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Antioxidant Activity


Oxid Med Cell Longev.2013;2013:575482. doi: 10.1155/2013/575482. Epub 2013 Apr 4.

A review of pterostilbene antioxidant activity and disease modification.

McCormack D1, McFadden D.

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Pterostilbene (trans-3,5-dimethoxy-4-hydroxystilbene) is a natural dietary compound and the primary antioxidant component of blueberries. It has increased bioavailability in comparison to other stilbene compounds, which may enhance its dietary benefit and possibly contribute to a valuable clinical effect. Multiple studies have demonstrated the antioxidant activity of pterostilbene in both in vitro and in vivo models illustrating both preventative and therapeutic benefits. The antioxidant activity of pterostilbene has been implicated in anticarcinogenesis, modulation of neurological disease, anti-inflammation, attenuation of vascular disease, and amelioration of diabetes. In this review, we explore the antioxidant properties of pterostilbene and its relationship to common disease pathways and give a summary of the clinical potential of pterostilbene in the prevention and treatment of various medical conditions.

PMID: 23691264 PMCID: PMC3649683DOI: 10.1155/2013/575482

PLoS One.2014 Aug 15;9(8):e104459. doi: 10.1371/journal.pone.0104459. eCollection 2014.

Estrogen receptor-α36 is involved in pterostilbene-induced apoptosis and anti-proliferation in in vitro and in vivo breast cancer.

Pan C1, Hu Y2, Li J3, Wang Z4, Huang J5, Zhang S1, Ding L5.

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Pterostilbene (trans-3,5-dimethoxy-4′-hudroxystilbene) is an antioxidant primarily found in blueberries. It also inhibits breast cancer regardless of conventional estrogen receptor (ER-α66) status by inducing both caspase-dependent and caspase-independent apoptosis. However, the pterostilbene-induced apoptosis rate in ER-α66-negative breast cancer cells is much higher than that in ER-α66-positive breast cancer cells. ER-α36, a variant of ER-α66, is widely expressed in ER-α66-negative breast cancer, and its high expression mediates the resistance of ER-α66-positive breast cancer patients to tamoxifen therapy. The aim of the present study is to determine the relationship between the antiproliferation activity of pterostilbene and ER-α36 expression in breast cancer cells. Methyl-thiazolyl-tetrazolium (MTT) assay, apoptosis analysis, and an orthotropic xenograft mouse model were used to examine the effects of pterostilbene on breast cancer cells. The expressions of ER-α36 and caspase 3, the activation of ERK and Akt were also studied through RT-PCR, western blot analysis, and immunohistochemical (IHC) staining. ER-α36 knockdown was found to desensitize ER-α66-negative breast cancer cells to pterostilbene treatment both in vitro and in vivo, and high ER-α36 expression promotes pterostilbene-induced apoptosis in breast cancer cells. Western blot analysis data indicate that MAPK/ERK and PI3K/Akt signaling in breast cancer cells with high ER-α36 expression are mediated by ER-α36, and are inhibited by pterostilbene. These results suggest that ER-α36 is a therapeutic target in ER-α36-positive breast cancer, and pterostilbene is an inhibitor that targets ER-α36 in the personalized therapy against ER-α36-positive breast cancer.

PMID: 25127034 PMCID: PMC4134202DOI: 10.1371/journal.pone.0104459

Int J Clin Exp Pathol.2015 Oct 1;8(10):12589-94. eCollection 2015.

Pterostilbene impact on retinal endothelial cells under high glucose environment.

Shen H1, Rong H2.

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Diabetic retinopathy (DR) has complicated pathogenic factors. Studies showed that DR belongs to chronic inflammatory disease, and retinal endothelial cells oxidation by free radicals is one of its mechanisms. Pterostilbene, as the homologous derivative of resveratrol, has obvious antioxidant effect. Its influence on the DR has not been studied. This study intended to investigate the effect and mechanism of pterostilbene on human retinal endothelial cells (hRECs) under high glucose environment to illustrate pterostilbene impact on DR and provide basis for DR clinical treatment. hRECs cultured in high glucose environment were treated by 1.0 mmol/L pterostilbene. MTT assay was applied to test cell proliferation. ELISA was used to detect inflammatory factor TNF-α and IL-1β content. Real time PCR and Western blot were performed to examine NF-κB mRNA and protein expression. ROS and SOD activities were analyzed. Under high glucose environment, hRECs proliferation increased, TNF-α and IL-1β expression elevated, and NF-κB protein level upregulated significantly. On the other side, ROS production increased and SOD activity decreased obviously (P < 0.05). Pterostilbene can suppress hRECs over proliferation, decrease TNF-α and IL-1β, inhibit NF-κB protein expression, reduce ROS production, and increase SOD activity markedly compared with high glucose group (P < 0.05). Pterostilbene may delay DR progress through alleviating inflammation and antioxidation to suppress hRECs over proliferation.

KEYWORDS: Diabetic retinopathy; inflammatory factor; pterostilbene; retinal endothelial cell

PMID: 26722449 PMCID: PMC4680394

Oral Oncol.2015 Jun;51(6):593-601. doi: 10.1016/j.oraloncology.2015.03.007. Epub 2015 Apr 14.

Pterostilbene induce autophagy on human oral cancer cells through modulation of Akt and mitogen-activated protein kinase pathway. 

Ko CP1, Lin CW2, Chen MK3, Yang SF4, Chiou HL5, Hsieh MJ6.

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OBJECTIVES: Extensive research supports the administration of herbal medicines or natural foods during cancer therapy. Pterostilbene, a naturally occurring phytoalexin, has various pharmacological activities, including antioxidant activity, cancer prevention activity, and cytotoxicity to many cancers. However, the effect of pterostilbene on the autophagy of tumor cells has not been clarified.

MATERIALS AND METHODS: In this study, the unique effects of pterostilbene on the autophagy of human oral cancer cells were investigated.

RESULTS: The results of this study showed that pterostilbene effectively inhibited the growth of human oral cancer cells by inducing cell cycle arrest and apoptosis. In addition, the formation of acidic vesicular organelles and LC3-II production also demonstrated that pterostilbene induced autophagy. Administering 3-methylamphetamine (3-MA) and bafilomycin A1 (BafA1) exerted differing effects on the pterostilbene-induced death of human oral cancer cells. Pterostilbene-induced autophagy was triggered by activation of JNK1/2 and inhibition of Akt, ERK1/2, and p38.

CONCLUSION: In conclusion, this study demonstrated that pterostilbene caused autophagy and apoptosis in human oral cancer cells, suggesting that pterostilbene could serve as a new and promising agent for treating human oral cancer.

Copyright © 2015 Elsevier Ltd. All rights reserved.

KEYWORDS: Apoptosis; Autophagy; MAPK; Oral cancer; Phytoalexin; Pterostilbene

PMID: 25883032 DOI: 10.1016/j.oraloncology.2015.03.007

Neuro Endocrinol Lett.2010;31 Suppl 2:84-90.

Molecular targets of the natural antioxidant pterostilbene: effect on protein kinase C, caspase-3 and apoptosis in human neutrophils in vitro. 

Perecko T1, Drabikova K, Rackova L, Ciz M, Podborska M, Lojek A, Harmatha J, Smidrkal J, Nosal R, Jancinova V.

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OBJECTIVE: Pterostilbene, a naturally occurring phenolic derivative, exhibits various pharmacological effects, e.g. anti-cancerous, antioxidant, anti-inflammatory and anti-diabetic. Based on our previous study, we assessed the cellular and molecular effects of pterostilbene on human neutrophils and in cell free systems. Experimental and theoretical molecular descriptors of stilbene derivatives were also determined.

METHODS: We assessed the antioxidant properties of pterostilbene using cell free system and computational methods. The effect of pterostilbene on protein kinase C activation/phosphorylation was detected by special anti-phospho protein kinase C antibodies. Membrane associated changes determining the life span of neutrophils and human recombinant caspase-3 assay were examined.

RESULTS: Pterostilbene possessed comparable antioxidant properties as resveratrol in cell free system. Computational methods were used to establish the molecular characteristics of stilbene derivatives. The values of electronic parameters suggest a slight enhancement of electron donor properties of pterostilbene compared to resveratrol. Phosphorylation and thus activation of protein kinase C alpha/beta II in activated neutrophils was not decreased by pterostilbene. Pterostilbene in concentrations of 10-100 μM was found to inhibit the activity of human caspase-3 purified enzyme and did not influence cell viability significantly.

CONCLUSION: Pterostilbene, an analog of resveratrol, was identified as a good natural antioxidant compound. However, reducing the oxidative burst of human neutrophils during their activation in vitro with pterostilbene does not include protein kinase C phosphorylation pathway. Pterostilbene showed dose dependentactivation/inhibition of caspase-3 enzyme activity.

PMID: 21187824

Food Chem Toxicol.2014 Oct;72:303-11. doi: 10.1016/j.fct.2014.07.038. Epub 2014 Aug 8.

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

Saw CL1, Guo Y2, Yang AY2, Paredes-Gonzalez X2, Ramirez C3, Pung D4, Kong AN5.

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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.

KEYWORDS: Antioxidant response element (ARE); Kaempferol; Nuclear factor (erythroid-derived 2)-like 2 (Nrf2); Pterostilbene; Quercetin; Reactive oxygen species

PMID: 25111660 DOI: 10.1016/j.fct.2014.07.038

Expert Opin Ther Targets.2014 Oct;18(10):1109-20. doi: 10.1517/14728222.2014.947962. Epub 2014 Aug 9.

Pterostilbene suppresses oral cancer cell invasion by inhibiting MMP-2 expression.

Lin CW1, Chou YE, Chiou HL, Chen MK, Yang WE, Hsieh MJ, Yang SF.

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OBJECTIVE: Polyphenol compounds, present in a wide variety of natural plants, exhibit antioxidant and free radical scavenging ability and induce apoptosis in various cancer cells. However, the effect of pterostilbene on oral cancer cell metastasis has not been clarified.

RESEARCH DESIGN AND METHODS: The present study aimed to examine the anti-metastatic properties of pterostilbene in human oral squamous cell carcinoma (SCC)-9 cells.

RESULTS: In this study, pterostilbene treatment significantly inhibited migration/invasion capacities of SCC-9 cells in vitro. The results of zymography and western blotting revealed that the activities and protein levels of the MMP-2 and urokinase-type plasminogen activator (u-PA) was inhibited by pterostilbene. Western blot analysis also showed that pterostilbene inhibits the phosphorylation of Akt, extracellular signal-regulated kinase 1/2 and p38. Determinations of the mRNA levels, real-time polymerase chain reaction and promoter assays were conducted to evaluate the inhibitory effects of pterostilbene on MMP-2 and u-PA expression in SCC-9 cells. Such inhibitory effects were associated with the upregulation of tissue inhibitor of metalloproteinase-2, plasminogen activator inhibitor-1 and the downregulation of the transcription factors of NF-κB, SP-1 and CREB signaling pathways.

CONCLUSIONS: Pterostilbene may have potential use as a chemopreventive agent against oral cancer metastasis.

KEYWORDS: MMP-2; migration; oral cancer; pterostilbene; urokinase-type plasminogen activator

PMID: 25109417 DOI: 10.1517/14728222.2014.947962

J Surg Res.2013 Apr;180(2):208-15. doi: 10.1016/j.jss.2012.04.027. Epub 2012 Apr 29.

Pterostilbene induces mitochondrially derived apoptosis in breast cancer cells in vitro.

Moon D1, McCormack D, McDonald D, McFadden D.

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BACKGROUND: The ability of a breast cancer cell to evade apoptosis has a key role in tumor progression and sensitivity to treatment. High levels of Bcl-2-associated X protein (Bax) in tumor cells have been found to promote apoptosis and sensitize cells to anti-cancer therapies. Bcl-2-associated X protein redistribution to the mitochondrial membrane results in the release of proapoptotic factors including cytochrome C, second-mitochondrial-derived activator of caspase/direct inhibitor of apoptosis-binding protein with low PI (Smac/DIABLO), and Ca(2+). We aimed to explore this pathway in cancerous breast cell lines treated with the naturally occurring antioxidant 3,5-dimethoxy-4-hydroxystilbene (pterostilbene).

METHODS: We used whole cell lysates +/- Bax SiRNA from the cell lines MCF-7 and MDA-MB-231 in an enzyme-linked immunosorbent assay to quantify Bax, cytochrome C, Smac/DIABLO expression, and manganese superoxide dismutase (MnSOD) activity after treatment with pterostilbene. We quantified cell death using histone-related DNA complexes from cytosolic and mitochondrial fractions and used methylthiazol tetrazolium assay to analyze cell proliferation, in the presence of Bax-silencing or scrambled RNA. We measured changes in cytosolic calcium using the ratiometric calcium-sensitive dye fura-2-AM using an inverted ratiometric monochromator microscope.

RESULTS: Treatment of MCF-7 and MDA-MB-231 (MDA) cells with pterostilbene caused concentration-dependent increases in intracellular Bax at all doses tested. RNA silencing of Bax resulted in reduced rates of apoptosis in both cells types and increased cell survival when treated with pterostilbene. We observed an increase in cytochrome C in MDA cells after treatment with pterostilbene. The MCF-7 cells showed a net increase in cytosolic cytochrome C, with a corresponding reduction in mitochondrial cytochrome C after treatment with 50 and 75 μmol/L pterostilbene. We observed this again in Smac/DIABLO expression in both cell types. In MCF-7 cells, pterostilbene treatment caused an increase in cytosolic but a decrease in mitochondrial Smac/DIABLO protein concentrations. Pterostilbene significantly increase MnSOD activity in MDA-MB-231 cells. Finally, pterostilbene resulted in significant increases in cytosolic calcium concentrations.

CONCLUSIONS: The natural dietary compound pterostilbene has an anti-proliferative effect and induces apoptosis in breast cancer cells in vitro via Bax activation and overexpression, resulting in increased MnSOD, Smac/DIABLO, and cytochrome C activity and cytosolic Ca(2+) overload.

Copyright © 2013 Elsevier Inc. All rights reserved.

PMID: 22572619 DOI: 10.1016/j.jss.2012.04.027

Ann N Y Acad Sci.2015 Aug;1348(1):141-9. doi: 10.1111/nyas.12836. Epub 2015 Aug 6.

Synthesis and pharmacological evaluation of glycosides of resveratrol, pterostilbene, and piceatannol.

Shimoda K1, Kubota N1, Uesugi D2, Hamada H3, Tanigawa M4, Hamada H2.

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To enhance their water solubility and pharmacological activities, the stilbenes resveratrol, pterostilbene, and piceatannol were glycosylated to their monoglucosides(β-glucosides) and diglycosides (β-maltosides) by cultured cells and cyclodextrin glucanotransferase (CGTase). Cultured cells of Phytolacca americana and glucosyltransferase (PaGT) were capable of glucosylation of resveratrol to its 3- and 4′-β-glucosides. Pterostilbene was slightly transformed into its 4′-β-glucoside by P. americana cells. Piceatannol was readily converted into piceatannol 4′-β-glucoside, with the highest yield among the three substrates. The 3- and 4′-β-glucosides of resveratrol were subjected to further glycosylation by CGTase to give 3- and 4′-β-maltoside derivatives. The inhibitory action of resveratrol and pterostilbene toward histamine release induced with compound 48/80 from rat peritoneal mast cells was improved by β-glucosylation and/or β-maltosylation (i.e., the inhibitory activity for histamine release of the 3- and 4′-β-glucosides of resveratrol, the 3- and 4′-β-maltosides of resveratrol, and the 4′-β-glucoside of pterostilbene was higher than that of the corresponding aglycones, resveratrol and pterostilbene, respectively). In addition, the phosphodiesterase (PDE) inhibitory activity of resveratrol and pterostilbene was enhanced by β-glucosylation and/or β-maltosylation (i.e., the PDE inhibitory activities of the 3- and 4′-β-glucosides of resveratrol, the 4′-β-maltoside of resveratrol, and the 4′-β-glucoside of pterostilbene were higher than those of the corresponding aglycones, resveratrol andpterostilbene, respectively).

