1.
Sources and Structure
1.1
Sources
Pterostilbene (trans-3,5-dimethoxy-4-hydroxystilbene[1]) is a stilbene compound that is structurally similar to other popular stilbenes such as resveratrol or piceatannol;[2] it is named after its first discovered source (the pterocarpus genus)[3] but is also a component of blueberries and grape products. It is a phytoalexin (compound produced by plants as a defense against parasites and insects) similar to resveratrol[4] albeit more potent.[5][6]
Pterostilbene is a phytoalexin (plant chemical defense) similar to resveratrol, belonging to the stilbene class of molecules; it is named after the pterocarpus genus of plants
Its sources include:
- Pterocarpus marsupium (Indian Kino Tree)[7] and pterocarpus santalinus (Sandalwood)[8]
- Blueberries (92-550ng/g dry weight)[9][2]
- Grape (Vitis vinifera) leaves[6] and berries[10]
- Anogeissus acuminata[11]
- The Dracaena genus[12]
- Rheum rhaponticum (root)[13]
- Peanuts (Arachis hypogaea)[14]
Pterostilbene is contained in low quantities in a few plants, most notably blueberries and grapes. Despite being in low concentrations, it is likely bioactive following oral ingestion of these fruits and their products (such as wine)
1.2
Structure and Properties
The structure of pterostilbene is very similar to resveratrol, although the 3,5-dihydroxy part of resveratrol (the two hydroxyl groups on the benzene ring to the left) are replaced with methoxy groups.
The antioxidant capacities of resveratrol requires that there is a hydroxylation at the 4' position (right side of the molecule) and that the overall molecule is in a trans configuration rather than cis.[15][16][17][18] The above stilbenes all abide by these requirements while others such as pinosylvin do not. The methoxy groups on perostilbene appear to allow a greater antioxidative capacity relative to resveratrol.[15][16]
Pterostilbene is a methoxylated resveratrol, essentially. It has a larger difference in structure from resveratrol than piceatannol (another common stilbene compound, which is more similar to resveratrol). These three structures form the common dietary stilbenes
2.
Pharmacology
2.1
Absorption
Pterostilbene, due to the two methoxy groups, exhibits increased hydrophobicity and oral absorption relative to resveratrol.[19] Relative to the approximate 20% bioavailability of resveratrol following oral ingestion,[20] pterostilbene's is near 80% at oral doses of 56-168mg/kg[19] and a bit lower (59.2+/-19.6% when paired with 2-hydroxypropyl-β-cyclodextrin, a delivery system[21] that complexes pterostilbene[22]) at 15mg/kg.[23] The general idea of methylated flavonoids or polyphenols having greater absorption is well known.[24]
Taking pterostilbene by itself has been noted to have a lower bioavailability (15.9+/-7.8%) than when taken as part of a delivery system, and bioavailability is further significantly reduced when taken in a fasted state (less than 5.5%).[23] Increasing the dosage to 60mg/kg under these same conditions increases the bioavailability two-fold.[23]
Sublingual absorption of pterostilbene has a bioavailability of 25.8+/-13.1%.[23]
Pterostilbene appears to be well absorbed, and better absorbed than resveratrol. While its absorption is somewhat respectable (for a polyphenolic) at lower oral doses, higher oral doses appear to actually be better absorbed than lower doses. Pterostilbene can be absorbed sublingually
2.2
Serum
A single dose of 56-168mg/kg pterostilbene has noted a Cmax of 2,820ng/mL (56mg/kg) and 7,780ng/mL (168mg/kg) at a Tmax of 2 or 4 hours and half-lives of 90 and 114 minutes, respectively.[19]
56-168mg/kg pterostilbene daily for two weeks has noted a Cmax of 2,550ng/mL (56mg/kg) or 5,560ng/mL (168mg/kg) at a Tmax of 2 and 8 hours with half-lives of 96 and 114 minutes, respectively.[19] Repeated dosing appears to be associated with a higher overall AUC for 56mg/kg (15,000ng/h/mL versus 13,700ng/h/mL) but not 168mg/kg (49,600ng/h/mL versus 57,700ng/h/mL).[19]
Chronic dosing of pterostilbene appears to reduce the peak serum values while prolonging the time to reach peak levels. When looking at overall bodily exposure to pterostilbene, there isn't a predictable difference
2.4
Metabolism
While resveratrol appears to mostly be metabolized into a glucuronide conjugate, pterostilbene is mostly metabolized into pterostilbene sulfate.[19]
2.5
Enzymatic Interactions
Pterostilbene has been noted to activate AMPK (albeit in prostatic cancer cells).[26]
3.
