400

Pol Merkur Lekarski. 2010 Jun;28(168):496-500.

[Chemopreventive and chemotherapeutic effect of trans-resveratrol and its analogues in cancer].

[Article in Polish]

Mikstacka R1, Ignatowicz E.

Author information

Abstract
Trans-resveratrol (3,5,4′-trihydroxy-trans-stilbene), a naturalpolyphenol, displays diversified bioactivities that are crucial in chemoprevention of cancer and cardiovascular diseases. Equally promising action is exerted by resveratrol analogues, mainly pterostilbene (3,5-dimethoxy-4′-hydroxy-trans-stilbene) and piceatannol (3,5,3′, 4′-tetrahydroxy-trans-stilbene). Although fruits and their products are the main natural source of resveratrol and their analogues, recently these polyphenols have been commercially available in numerous pharmaceutical preparations and diet supplements. The aim of this review is to present the status of clinical studies on chemopreventive/chemotherapeutic effect of resveratrol and its analogues.

PMID: 20642113

Int Immunopharmacol. 2017 Feb;43:7-15. doi: 10.1016/j.intimp.2016.11.018. Epub 2016 Dec 6.

Pterostilbene protects against myocardial ischemia/reperfusion injury via suppressing oxidative/nitrative stress and inflammatory response.

Yu Z1, Wang S2, Zhang X3, Li Y1, Zhao Q4, Liu T5.

Author information

Abstract
Recent studies have shown that pterostilbene (Pte) confers protection against myocardial ischemia/reperfusion injury. The oxidative/nitrative stress and inflammation induce injury after myocardial ischemia/reperfusion. The present study was designed to evaluate whether treatment with Pte attenuates oxidative/nitrative stress and inflammation in myocardial ischemia/reperfusion (MI/R). Rats were subjected to 30min of myocardial ischemia and 3h of reperfusion, and the rats were administered with vehicle or Pte. The results showed that Pte (10mg/kg) dramatically improved cardiac function and reduced myocardial infarction and myocardial apoptosis following MI/R. As an indicator of oxidative/nitrative stress, myocardial ONOO- content was markedly reduced after Pte treatment. And, Pte led to a dramatic decrease in superoxide generation and malondialdehyde (MDA) content and a dramatic increase in superoxide dismutase (SOD) activity. In addition, Pte treatment significantly reduced p38 MAPK activation and the expression of iNOS and gp91phox and increased phosphorylated eNOS expression. Pte treatment dramatically decreased myocardial TNF-α, and IL-1β levels and myeloperoxidase (MPO) activity. Furthermore, ONOO- suppression by either Pte or uric acid (UA), an ONOO- scavenger, reduced myocardial injury. In conclusion, Pte exerts a protective effect against MI/R injury by suppressing oxidative/nitrative stress. These results provide evidence that Pte might be a therapeutic approach for the treatment of MI/R injury.

KEYWORDS:
Inflammation; Myocardial ischemia/reperfusion injury; Oxidative/nitrative stress; Pterostilbene

PMID: 27936461 DOI: 10.1016/j.intimp.2016.11.018

J Biol Chem. 2007 Feb 2;282(5):2880-90. Epub 2006 Nov 29.

Nitric oxide mediates natural polyphenol-induced Bcl-2 down-regulation and activation of cell death in metastatic B16 melanoma.

Ferrer P1, Asensi M, Priego S, Benlloch M, Mena S, Ortega A, Obrador E, Esteve JM, Estrela JM.

Author information

Abstract
Intravenous administration to mice of trans-pterostilbene (t-PTER; 3,5-dimethoxy-4′-hydroxystilbene) and quercetin (QUER; 3,3′,4′,5,6-pentahydroxyflavone), two structurally related and naturally occurring small polyphenols, inhibits metastatic growth of highly malignant B16 melanoma F10 (B16M-F10) cells. t-PTER and QUER inhibit bcl-2 expression in metastatic cells, which sensitizes them to vascular endothelium-induced cytotoxicity. However, the molecular mechanism(s) linking polyphenol signaling and bcl-2 expression are unknown. NO is a potential bioregulator of apoptosis with controversial effects on Bcl-2 regulation. Polyphenols may affect NO generation. Short-term exposure (60 min/day) to t-PTER (40 microM) and QUER (20 microM) (approximate mean values of the plasma concentrations measured within the first hour after intravenous administration of 20 mg of each polyphenol/kg) down-regulated inducible NO synthetase in B16M-F10 cells and up-regulated endothelial NO synthetase in the vascular endothelium and thereby facilitated endothelium-induced tumor cytotoxicity. Very low and high NO levels down-regulated bcl-2 expression in B16M-F10 cells. t-PTER and QUER induced a NO shortage-dependent decrease in cAMP-response element-binding protein phosphorylation, a positive regulator of bcl-2 expression, in B16M-F10 cells. On the other hand, during cancer and endothelial cell interaction, t-PTER- and QUER-induced NO release from the vascular endothelium up-regulated neutral sphingomyelinase activity and ceramide generation in B16M-F10 cells. Direct NO-induced cytotoxicity and ceramide-induced mitochondrial permeability transition and apoptosis activation can explain the increased endothelium-induced death of Bcl-2-depleted B16M-F10 cells.