KEYWORDS: glycoside; pharmacological activity; piceatannol; pterostilbene; resveratrol; synthesis

PMID: 26250502 DOI: 10.1111/nyas.12836

Plant Foods Hum Nutr.2010 Mar;65(1):57-63. doi: 10.1007/s11130-010-0154-8.

Antioxidant effect of trans-resveratrol, pterostilbene, quercetin and their combinations in human erythrocytes in vitro. 

Mikstacka R1, Rimando AM, Ignatowicz E.

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There is evidence that a diet rich in fruit and vegetables may reduce the risk of cancer and other degenerative diseases. However, potential health impact of bioactive phytochemicals is limited by their low amount and relatively poor bioavailability. It has been suggested that the health benefits associated with fruit and red wine consumption could be due to the whole antioxidant pool of the diet microcomponents. In this study, the antioxidant activities of trans-resveratrol, pterostilbene and quercetin, and the effect of their combination were investigated in human erythrocytes in vitro. H(2)O(2)-induced lipid peroxidation was assessed by measuring the amount of thiobarbituric acid reactive species. Quercetin and pterostilbene protected erythrocyte membranes against lipid peroxidation (IC(50) values = 64 +/- 8.7 microM and 44.5 +/- 7.8 microM, respectively). Resveratrol was significantly less effective. However, the three compounds protected the erythocytes against hemolysis and GSH (reduced glutathione) depletion to the same extent. Combinations consisting of two compounds (molar ratio 1:1) influenced lipid peroxidation in a concentration-dependent manner. At lower concentrations, resveratrol with quercetin or pterostilbene inhibited synergistically the oxidative injury of membrane lipids At higher concentrations, an additive effect was observed. These protective effects may partially explain the health benefit of these bioactive microcomponents when together in the diet.

PMID: 20108046 DOI: 10.1007/s11130-010-0154-8

Biosci Biotechnol Biochem.2014;78(7):1123-8. doi: 10.1080/09168451.2014.921551. Epub 2014 Jun 9.

Synthesis of glycosides of resveratrol, pterostilbene, and piceatannol, and their anti-oxidant, anti-allergic, and neuroprotective activities. 

Sato D1, Shimizu N, Shimizu Y, Akagi M, Eshita Y, Ozaki S, Nakajima N, Ishihara K, Masuoka N, Hamada H, Shimoda K, Kubota N.

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Resveratrol was glucosylated to its 3- and 4′-β-glucosides by cultured cells of Phytolacca americana. On the other hand, cultured P. americana cells glucosylated pterostilbene to its 4′-β-glucoside. P. americana cells converted piceatannol into its 4′-β-glucoside. The 3- and 4′-β-glucosides of resveratrol were further glucosylated to 3- and 4′-β-maltosides of resveratrol, 4′-β-maltoside of which is a new compound, by cyclodextrin glucanotransferase. Resveratrol 3-β-glucoside and 3-β-maltoside showed low 2,2-diphenyl-1-picrylhydrazyl free-radical-scavenging activity, whereas other glucosides had no radical-scavenging activity. Piceatannol 4′-β-glucoside showed the strongest inhibitory activity among the stilbene glycosides towards histamine release from rat peritoneal mast cells. Pterostilbene 4′-β-glucoside showed high phosphodiesterase inhibitory activity.

KEYWORDS: glycoside; piceatannol; pterostilbene; resveratrol

PMID: 25229845 DOI: 10.1080/09168451.2014.921551

Toxicol Sci.2014 Jan;137(1):65-75. doi: 10.1093/toxsci/kft238. Epub 2013 Oct 23.

A combination of pterostilbene with autophagy inhibitors exerts efficient apoptotic characteristics in both chemosensitive and chemoresistant lung cancer cells.

Hsieh MJ1, Lin CW, Yang SF, Sheu GT, Yu YY, Chen MK, Chiou HL.

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The emergence of multidrug resistance (MDR), meaning that cancer cells develop simultaneous resistance to different drugs, has limited the clinical efficacy and application of chemotherapy. Pterostilbene, a naturally occurring phytoalexin exerts a variety of pharmacologic activities, including cancer prevention, cytotoxicity, and antioxidant activity. In this study, results proved the capability of pterostilbene to effectively inhibit the cell viability of docetaxel-induced MDR human lung cancer cell lines through cell cycle arrest and apoptosis. Meanwhile, the observation of LC3-II production and formation of acidic vesicular organelles revealed an inductionof autophagy at an early stage by pterostilbene, which was triggered by an inhibition of the AKT and JNK pathways and activation of ERK1/2. Furthermore, pretreatment with the autophagy inhibitors 3-methyladenine and bafilomycin A1 or with beclin-1 small interfering RNA was able to enhance pterostilbene-triggered apoptosis. In conclusion, this study demonstrated that pterostilbene causes autophagy and apoptosis in lung cancer cells. Furthermore, pterostilbene in combination with autophagy inhibitors may strengthen the efficiency of chemotherapeutic strategies in both chemosensitive and chemoresistant lung cancer cells, which may be of immense value for the clinical management of lung cancer patients with MDR.

KEYWORDS: apoptosis; autophagy.; multidrug resistance; pterostilbene

PMID: 24154491 DOI: 10.1093/toxsci/kft238

Phytother Res.2008 Feb;22(2):169-79.

Pharmacometrics of pterostilbene: preclinical pharmacokinetics and metabolism, anticancer, antiinflammatory, antioxidant and analgesic activity.

Remsberg CM1, Yáñez JA, Ohgami Y, Vega-Villa KR, Rimando AM, Davies NM.

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The present study evaluated the preclinical pharmacokinetics and pharmacodynamics of trans-pterostilbene, a constituent of some plants. Right jugular vein cannulated male Sprague-Dawley rats were dosed i.v. with 20 mg/kg of pterostilbene and samples were analysed by the reverse phase HPLC method. Serum AUC, serum t(1/2), urine t(1/2), Cl(total) and Vd(beta) were 17.5 +/- 6.6 microg/h/mL, 1.73 +/- 0.78 h, 17.3 +/- 5.6 h, 0.960 +/- 0.025 L/h/kg and 2.41 +/- 1.13 L/kg (mean +/- SEM), respectively. A pterostilbene glucuronidated metabolite was detected in both serum and urine. The in vitro metabolism in rat liver microsomes furthermore suggests phase II metabolism of pterostilbene. Pterostilbene demonstrated concentration-dependent anticancer activity in five cancer cell lines (1-100 microg/mL). An in vitro colitis model showed concentration-dependent suppression of PGE(2) production in the media of HT-29 cells. Antiinflammatory activity was examined by inducing inflammation in canine chondrocytes followed by treatment with pterostilbene (1-100 microg/mL). The results showed decreased levels of MMP-3, sGAG andTNF-alpha compared with control levels. Pterostilbene exhibited concentration-dependent antioxidant capacity measured by the ABTS method. Pterostilbene increased the latency period to response in both tail-flick and hot-plate analgesic tests.

PMID: 17726731 DOI: 10.1002/ptr.2277

Phytochemistry.2014 Feb;98:164-73. doi: 10.1016/j.phytochem.2013.11.019. Epub 2013 Dec 19.

The stilbenes resveratrol, pterostilbene and piceid affect growth and stress resistance in mammalian cells via a mechanism requiring estrogen receptor beta and the induction of Mn-superoxide dismutase.

Robb EL1, Stuart JA2.

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The mitochondrial antioxidant enzyme, Mn superoxide dismutase (MnSOD), has been shown to confer cytoprotection and to regulate cell cycle progression. Resveratrol, a phytoestrogen found in red wines and other foods, has been previously reported to increase MnSOD protein levels and activity both in vitro and in vivo. Numerous structural analogues of resveratrol produced via the same stilbene synthesis pathway (e.g. pterostilbene and piceid) and also present in foods and red wine may be capable of eliciting the same effects. Furthermore, in humans resveratrol is rapidly metabolized to resveratrol-4′-sulfate, resveratrol-3-glucuronide and other metabolites in vivo. Although these metabolites may accumulate to relatively high levels in plasma and tissues, little is known about their biological activities. Here the activities were compared of these stilbenes and stilbene metabolites in mammalian cells. Two key cellular activities associated with resveratrol were examined: inhibition of proliferative growth and increased stress resistance (important anti-cancer and cell protective activities, respectively). While resveratrol-4′-sulfate and resveratrol-3-glucuronide had no effect on either cell growth or stress resistance, both pterostilbene and piceid were at least as effective as resveratrol. Using pharmacological and genetic approaches, it was found that the effects of pterostilbene and piceid required an induction of the mitochondrial enzyme MnSOD and intact mitochondrial respiration. In addition, using estrogen receptor beta (ERbeta) knockout mouse myoblasts, it was demonstrated that the effects of stilbene compounds on cell growth and stress resistance all require ERbeta. Taken together, these results indicate that resveratrol, pterostilbene andpiceid all activate the same mitochondrial response in mammalian cells, and therefore these latter two molecules might be as effective as resveratrol in eliciting positive health outcomes in vivo.

KEYWORDS: Cell growth; Estrogen receptor beta; Mitochondria; Reactive oxygen species; Stilbene; Stress resistance; Superoxide dismutase

PMID: 24361291 DOI: 10.1016/j.phytochem.2013.11.019

J Biochem Mol Toxicol.2015 Jan;29(1):35-42. doi: 10.1002/jbt.21604. Epub 2014 Sep 9.

Protective effects of pterostilbene against acetaminophen-induced hepatotoxicity in rats.

El-Sayed el-SM1, Mansour AM, Nady ME.

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The present study was undertaken to evaluate the protective effect of pterostilbene against acetaminophen-induced hepatotoxicity. Silymarin was used as a standard hepatoprotective agent. A single dose of acetaminophen (800 mg/kg i.p.), injected to male rats, caused significant increases in serum levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, bilirubin, total cholesterol, triglycerides, tumor necrosis factor alpha, and hepatic contents of malondialdehyde, nitric oxide, caspase-3, hydroxyproline, with significant decreases in serum HDL-cholesterol, total proteins, albumin, and hepatic activities of reduced glutathione, superoxide dismutase and catalase as compared with the control group. On the other hand, administration of each of pterostilbene (50 mg/kg, p.o.) and silymarin (100 mg/kg, p.o.) for 15 days before acetaminophen ameliorated liver function and oxidative stress parameters. Histopathological evidence confirmed the protection offered by pterostilbene from the tissue damage caused by acetaminophen. In conclusion, pterostilbene possesses multimechanistic hepatoprotective activity that can be attributed to its antioxidant, anti-inflammatory, and antiapoptotic actions.

KEYWORDS: Acetaminophen; Antioxidant; Hepatotoxicity; Pterostilbene; Silymarin

PMID: 25201704 DOI: 10.1002/jbt.21604

Food Chem.2013 Jun 1;138(2-3):802-7. doi: 10.1016/j.foodchem.2012.11.094. Epub 2012 Dec 1.

Pterostilbene inhibits dimethylnitrosamine-induced liver fibrosis in rats. 

Lee MF1, Liu ML, Cheng AC, Tsai ML, Ho CT, Liou WS, Pan MH.

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Pterostilbene, found in grapes and berries, exhibits pleiotropic effects, including anti-inflammatory, antioxidant, and anti-proliferative activities. This study was conducted to investigate the effect of pterostilbene on liver fibrosis and the potential underlying mechanism for such effect. Sprague-Dawley rats were intraperitoneally given dimethyl n-nitrosamine (DMN) (10mg/kg) 3 days per week for 4 weeks. Pterostilbene (10 or 20mg/kg) was administered by oral gavage daily. Liver function, morphology, histochemistry, and fibrotic parameters were examined. Pterostilbene supplementation alleviated the DMN-induced changes in the serum levels of alanine transaminase and aspartate transaminase (p<0.05). Fibrotic status and the activation of hepatic stellate cells were improved upon pterostilbene supplementation as evidenced by histopathological examination as well as the expression of α-smooth muscle actin (α-SMA), transforming growth factor-β1 (TGF-β1), and matrix metalloproteinase 2 (MMP2). These data demonstrated that pterostilbene exhibited hepatoprotective effects on experimental fibrosis, potentially by inhibiting the TGF-β1/Smad signaling.

PMID: 23411180 DOI: 10.1016/j.foodchem.2012.11.094

J Gastrointest Surg.2012 Jun;16(6):1136-43. doi: 10.1007/s11605-012-1869-7. Epub 2012 Mar 27.

Genomic analysis of pterostilbene predicts its antiproliferative effects against pancreatic cancer in vitro and in vivo.

McCormack DE1, Mannal P, McDonald D, Tighe S, Hanson J, McFadden D.

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BACKGROUND: To investigate the inhibitory role of pterostilbene in pancreatic cancer, we conducted a genomic analysis of pterostilbene-treated pancreatic cancer cells. We also investigated the effect of pterostilbene upon the carcinogenic markers, manganese superoxide dismutase, cytochrome C, Smac/DIABLO, and STAT3 phosphorylation in vitro. The antiproliferative effects of pterostilbene were further evaluated in an in vivo model.

METHODS: Pancreatic cancer cells were treated with pterostilbene and evaluated with DNA microarray analysis. Pterostilbene-treated cells were analyzed for cytochrome C, Smac/DIABLO, manganese superoxide dismutase (MnSOD)/antioxidant activity, and STAT3 phosphorylation using ELISA. Data were statistically analyzed using ANOVA. Pterostilbene was then administered to nude mice for 8 weeks, and tumor growth rates were recorded and statistically analyzed.

RESULTS: Microarray analysis of pterostilbene-treated cells revealed upregulation of pro-apoptosis genes. In vitro, pterostilbene treatment altered levels of phosphorylated STAT3, MnSOD/antioxidant activity, cytochrome C, and Smac/DIABLO. In nude mice, oral pterostilbene inhibited tumor growth rates.

CONCLUSION: Pterostilbene alters gene expression in pancreatic cancer and increases the antiproliferative markers cytochrome C, Smac/DIABLO, and MnSOD/antioxidant activity. It was also shown to inhibit phosphorylated STAT3, a marker of accelerated tumorigenesis, and decrease pancreatic tumor growth in vivo. Further studies are warranted to elucidate the effects of pterostilbene in humans.

PMID: 22450950 PMCID: PMC4237162DOI: 10.1007/s11605-012-1869-7

Free Radic Biol Med.2015 Jun;83:214-26. doi: 10.1016/j.freeradbiomed.2015.02.029. Epub 2015 Mar 5.

Pterostilbene and allopurinol reduce fructose-induced podocyte oxidative stress and inflammation via microRNA-377. 

Wang W1, Ding XQ1, Gu TT1, Song L1, Li JM1, Xue QC1, Kong LD2.

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High dietary fructose is an important causative factor in the development of metabolic syndrome-associated glomerular podocyte oxidative stress and injury. Here, we identified microRNA-377 (miR-377) as a biomarker of oxidative stress in renal cortex of fructose-fed rats, which correlated with podocyte injury and albuminuria in metabolic syndrome. Fructose feeding increased miR-377 expression, decreased superoxide dismutase (SOD) expression and activity, and caused O2(-) and H2O2 overproduction in kidney cortex or glomeruli of rats. This reactive oxygen species induction increased p38 MAPK phosphorylation and thioredoxin-interacting protein (TXNIP) expression and activated the NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome to produce interleukin-1β in kidney glomeruli of fructose-fed rats. These pathological processes were further evaluated in cultured differentiated podocytes exposed to 5mM fructose, or transfected with miR-377 mimic/inhibitor and TXNIP siRNA, or co-incubated with p38 MAPK inhibitor, demonstrating that miR-377 overexpression activates the O2(-)/p38 MAPK/TXNIP/NLRP3 inflammasome pathway to promote oxidative stress and inflammation in fructose-induced podocyte injury. Antioxidants pterostilbene and allopurinol were found to ameliorate fructose-induced hyperuricemia, podocyte injury, and albuminuria in rats. More importantly, pterostilbene and allopurinol inhibited podocyte miR-377 overexpression to increase SOD1 and SOD2 levels and suppress the O2(-)/p38 MAPK/TXNIP/NLRP3 inflammasome pathway activation in vivo and in vitro, consistent with the reduction of oxidative stress and inflammation. These findings suggest that miR-377 plays an important role in glomerular podocyte oxidative stress, inflammation, and injury driven by high fructose. Inhibition of miR-377 by antioxidants may be a promising therapeutic strategy for the prevention of metabolic syndrome-associated glomerular podocyte injury.