Neurology
3.2
Anxiety
Pterostilbene appears to exert anxiolytic effects in the 1-2mg/kg oral dosing range in mice subjected to an elevated maze test, although it appears ineffective at 5-10mg/kg; this is thought to be related to ERK phosphorylation in the hippocampus[29] which is known to be related to anxiety and mood.[30]
3.3
Memory and Learning
Isolated pterostilbene has been noted to improve cognition in aged rats when fed in the diet at 0.004-0.016% over 12-13 weeks, with the improvements correlating with hippocampal concentrations of pterostilbene.[31]
4.
Cardiovascular Health
4.1
Blood Pressure
Supplementation of pterostilbene at 125mg twice daily appeared to reduce blood pressure (diastolic and systolic) in hypercholesteromic adults, an effect not observed with 50mg taken twice daily but partially replicated (systolic only) when 50mg was paired with 100mg grape seed extract (GSE) also taken twice daily.[32]
4.2
Cholesterol
Pterostilbene has been noted to increase the signalling of PPARα receptors at 100µM (8-fold) and 300µM (14-fold) concentrations, with 100µM of pterostilbene being 74.2% more effective than 100µM ciprofibrate as assessed by relative luciferase units.[33] At concentrations of 1-10µM pterostilbene, the receptors were mostly inactive.[33] Since pterostilbene is known to bind to PPARα[34] it appeared to be an agonist of this receptor.
Pterostilbene may be a PPARα ligand
Oral ingestion of pterostilbene at 25mcg/kg of the diet of hamsters with high cholesterol is able to subsequently reduce LDL-C (29%) and increase HDL-C (7%),[33] and reductions in LDL-C (57%) and improvements in HDL-C (73.1%) have been noted in diabetic rats given 40mg/kg pterostilbene.[35]
Animal studies show an improvement in cholesterol metabolism with low dose supplementation of pterostilbene
When supplemented to subjects with high cholesterol (200mg/dL) and high LDL-C, pterostilbene at both doses (50mg or 125mg, both taken twice daily) appeared to increase total cholesterol and LDL cholesterol relative to placebo, with the group given the low dose pterostilbene with grape seed extract (GSE; 100mg twice daily) not seeing this increase;[32] the benefits to blood pressure seen with high dose pterostilbene were replicated with GSE.[32]
HDL cholesterol was noted to be unchanged overall, but in people not on cholesterol medication taking the higher dose of pterostilbene there was a decrease relative to control.[32]
High doses of pterostilbene supplementation (50-125mg twice daily) appear to increase, rather than decrease, cholesterol and LDL levels in subjects who already have high LDL concentrations; those not on cholesterol lowering medications also noted a decrease in HDL cholesterol
4.3
Triglycerides
Serum triglycerides were reduced by 30% following six weeks of supplementation with 40mg/kg pterostilbene in diabetic rats, the potency exceeding that of 500mg/kg metformin but not fully normalizing relative to nondiabetic control.[35]
In humans (hypercholesterolemic but with normal triglycerides) given 50mg or 125mg pterostilbene twice daily over the course of 52 days, there were no observable changes in serum triglyceride concentrations relative to control; the addition of 100mg grape seed extract to the low dose group also did not confer any beenfits.[32]
5.
Interactions with Glucose Metabolism
5.1
Blood Glucose
25mcg/kg of pterostilbene to the diets of hypercholesterolemic hamsters is able to reduce blood glucose by 14%[33] and in diabetic rats 40mg/kg pterostilbene for six weeks a reduction in glucose with a concomitant increase in insulin was noted;[35] this extended to otherwise healthy rats to a lesser degree (6.3% reduction)[35] and in hyperglycemic rats the potency of pterostilbene (40mg/kg) is comparable to metformin (500mg/kg).[35][36]
6.