PMID: 17135264 DOI: 10.1074/jbc.M605934200

Med Hypotheses. 2016 Mar;88:1-5. doi: 10.1016/j.mehy.2015.12.008. Epub 2016 Jan 6.

Direct ingestion method for enhancing production and bioavailability of resveratrol and other phytoalexins in Vitis vinifera.

Leifer A, Barberio DM.

Author information

Abstract
Phytoalexins such as resveratrol and pterostilbene, produced de novo by many plant species, including grapevine (Vitis vinifera), play a role in plant defense against injury and pathogens. In human cell lines and in animal studies, phytoalexins have been shown to be highly beneficial, with protective effects against cancer, cardiovascular disease, neurodegenerative diseases, diabetes, hyperglycemia, as well as potential effects on longevity. However, in clinical studies, there are multiple factors that restrict this plethora of health benefits attributed to phytoalexins. One of these barriers is rapid metabolism in the intestines and liver. As a means to overcome this barrier, there is evidence that retaining resveratrol in the mouth for extended periods allows for higher plasma levels of resveratrol. Processing, transport or storage may cause degradation due to light and air exposure. When the berries have been picked, they may not be at their peak phytoalexin production due to lack of elicitor induction. To overcome these barriers inherent in phytoalexin production and uptake, it is proposed that berries and possibly the edible leaves be directly ingested off of a grapevine, without harvesting. In addition to the benefit of removing these barriers to potential health benefits, this method introduces a variety of known phytoalexin elicitors, in the form of plant wounding and human saliva, which may enhance the levels of phytoalexins dramatically. The combined effect of multiple phytoalexins may also play a role in enhanced health benefits. To test this hypothesis, experiments with direct ingestion would be performed, followed by testing the participants’ plasma levels of resveratrol and potentially other phytoalexins. Proposed variables to be tested include: different subjects, elicitors, cultivars of grapevine, ripeness of fruit, and a range of time for the ingestion process. The potential implications include a direct means of obtaining, in clinically beneficial doses, the tremendous health benefits that have been documented for phytoalexins in vitro and in animal studies, but that have so far remained elusive in clinical studies. This study on direct ingestion may lead to alternative methods for obtaining these clinically beneficial doses.

PMID: 26880624 DOI: 10.1016/j.mehy.2015.12.008

Int Urol Nephrol. 2017 Nov 1. doi: 10.1007/s11255-017-1734-4. [Epub ahead of print]

Pterostilbene protects against uraemia serum-induced endothelial cell damage via activation of Keap1/Nrf2/HO-1 signaling.

Chen ZW1, Miu HF1, Wang HP2, Wu ZN2, Wang WJ1, Ling YJ2, Xu XH2, Sun HJ2, Jiang X3.

Author information

Abstract
Chronic kidney disease causes uremia-related endothelial cell dysfunction associated with high risk for cardiovascular diseases. The vascular endothelium is permanently exposed to uraemic toxins including indoxyl sulfate, which provokes endothelial damage in subjects with end-stage renal disease. Pterostilbene (PT) is identified to be homologous derivative of resveratrol and exerts antioxidant and anti-inflammatory actions. However, the effects of PT on uraemic serum-induced endothelial cell damage have not been elucidated. In this study, we investigated the effects and mechanisms of PT on uraemic serum (US)-mediated injury in human umbilical vein endothelial cells (HUVECs). Treatment of US obviously reduced cell viability, inhibited superoxide dismutase activity and catalase activity, suppressed phosphorylated endothelial nitric oxide synthase (eNOS) protein level and eNOS activity, whereas promoted lactate dehydrogenase leakage, increased malondialdehyde, hydrogen peroxide, superoxide anions levels and NAD(P)H activity accompanied with increased nitrative stress and inflammatory response in HUVECs, and these changes were reversed after PT treatment. Under US environment, PT downregulated Kelch-like ECH-associated protein 1 (Keap1) and upregulated nuclear factor erythroid-2-related factor 2 (Nrf2) and its downstream target heme oxygenase-1 (HO-1) protein levels. Of note, the level of HO-1 was decreased after the transfection of cells with Nrf2-siRNA, and HO-1 inhibitor Snpp abolished the protective effects of PT on HUVECs in response to US. Collectively, our study demonstrated that PT is effective in reducing US-evoked endothelial cell dysfunction via suppression of oxidative/nitrative stress and inflammatory response, which at least partly depended on Keap1/Nrf2/HO-1 signaling pathway.