KEYWORDS: Allopurinol; Free radicals; Fructose; MiR-377; NLRP3 inflammasome; Oxidative stress; Podocyte injury; Pterostilbene; TXNIP

PMID: 25746774 DOI: 10.1016/j.freeradbiomed.2015.02.029

Sci Rep.2016 Nov 21;6:37417. doi: 10.1038/srep37417.

Pterostilbene induces apoptosis and cell cycle arrest in diffuse large B-cell lymphoma cells.

Kong Y1, Chen G1, Xu Z2, Yang G1, Li B2, Wu X1, Xiao W1, Xie B1, Hu L1, Sun X1, Chang G1, Gao M1, Gao L1, Dai B3, Tao Y1, Zhu W2, Shi J1.

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Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma (NHL). Pterostilbene, a natural dimethylated analog of resveratrol, has been shown to possess diverse pharmacological activities, including anti-inflammatory, antioxidant and anticancer properties. However, to the best of our knowledge, there has been no study of the effects of pterostilbene upon hematological malignancies. Herein, we report the antitumor activity and mechanism of pterostilbene against DLBCL cells both in vitro and in vivo. We found that pterostilbene treatment resulted in a dose-dependent inhibition of cell viability. In addition, pterostilbene exhibited a strong cytotoxic effect, as evidenced not only by reductions of mitochondrial membrane potential (MMP) but also by increases in cellular apoptotic index and reactive oxygen species (ROS) levels, leading to arrest in the S-phase of the cell cycle. Furthermore, pterostilbene treatment directly up-regulated p-p38MAPK and down-regulated p-ERK1/2. In vivo, intravenous administration of pterostilbene inhibited tumor development in xenograft mouse models. Overall, the results suggested that pterostilbene is a potential anti-cancer pharmaceutical against human DLBCL by a mechanism involving the suppression of ERK1/2 and activation of p38MAPK signaling pathways.

PMID: 27869173 PMCID: PMC5116667DOI: 10.1038/srep37417

Hum Exp Toxicol.2011 Feb;30(2):138-44. doi: 10.1177/0960327110368739. Epub 2010 Apr 12.

Cytotoxic and antioxidant effects of methoxylated stilbene analogues on HepG2 hepatoma and Chang liver cells: Implications for structure activityrelationship.

Hasiah AH1, Ghazali AR, Weber JF, Velu S, Thomas NF, Inayat Hussain SH.

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Stilbenes possess a variety of biological activities including chemopreventive activity. This study was conducted to evaluate the structural activity relationships of six methoxylated stilbene analogues with respect to their cytotoxic effects and antioxidant activities on HepG2 hepatoma and Chang liver cells. The cytotoxic and total antioxidant activities of six stilbene analogues were determined by MTT and Ferric Reducing Antioxidant Power (FRAP) assays, respectively. We found that the cis-methoxylated stilbene: (Z)-3,4,4′-trimethoxystilbene was the most potent and selective antiproliferative agent (IC₅₀89 µM) in HepG2 cells. For the total antioxidant activity, compounds possessing hydroxyl groups at the 4′ position namely (E)-3-methoxy-4′-hydroxystilbene, (E)-3,5-dimethoxy-4′-hydroxystilbene (pterostilbene), (E)-4-methoxy-4′-hydroxystilbene showed the highest antioxidant activity. Structure activity relationship studies of these compounds demonstrated that the cytotoxic effect and antioxidant activities of the tested compounds in this study were structurally dependent.

PMID: 20385705 DOI: 10.1177/0960327110368739

BMC Complement Altern Med.2013 Sep 26;13:238. doi: 10.1186/1472-6882-13-238.

Protective effect of Pterostilbene against free radical mediated oxidative damage.

Acharya JD1, Ghaskadbi SS.

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BACKGROUND: Pterostilbene, a methoxylated analog of Resveratrol, is gradually gaining more importance as a therapeutic drug owing to its higher lipophilicity, bioavailability and biological activity than Resveratrol. This study was undertaken to characterize its ability to scavenge free radicals such as superoxide, hydroxyl andhydrogen peroxide and to protect bio-molecules within a cell against oxidative insult.

METHODS: Anti-oxidant activity of Pterostilbene was evaluated extensively by employing several in vitro radical scavenging/inhibiting assays and pulse radiolysis study. In addition, its ability to protect rat liver mitochondria against tertiary-butyl hydroperoxide (TBHP) and hydroxyl radical generated oxidative damage was determined by measuring the damage markers such as protein carbonyls, protein sulphydryls, lipid hydroperoxides, lipid peroxides and 8-hydroxy-2′-deoxyguanosine. Pterostilbene was also evaluated for its ability to inhibit •OH radical induced single strand breaks in pBR322 DNA.

RESULT: Pterostilbene exhibited strong anti-oxidant activity against various free radicals such as DPPH, ABTS, hydroxyl, superoxide and hydrogen peroxide in a concentration dependent manner. Pterostilbene conferred protection to proteins, lipids and DNA in isolated mitochondrial fractions against TBHP and hydroxyl radical induced oxidative damage. It also protected pBR322 DNA against oxidative assault.

CONCLUSIONS: Thus, present study provides an evidence for the strong anti-oxidant property of Pterostilbene, methoxylated analog of Resveratrol, thereby potentiating its role as an anti-oxidant.

PMID: 24070177 PMCID: PMC3849269DOI: 10.1186/1472-6882-13-238

J Surg Res.2010 Jun 15;161(2):195-201. doi: 10.1016/j.jss.2009.07.027. Epub 2009 Aug 18.

Pterostilbene inhibits breast cancer in vitro through mitochondrial depolarization and induction of caspase-dependent apoptosis.

Alosi JA1, McDonald DE, Schneider JS, Privette AR, McFadden DW.

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BACKGROUND: Epidemiologic studies suggest that diets high in fruits and vegetables reduce cancer risk. Resveratrol, a compound present in grapes, has been shown to inhibit a variety of primary tumors. Pterostilbene, an analogue of resveratrol found in blueberries, has both antioxidant and antiproliferative properties. We hypothesized that pterostilbene would induce apoptosis and inhibit breast cancer cell growth in vitro.

METHODS: Breast cancer cells were treated with graduated doses of pterostilbene. Cell viability was measured by MTT assay. Apoptosis was evaluated via DNA fragmentation assay and TUNEL assay. Apo-ONE caspase-3/7 assay was used to evaluate caspase activity. Flow cytometry was used to evaluate mitochondrial depolarization, superoxide formation, and cell cycle. Student’s t-test and two-way ANOVA with Bonferroni posttests were utilized for statistical analysis.

RESULTS: Pterostilbene decreased breast cancer cell viability in a concentration- and time-dependent manner. Pterostilbene treatment increased caspase-3/7 activity and apoptosis in both cell lines. Caspase-3/7 inhibitors completely reversed pterostilbene’s effects on cell viability. Pterostilbene treatment triggered mitochondrial depolarization, increased superoxide anion, and caused alteration in cell cycle.

CONCLUSIONS: Pterostilbene treatment inhibits the growth of breast cancer in vitro through caspase-dependent apoptosis. Mitochondrial membrane depolarization and increased superoxide anion may contribute to the activation downstream effector caspases. Caspase inhibition leads to complete reversal of pterostilbene’s effect on cell viability. Further in vitro mechanistic studies and in vivo experiments are warranted to determine its potential for the treatment of breast cancer.

Copyright 2010 Elsevier Inc. All rights reserved.

PMID: 20031172 DOI: 10.1016/j.jss.2009.07.027

J Agric Food Chem.2002 Jun 5;50(12):3453-7.

Cancer chemopreventive and antioxidant activities of pterostilbene, a naturally occurring analogue of resveratrol.

Rimando AM1, Cuendet M, Desmarchelier C, Mehta RG, Pezzuto JM, Duke SO.

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Pterostilbene, a natural methoxylated analogue of resveratrol, was evaluated for antioxidative potential. The peroxyl-radical scavenging activity of pterostilbene was the same as that of resveratrol, having total reactive antioxidant potentials of 237 +/- 58 and 253 +/- 53 microM, respectively. Both compounds were found to be more effective than Trolox as free radical scavengers. Using a plant system, pterostilbene also was shown to be as effective as resveratrol in inhibiting electrolyte leakage caused by herbicide-induced oxidative damage, and both compounds had the same activity as alpha-tocopherol. Pterostilbene showed moderate inhibition (IC50 = 19.8 microM) of cyclooxygenase (COX)-1, and was weakly active (IC50 = 83.9 microM) against COX-2, whereas resveratrol strongly inhibited both isoforms of the enzyme with IC50 values of approximately 1 microM. Using a mouse mammary organ culture model, carcinogen-induced preneoplastic lesions were, similarly to resveratrol, significantly inhibited by pterostilbene (ED50 = 4.8 microM), suggesting antioxidant activity plays an important role in this process.

PMID: 12033810

J Surg Res.2010 Jun 1;161(1):18-22. doi: 10.1016/j.jss.2009.06.027. Epub 2009 Jul 21.

Pterostilbene inhibits lung cancer through induction of apoptosis.

Schneider JG1, Alosi JA, McDonald DE, McFadden DW.

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BACKGROUND: Lung cancer remains the leading cause of cancer mortality in the United States. Resveratrol is a potent antioxidant found in grapes that inhibits several types of cancer, including lung cancer. Herein, we investigated the effects of pterostilbene, an analog of resveratrol found in blueberries, on lung cancer, in vitro. We hypothesized that pterostilbene would inhibit lung cancer cell growth in vitro by a pro-apoptotic mechanism.

METHODS: Two lung cancer cell lines (NCI-H460 and SK-MES-1) were cultured using standard techniques. Cells were treated with increasing doses of pterostilbene (10-100 microM). Cell viability was measured at 24, 48, and 72h using a MTT assay. Apo-ONE Caspase-3/7 assay was used to evaluate caspase activity. T-test and two-way ANOVA were used for statistical analysis.

RESULTS: Pterostilbene significantly decreased cell viability in lung cancer cells in a concentration- and time-dependent manner (P<0.001). Concentrations greater than 20 microM of pterostilbene produced significant growth inhibition by 72h (P<0.001). Apoptosis and caspase-3/7 activity were significantly increased by pterostilbene treatment (P<0.05).

CONCLUSIONS: Pterostilbene inhibits growth via apoptosis induction in vitro. Further in vitro mechanistic studies and in vivo experiments are warranted to determine the potential role for pterostilbene in lung cancer treatment or prevention.

Copyright (c) 2010 Elsevier Inc. All rights reserved.

PMID: 20031166 DOI: 10.1016/j.jss.2009.06.027

J Pharm Pharmacol.2006 Nov;58(11):1483-90.

The antioxidant role of pterostilbene in streptozotocin-nicotinamide-induced type 2 diabetes mellitus in Wistar rats.

Amarnath Satheesh M1, Pari L.

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The antioxidant effect of pterostilbene on streptozotocin-nicotinamide-induced diabetic rats has been assessed. The activity of superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase and reduced glutathione was significantly decreased in liver and kidney of diabetic animals when compared with normal control. There were significant improvements in these activities after treatment with pterostilbene at a dose of 40 mg kg(-1) for six weeks. The increased levels of lipid peroxidation measured as thiobarbituric acid reactive substances (TBARS) in liver and kidney of diabetic rats were also normalized by treatment with pterostilbene. Chronic treatment of pterostilbene remarkably reduced the pathological changes observed in liver and kidney of diabetic rats. These results indicated the antioxidant property of pterostilbene.

PMID: 17132211 DOI: 10.1211/jpp.58.11.0009

J Surg Res.2012 Oct;177(2):255-62. doi: 10.1016/j.jss.2012.04.023. Epub 2012 May 3.

Inhibitory effects of (-)-epigallocatechin-3-gallate and pterostilbene on pancreatic cancer growth in vitro.

Kostin SF1, McDonald DE, McFadden DW.

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BACKGROUND: It has been previously shown that the naturally occurring antioxidant (-)-epigallocatechin-3-gallate (EGCG), found in green tea, and pterostilbene, a stilbenoid derived from blueberries, inhibit pancreatic cancer in vitro when used individually. We hypothesized that the combination of EGCG and pterostilbene would reveal additive effects in vitro.

METHODS: Using the pancreatic cancer cell lines MIA PaCa-2 and PANC-1, efficacy and synergism were evaluated for cell proliferation and viability (3-(4,5-dimethyltiazol-2-y1)-2,5-diphenltetrazolium bromide assays, cell cycle analysis) and mitochondrial apoptosis (mitochondrial depolarization, cytochrome C release, caspase-3/7 activity, cell death detection using enzyme-linked immunosorbent assay).

RESULTS: Cell proliferation assays revealed significant additive antiproliferative effects with pterostilbene and EGCG in both cell lines at the later, 72-h, point (P < 0.05). MIA underwent S-phase arrest with the combination (10-12% increase); however, cell cycle arrest was not observed in PANC. The combination induced mitochondrial depolarization and upregulated cytochrome C (P < 0.05) in MIA, but these effects were not observed in PANC. EGCG increased caspase-3/7 in MIA; however, the combination did not significantly increase the activity in either cell line (P < 0.05). Apoptosis was only observed in PANC (P < 0.05). The reduction in proliferation in MIA in the 3-(4,5-dimethyltiazol-2-y1)-2,5-diphenltetrazolium bromide assays with the combination indicated that cell death occurs, possibly through another mechanism.

CONCLUSIONS: Our results are encouraging regarding the future use of EGCG and pterostilbene to improve traditional pancreatic cancer therapies. In conclusion, EGCG and pterostilbene have additive, antiproliferative effects in vitro and alter the apoptotic mechanisms in both cell lines by modulation at different points in the mechanism.

Copyright © 2012 Elsevier Inc. All rights reserved.

PMID: 22583593 DOI: 10.1016/j.jss.2012.04.023

Toxicol In Vitro.2010 Jun;24(4):1215-28. doi: 10.1016/j.tiv.2010.02.007. Epub 2010 Feb 10.

In vitro evaluation of the cytotoxic, anti-proliferative and anti-oxidant properties of pterostilbene isolated from Pterocarpus marsupium. 

Chakraborty A1, Gupta N, Ghosh K, Roy P.

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Pterostilbene, a dimethyl ester derivative of resveratrol, may act as an cytotoxic and hence as an anti-cancer agent. The present study was conducted to test the anti-cancer activity of pterostilbene purified from Pterocarpus marsupium on breast (MCF-7) and prostate (PC3) cancer cell lines. The purified pterostilbene was found to cause apoptosis in both the cell lines, which was marked by DNA fragmentation, formation of apoptotic bodies and membrane distortions. Apoptosis probably was due to the production of reactive oxygen species in MCF-7 and nitric oxide over production in PC3 cells. Even the drug detoxifying anti-oxidant enzymes could not nullify the effect of pterostilbene as required by the cancer cells for survival. Pterostilbene was found to inhibit the cell proliferating factors like Akt, Bcl-2 and induced the mitochondrial apoptotic signals like Bax, and the series of caspases. It also inhibited Matrix metalloproteinase 9 (MMP9) and alpha-methylacyl-CoA recemase(AMACR), two very well known metastasis inducers. In conclusion, pterostilbene has multiple target sites to induce apoptosis. Hence, after proper validation it can be used as a potential agent for the cure of breast and prostate cancer.

PMID: 20152895 DOI: 10.1016/j.tiv.2010.02.007

Cancer Chemother Pharmacol.2011 Sep;68(3):593-601. doi: 10.1007/s00280-010-1525-4. Epub 2010 Nov 30.

Pharmacokinetics, oral bioavailability, and metabolic profile of resveratrol and its dimethylether analog, pterostilbene, in rats.

Kapetanovic IM1, Muzzio M, Huang Z, Thompson TN, McCormick DL.

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PURPOSE: Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is a naturally occurring polyphenol with a broad range of possible health benefits, including anti-cancer activity. However, the biological activity of resveratrol may be limited by poor absorption and first-pass metabolism: only low plasma concentrations of resveratrol are seen following oral administration, and metabolism to glucuronide and sulfate conjugates is rapid. Methylated polyphenol analogs (such as pterostilbene [3,5-dimethoxy-4′-hydroxy-trans-stilbene], the dimethylether analog of resveratrol) may overcome these limitations to pharmacologic efficacy. The present study was designed to compare the bioavailability, pharmacokinetics, and metabolism of resveratrol and pterostilbene following equimolar oral dosing in rats.