Inflammation and Immunology
6.1
Mechanisms
Pterostilbene has been noted to inhibit LPS-induced PGE2 production from white blood cells with an IC50 value of 1.0+/-0.6µM (compared to the IC50 of resveratrol at 3.2+/-1.4µM)[3] and can inhibit iNOS activity in macrophages with an IC50 of 9.9µg/mL (comparable to resveratrol and weaker than parthenolide from feverfew at 0.42µg/mL).[14]
Pterostilbene may exert antiinflammatory effects at low concentrations with a potency greater than resveratrol; these effects may be relevant to oral supplementation of higher doses of pterostilbene
Neutrophils are known to produce oxidation when activated via the NADPH oxidase enzyme[37] which may lead to injury in excessive levels (despite being protective against bacterial invaders at lower activity);[38] resveratrol has previously been implicated as an NADPH oxidase inhibitor, and this activity appears to extend to pterostilbene as it can reduce chemiluminescence of neutrophils (an indication of antioxidant activity[39]).[40] And while pterostilbene doesn't inherently affect superoxide levels in neutrophils,[41] 100µM is able to reduce superoxide production and subsequent myeloperoxidase (MPO) production to around 60% of control with lower concentrations ineffective.[41]
When comparing potencies, pterostilbene appears to be less effective than resveratrol[42] (assessed by IC50 values of reducing extracellular chemiluminescence) with pterostilbene also being less potent than piceatannol, and the potency of curcumin lying between resveratrol and piceatannol.[43][40][44] When looking at intracellular chemiluminescence, curcumin seems most potent (IC50 3.57µM to pterostilbene's 21.58µM) and resveratrol is intermediate to the two.[42]
Reduced chemiluminescence has been noted in rats following ingestion of 30mg/kg pterostilbene (partial reduction), suggesting that the above is biologically relevant in higher doses to a small degree.[45]
Pterostilbene appears to reduce oxidation in neutrophils (the main mechanism of action of spirulina), although the effect seems to occur only at very high concentrations. It appears to be active following oral ingestion, but not to a large degree
6.2
Joint Inflammation
30mg/kg pterostilbene in a rat model of arthritis has shown weak anti-inflammatory effects, having no significant effect on hind paw volume (a marker of edema) or MPO while minorly reducing chemiluminescence (a marker of neutrophil oxidation).[45]
Current preliminary evidence suggests no significant benefit of pterostilbene on inflammation, just a minor antioxidative effect
7.
Interactions with Cancer Metabolism
7.1
Lung
Resveratrol has previously been noted to increase apoptosis via the Notch signalling pathway[46][47] (which induces Cyclin D1 and survivin as it is prosurvival[48][49]) which appears to extend to pterostilbene in lung cancer cells (A549) with an IC50 value on cell growth of 3.476µM.[50] Pterostilbene appears to reduce the Notch1-dependent survial while induces production of reactive oxygen species, leading to apoptosis.[50]
Pterostilbene appears to reduce viability of lung cancer cells in vitro, and does so at a concentration that is probably relevant to oral supplementation
8.
Longevity and Life Extension
8.1
Mechanisms
Pterostilbene (70μM) has been noted to upregulate a variety of mitochondrial genes in a yeast assay (148 up and 13 downregulated) involved in respiration, electron transport, mitochondrial protein targeting, and mitochondrial protein synthesis.[51]
The oxidative stress seen during the aging process in neurons appears to be attenuated with low dietary levels of pterostilbene (0.004-0.016% of the diet), with a potency greater than resveratrol.[31][52]
9.