KEYWORDS:
Chronic kidney disease; Endothelial cell; Nrf2; Pterostilbene; Uremia

PMID: 29094331 DOI: 10.1007/s11255-017-1734-4

Inflammation. 2017 Apr;40(2):578-588. doi: 10.1007/s10753-016-0504-2.

Protective Effects of Pterostilbene Against Myocardial Ischemia/Reperfusion Injury in Rats.

Wu M1,2, Lu S1, Zhong J1, Huang K1, Zhang S3.

Author information

Abstract
Pterostilbene (PTB) has been suggested to protect against myocardial ischemia/reperfusion (MI/R) injury. Gas6/Axl signaling has been suggested to play an important role in cell survival. However, the interaction between PTB and Gas6/Axl signaling in MI/R remains unclear. This study aims to evaluate the role of Gas6/Axl signaling in the protective effects of PTB against MI/R injury. In experiment 1, the rats were subjected to 30 min of ischemia, followed by 3, 6, and 12 h of reperfusion, respectively. In experiment 2, the rats were administered intraperitoneally with PTB or vehicle and subjected to MI/R injury. The results suggested that the expression of Gas6 and Axl decreased significantly after MI/R injury. PTB treatment conferred a cardioprotective effect with an improved post-ischemic cardiac function, a reduced myocardial infarct size, and decreased lactate dehydrogenase and creatine kinase-MB in the serum, a decreased oxidative stress and inflammation, and a reduced number of apoptotic cardiomyocytes. Moreover, PTB treatment up-regulated the expression of Gas6, Axl, and Bcl-2 and down-regulated Bax expression. Our findings suggest that PTB treatment exerts cardioprotection against MI/R injury via attenuating inflammatory response, oxidative stress, and apoptosis and up-regulating the expression of Gas6 and Axl. The application of PTB may be a new strategy for the treatment of MI/R injury.

KEYWORDS:
Gas6/Axl signaling; inflammation; myocardial ischemia/reperfusion injury; oxidative stress; pterostilbene

PMID: 28054238 DOI: 10.1007/s10753-016-0504-2

Biochim Biophys Acta. 2017 Apr;1863(4):827-837. doi: 10.1016/j.bbadis.2017.01.005. Epub 2017 Jan 9.

Pterostilbene attenuates high glucose-induced oxidative injury in hippocampal neuronal cells by activating nuclear factor erythroid 2-related factor 2.

Yang Y1, Fan C2, Wang B3, Ma Z2, Wang D4, Gong B4, Di S2, Jiang S5, Li Y6, Li T6, Yang Z6, Luo E7.

Author information

Abstract
In the present study, neuroblastoma (SH-SY5Y) cells were used to investigate the mechanisms mediating the potential protective effects of pterostilbene (PTE) against mitochondrial metabolic impairment and oxidative stress induced by hyperglycemia for mimicking the diabetic encephalopathy. High glucose medium (100mM) decreased cellular viability after 24h incubation which was evidenced by: (i) reduced mitochondrial complex I and III activities; (ii) reduced mitochondrial cytochrome C; (iii) increased reactive oxygen species (ROS) generation; (iv) decreased mitochondrial membrane potential (ΔΨm); and (v) increased lactate dehydrogenase (LDH) levels. PTE (2.5, 5, and 10μM for 24h) was nontoxic and induced the nuclear transition of Nrf2. Pretreatment of PTE (2.5, 5, and 10μM for 2h) displayed a dose-dependently neuroprotective effect, as indicated by significantly prevented high glucose-induced loss of cellular viability, generation of ROS, reduced mitochondrial complex I and III activities, reduced mitochondrial cytochrome C, decreased ΔΨm, and increased LDH levels. Moreover, the levels of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and glutathione S-transferase (GST) were elevated after PTE treatment. In addition, the elevation of nuclear Nrf2 by PTE treatment (10μM for 2h) was abolished by Nrf2 siRNA. Importantly, Nrf2 siRNA induced the opposite changes in mitochondrial complex I and III activities, mitochondrial cytochrome C, reactive species generation, ΔΨm, and LDH. Overall, the present findings were the first to show that pterostilbene attenuated high glucose-induced central nervous system injury in vitro through the activation of Nrf2 signaling, displaying protective effects against mitochondrial dysfunction-derived oxidative stress.