METHODS: The agents were administered orally via gavage for 14 consecutive days at 50 or 150 mg/kg/day for resveratrol and 56 or 168 mg/kg/day for pterostilbene. Two additional groups were dosed once intravenously with 10 and 11.2 mg/kg for resveratrol and pterostilbene, respectively. Plasma concentrations of agents and metabolites were measured using a high-pressure liquid chromatograph-tandem mass spectrometer system. Noncompartmental analysis was used to derive pharmacokinetic parameters.

RESULTS: Resveratrol and pterostilbene were approximately 20 and 80% bioavailable, respectively. Following oral dosing, plasma levels of pterostilbene and pterostilbene sulfate were markedly greater than were plasma levels of resveratrol and resveratrol sulfate. Although plasma levels of resveratrol glucuronide exceeded those of pterostilbene glucuronide, those differences were smaller than those of the parent drugs and sulfate metabolites.

CONCLUSIONS: When administered orally, pterostilbene demonstrates greater bioavailability and total plasma levels of both the parent compound and metabolites than does resveratrol. These differences in agent pharmacokinetics suggest that the in vivo biological activity of equimolar doses of pterostilbene may be greater than that of resveratrol.

PMID: 21116625 PMCID: PMC3090701DOI: 10.1007/s00280-010-1525-4

Free Radic Biol Med.2015 Aug;85:1-11. doi: 10.1016/j.freeradbiomed.2015.03.027. Epub 2015 Apr 4.

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

Sirerol JA1, Feddi F2, Mena S1, Rodriguez ML1, Sirera P1, Aupí M1, Pérez S1, Asensi M3, Ortega A3, Estrela JM4.

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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.

KEYWORDS: Free radicals; Oxidative stress; Photocarcinogenesis; Phytochemicals; Polyphenols; Pterostilbene; Resveratrol; Skin damage; Stilbenes; UV radiation

PMID: 25845487 DOI: 10.1016/j.freeradbiomed.2015.03.027

Genet Mol Res.2016 Aug 12;15(3). doi: 10.4238/gmr.15038330.

Pterostilbene as treatment for severe acute pancreatitis.

Lin YJ1, Ding Y2, Wu J1, Ning BT3.

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Acute pancreatitis (AP) has a fast onset and progression, which lead to an unfavorable prognosis. Therefore, the development of novel drugs for its treatment is critical. As a homologous derivative of resveratrol, pterostilbene exerts a variety of effects including anti-inflammatory, antioxidant, and antitumor effects. This study investigated the potential of pterostilbene for treatment of severe AP (SAP) and related mechanisms. Effects of pterostilbene were evaluated in a Wistar rat model of AP. Serum levels of amylase (AMY), creatinine (Cr), and alanine aminotransferase (ALT) were quantified. Furthermore, serum levels of tumor necrosis factor (TNF)-a and interleukin (IL)-1b were quantified using enzyme-linked immunosorbent assay. Nuclear factor (NF)-kB expression in pancreatic tissues was quantified by real-time PCR and western blotting. The production of reactive oxygen species (ROS) was determined using a spectrometer, while superoxide dismutase (SOD) activity was assayed. In the AP rat model, the expression of inflammatory markers TNF-a and IL-1b, expression of NF-kB, and serum indices (AMY, Cr, and ALT) increased compared to the corresponding levels in the control group (P < 0.05). Pterostilbene reduced serum levels of TNF-a and IL-1b; decreased NF-kB gene expression, serum indices, and ROS generation; and increased SOD activity in a dose-dependent manner. In conclusion, pterostilbene can alleviate SAP-induced tissue damage by decreasing the inflammatory response and by promoting antioxidation leading to the protection of pancreatic tissues.

PMID: 27525946 DOI: 10.4238/gmr.15038330

Bioorg Med Chem Lett.2016 Apr 15;26(8):2035-9. doi: 10.1016/j.bmcl.2016.02.079. Epub 2016 Feb 27.

Pterostilbene-O-acetamidoalkylbenzylamines derivatives as novel dual inhibitors of cholinesterase with anti-β-amyloid aggregation and antioxidant properties for the treatment of Alzheimer’s disease.

Li Y1, Qiang X1, Li Y1, Yang X1, Luo L1, Xiao G1, Cao Z1, Tan Z2, Deng Y3.

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A series of pterostilbene-O-acetamidoalkylbenzylamines were designed, synthesized and evaluated as dual inhibitors of AChE and BuChE. To further explore the multifunctional properties of the new derivatives, their antioxidant activities and inhibitory effects on self-induced Aβ1-42 aggregation and HuAChE-induced Aβ1-40 aggregation were also tested. The results showed that most of these compounds could effectively inhibit AChE and BuChE. Particularly, compound 21d exhibited the best AChE inhibitory activity (IC50=0.06 μM) and good inhibition of BuChE (IC50=28.04 μM). Both the inhibition kinetic analysis and molecular modeling study revealed that these compounds showed mixed-type inhibition, binding simultaneously to the CAS and PAS of AChE. In addition to cholinesterase inhibitory activities, these compounds showed different levels of antioxidant activity. However, the inhibitory activities against self-induced and HuAChE-induced Aβ aggregation of these new derivatives were unsatisfied. Taking into account the results of the biological evaluation, further modifications will be designed in order to increase the potency on the different targets. The results displayed in this Letter can be a new starting point for further development of multifunctional agents for Alzheimer’s disease.

KEYWORDS: Alzheimer’s disease; Antioxidant; Aβ aggregation inhibitors; Dual cholinesterase inhibitors; Pterostilbene-O-acetamidoalkylbenzylamines

PMID: 26947607 DOI: 10.1016/j.bmcl.2016.02.079

J Agric Food Chem.2010 Aug 11;58(15):8833-41. doi: 10.1021/jf101571z.

Pterostilbene inhibits colorectal aberrant crypt foci (ACF) and colon carcinogenesis via suppression of multiple signal transduction pathways in azoxymethane-treated mice. 

Chiou YS1, Tsai ML, Wang YJ, Cheng AC, Lai WM, Badmaev V, Ho CT, Pan MH.

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Pterostilbene (PS), a natural dimethylated analogue of resveratrol, is known to have diverse pharmacologic activities including anticancer, anti-inflammation, antioxidant, apoptosis, antiproliferation, and analgesic potential. This paper reports the inhibitory effect of dietary administration of pterostilbene against the formation of azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) preneoplastic lesions and adenomas in male ICR mice and delineates its possible molecular mechanisms. ICR mice were given two AOM injections intraperitoneal and continuously fed a 50 or 250 ppm pterostilbene diet for 6 or 23 weeks. It was found that the dietary administration of pterostilbene effectively reduced AOM-induced formation of ACF and adenomas and inhibited the transcriptional activation of iNOS and COX-2 mRNA and proteins in mouse colon stimulated by AOM. Treatment with pterostilbene resulted in the induction of apoptosis in mouse colon. Moreover, administration of pterostilbene for 23 weeks significantly suppressed AOM-induced GSK3beta phosphorylation and Wnt/beta-catenin signaling. It was also found that pterostilbene significantly inhibited AOM-induced expression of VEGF, cyclin D1, and MMPs in mouse colon. Furthermore, pterostilbene markedly inhibited AOM-induced activation of Ras, phosphatidylinositol 3 kinase/Akt, and EGFR signaling pathways. All of these results revealed that pterostilbene is an effective antitumor agent as well as its inhibitory effect through the down-regulation of inflammatory iNOS and COX-2 gene expression and up-regulation of apoptosis in mouse colon, suggesting that pterostilbene is a novel functional agent capable of preventing inflammation-associated colon tumorigenesis.

PMID: 20681671 DOI: 10.1021/jf101571z

Eur J Gynaecol Oncol.2016;37(3):342-7.

Pterostilbene induces apoptosis through caspase activation in ovarian cancer cells.

Dong J, Guo H, Chen Y.

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AIM: Pterostilbene, an analog of resveratrol increasing bioavailability has shown to offer antioxidant and anticancer properties in vitro and in vivo. Dietary compounds with anti-oxidant properties have been shown to gain importance due to therapeutic applications. In addition, compounds with higher bioavailability levels show great interest in present scenario. Thus, the present study aimed at investigating the cytotoxic role of pterostilbene and its mechanism of cell death in ovarian cancer cells line.

MATERIALS AND METHODS: The effect of pterostilbene was determined on SKOV-3 cells, by cytotoxicity assays, oxidative stress levels, [Ca2+]i levels, mitochondrial depolarization, cell cycle analysis and caspase 3, 8, and 9 activities.

RESULTS: The study revealed that pterostilbene offered cytotoxic effect at a concentration of IC50-55 uM. Further, pterostilbene induced reactive oxygen species (ROS) mediated intrinsic pathway of apoptosis through enhancing oxidative stress, [Ca2+]i levels, mitochondrial depolarization, Sub G1 accumulation, and activation of caspase 3 and 9.

CONCLUSION: The study demonstrates for the first time the cytotoxic potential of pterostilbene against ovarian cancer cells.

PMID: 27352561

Carcinogenesis.2009 Jul;30(7):1234-42. doi: 10.1093/carcin/bgp121. Epub 2009 May 15.

Pterostilbene inhibited tumor invasion via suppressing multiple signal transduction pathways in human hepatocellular carcinoma cells.

Pan MH1, Chiou YS, Chen WJ, Wang JM, Badmaev V, Ho CT.

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Pterostilbene, a natural dimethylated analog of resveratrol, is known to have diverse pharmacologic activities including anticancer, anti-inflammation, antioxidant, apoptosis, anti-proliferation and analgesic potential. However, the effects of pterostilbene in preventing invasion of cancer cells have not been studied. Here, we report our finding that pterostilbene significantly suppressed 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced invasion, migration and metastasis of human hepatoma cells (HepG(2) cells). Increase in the enzyme activity, protein and messenger RNA levels of matrix metalloproteinase (MMP)-9 were observed in TPA-treated HepG(2) cells, and these were blocked by pterostilbene. In addition, pterostilbene can inhibit TPA-induced expression of vascular endothelial growth factor, epidermal growth factor and epidermal growth factor receptor. Transient transfection experiments also showed that pterostilbene strongly inhibited TPA-stimulated nuclear factor kappa B (NF-kappaB) and activator protein-1 (AP-1)-dependent transcriptional activity in HepG(2) cells. Moreover, pterostilbene can suppress TPA-induced activation of extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase, c-Jun N-terminal kinases 1/2 and phosphatidylinositol 3-kinase/Akt and protein kinase C that are upstream of NF-kappaB and AP-1. Significant therapeutic effects were further demonstrated in vivo by treating nude mice with pterostilbene (50 and 250 mg/kg intraperitoneally) after inoculation with HepG(2) cells into the tail vein. Presented data reveal that pterostilbene is a novel, effective, anti-metastatic agent that functions by downregulating MMP-9 gene expression.

PMID: 19447859 DOI: 10.1093/carcin/bgp121

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-dependentpathway.

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

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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

Int Immunopharmacol.2015 Sep;28(1):10-21. doi: 10.1016/j.intimp.2015.05.003. Epub 2015 May 13.

Understanding the mode of action of a pterostilbene derivative as anti-inflammatory agent.

Nikhil K1, Sharan S1, Palla SR2, Sondhi SM2, Peddinti RK2, Roy P3.

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Inflammatory response plays an important role not only in the normal physiology, but also in the pathology of certain diseases such as cancers. In our previous study, we found a novel derivative of pterostilbene (PTER), to be an effective inducer of apoptosis in human breast and prostate cancer cells affecting various cellular targets. Herein, we further attempted to investigate its anti-inflammatory potential followed by its probable mode of action. The newly developed compound was tested for its anti-inflammatory actions in lipopolysaccharide (LPS) stimulated RAW264.7 macrophages and carrageenan induced rat paw edema models. Our data showed that the derivative inhibited the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) as well as the downstream products like nitric oxide (NO) and PGE2, at much lower doses as compared to PTER. This effect was found to be associated with the inhibition of phosphorylation/degradation of IκB-α and nuclear translocation of the p-NFκB p65. Moreover, inhibition of mitogen-activated protein kinases (MAPKs) and activator protein-1 (AP-1) was also observed. In addition, the newly developed compound also reduced the paw edema, the tissue content of NO, PGE2 and expression of iNOS and COX-2 proteins within the tissues after λ-carrageenan stimulation. Taken together, our findings provide the possibility that the PTER derivative might have enhanced cancer chemopreventive potential based on its stronger anti-NFκB and anti-inflammatory activities as compared to its natural counterpart, i.e., PTER. Thus, this compound can be used towards the development of an effective anti-inflammatory agent.

KEYWORDS: Anti-inflammatory; Carrageenan; Lipopolysaccharide; NFκB; Pterostilbene derivative; RAW 264.7 macrophage

PMID: 25981112 DOI: 10.1016/j.intimp.2015.05.003

Exp Cell Res.2015 Nov 15;339(1):147-53. doi: 10.1016/j.yexcr.2015.10.014. Epub 2015 Oct 17.

Plant stilbenes induce endoplasmic reticulum stress and their anti-cancer activity can be enhanced by inhibitors of autophagy.

Papandreou I1, Verras M2, McNeil B3, Koong AC4, Denko NC5.

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BACKGROUND: Environmental conditions or chemical agents can interfere with the function of the endoplasmic reticulum, and the resulting endoplasmic reticulum (ER) stress can be toxic to the cell if it is not relieved. The classical compensatory response to ER stress is the unfolded protein response (UPR) that reduces protein load in the ER. However, autophagy may also compensate by removing large insoluble protein aggregates. Agents that stress the ER can have anti-cancer activity, and novel applications of ER stress inducing agents are being investigated. Plant stilbenes are a class of stress responsive molecules that includes resveratrol, which arebeing investigated as potential therapeutics in humans for conditions such as aging or cancer.

RESULTS: We performed a screen of 1726 small, drug like molecules to identify those that could activate an ER-stress responsive luciferase gene. After secondaryscreening, we determined that the plant stilbenes pterostilbene and piceatannol were the most potent inducers of ER stress from this group. ER stress can be particularly toxic to cells with high ER load, so we examined their effect on cells expressing the Wnt family of secreted glycoprotein growth factors. Molecularanalysis determined that these ER stress-inducing stilbenes could block Wnt processing and also induce autophagy in acute lymphoblastic leukemia cells expressing Wnt16. Combining pterostilbene (to induce ER stress) with chloroquine (to inhibit autophagy) lead to significant cellular toxicity in cells from aggressive acute lymphoblastic leukemia.

CONCLUSIONS: Plant stilbenes are potent inducers of ER stress. However, their toxicity is more pronounced in cancer cells expressing Wnt growth factors. The toxicity of stilbenes in these ALL cells can be potentiated by the addition of autophagy inhibitors, suggesting a possible therapeutic application.

Copyright © 2015 Elsevier Inc. All rights reserved.

KEYWORDS: High throughput screen; Stilbenes; Stress responses; Unfolded Protein Response; Wnt growth factors

PMID: 26477823 PMCID: PMC4822495DOI: 10.1016/j.yexcr.2015.10.014

Neuro Endocrinol Lett.2010;31 Suppl 2:91-5.

In vivo effect of pinosylvin and pterostilbene in the animal model of adjuvant arthritis.

Macickova T1, Drabikova K, Nosal R, Bauerova K, Mihalova D, Harmatha J, Pecivova J.

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OBJECTIVE: The aim of this study was to evaluate the effects of pinosylvin (PIN) and pterostilbene (PTE), natural substances from the stilbenoid group, on the development of adjuvant arthritis in rats.

METHODS: Adjuvant arthritis (AA) was induced by a single intradermal injection of Mycobacterium butyricum in incomplete Freund’s adjuvant in male Lewis rats. Our experiments included healthy intact animals as reference controls, arthritic animals without any drug administration, and arthritic animals with administrationof PIN and PTE in the oral daily dose of 30 mg/kg b.w. The treatment involved administration of the substances tested from day 0, i.e. the day of immunization, to the experimental day 28. The following parameters were monitored: change of the hind paw volume (HPV) on day 14, 21 and 28, luminol-enhanced chemiluminescence (CL) of the joint and myeloperoxidase (MPO) activity in hind paw joint homogenates (day 28).