Safety and Toxicology
9.1
General
In mice, doses of pterostilbene up to 3,000mg/kg daily (500-fold the estimated human intake) have failed to exert any significant clinical or biochemical toxicity.[53]
Pterostilbene up to 250mg daily (125mg twice daily) in humans over the course of 6-8 weeks has failed to cause any biochemical or clinical signs of toxicity, with side effects not significantly different than placebo aside from one dropout due to worsening cholesterol[54] which may be related to an increase in LDL-C seen with this dose when tested elsewhere in hypercholesterolemic adults.[32]
References
- ^McCormack D, McFadden DA review of pterostilbene antioxidant activity and disease modificationOxid Med Cell Longev.(2013)
- ^Rimando AM, Kalt W, Magee JB, Dewey J, Ballington JRResveratrol, pterostilbene, and piceatannol in vaccinium berriesJ Agric Food Chem.(2004 Jul 28)
- ^Hougee S, Faber J, Sanders A, de Jong RB, van den Berg WB, Garssen J, Hoijer MA, Smit HFSelective COX-2 inhibition by a Pterocarpus marsupium extract characterized by pterostilbene, and its activity in healthy human volunteersPlanta Med.(2005 May)
- ^Langcake PDisease resistance of Vitis spp. and the production of the stress metabolites resveratrol, epsiton-viniferin, alpha-viniferin and pterostilbenePhysiol Plant Pathol.(1981 Mar)
- ^Alessandro M, Di Marco S, Osti F, Cesari ABioassays on the Activity of Resveratrol, Pterostilbene and Phosphorous Acid towards Fungi Associated with Esca of GrapevinePytopathol Mediterr.(2000)
- ^Langcake P, Cornford CA, Pryce RJIdentification of pterostilbene as a phytoalexin from Vitis vinifera leavesPhytochem.(1979)
- ^Maurya R, Singh R, Deepak M, Handa SS, Yadav PP, Mishra PKConstituents of Pterocarpus marsupium: an ayurvedic crude drugPhytochemistry.(2004 Apr)
- ^Seshadri TRPolyphenols of Pterocarpus and Dalbergia woodsPhytochem.(1972 Mar)
- ^Rodríguez-Bonilla P, López-Nicolás JM, Méndez-Cazorla L, García-Carmona FDevelopment of a reversed phase high performance liquid chromatography method based on the use of cyclodextrins as mobile phase additives to determine pterostilbene in blueberriesJ Chromatogr B Analyt Technol Biomed Life Sci.(2011 May 1)
- ^Adrian M, Jeandet P, Douillet-Breuil AC, Tesson L, Bessis RStilbene content of mature Vitis vinifera berries in response to UV-C elicitationJ Agric Food Chem.(2000 Dec)
- ^Rimando AM, Pezzuto JM, Farnsworth NR, Santisuk T, Reutrakul VRevision of the NMR Assignments of Pterostilbene and of Dihydrodehydrodiconieferyl alcohol: Cytotoxic Constituents from Anogeissus acuminataNat Prod Lett.(1994)
- ^Fan LL, Tu PF, Chen HB, Cai SQSimultaneous quantification of five major constituents in stems of Dracaena plants and related medicinal preparations from China and Vietnam by HPLC-DADBiomed Chromatogr.(2009 Nov)
- ^Püssa T, Raudsepp P, Kuzina K, Raal APolyphenolic composition of roots and petioles of Rheum rhaponticum LPhytochem Anal.(2009 Mar-Apr)
- ^Sobolev VS, Khan SI, Tabanca N, Wedge DE, Manly SP, Cutler SJ, Coy MR, Becnel JJ, Neff SA, Gloer JBBiological activity of peanut (Arachis hypogaea) phytoalexins and selected natural and synthetic StilbenoidsJ Agric Food Chem.(2011 Mar 9)
- ^Ovesná Z, Horváthová-Kozics KStructure-activity relationship of trans-resveratrol and its analoguesNeoplasma.(2005)
- ^Hasiah AH, Ghazali AR, Weber JF, Velu S, Thomas NF, Inayat Hussain SHCytotoxic and antioxidant effects of methoxylated stilbene analogues on HepG2 hepatoma and Chang liver cells: Implications for structure activity relationshipHum Exp Toxicol.(2011 Feb)
- ^Cheng JC, Fang JG, Chen WF, Zhou B, Yang L, Liu ZLStructure-activity relationship studies of resveratrol and its analogues by the reaction kinetics of low density lipoprotein peroxidationBioorg Chem.(2006 Jun)