KEYWORDS:
High glucose; Neuroprotection; Nuclear factor erythroid 2-related factor 2 signaling; Oxidative stress; Pterostilbene

PMID: 28089584 DOI: 10.1016/j.bbadis.2017.01.005

Sci Rep. 2017 Aug 14;7(1):8091. doi: 10.1038/s41598-017-08547-0.

Pterostilbene exerts anticancer activity on non-small-cell lung cancer via activating endoplasmic reticulum stress.

Ma Z1, Yang Y2,3,4, Di S1, Feng X5, Liu D6, Jiang S7, Hu W4, Qin Z5, Li Y4, Lv J4, Fan C8, Yan X9, Li X10.

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Abstract
Pterostilbene (PT), the natural dimethylated analog of resveratrol (RSV), is a potent anticarcinogen for non-small-cell lung cancer (NSCLC), but its anti-NSCLC mechanisms remain unclear. In this study, we show that PT treatment time- and dose-dependently enhanced the endoplasmic reticulum stress (ERS) signaling (i.e., p-PERK, IRE1, ATF4, CHOP), thus decreasing the cell viability and inducing apoptosis in human PC9 and A549 NSCLC cell lines. Moreover, the decreased migratory and adhesive abilities, downregulation of intracellular glutathione (GSH) level, enhanced reactive oxygen species (ROS) generation, Caspase 3 activity and mitochondrial membrane depolarization were observed in NSCLC cells treated with PT. These effects were reversed by CHOP siRNA which inhibited the ERS signaling pathway, but were promoted by thapsigargin (a classical ERS inducer) in vitro. Besides, in vivo studies also verify that PT exerted anticancer activity by mobilizing ERS signaling and apoptosis-related proteins, and these effects were enhanced by thapsigargin. Therefore, ERS activation may represent a new mechanism of anti-NSCLC action by PT, and a novel therapeutic intervention for lung cancer.

PMID: 28808300 PMCID: PMC5556085 DOI: 10.1038/s41598-017-08547-0

Pharmacol Res. 2017 Oct;124:126-145. doi: 10.1016/j.phrs.2017.08.002. Epub 2017 Aug 9.

Anti-inflammatory activity of natural stilbenoids: A review.

Dvorakova M1, Landa P2.

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Abstract
Resveratrol and other natural stilbenoids, including piceatannol, pterostilbene, and gnetol, are well-known anti-inflammatory compounds with indisputable activity in vitro as well as in vivo. Their molecular targets include inducible nitric oxide synthase, cyclooxygenases, leukotrienes, nuclear factor kappa B, tumor necrosis factor α, interleukins and many more. This anti-inflammatory activity together with their antioxidant activity is believed to stand behind their other positive health effects against cancer, cardiovascular and neurodegenerative diseases or diabetes. Thus, they are nowadays commercially marketed as nutraceuticals. Naturally, they are present in wine, grapes or berries. However, there is a rigorous debate about the real effect of these compounds on human health. It is argued that the concentration of stilbenoids in food and beverages is too low to have any therapeutic potential and this concentration is further reduced by their low bioavailability and extensive metabolism. Therefore, this review focuses on in vitro, in vivo, preclinical as well as clinical data available for various natural stilbenoids and summarizes the anti-inflammatory targets on molecular level, compares the relevance of the experimental studies, discusses the metabolism of stilbenoids and the potential activity of their metabolites and relates this knowledge to human health. Moreover, the ways to augment stilbenoidś efficacy are suggested with special focus on multitargeted therapy and nanocarriers.

KEYWORDS:
Bioavailability; Encapsulation; Inflammation; Metabolites; Multi-targeted therapy; Natural stilbenes

PMID: 28803136 DOI: 10.1016/j.phrs.2017.08.002

Molecules. 2017 Feb 1;22(2). pii: E204. doi: 10.3390/molecules22020204.