RESULTS: Arthritic animals treated with PIN showed a decrease in HPV, significantly on days 14 and 28. PIN decreased CL of the joint as well as MPO activity of the joint homogenate, in comparison with untreated animals. PTE had no effect on HPV and MPO activity in hind paw joint homogenates and exerted only a partial effect on luminol-enhanced CL.

CONCLUSIONS: On the basis of our results we conclude that the effect of PTE on CL was only partial. PIN, on the other hand, had a beneficial anti-inflammatory and antioxidant effect on oxidative stress induced biochemical changes occurring in AA, as determined by all three functional parameters.

PMID: 21187826

Mol Neurobiol.2016 May;53(4):2339-53. doi: 10.1007/s12035-015-9194-2. Epub 2015 May 16.

HO-1 Signaling Activation by Pterostilbene Treatment Attenuates Mitochondrial Oxidative Damage Induced by Cerebral Ischemia ReperfusionInjury.

Yang Y1,2, Wang J1, Li Y3, Fan C4, Jiang S1, Zhao L1, Di S4, Xin Z1, Wang B1, Wu G1, Li X1, Li Z5, Gao X5, Dong Y6, Qu Y7.

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Ischemia reperfusion (IR) injury (IRI) is harmful to the cerebral system and causes mitochondrial oxidative stress. The antioxidant response element (ARE)-mediated antioxidant pathway plays an important role in maintaining the redox status of the brain. Heme oxygenase-1 (HO-1), combined with potent AREs in the promoter of HO-1, is a highly effective therapeutic target for protection against cerebral IRI. Pterostilbene (PTE), a natural dimethylated analog of resveratrol from blueberries, is a strong natural antioxidant. PTE has been shown to be beneficial for some nervous system diseases and may regulate HO-1 signaling. This study was designed to investigate the protective effects of PTE on cerebral IRI and to elucidate potential mechanisms underlying those effects. Mouse brains and cultured HT22 neuron cells were subjected to IRI. Prior to this procedure, the brains or cells were exposed to PTE in the absence or presence of the HO-1 inhibitor ZnPP or HO-1 small interfering RNA (siRNA). PTE conferred a cerebral protective effect, as shown by increased neurological scores, viable neurons and decreased brain edema as well as a decreased ion content and apoptotic ratio in vivo. PTE also increased the cell viability and decreased the lactate dehydrogenase (LDH) leakage and apoptotic ratio in vitro. ZnPP and HO-1 siRNA both blocked PTE-mediated cerebral protection by inhibiting HO-1 signaling and further inhibited two HO-1 signaling-related antioxidant molecules:

NAD(P)H: quinone oxidoreductase 1 (NQO1) and glutathione S-transferases (GSTs), which are induced by PTE. PTE also promoted a well-preserved mitochondrial membrane potential (MMP), mitochondria complex I activity, and mitochondria complex IV activity, increased the mitochondrial cytochrome c level, and decreased the cytosolic cytochrome c level. However, this PTE-elevated mitochondrial function was reversed by ZnPP or HO-1 siRNA treatment. In summary, our results demonstrate that PTE treatment attenuates cerebral IRI by reducing IR-induced mitochondrial oxidative damage through the activation of HO-1 signaling.

KEYWORDS: Cerebral protection; HO-1 signaling; Ischemia reperfusion; Mitochondrial oxidative damage; Pterostilbene

PMID: 25983033 DOI: 10.1007/s12035-015-9194-2

Food Chem Toxicol.2015 Oct;84:37-46. doi: 10.1016/j.fct.2015.07.013. Epub 2015 Jul 29.

Effect of tannic acid, resveratrol and its derivatives, on oxidative damage and apoptosis in human neutrophils.

Zielińska-Przyjemska M1, Ignatowicz E1, Krajka-Kuźniak V1, Baer-Dubowska W2.

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In this study we compared the antioxidant and DNA protective activity of tannic acid and stilbene derivatives, resveratrol, 3,5,4(‘)-trimethoxystilbene (TMS) and pterostilbene in human neutrophils stimulated to oxidative burst by 12-O-tetradecanoyl-phorbol-13-acetate (TPA) in relation to apoptosis induction. All polyphenols within the concentration range 1-100 μM reduced the intracellular ROS and H2O2 production in the TPA-stimulated cells. Tannic acid was the most effective polyphenol in protection against DNA damage induced by TPA. In the resting neutrophils resveratrol and to lesser extent other polyphenols increased DNA damage and increased the level of p53. Pretreatment of the TPA-stimulated cells with tannic acid or stilbenes led to the induction of apoptosis. The most significant effect was observed as a result of treatment with TMS and resveratrol. These compounds appeared the most effective inducers of p53 in the TPA-challenged neutrophils, whatmay suggest that pro-apoptotic activity of these stilbenes might be related to p53 activation. Overall, the results of our present study demonstrate that tannic acid and stilbenes modulate the ROS production, ultimately leading to cell apoptosis in human neutrophils stimulated to oxidative burst. In resting neutrophils they exhibit pro-oxidant activity, which is accompanied by p53 induction.

KEYWORDS: Apoptosis; DNA damage; Neutrophils; Stilbene derivatives; Tannic acid

PMID: 26231140 DOI: 10.1016/j.fct.2015.07.013

J Agric Food Chem.2005 May 4;53(9):3403-7.

Pterostilbene, a new agonist for the peroxisome proliferator-activated receptor alpha-isoform, lowers plasma lipoproteins and cholesterol in hypercholesterolemic hamsters.

Rimando AM1, Nagmani R, Feller DR, Yokoyama W.

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Resveratrol, a stilbenoid antioxidant found in grapes, wine, peanuts and other berries, has been reported to have hypolipidemic properties. We investigated whether resveratrol and its three analogues (pterostilbene, piceatannol, and resveratrol trimethyl ether) would activate the peroxisome proliferator-activated receptor alpha (PPARalpha) isoform. This nuclear receptor is proposed to mediate the activity of lipid-lowering drugs such as the fibrates. The four stilbenes were evaluated at 1, 10, 100, and 300 microM along with ciprofibrate (positive control), for the activation of endogenous PPARalpha in H4IIEC3 cells. Cells were transfected with a peroxisome proliferator response element-AB (rat fatty acyl CoA beta-oxidase response element)-luciferase gene reporter construct. Pterostilbene demonstrated the highest induction of PPARalpha showing 8- and 14-fold increases in luciferase activity at 100 and 300 microM, respectively, relative to the control. The maximal luciferase activity responses to pterostilbene were higher than those obtained with the hypolipidemic drug, ciprofibrate (33910 and 19460 relative luciferase units, respectively), at 100 microM. Hypercholesterolemic hamsters fed with pterostilbene at 25 ppm of the diet showed 29% lower plasma low density lipoprotein (LDL) cholesterol, 7% higher plasma high density lipoprotein (HDL) cholesterol, and 14% lower plasma glucose as compared to the control group. The LDL/HDL ratio was also statistically significantly lower for pterostilbene, as compared to results for the control animals, at this diet concentration. Results from in vitro studies showed that pterostilbene acts as a PPARalpha agonist and may be a more effective PPARalpha agonist and hypolipidemic agent than resveratrol. In vivo studies demonstrate that pterostilbene possesses lipid and glucose lowering effects.

PMID: 15853379 DOI: 10.1021/jf0580364

Chem Biol Interact.2013 Nov 25;206(2):175-85. doi: 10.1016/j.cbi.2013.09.013. Epub 2013 Sep 25.

Scavenging of hydroxyl radical by resveratrol and related natural stilbenes after hydrogen peroxide attack on DNA.

Rossi M1, Caruso F, Antonioletti R, Viglianti A, Traversi G, Leone S, Basso E, Cozzi R.

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Resveratrol (3,5,4′-trihydroxystilbene) is of interest due to its role in prevention and therapy of degenerative diseases as cancer and aging. However, depending on its concentration and cell type studied, resveratrol activity appears conflicting. It exerts antioxidant action, as a scavenger of free radicals and as promoter of antioxidant enzyme activity, but resveratrol acts also as a pro-oxidant. Here we present experimental and theoretical studies for resveratrol and two methoxy-derivatives found in plants, pterostilbene and 3,5,4′-trimethoxystilbene. We show that both methoxy-derivatives induce less DNA damage than resveratrol. The protective effects of the three molecules against oxidative DNA damage induced by hydrogen peroxide treatment were analyzed on mammalian cells in vitro. Our data show for the first time that methoxylated derivatives of resveratrol are very efficient in reducing DNA damage: using the same concentration of the three molecules we obtain a relative reduction of 85.5% (pterostilbene), 43.7% (trimethoxystilbene) and 21.1% (resveratrol). Analysis of the crystal structures of pterostilbene and 3,5,4′-trimethoxystilbene, compared to resveratrol, show fewer intermolecular interactions and a lack of planarity, due to packing forces, which is confirmed by density functional theory (DFT) calculations. We also describe the results of DFT calculations (including water solvent effects) in which the three stilbene species scavenge the hydroxyl radical (associated with the H2O2 insult).

KEYWORDS: DNA protection; Hydrogen peroxide; Hydroxyl radical; Pterostilbene; Resveratrol

PMID: 24075811 DOI: 10.1016/j.cbi.2013.09.013

Phytother Res.2015 Oct;29(10):1605-9. doi: 10.1002/ptr.5442. Epub 2015 Aug 27.

Stilbenoids from Rheum undulatum Protect Hepatocytes Against Oxidative Stress Through AMPK Activation.

Dong GZ1, Lee YI1, Jeong JH1, Zhao HY1, Jeon R1, Lee HJ2, Ryu JH1.

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Oxidative stress promotes several diseases, including liver disease. We have isolated several stilbenoids from Rheum undulatum to investigate their hepatoprotective activities and mechanism. Stilbenoids from R. undulatum protects hepatocytes against arachidonic acid + iron (AA + Fe) induced oxidative stress. Pterostilbene (compound 5) shows stronger activity than the others. Trimethoxystilbenoid (compound 6) shows best activity on protection of HepG2 cells from AA + Fe-induced oxidative stress, and trans-stilbenoid (compound 7) shows weak activity. These stilbenoids suppress ROS generation in AA + Fe-treated HepG2 cells and also suppress AA + Fe-induced MMP disruption. Their protective effects on AA + Fe-induced MMP disruption were abrogated by treatment of AMP-activated protein kinase (AMPK) inhibitor, compound C or transfection of dominant negative form of AMPK. Taken together, stilbenoids from R. undulatum protect hepatocytes against AA + Fe-induced oxidative stress through AMPK activation. And the methoxy groups in the aryl groups are important for their cytoprotective activity.

KEYWORDS: AMPK; Rheum undulatum; antioxidant; hepatocyte protection; stilbenoid

PMID: 26449499 DOI: 10.1002/ptr.5442

J Agric Food Chem.2011 Mar 9;59(5):1673-82. doi: 10.1021/jf104742n. Epub 2011 Feb 11.

Biological activity of peanut (Arachis hypogaea) phytoalexins and selected natural and synthetic Stilbenoids.

Sobolev VS1, Khan SI, Tabanca N, Wedge DE, Manly SP, Cutler SJ, Coy MR, Becnel JJ, Neff SA, Gloer JB.

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The peanut plant (Arachis hypogaea L.), when infected by a microbial pathogen, is capable of producing stilbene-derived compounds that are considered antifungal phytoalexins. In addition, the potential health benefits of other stilbenoids from peanuts, including resveratrol and pterostilbene, have been acknowledged by several investigators. Despite considerable progress in peanut research, relatively little is known about the biological activity of the stilbenoid phytoalexins. This study investigated the activities of some of these compounds in a broad spectrum of biological assays. Since peanut stilbenoids appear to play roles in plant defense mechanisms, they were evaluated for their effects on economically important plant pathogenic fungi of the genera Colletotrichum, Botrytis, Fusarium, and Phomopsis. We further investigated these peanut phytoalexins, together with some related natural and synthetic stilbenoids (a total of 24 compounds) in a panel of bioassays to determine their anti-inflammatory, cytotoxic, and antioxidant activities in mammalian cells. Several of these compounds were also evaluated as mammalian opioid receptor competitive antagonists. Assays for adult mosquito and larvae toxicity were also performed. The results of these studies reveal that peanut stilbenoids, as well as related natural and synthetic stilbene derivatives, display a diverse range of biological activities.

PMID: 21314127 PMCID: PMC3063522DOI: 10.1021/jf104742n

Mol Nutr Food Res.2010 Dec;54(12):1819-32. doi: 10.1002/mnfr.201000067.

Pterostilbene induces autophagy and apoptosis in sensitive and chemoresistant human bladder cancer cells.

Chen RJ1, Ho CT, Wang YJ.

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SCOPE: Bladder cancer is one of the most common malignancies in the world. The majority of bladder cancer deaths are due to unresectable lesions that are resistant to chemotherapy. Pterostilbene (PT), a naturally occurring phytoalexin, possesses a variety of pharmacologic activities, including antioxidant, cancer prevention activity and cytotoxicity to many cancers. We found that PT effectively inhibits the growth of sensitive and chemoresistant human bladder cancer cells by inducing cell cycle arrest, autophagy and apoptosis. Down-regulations of Cyclin A, B and D1 and pRB are the results of PT-induced cell cycle arrest.

METHODS AND RESULTS: Autophagy occurred at an early stage and was observed through the formation of acidic vesicular organelles (the marker for autophagy) and microtubule-associated protein 1 light chain 3-II production. Apoptosis occurred at a later stage and was detected by Annexin V and 4′,6-diamidino-2-phenylindole staining. PT-induced autophagy was triggered by the inhibition of active human protein kinase/the mammalian TOR/p70S6K pathway and activation of extracellular signal-regulated kinase pathway. Inhibition of autophagy by pretreatment with 3-methyladenine, bafilomycin A1, Beclin 1 or extracellular signal-regulated kinase short hairpin RNA enhanced PT-triggered apoptosis.

CONCLUSION: This is the first study to demonstrate that PT causes autophagy in cancer cells and suggests that PT could serve as a new and promising agent for the treatment of sensitive and chemoresistant bladder cancer cells.

Copyright © 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

PMID: 20603834 DOI: 10.1002/mnfr.201000067

Sci Rep.2016 Jan 14;6:19408. doi: 10.1038/srep19408.

Blueberry Component Pterostilbene Protects Corneal Epithelial Cells from Inflammation via Anti-oxidative Pathway.

Li J1,2, Ruzhi Deng1,2, Hua X2,3, Zhang L2, Lu F1, Coursey TG2, Pflugfelder SC2, Li DQ2.

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Blueberries have been recognized to possess protective properties from inflammation and various diseases, but not for eye and ocular disorders. This study explores potential benefits of pterostilbene (PS), a natural component of blueberries, in preventing ocular surface inflammation using an in vitro culture model of human corneal epithelial cells (HCECs) exposed to hyperosmotic medium at 450 mOsM. Gene expression was detected by RT-qPCR, and protein production or activity was determined by ELISA, zymography, Western blotting and immunofluorescent staining. Reactive oxygen species (ROS) production was measured using DCFDA kit. The addition of PS significantly reduced the expression of pro-inflammatory mediators, TNF-α, IL-1 β, IL-6, MMP-2 and MMP-9 in HCECs exposed to hyperosmotic medium. Pre-treatment with PS (5 to 20 μM) suppressed ROS overproduction in a dose-dependent manner. Additionally, PS significantly decreased the levels of oxidative damage biomarkers, malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), aconitase-2 and 8-hydroxydeoxyguanosine (8-OHdG). Importantly, PS was found to rebalance homeostasis between oxygenases and anti-oxidative enzymes by decreasing cyclooxygenase 2 (COX2) expression and restoring the activity of antioxidant enzymes, superoxide dismutase 1 (SOD1) and peroxiredoxin-4 (PRDX4) during hyperosmotic stress. Our findings demonstrate that PS protects human cornea from hyperosmolarity-induced inflammation and oxidative stress, suggesting protective effects of PS on dry eye.