- ^Stivala LA, Savio M, Carafoli F, Perucca P, Bianchi L, Maga G, Forti L, Pagnoni UM, Albini A, Prosperi E, Vannini VSpecific structural determinants are responsible for the antioxidant activity and the cell cycle effects of resveratrolJ Biol Chem.(2001 Jun 22)
- ^Kapetanovic IM, Muzzio M, Huang Z, Thompson TN, McCormick DLPharmacokinetics, oral bioavailability, and metabolic profile of resveratrol and its dimethylether analog, pterostilbene, in ratsCancer Chemother Pharmacol.(2011 Sep)
- ^Athar M, Back JH, Tang X, Kim KH, Kopelovich L, Bickers DR, Kim ALResveratrol: a review of preclinical studies for human cancer preventionToxicol Appl Pharmacol.(2007 Nov 1)
- ^Thatiparti TR, Shoffstall AJ, von Recum HACyclodextrin-based device coatings for affinity-based release of antibioticsBiomaterials.(2010 Mar)
- ^López-Nicolás JM, Rodríguez-Bonilla P, Méndez-Cazorla L, García-Carmona FPhysicochemical study of the complexation of pterostilbene by natural and modified cyclodextrinsJ Agric Food Chem.(2009 Jun 24)
- ^Yeo SC, Ho PC, Lin HSPharmacokinetics of pterostilbene in Sprague-Dawley rats: The impacts of aqueous solubility, fasting, dose escalation, and dosing route on bioavailabilityMol Nutr Food Res.(2013 Jun)
- ^Wen X, Walle TMethylated flavonoids have greatly improved intestinal absorption and metabolic stabilityDrug Metab Dispos.(2006 Oct)
- ^Lin HS, Yue BD, Ho PCDetermination of pterostilbene in rat plasma by a simple HPLC-UV method and its application in pre-clinical pharmacokinetic studyBiomed Chromatogr.(2009 Dec)
- ^Lin VC, Tsai YC, Lin JN, Fan LL, Pan MH, Ho CT, Wu JY, Way TDActivation of AMPK by pterostilbene suppresses lipogenesis and cell-cycle progression in p53 positive and negative human prostate cancer cellsJ Agric Food Chem.(2012 Jun 27)
- ^Carey AN, Fisher DR, Rimando AM, Gomes SM, Bielinski DF, Shukitt-Hale BStilbenes and Anthocyanins Reduce Stress Signaling in BV-2 Mouse MicrogliaJ Agric Food Chem.(2013 Jun 13)
- ^Meng XL, Yang JY, Chen GL, Wang LH, Zhang LJ, Wang S, Li J, Wu CFEffects of resveratrol and its derivatives on lipopolysaccharide-induced microglial activation and their structure-activity relationshipsChem Biol Interact.(2008 Jul 10)
- ^Al Rahim M, Rimando AM, Silistreli K, El-Alfy ATAnxiolytic Action of Pterostilbene: Involvement of Hippocampal ERK PhosphorylationPlanta Med.(2013 Jun)
- ^Einat H, Yuan P, Gould TD, Li J, Du J, Zhang L, Manji HK, Chen GThe role of the extracellular signal-regulated kinase signaling pathway in mood modulationJ Neurosci.(2003 Aug 13)
- ^Joseph JA, Fisher DR, Cheng V, Rimando AM, Shukitt-Hale BCellular and behavioral effects of stilbene resveratrol analogues: implications for reducing the deleterious effects of agingJ Agric Food Chem.(2008 Nov 26)
- ^Riche DM1, Riche KD2, Blackshear CT3, McEwen CL4, Sherman JJ5, Wofford MR6, Griswold ME7Pterostilbene on metabolic parameters: a randomized, double-blind, and placebo-controlled trialEvid Based Complement Alternat Med.(2014)
- ^Rimando AM, Nagmani R, Feller DR, Yokoyama WPterostilbene, a new agonist for the peroxisome proliferator-activated receptor alpha-isoform, lowers plasma lipoproteins and cholesterol in hypercholesterolemic hamstersJ Agric Food Chem.(2005 May 4)
- ^Mizuno CS, Ma G, Khan S, Patny A, Avery MA, Rimando AMDesign, synthesis, biological evaluation and docking studies of pterostilbene analogs inside PPARalphaBioorg Med Chem.(2008 Apr 1)
- ^Pari L, Satheesh MAEffect of pterostilbene on hepatic key enzymes of glucose metabolism in streptozotocin- and nicotinamide-induced diabetic ratsLife Sci.(2006 Jul 10)