Disparate Effects of Stilbenoid Polyphenols on Hypertrophic Cardiomyocytes In Vitro vs. in the Spontaneously Hypertensive Heart Failure Rat.

Akinwumi BC1,2, Raj P3,4,5, Lee DI6,7, Acosta C8,9, Yu L10,11, Thomas SM12, Nagabhushanam K13, Majeed M14,13, Davies NM15,16, Netticadan T17,18,19, Anderson HD20,21,22.

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Abstract
Stilbenoids are bioactive polyphenols, and resveratrol (trans-3,5,40-trihydroxystilbene) is a representative stilbenoid that reportedly exerts cardioprotective actions. As resveratrol exhibits low oral bioavailability, we turned our attention to other stilbenoid compounds with a history of medicinal use and/or improved bioavailability. We determined the effects of gnetol (trans-3,5,20,60-tetrahydroxystilbene) and pterostilbene (trans-3,5-dimethoxy-40-hydroxystilbene) on cardiac hypertrophy. In vitro, gnetol and pterostilbene prevented endothelin-1-induced indicators of cardiomyocyte hypertrophy including cell enlargement and protein synthesis. Gnetol and pterostilbene stimulated AMP-activated protein kinase (AMPK), and inhibition of AMPK, using compound C or shRNA knockdown,abolished these anti-hypertrophiceffects. In contrast,resveratrol, gnetol, nor pterostilbene reduced blood pressure or hypertrophy in the spontaneously hypertensive heart failure (SHHF) rat. In fact, AMPK levels were similar between Sprague-Dawley and SHHF rats whether treated by stilbenoids or not. These data suggest that the anti-hypertrophic actions of resveratrol (and other stilbenoids?) do not extend to the SHHF rat, which models heart failure superimposed on hypertension. Notably, SHHF rat hearts exhibited prolonged isovolumic relaxationtime(an indicator of diastolicdys function),and this was improved by stilbenoid treatment.In conclusion, stilbenoid-based treatment as a viable strategy to prevent pathological cardiac hypertrophy,a major risk factor for heart failure,may be context-dependent and requires furtherstudy.

KEYWORDS:
heart failure; hypertension; polyphenol; resveratrol; stilbenoid

PMID: 28157155 DOI: 10.3390/molecules22020204

Molecules. 2017 Feb 28;22(3). pii: E380. doi: 10.3390/molecules22030380.

Peripheral and Cerebral Resistance Arteries in the Spontaneously Hypertensive Heart Failure Rat: Effects of Stilbenoid Polyphenols.

Lee DI1,2, Acosta C3,4,5, Anderson CM6,7, Anderson HD8,9,10.

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Abstract
Hypertension is associated with aberrant structure and mechanical properties of resistance arteries. We determined the effects of resveratrol, a non-flavonoid polyphenol found in foods such as red grapes, and structurally-similar analogues (pterostilbene and gnetol) on systolic blood pressure (SBP) and resistance arteries from the spontaneously hypertensive heart failure (SHHF) rat. SBP was elevated in 17-week-old SHHF vs. Sprague-Dawley rats (normotensive control; 194 ± 3 vs. 142 ± 6 mmHg, p < 0.01) and was unaffected by resveratrol, pterostilbene, or gnetol (2.5 mg/kg/d). Geometry and mechanical properties of pressurized mesenteric resistance arteries and middle cerebral arteries were calculated from media and lumen dimensions measured at incremental intraluminal pressures. SHHF arteries exhibited remodeling which consisted of augmented media-to-lumen ratios, and this was attenuated by stilbenoid treatment. Compliance was significantly reduced in SHHF middle cerebral arteries but not mesenteric arteries vis-à-vis increased wall component stiffness; stilbenoid treatment failed to normalize compliance and wall component stiffness. Our data suggest that neither AMPK nor ERK mediate stilbenoid effects. In conclusion, we observed arterial bed-specific abnormalities, where mesenteric resistance arteries exhibited remodeling and cerebral arteries exhibited remodeling and stiffening. Resveratrol, pterostilbene, and gnetol exhibited similar abilities to attenuate vascular alterations.

KEYWORDS:
compliance; polyphenol; remodeling; resistance arteries; resveratrol; stilbenoid

PMID: 28264510 DOI: 10.3390/molecules22030380