PMID: 26762881 PMCID: PMC4725955DOI: 10.1038/srep19408

J Org Chem.2004 Oct 15;69(21):7101-7.

Antioxidant activity of hydroxystilbene derivatives in homogeneous solution. 

Amorati R1, Lucarini M, Mugnaini V, Pedulli GF, Roberti M, Pizzirani D.

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The antioxidant activity of the cis and trans isomers of several analogues of resveratrol and pterostilbene has been investigated, especially with regard to the effect of the stereochemistry about the olefinic double bond. The antioxidant power of these compounds was estimated by measuring the rate constants for their reactions with peroxyl radicals and, with two of them, the bond dissociation enthalpy (BDE) of the phenolic O-H bond which is cleaved in the inhibition reaction. The present data show that in homogeneous solution the various hydroxystilbenes investigated behave as mild antioxidants with the notable exceptions of the trans isomer of 4 and 6, whose activities are only slightly lower than that of alpha-tocopherol (vitamin E). The rate constants of the inhibition reaction show that the antioxidant activity of the cis-hydroxystilbene is in all the examined cases worse, by a factor ranging between 2 and 6, than that of the corresponding trans isomers. This lower reactivity depends on enthalpy factors as it can be inferred by the experimental values of the O-H bond dissociation enthalpy in the two geometric isomers of 3′,5′-di-tert-butyl-4′-hydroxy-3,5-dimethoxystilbene showing that the strength of the O-H bond in the cis isomer is larger by 1.8 kcal/mol. DFT calculations provide a rationalization of this result, indicating that, although the cis geometry implies a destabilization with respect to the trans species of both phenoxyl radical and parent hydroxystilbene, the destabilization of the radical is larger because the folding of the structure strongly reduces the delocalization of the unpaired electron on the styryl group. A comparison of these results with previously reported data on the proapoptotic activity of these stilbenoids suggests that these two properties are not correlated.

PMID: 15471458 DOI: 10.1021/jo0497860

Apoptosis.2012 Jan;17(1):25-36. doi: 10.1007/s10495-011-0653-6.

Pterostilbene protects vascular endothelial cells against oxidized low-density lipoprotein-induced apoptosis in vitro and in vivo.

Zhang L1, Zhou G, Song W, Tan X, Guo Y, Zhou B, Jing H, Zhao S, Chen L.

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Vascular endothelial cell (VEC) apoptosis is the main event occurring during the development of atherosclerosis. Pterostilbene (PT), a natural dimethylated analog of resveratrol, has been the subject of intense research in cancer and inflammation. However, the protective effects of PT against oxidized low-density lipoprotein (oxLDL)-induced apoptosis in VECs have not been clarified. We investigated the anti-apoptotic effects of PT in vitro and in vivo in mice. PT at 0.1-5 μM possessed antioxidant properties comparable to that of trolox in a cell-free system. Exposure of human umbilical vein VECs (HUVECs) to oxLDL (200 μg/ml) induced cell shrinkage, chromatin condensation, nuclear fragmentation, and cell apoptosis, but PT protected against such injuries. In addition, PT injection strongly decreased the number of TUNEL-positive cells in the endothelium of atherosclerotic plaque from apoE(-/-) mice. OxLDL increased reactive oxygen species (ROS) levels, NF-κB activation, p53 accumulation, apoptotic protein levels and caspases-9 and -3 activities and decreased mitochondrial membrane potential (MMP) and cytochrome c release in HUVECs. These alterations were attenuated by pretreatment with PT. PT inhibited the expression of lectin-like oxLDL receptor-1 (LOX-1) expression in vitro and in vivo. Cotreatment with PT and siRNA of LOX-1 synergistically reduced oxLDL-induced apoptosis in HUVECs. Overexpression of LOX-1 attenuated the protection by PT and suppressed the effects of PT on oxLDL-induced oxidative stress. PT may protect HUVECs against oxLDL-induced apoptosis by downregulating LOX-1-mediated activation through a pathway involving oxidative stress, p53, mitochondria, cytochrome c and caspase protease. PT might be a potential natural anti-apoptotic agent for the treatment of atherosclerosis.

PMID: 21928089 DOI: 10.1007/s10495-011-0653-6

Neuro Endocrinol Lett.2008 Oct;29(5):802-5.

Structure-efficiency relationship in derivatives of stilbene. Comparison of resveratrol, pinosylvin and pterostilbene.

Perecko T1, Jancinova V, Drabikova K, Nosal R, Harmatha J.

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OBJECTIVES: Oxidative stress is related to a number of autoimmune diseases, e.g. rheumatoid arthritis, cancer, etc. The main source of pathologically working reactive oxygen species (ROS) are activated polymorphonuclear leukocytes (PMNL).

OBJECTIVE: There are some papers comparing structure – pharmacological efficiency relationship of vegetal substances from the stilbenoid group. We compared the effect of trans-resveratrol, which is well-known by its antioxidative activity, with the effect of pinosylvin and pterostilbene.

METHODS: Luminol-enhanced chemiluminescence (CL) was used to study the antioxidative action. The effect was observed in whole blood and in isolated PMNL. The concentrations of substances tested were 0.01-100 microM. Due to the different abilities of luminol and isoluminol to pass through the cell membrane, we studied the effect of the substances tested on intracellular and extracellular ROS. To stimulate the production of ROS we used phorbol-myristate-acetate (PMA), which activates PMNL via protein kinase C.

RESULTS: Resveratrol, pinosylvin and pterostilbene inhibited significantly the CL of whole blood and extra- and intracellular CL of isolated PMNL in a dosedependent manner. Depending on different functional groups of the stilbene molecule, resveratrol inhibited CL of whole blood and isolated PMNL, whereas pinosylvin influenced mainly intracellular CL and pterostilbene extracellular CL.

CONCLUSION: The presence of different functional groups in the molecules of stilbenoids influence their antioxidative effect. Modification of these functional groups may result in derivatives with required antioxidative properties, targeting mainly extracellular ROS which are responsible for tissue damage during chronic inflammation.

PMID: 18987580

Int J Dev Neurosci.2016 Nov;54:22-31. doi: 10.1016/j.ijdevneu.2016.08.005. Epub 2016 Aug 26.

Neuroprotective actions of pterostilbene on hypoxic-ischemic brain damage in neonatal rats through upregulation of heme oxygenase-1. 

Li D1, Song T1, Yang L2, Wang X1, Yang C1, Jiang Y1.

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Neonatal hypoxic-ischemic (HI) brain damage causes acute mortality and morbidity in newborns and long-term neurological disorders in the survivors. Pterostilbene (PTE) is a natural compound possessing various biological and pharmacological activities. In the present study, we aimed to investigate the effect of PTE on neonatal HI brain damagein P7 rat model and to explore the possible mechanisms. Neonatal HI brain damage was induced in rat pups (P7). Prior to the induction of HI injury, PTE was injected with or without zinc protoporphyrin IX (ZnPP), an inhibitor of heme oxygenase-1 (HO-1). ZnPP was used to test whether abnormal changes of HO-1 expression were involved in the effect of PTE. The results showed that PTE exhibited excellent neuroprotective effects against neonatal HI brain injury, as evidenced by the decrease of brain infarct volume, brain edema, neurological score, and improvement in motor coordination motor deficit and working memory deficit. PTE pretreatment decreased the expression of several proinflammatory cytokines, including TNFα, IL-1β, IL-6, and key transcription factor p65 NF-κB, and reduced the number of TUNEL-stained neurons, indicating the inhibition of inflammation and programmed cell death. Moreover, PTE pretreatment decreased thiobarbituric acid reactive substances content, increased superoxide dismutase activity and decreased reactive oxygen species level, indicating that PTE played an important antioxidant role. Furthermore, ZnPP was able to inhibit PTE-induced suppression of oxidative stress, programmed cell death, inflammation and brain damage. In conclusion, PTE pretreatment prevented HI-induced brain injury in newborns through HO-1-mediated reduction of oxidative stress, programmed cell death, and inflammation, and final improvement of histological and functional injury. Overall, the data that obtained in rat model provide novel insights into the pathogenesis of neonatal HI brain injury and may be translational to human clinical intervention for HI-associated brain injury in newborns.

KEYWORDS: Brain damage; HI; Heme oxygenase-1; Neonatal rat; Pterostilbene

PMID: 27576146 DOI: 10.1016/j.ijdevneu.2016.08.005

J Biochem Mol Toxicol.2013 Jun;27(6):313-22. doi: 10.1002/jbt.21490. Epub 2013 May 6.

Ebselen reduces the toxicity of mechlorethamine in A-431 cells via inhibition of apoptosis.

Lulla A1, Pino MA, Piętka-Ottlik M, Młochowski J, Sparavalo O, Billack B.

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A series of test compounds were evaluated for an ability to reduce the toxicity of the nitrogen mustard mechlorethamine (HN2) in vitro. The test compounds included resveratrol, pterostilbene, vitamin C, ebselen, ebselen diselenide, and ebselen-sulfur. Among them, ebselen demonstrated the highest degree of protection against HN2 toxicity. To this end, pretreatment of the cells with ebselen offered protection against the toxicant whereas no protection was observed when cells were first incubated with HN2 and then treated with ebselen. Significant increases in caspase 3 and caspase 9 activities were observed in response to HN2, and ebselen was found to reduce these effects. Taken together, the data presented here indicate that ebselen is an effective countermeasure to nitrogen mustard in vitro, which is worthy of future investigation in vivo.

PMID: 23649643 DOI: 10.1002/jbt.21490

Curr Med Chem.2016;23(23):2439-89.

The Use of Stilbene Scaffold in Medicinal Chemistry and Multi- Target Drug Design.

Giacomini E, Rupiani S, Guidotti L, Recanatini M, Roberti M1.

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The stilbene scaffold is a basic element for a number of biologically active natural and synthetic compounds, and it is considered as a privileged structure. Stilbenes exemplified by resveratrol, combretastatin A-4 and pterostilbene are of significant interest for drug research and development because of their potential in therapeutic and preventive application. Resveratrol, present in grapes and other food products, plays a role in the prevention of several human pathological processes and has been suggested as an anticancer agent. Moreover, recent evidence has revealed its potential effect on the aging process, diabetes and neurological dysfunction. Combretastatin A-4, from the bark of South African bush willow Combretum caffrum, also shows significant antitumor activity. Pterostilbene is closely related to resveratrol, sharing the same unique therapeutic potential as anti-inflammatory, antineoplastic and antioxidant agent. Therefore, research and development of stilbene-based medicinal chemistry have become rapidly evolving and increasingly active topics covering almost the whole range of therapeutic fields. In the present review, we provide an overview of the role of stilbenes in medicinal chemistry. In this context, we highlight the chemical methodologies adopted for the synthesis of stilbene derivatives, and outline the successful design of novel stilbene based hybrids in the field of cancer, Alzheimer’s and other relevant diseases. This information may be useful in further design of stilbene-based molecules as new leads for the development of novel agents with clinical potential or as effective chemical probes to dissect biological processes.

PMID: 27183980

Eur J Pharmacol.2016 Apr 15;777:9-16. doi: 10.1016/j.ejphar.2016.02.054. Epub 2016 Feb 24.

Anti-hyperlipidemic and anti-peroxidative role of pterostilbene via Nrf2 signaling in experimental diabetes.

Bhakkiyalakshmi E1, Sireesh D1, Sakthivadivel M2, Sivasubramanian S2, Gunasekaran P2, Ramkumar KM3.

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Nuclear factor erythroid 2-related factor (Nrf2), a key transcription factor triggers the expression of antioxidant and detoxification genes thereby providing cellular protective functions against oxidative stress-mediated disorders. Recent research has identified that pharmacological activation of Nrf2 also regulates the largest cluster of genes associated with lipid metabolism. With this background, this paper highlights the anti-hyperlipidemic and anti-peroxidative role of pterostilbene (PTS), an Nrf2 activator, in streptozotocin (STZ)-induced diabetic model. PTS administration to diabetic mice for 5 weeks significantly regulated blood glucose levels through the elevation of insulin secretion. The circulatory and liver lipid profiles of total cholesterol (TC), triglycerides (TG) and non-esterified fatty acids (NEFA) were maintained to normal levels upon PTS treatment. Moreover, PTS administration also normalized the circulatory levels of very low-, low- and high density lipoprotein cholesterols (VLDL-, LDL-, HDL-C) and also reduced lipid peroxidation in STZ-induced diabetic mice. In addition, Nrf2 and its downstream targets, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) enzyme activities and glutathione (GSH) levels were significantly elevated in liver tissues of diabetic mice upon PTS administration. Further, H&E staining of diabetic mouse liver showed collapse in hepatic microvesicles due to altered lipid metabolism. Both structural and functional alterations were attenuated by PTS indicating its role in diabetic dyslipidemia through Nrf2-mediated mechanism that could be considered as a promising therapeutic agent.

KEYWORDS: Diabetes; Dyslipidemia; Lipids; Nrf2; Pterostilbene; Streptozotocin

PMID: 26921755 DOI: 10.1016/j.ejphar.2016.02.054

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.

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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: PMC3486425DOI: 10.4172/2155-9880.S5-008

J Agric Food Chem.2004 Jul 28;52(15):4713-9.

Resveratrol, pterostilbene, and piceatannol in vaccinium berries.

Rimando AM1, Kalt W, Magee JB, Dewey J, Ballington JR.

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A study was conducted to determine the presence of resveratrol, pterostilbene, and piceatannol in Vaccinium berries. Samples representing selections and cultivars of 10 species from Mississippi, North Carolina, Oregon, and Canada were analyzed by gas chromatography/mass spectrometry. Resveratrol was found in Vaccinium angustifolium (lowbush blueberry), Vaccinium arboretum (sparkleberry), Vaccinium ashei (rabbiteye blueberry), Vaccinium corymbosum (highbush blueberry), Vaccinium elliottii (Elliott’s blueberry), Vaccinium macrocarpon (cranberry), Vaccinium myrtillus (bilberry), Vaccinium stamineum (deerberry), Vaccinium vitis-ideae var. vitis-ideae (lingonberry), and Vaccinium vitis-ideae var. minor (partridgeberry) at levels between 7 and 5884 ng/g dry sample. Lingonberry was found to have the highest content, 5884 ng/g dry sample, comparable to that found in grapes, 6471 ng/g dry sample. Pterostilbene was found in two cultivars of V. ashei and in V. stamineum at levels of 99-520 ng/g dry sample. Piceatannol was found in V. corymbosum and V. stamineum at levels of 138-422 ng/g dry sample. These naturally occurring stilbenes, known to be strong antioxidants and to have cancer chemopreventive activities, will add to the purported health benefits derived from the consumption of these small fruits.

PMID: 15264904 DOI: 10.1021/jf040095e

Brain Res.2016 Jul 15;1643:70-9. doi: 10.1016/j.brainres.2016.04.048. Epub 2016 Apr 21.

Neuroprotective effects of pterostilbene against oxidative stress injury: Involvement of nuclear factor erythroid 2-related factor 2 pathway.

Wang B1, Liu H1, Yue L1, Li X1, Zhao L1, Yang X1, Wang X1, Yang Y2, Qu Y3.

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Nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) regulates multiple anti-oxidative enzymes and has neuroprotective effects. Pterostilbene (PTE) is a natural anti-oxidant found in blueberries. Its non-metabolized form exhibits high distribution in the brain after dietary administration. In this study, we aimed to explore the potential of PTE in protecting murine hippocampal neuronal HT22 cells against glutamate-induced oxidative stress injury and possible underlying mechanisms. PTE was nontoxic and induced the nuclear translocation of Nrf2 when HT22 cell cultures were incubated with different concentrations of PTE. Further, PTE displayed a dose-dependent neuroprotective effect, as indicated by increased cell viability and a reduction in lactate dehydrogenase (LDH) release after glutamate treatment. Nrf2 siRNA treatment inhibited PTE-induced neuroprotective effects. Moreover, the levels of nuclear Nrf2 and downstream heme oxygenase-1 (HO-1) and

NAD(P)H: quinone oxidoreductase 1 (NQO1) were elevated after PTE treatment. The PTE-induced elevation of nuclear Nrf2, as well as the increases in HO-1 and NQO1 levels, was abolished by Nrf2 siRNA. PTE treatment reduced the production of reactive oxygen species (ROS) and significantly enhanced the activities of the cellular anti-oxidants glutathione (GSH) and superoxide dismutase (SOD), indicating an attenuation of glutamate-induced oxidative stress. These changes in ROS and GSH and SOD activity were reversed by Nrf2 siRNA. Our results indicate that PTE treatment attenuates glutamate-induced oxidative stress injury in neuronal cells via the Nrf2 signaling pathway.