- ^Manickam M, Ramanathan M, Jahromi MA, Chansouria JP, Ray ABAntihyperglycemic activity of phenolics from Pterocarpus marsupiumJ Nat Prod.(1997 Jun)
- ^El-Benna J, Dang PM, Gougerot-Pocidalo MAPriming of the neutrophil NADPH oxidase activation: role of p47phox phosphorylation and NOX2 mobilization to the plasma membraneSemin Immunopathol.(2008 Jul)
- ^Babior BMPhagocytes and oxidative stressAm J Med.(2000 Jul)
- ^Jancinová V, Drábiková K, Nosál R, Racková L, Májeková M, Holománová DThe combined luminol/isoluminol chemiluminescence method for differentiating between extracellular and intracellular oxidant production by neutrophilsRedox Rep.(2006)
- ^Perecko T, Jancinova V, Drabikova K, Nosal R, Harmatha JStructure-efficiency relationship in derivatives of stilbene. Comparison of resveratrol, pinosylvin and pterostilbeneNeuro Endocrinol Lett.(2008 Oct)
- ^Mačičková T, Pečivová J, Harmatha J, Sviteková K, Nosáľ REffect of stilbene derivative on superoxide generation and enzyme release from human neutrophils in vitroInterdiscip Toxicol.(2012 Jun)
- ^Drábiková K, Perečko T, Nosáľ R, Harmatha J, Smidrkal J, Jančinová VPolyphenol derivatives - potential regulators of neutrophil activityInterdiscip Toxicol.(2012 Jun)
- ^Jancinová V, Perecko T, Nosál R, Kostálová D, Bauerová K, Drábiková KDecreased activity of neutrophils in the presence of diferuloylmethane (curcumin) involves protein kinase C inhibitionEur J Pharmacol.(2009 Jun 10)
- ^Nosal R, Perecko T, Jancinova V, Drabikova K, Harmatha J, Svitekova KSuppression of oxidative burst in human neutrophils with the naturally occurring serotonin derivative isomer from Leuzea carthamoidesNeuro Endocrinol Lett.(2010)
- ^Macickova T, Drabikova K, Nosal R, Bauerova K, Mihalova D, Harmatha J, Pecivova JIn vivo effect of pinosylvin and pterostilbene in the animal model of adjuvant arthritisNeuro Endocrinol Lett.(2010)
- ^Lin H, Xiong W, Zhang X, Liu B, Zhang W, Zhang Y, Cheng J, Huang HNotch-1 activation-dependent p53 restoration contributes to resveratrol-induced apoptosis in glioblastoma cellsOncol Rep.(2011 Oct)
- ^Truong M, Cook MR, Pinchot SN, Kunnimalaiyaan M, Chen HResveratrol induces Notch2-mediated apoptosis and suppression of neuroendocrine markers in medullary thyroid cancerAnn Surg Oncol.(2011 May)
- ^Meng RD, Shelton CC, Li YM, Qin LX, Notterman D, Paty PB, Schwartz GKgamma-Secretase inhibitors abrogate oxaliplatin-induced activation of the Notch-1 signaling pathway in colon cancer cells resulting in enhanced chemosensitivityCancer Res.(2009 Jan 15)
- ^Chen Y, Li D, Liu H, Xu H, Zheng H, Qian F, Li W, Zhao C, Wang Z, Wang XNotch-1 signaling facilitates survivin expression in human non-small cell lung cancer cellsCancer Biol Ther.(2011 Jan 1)
- ^Yang Y, Yan X, Duan W, Yan J, Yi W, Liang Z, Wang N, Li Y, Chen W, Yu S, Jin Z, Yi DPterostilbene exerts antitumor activity via the Notch1 signaling pathway in human lung adenocarcinoma cellsPLoS One.(2013 May 3)
- ^Pan Z, Agarwal AK, Xu T, Feng Q, Baerson SR, Duke SO, Rimando AMIdentification of molecular pathways affected by pterostilbene, a natural dimethylether analog of resveratrolBMC Med Genomics.(2008 Mar 20)
- ^Chang J, Rimando A, Pallas M, Camins A, Porquet D, Reeves J, Shukitt-Hale B, Smith MA, Joseph JA, Casadesus GLow-dose pterostilbene, but not resveratrol, is a potent neuromodulator in aging and Alzheimer's diseaseNeurobiol Aging.(2012 Sep)
- ^Ruiz MJ, Fernández M, Picó Y, Mañes J, Asensi M, Carda C, Asensio G, Estrela JMDietary administration of high doses of pterostilbene and quercetin to mice is not toxicJ Agric Food Chem.(2009 Apr 22)
- ^Riche DM, McEwen CL, Riche KD, Sherman JJ, Wofford MR, Deschamp D, Griswold MAnalysis of safety from a human clinical trial with pterostilbeneJ Toxicol.(2013)