Copyright © 2016 Elsevier B.V. All rights reserved.

KEYWORDS: Glutamate; Neuroprotection; Nuclear factor erythroid 2 (NF-E2)-related factor 2 signaling; Oxidative stress; Pterostilbene

PMID: 27107941 DOI: 10.1016/j.brainres.2016.04.048

PLoS One.2015 Oct 30;10(10):e0141778. doi: 10.1371/journal.pone.0141778. eCollection 2015.

Leishmanicidal Effect of Synthetic trans-Resveratrol Analogs.

Passos CL1, Ferreira C1, Soares DC1, Saraiva EM1.

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BACKGROUND: Stilbene-based compounds show antitumoral, antioxidant, antihistaminic, anti-inflammatory and antimicrobial activities. Here, we evaluated the effect of the trans-resveratrol analogs, pterostilbene, piceatannol, polydatin and oxyresveratrol, against Leishmania amazonensis.

METHODOLOGY/PRINCIPAL FINDINGS: Our results demonstrated a low murine macrophage cytotoxicity of all four analogs. Moreover, pterostilbene, piceatannol, polydatin and oxyresveratrol showed an anti-L. amazonensis activity with IC50 values of 18 μM, 65 μM, 95 μM and 65 μM for promastigotes, respectively. For intracellular amastigotes, the IC50 values of the analogs were 33.2 μM, 45 μM, 29 μM and 30.5 μM, respectively. Among the analogs assayed only piceatannol altered the cell cycle of the parasite, increasing 5-fold the cells in the Sub-G0 phase and decreasing 1.7-fold the cells in the G0-G1 phase. Piceatannol also changed the parasite mitochondrial membrane potential (ΔΨm) and increased the number of annexin-V positive promastigotes, which suggests incidental death.

CONCLUSION/SIGNIFICANCE: Among the analogs tested, piceatannol, which is a metabolite of resveratrol, was the more promising candidate for future studies regarding treatment of leishmaniasis.

PMID: 26517558 PMCID: PMC4627731DOI: 10.1371/journal.pone.0141778

Chem Biol Interact.2008 Jul 10;174(1):51-9. doi: 10.1016/j.cbi.2008.04.015. Epub 2008 Apr 22.

Effects of resveratrol and its derivatives on lipopolysaccharide-induced microglial activation and their structure-activity relationships.

Meng XL1, Yang JY, Chen GL, Wang LH, Zhang LJ, Wang S, Li J, Wu CF.

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The inhibitory effects of 21 resveratrol derivatives on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in microglia and their structure-activity relationships were studied. It was found, for the first time, that certain resveratrol derivatives that have 3,5-dimethoxyl groups in the A-ring, such as (E)-4-(3,5-dimethoxystyryl)phenol (pterostilbene, compound 2), or have substituted the B-ring of resveratrol with quinolyl, such as (E)-5-[2-(quinolin-4-yl)vinyl]benzene-1,3-diol (compound 18) and (E)-4-(3,5-dimethoxystyryl)quinoline (compound 19), strongly inhibited NO production. Compounds 2, 18, and 19 reduced LPS-induced protein and mRNA expression of inducible NO synthase (iNOS), but did not display direct NO-scavenging activity up to 30 microM in sodium nitroprusside (SNP) solution. Moreover, compounds 2, 18, and 19 could also significantly inhibit the production of TNF-alpha by LPS-activated microglia. Further studies revealed that compounds 2, 18, and 19 inhibited LPS-induced NO and TNF-alpha production in microglia by blocking IkappaBalpha phosphorylation and degradation. The potent inhibitory effects of compounds 2, 18, and 19 on microglial activation suggest their potential for treatment of neurodegenerative diseases accompanied by microglial activation.

PMID: 18513711 DOI: 10.1016/j.cbi.2008.04.015

Food Chem Toxicol.2013 Nov;61:112-20. doi: 10.1016/j.fct.2013.03.038. Epub 2013 Apr 6.

Resveratrol and related stilbenes: their anti-aging and anti-angiogenic properties.

Kasiotis KM1, Pratsinis H, Kletsas D, Haroutounian SA.

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Dietary stilbenes comprise a class of natural compounds that display significant biological activities of medicinal interest. Among them, their antioxidant, anti-aging and anti-angiogenesic properties are well established and subjects of numerous research endeavors. This mini-review aspires to account and present the literature reports published on research concerning various natural and synthetic stilbenes, such as trans-resveratrol. Special focus was given to most recent research findings, while the mechanisms underlying their anti-aging and anti-angiogenic effects as well as the respective signaling pathways involved were also presented and discussed.

KEYWORDS: Aging; Angiogenesis; Lifespan; Polyphenol; Resveratrol; Stilbenes

PMID: 23567244 DOI: 10.1016/j.fct.2013.03.038

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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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: PMC3851026DOI: 10.4172/2155-9880.1000238

Oxid Med Cell Longev.2016;2016:2427618. doi: 10.1155/2016/2427618. Epub 2016 Jan 5.

Dietary Phenolic Compounds Interfere with the Fate of Hydrogen Peroxide in Human Adipose Tissue but Do Not Directly Inhibit Primary Amine Oxidase Activity. 

Carpéné C1, Hasnaoui M1, Balogh B2, Matyus P2, Fernández-Quintela A3, Rodríguez V3, Mercader J4, Portillo MP3.

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Resveratrol has been reported to inhibit monoamine oxidases (MAO). Many substrates or inhibitors of neuronal MAO interact also with other amine oxidases (AO) in peripheral organs, such as semicarbazide-sensitive AO (SSAO), known as primary amine oxidase, absent in neurones, but abundant in adipocytes. We asked whether phenolic compounds (resveratrol, pterostilbene, quercetin, and caffeic acid) behave as MAO and SSAO inhibitors. AO activity was determined in human adipose tissue. Computational docking and glucose uptake assays were performed in 3D models of human AO proteins and in adipocytes, respectively. Phenolic compounds fully inhibited the fluorescent detection of H2O2 generated during MAO and SSAO activation by tyramine and benzylamine. They also quenched H2O2-induced fluorescence in absence of biological material and were unable to abolish the oxidation of radiolabelled tyramine and benzylamine. Thus, phenolic compounds hampered H2O2 detection but did not block AO activity. Only resveratrol and quercetin partially impaired MAO-dependent [(14)C]-tyramine oxidation and behaved as MAO inhibitors. Phenolic compounds counteracted the H2O2-dependent benzylamine-stimulated glucose transport. This indicates that various phenolic compounds block downstream effects of H2O2 produced by biogenic or exogenous amine oxidation without directly inhibiting AO. Phenolic compounds remain of interest regarding their capacity to limit oxidative stress rather than inhibiting AO.

PMID: 26881018 PMCID: PMC4736399DOI: 10.1155/2016/2427618

Mutagenesis.2016 Jul;31(4):433-41. doi: 10.1093/mutage/gew002. Epub 2016 Jan 26.

Resveratrol and its methoxy-derivatives as modulators of DNA damage induced by ionising radiation.

Traversi G1, Fiore M2, Leone S1, Basso E1, Di Muzio E1, Polticelli F3, Degrassi F2, Cozzi R4.

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Various naturally occurring stilbene-like compounds that are related to resveratrol (RSV) possess some of the beneficial effects of the parent molecule and provide even further benefits. Therefore, a series of methoxylated analogues of RSV were prepared with the aim of increasing antitumour and proapoptotic activity. In a previous article, we studied two methoxy-derivatives, pterostilbene (PTERO) and trimethoxystilbene (TRIMETHOXY), in which the first was formed by the substitution of two hydroxyl groups with two methoxy groups (trans-3,5-dimethoxy-4′-hydroxystilbene) and the second was formed by the replacement of all three OH groups with methoxy groups (trans-3,5,4′-trimethoxystilbene). Both methoxy-derivatives showed stronger antioxidant activity when compared with RSV. In the present article, we focused on the analysis of the ability of RSV and its two methoxylated derivatives to protect proliferating non-tumoural cells from the damage induced by ionising radiation (IR). First we showed that the methoxy derivatives, contrary to their parental compound, are unable to affect topoisomerase enzyme and consequently are not clastogenic per se Second we showed that both PTERO and TRIMETHOXY more efficiently reduce the chromosome damage induced by IR. Furthermore, TRIMETHOXY, but not PTERO, causes a delay in cell proliferation, particularly in mitosis progression increasing the number of cells in metaphase at the expense of prophases and ana/telophases.

PMID: 26819346 DOI: 10.1093/mutage/gew002

Interdiscip Toxicol.2011 Mar;4(1):33-9. doi: 10.2478/v10102-011-0007-9.

Utilization of adjuvant arthritis model for evaluation of new approaches in rheumatoid arthritis therapy focused on regulation of immune processes and oxidative stress.

Bauerová K1, Poništ S, Mihalová D, Dráfi F, Kuncírová V.

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As a number of disease-modifying anti-rheumatic drugs often have side effects at high doses and/or during long-term administration, increased efficacy without increased toxicity is expected for combination therapy of rheumatoid arthritis (RA). The safety of long-term therapy of RA is very important as patients with RA are usually treated for two or more decades. This experimental overview is focused on some promising substances and their combinations with the standard antirheumatic drug – methotrexate (Mtx) for treatment of rheumatoid arthritis. The adjuvant arthritis model in Lewis rats was used for evaluation of antiinflammatory efficacy of the substances evaluated. Mtx was administered in the oral dose of 0.3 mg/kg b.w. twice a week. Natural and synthetic antioxidants were administered in the daily oral dose of 20 mg/kg b.w for coenzyme Q(10) (CoQ(10)), 150 mg/kg b.w for carnosine (Carn), 15 mg/kg b.w. for stobadine dipalmitate (Stb) and its derivative SMe1.2HCl (SMe1), and 30 mg/kg b.w. for pinosylvin (Pin) or pterostilbene (Pte). Mtx in the oral dose of 0.4 mg/kg b.w. twice a week was combined with Pin in the oral daily dose of 50 mg/kg b.w. Clinical (hind paw volume – HPV), biochemical (activity of GGT in joint and level of TBARS in plasma), and immunological (IL-1 in plasma) parameters were assessed. Our results achieved with different antioxidants in monotherapies showed a reduction of oxidative stress in adjuvant arthritis independently of the chemical structure of the compounds. Pin was the most effective antioxidant tested in decreasing HPV. All combinations tested showed a higher efficacy in affecting biochemical or immunological parameters than Mtx administered in monotherapy. The findings showed the benefit of antioxidant compounds for their use in combination therapy with methotrexate.

KEYWORDS: arthritis; carnosine; coenzyme Q10; combination therapy; methotrexate; oxidative stress; pyridoindoles; stilbenoids

PMID: 21577282 PMCID: PMC3090052DOI: 10.2478/v10102-011-0007-9

Biofactors.2017 Nov 23. doi: 10.1002/biof.1396. [Epub ahead of print]

Resveratrol, pterostilbene, and dementia.

Lange KW1, Li S2.

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Resveratrol is a natural phytoestrogen with neuroprotective properties. Polyphenolic compounds including resveratrol exert in vitro antioxidant, anti-inflammatory, and antiamyloid effects. Resveratrol and its derivative pterostilbene are able to cross the blood-brain barrier and to influence brain activity. The present short review summarizes the available evidence regarding the effects of these polyphenols on pathology and cognition in animal models and human subjects with dementia. Numerous investigations in cellular and mammalian models have associated resveratrol and pterostilbene with protection against dementia syndromes such as Alzheimer’s disease (AD) and vascular dementia. The neuroprotective activity of resveratrol and pterostilbene demonstrated in in vitro and in vivo studies suggests a promising role for these compounds in the prevention and treatment of dementia. In comparison to resveratrol, pterostilbene appears to be more effective in combatting brain changes associated with aging. This may be attributed to the more lipophilic nature of pterostilbene with its two methoxyl groups compared with the two hydroxyl groups of resveratrol. The findings of available intervention trials of resveratrol in individuals with mild cognitive impairment or AD do not provide evidence of neuroprotective or therapeutic effects. Future clinical trials should be conducted with long-term exposure to preparations of resveratrol and pterostilbene with high bioavailability.

© 2017 BioFactors, 2017.

KEYWORDS: cognition; dementia; polyphenols; pterostilbene; resveratrol

PMID: 29168580 DOI: 10.1002/biof.1396

Planta Med.2008 Oct;74(13):1635-43. doi: 10.1055/s-0028-1088301. Epub 2008 Oct 8.

Biological/chemopreventive activity of stilbenes and their effect on colon cancer.

Rimando AM1, Suh N.

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Colon cancer is one of the leading causes of cancer death in men and women in Western countries. Epidemiological studies have linked the consumption of fruits and vegetables to a reduced risk of colon cancer, and small fruits are particularly rich sources of many active phytochemical stilbenes, such as resveratrol and pterostilbene. Recent advances in the prevention of colon cancer have stimulated an interest in diet and lifestyle as an effective means of intervention. As constituents of small fruits such as grapes, berries and their products, stilbenes are under intense investigation as cancer chemopreventive agents. One of the best-characterized stilbenes, resveratrol, has been known as an antioxidant and an anti-aging compound as well as an anti-inflammatory agent. Stilbenes have diverse pharmacological activities, which include cancer prevention, a cholesterol-lowering effect, enhanced insulin sensitivity, and increased lifespan. This review summarizes results related to the potential use of various stilbenes as cancer chemopreventive agents, their mechanisms of action, as well as their pharmacokinetics and efficacy for the prevention of colon cancer in animals and humans.

PMID: 18843589 DOI: 10.1055/s-0028-1088301

J Agric Food Chem.2008 Nov 26;56(22):10544-51. doi: 10.1021/jf802279h.

Cellular and behavioral effects of stilbene resveratrol analogues: implications for reducing the deleterious effects of aging.

Joseph JA1, Fisher DR, Cheng V, Rimando AM, Shukitt-Hale B.

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Research suggests that polyphenolic compounds contained in fruits and vegetables that are rich in color may have potent antioxidant and anti-inflammatory activities. The present studies determined if stilbene (e.g., resveratrol) compounds would be efficacious in reversing the deleterious effects of aging in 19 month old Fischer 344 rats. Experiment I utilized resveratrol and six resveratrol analogues and examined their efficacies in preventing dopamine-induced decrements in calcium clearance following oxotremorine-induced depolarization in COS-7 cells transfected with M1 muscarinic receptors (MAChR) that we have shown previously to be sensitive to oxidative stressors. Experiment II utilized the most efficacious analogue (pterostilbene) from experiment I and fed aged rats a diet with a low (0.004%) or a high (0.016%) concentration of pterostilbene. Results indicated that pterostilbene was effective in reversing cognitive behavioral deficits, as well as dopamine release, and working memory was correlated with pterostilbene levels in the hippocampus.

PMID: 18954071 DOI: 10.1021/jf802279h

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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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

Phytomedicine.2017 Sep 15;33:7-13. doi: 10.1016/j.phymed.2017.05.009. Epub 2017 Jul 8.

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

Seo YJ1, Kim KJ1, Koh EJ1, Choi J1, Lee BY2.

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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.

Copyright © 2017. Published by Elsevier GmbH.

KEYWORDS: Adipocytes; Adipogenesis; CHOP10; Heme oxygenase-1; Pterostilbene

PMID: 28887923 DOI: 10.1016/j.phymed.2017.05.009

Biomed Pharmacother.2016 Oct;83:1057-1063. doi: 10.1016/j.biopha.2016.08.031. Epub 2016 Aug 19.

Modulatory role of Pterocarpus santalinus against alcohol-induced liver oxidative/nitrosative damage in rats.

Bulle S1, Reddy VD1, Padmavathi P2, Maturu P3, N Ch V4.

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Pterocarpus santalinus, a traditional medicinal plant has shown protective mechanisms against various complications. The aim of the present study is to evaluate therapeutic efficacy of P. santalinus heartwood methanolic extract (PSE) against alcohol-induced oxidative/nitrosative stress leading to hepatotoxicity. In-vitro studies revealed that PSE possess strong DPPH (1,1-diphenyl-2-picryl hydrazyl) and nitric oxide radical scavenging activity. For in vivo studies male albino Wistar rats were treated with 20% alcohol (5g/kg b.wt/day) and PSE (250mg/kg b.wt/day) for 60days. Results showed that alcohol administration significantly altered plasma lipid profile with marked increase in the levels of plasma transaminases (ALT and AST), alkaline phosphatase (ALP), lactate dehydrogenase (LDH) and gamma glutamyl transferase (γGT). Moreover, lipid peroxides, nitric oxide (NOx) levels in plasma and liver were increased with increased iNOS protein expression in liver was noticed in alcohol administered rats and these levels were significantly brought back close to normal level by PSE administration except iNOS protein expression. Alcohol administration also decreased the content of reduced glutathione (GSH) and activities of glutathione peroxidase (GPx), glutathione-s transferase (GST), glutathione reductase (GR), superoxide dismutase (SOD) and catalase (CAT) in liver, which were significantly enhanced by administration of PSE. The active compounds pterostilbene, lignan and lupeols present in PSE might have shown protection against alcohol-induced hepatic damage by possibly reducing the rate of lipid peroxidation, NOx levels and increasing the antioxidant defence mechanism in alcohol administered rats. Both biochemical and histopathological results in the alcohol-induced liver damage model emphasize beneficial action of PSE as a hepatoprotective agent.

KEYWORDS: Alcohol; Hepatotoxicity; Nitrosative stress; Oxidative stress; P. santalinus

PMID: 27544549 DOI: 10.1016/j.biopha.2016.08.031

J Food Drug Anal.2017 Jan;25(1):125-133. doi: 10.1016/j.jfda.2016.10.022. Epub 2016 Dec 11.

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

Chen RJ1, Lee YH1, Yeh YL1, Wu WS1, Ho CT2, Li CY3, Wang BJ4, Wang YJ5.

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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.

KEYWORDS: autophagy; inflammation; pterostilbene; skin disorders

PMID: 28911530 DOI: 10.1016/j.jfda.2016.10.022

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.

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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

J Cell Biochem.2017 Nov 10. doi: 10.1002/jcb.26495. [Epub ahead of print]

Pterostilbene down-regulates hTERT at physiological concentrations in breast cancer cells: potentially through the inhibition of cMyc.

Daniel M1, Tollefsbol TO1,2,3,4,5.

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Human telomerase reverse transcriptase (hTERT) encodes the catalytic subunit of telomerase, which has been shown to be upregulated in many cancers. Pterostilbene is a naturally occurring stilbenoid and phytoalexin found primarily in blueberries that exhibits antioxidant activity and inhibits the growth of various cancer cell types. Therefore, the aim of this study was to determine whether treatment with pterostilbene, at physiologically achievable concentrations, can inhibit the proliferation of breast cancer cells and down-regulate the expression of hTERT. We found that pterostilbene inhibits the cellular proliferation of MCF-7 and MDA-MB-231 breast cancer cells in both a time- and dose-dependent manner, without significant toxicity to the MCF10A control cells. Pterostilbene was also shown to increase apoptosis in both breast cancer cell lines. Dose-dependent cell cycle arrest in G1 and G2/M phase was observed after treatment with pterostilbene in MCF-7 and MDA-231 cells, respectively. hTERT expression was down-regulated after treatment in both a time- and dose-dependent manner. Pterostilbene also reduced telomerase levels in both cell lines in a dose-dependent manner. Moreover, cMyc, a proposed target of the pterostilbene-mediated inhibition of hTERT, was down-regulated both transcriptionally and posttranscriptionally after treatment. Collectively, these findings highlight a promising use of pterostilbene as a natural, preventive and therapeutic agent against the development and progression of breast cancer. This article is protected by copyright. All rights reserved.

KEYWORDS: Blueberries; Breast cancer; Cancer; Physiological concentrations; Pterostilbene; Telomerase; cMyc; hTERT

PMID: 29125889 DOI: 10.1002/jcb.26495

Curr Clin Pharmacol.2006 Jan;1(1):81-101.

Pharmacometrics of stilbenes: seguing towards the clinic.

Roupe KA1, Remsberg CM, Yáñez JA, Davies NM.

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Stilbenes are small molecular weight (approximately 200-300 g/mol), naturally occurring compounds and are found in a wide range of plant sources, aromatherapy products, and dietary supplements. These molecules are synthesized via the phenylpropanoid pathway and share some structural similarities to estrogen. Upon environmental threat, the plant host activates the phenylpropanoid pathway and stilbene structures are produced and subsequently secreted. Stilbenes act as natural protective agents to defend the plant against viral and microbial attack, excessive ultraviolet exposure, and disease. One stilbene, resveratrol, has been extensively studied and has been shown to possess potent anti-cancer, antiinflammatory and anti-oxidant activities. Found primarily in the skins of grapes, resveratrol is synthesized by Vitis vinifera grapevines in response to fungal infection or other environmental stressors. Considerable research showing resveratrol to be an attractive candidate in combating a wide variety of cancers and diseases has fueled interest in determining the disease-fighting capabilities of other structurally similar stilbene compounds. The purpose of this review is to describe four such structurally similar stilbene compounds, piceatannol, pinosylvin, rhapontigenin, and pterostilbene and detail some current pharmaceutical research and highlight their potential clinical applications.

PMID: 18666380

Redox Rep.2017 Nov;22(6):501-507. doi: 10.1080/13510002.2017.1329917. Epub 2017 May 22.

Pterostilbene protects against UVB-induced photo-damage through a phosphatidylinositol-3-kinase-dependent Nrf2/ARE pathway in human keratinocytes. 

Li H1, Jiang N1,2, Liang B1, Liu Q1,3, Zhang E1, Peng L1, Deng H1, Li R1, Li Z1, Zhu H1.

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OBJECTIVE: Ultraviolet B (UVB) irradiation is the initial etiological factor for various skin disorders, including erythema, sunburn, photoaging, and photocarcinogenesis. Pterostilbene (Pter) displayed remarkable antioxidant, anti-inflammatory, and anticarcinogenic activities. This study aimed to investigate the effective mechanism of Pter against UVB-induced photodamage in immortalized human keratinocytes.

METHODS: Human keratinocytes were pretreated with Pter (5 and 10 μM) for 24 h prior to UVB irradiation (300 mJ/cm2). Harvested cells were analyzed by MTT, DCFH-DA, comet, western blotting, luciferase promoter, small interference RNA transfection, and quantitative real-time polymerase chain reaction assay.

RESULTS: Pter significantly attenuated UVB-induced cell death and reactive oxygen species (ROS) generation, and effectively increased nuclear translocation of NF-E2-related factor-2 (Nrf2), expression of Nrf2-dependent antioxidant enzymes, and DNA repair activity. Moreover, the protective effects of Pter were abolished by small interference RNA-mediated Nrf2 silencing. Furthermore, Pter was also found to induce the phosphorylation of Nrf2 and the known phosphatidylinositol-3-kinase (PI3K) phosphorylated kinase, Akt. The specific inhibitor of PI3K, LY294002, successfully abrogated Pter-induced Nrf2 phosphorylation, activation of Nrf2-antioxidant response element pathway, ROS scavenging ability, and DNA repair activity.

CONCLUSION: The present study indicated that Pter effectively protected against UVB-induced photodamage by increasing endogenous defense mechanisms, scavenging UVB-induced ROS, and aiding in damaged DNA repair through a PI3K-dependent activation of Nrf2/ARE pathway.

KEYWORDS: Nrf2; Pterostilbene; antioxidants; photoprotection; ultraviolet

PMID: 28532341 DOI: 10.1080/13510002.2017.1329917

Biosci Biotechnol Biochem.2017 Feb;81(2):226-230. doi: 10.1080/09168451.2016.1240606. Epub 2016 Oct 19.

Synthesis, oxygen radical absorbance capacity, and tyrosinase inhibitory activity of glycosides of resveratrol, pterostilbene, and pinostilbene.

Uesugi D1, Hamada H1, Shimoda K2, Kubota N2, Ozaki SI3, Nagatani N4

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The stilbene compound resveratrol was glycosylated to give its 4′-O-β-D-glucoside as the major product in addition to its 3-O-β-D-glucoside by a plant glucosyltransferase from Phytolacca americana expressed in recombinant Escherichia coli. This enzyme transformed pterostilbene to its 4′-O-β-D-glucoside, and converted pinostilbene to its 4′-O-β-D-glucoside as a major product and its 3-O-β-D-glucoside as a minor product. An analysis of antioxidant capacity showed that the above stilbene glycosides had lower oxygen radical absorbance capacity (ORAC) values than those of the corresponding stilbene aglycones. The 3-O-β-D-glucoside of resveratrol showed the highest ORAC value among the stilbene glycosides tested, and pinostilbene had the highest value among the stilbene compounds. The tyrosinase inhibitory activities of the stilbene aglycones were improved by glycosylation; the stilbene glycosides had higher activities than the stilbene aglycones. Resveratrol 3-O-β-D-glucoside had the highest tyrosinase inhibitory activity among the stilbene compounds tested.

KEYWORDS: glycoside; pinostilbene; pterostilbene; resveratrol

PMID: 27756183 DOI: 10.1080/09168451.2016.1240606

Cogn Neurodyn.2017 Feb;11(1):35-49. doi: 10.1007/s11571-016-9413-1. Epub 2016 Sep 30.

Pterostilbene ameliorates intracerebroventricular streptozotocin induced memory decline in rats.

Naik B1, Nirwane A1, Majumdar A1.

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There is strong evidence that mitochondrial dysfunction mediated oxidative stress results in aging and energy metabolism deficits thus playing a prime role in pathogenesis of Alzheimer’s disease, neuronal death and cognitive dysfunction. Evidences accrued in empirical studies suggest the antioxidant, anticancer and anti-inflammatory activities of the phytochemical pterostilbene (PTS). PTS also exhibits favourable pharmacokinetic attributes compared to other stilbenes. Hence, in the present study, we explored the neuroprotective role of PTS in ameliorating the intracerebroventricular administered streptozotocin (STZ) induced memory decline in rats. PTS at doses of 10, 30 and 50 mg/kg, was administered orally to STZ administered Sprague-Dawley (SD) rats. The learning and memory tests, Morris water maze test and novel object recognition test were performed which revealed improved cognition on PTS treatment. Further, there was an overall improvement in brain antioxidant parameters like elevated catalase and superoxide dismutase activities, GSH levels, lowered levels of nitrites, lipid peroxides and carbonylated proteins. There was improved cholinergic transmission as evident by decreased acetylcholinesterase activities. The action of ATPases (Na+ K+, Ca2+ and Mg2+) indicating the maintenance of cell membrane potential was also augmented. mRNA expression of battery of genes involved in cellular mitochondrial biogenesis and inflammation showed variations which extrapolate to hike in mitochondrial biogenesis and abated inflammation. The histological findings corroborated the effective role of PTS in countering STZ induced structural aberrations in brain.

KEYWORDS: AChE; ATPases; Brain; Fenofibrate; IL-6; Inflammation; Learning and memory; PGC1α; PPARα; Protein carbonylation; Pterostilbene; Rats; Streptozotocin; TNF-α

PMID: 28174611 PMCID: PMC5264756[Available on 2018-02-01] DOI: 10.1007/s11571-016-9413-1

Bioorg Med Chem.2017 Feb 15;25(4):1471-1480. doi: 10.1016/j.bmc.2017.01.010. Epub 2017 Jan 11.

Design, synthesis and evaluation of some N-methylenebenzenamine derivatives as selective acetylcholinesterase (AChE) inhibitor and antioxidant to enhance learning and memory.

Shrivastava SK1, Srivastava P2, Upendra TVR2, Tripathi PN2, Sinha SK3.

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Series of some 3,5-dimethoxy-N-methylenebenzenamine and 4-(methyleneamino)benzoic acid derivatives comprising of N-methylenebenzenamine nucleus were designed, synthesized, characterized, and assessed for their acetylcholinesterase (AChE), butyrylcholinesterase (BChE) inhibitory, and antioxidant activity thereby improving learning and memory in rats. The IC50 values of all the compound along with standard were determined on AChE and BChE enzyme. The free radical scavenging activity was also assessed by in vitro DPPH (2,2-diphenyl-1-picryl-hydrazyl) and hydrogen peroxide radical scavenging assay. The selective inhibitions of all compounds were observed against AChE in comparison with standard donepezil. The enzyme kinetic study of the most active compound 4 indicated uncompetitive AChE inhibition. The docking studies of compound 4 exhibited the worthy interaction on active-site gorge residues Phe330 and Trp279 responsible for its high affinity towards AChE, whereas lacking of the BChE inhibition was observed due to a wider gorge binding site and absence of important aromatic amino acids interactions. The ex vivo study confirmed AChE inhibition abilities of compound 4 at brain site. Further, a considerable decrease in escape latency period of the compound was observed in comparison with standard donepezil through in vivo Spatial Reference Memory (SRM) and Spatial Working Memory (SWM) models which showed the cognition-enhancing potential of compound 4. The in vivo reduced glutathione (GSH) estimation on rat brain tissue homogenate was also performed to evaluate free radical scavenging activity substantiated the antioxidant activity in learning and memory.

KEYWORDS: Acetylcholinesterase inhibitor; Antioxidant; Learning and memory; Pterostilbene; Schiff base

PMID: 28126439 DOI: 10.1016/j.bmc.2017.01.010

J Pharm Pharmacol.2017 Jan;69(1):73-81. doi: 10.1111/jphp.12657. Epub 2016 Nov 23.

The resveratrol derivatives trans-3,5-dimethoxy-4-fluoro-4′-hydroxystilbene and trans-2,4′,5-trihydroxystilbene decrease oxidative stress and prolong lifespan in Caenorhabditis elegans.

Fischer N1, Büchter C1, Koch K1, Albert S2, Csuk R2, Wätjen W1.

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OBJECTIVES: Resveratrol (trans-3,4′,5-trihydroxystilbene (1)) was previously shown to extend the lifespan of different model organisms. However, its pharmacological efficiency is controversially discussed. Therefore, the bioactivity of four newly synthesized stilbenes (trans-3,5-dimethoxy-4-fluoro-4′-hydroxystilbene (3), trans-4′-hydroxy-3,4,5-trifluorostilbene (4), trans-2,5-dimethoxy-4′-hydroxystilbene (5), trans-2,4′,5-trihydroxystilbene (6)) was compared to (1) and pterostilbene (trans-3,5-dimethoxy-4′-hydroxystilbene (2)) in the established model organism Caenorhabditis elegans.

METHODS: Trolox equivalent antioxidant capacity (TEAC), 2′,7′-dichlorofluorescein (DCF), thermotolerance assays, C. elegans lifespan analyses.

KEY FINDINGS: All compounds exert a strong in-vitro radical scavenging activity (6 > 1 > 5 > 2 = 3 = 4), but in vivo, only (3) and (6) reduce reactive oxygen species (ROS) accumulation. Furthermore, (3) and (6) increased the mobility of aged nematodes and prolonged their mean lifespans, while these compounds decreased the thermal stress resistance. Using daf-16 (FoxO), skn-1 (Nrf2) and sir-2.1 (sirtuin) loss-of-function mutant strains, the in vivo antioxidant effects of compounds (3) and (6) were abolished, showing the necessity of these evolutionary highly conserved factors. However, short-time treatment with stilbenes (3) and (6) did not modulate the cellular localization of the transcription factors DAF-16 and SKN-1.

CONCLUSION: In contrast to resveratrol, the synthetic stilbene derivatives (3) and (6) increase the lifespan of C. elegans, rendering them promising candidates for pharmacological anti-ageing purposes.

© 2016 Royal Pharmaceutical Society.

KEYWORDS: Nrf2; ageing; insulin-signalling; oxidative stress; secondary plant compounds

PMID: 27882602 DOI: 10.1111/jphp.12657