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J Ethnopharmacol.1999 Dec 15;68(1-3):71-6.

Occurrence of resveratrol and pterostilbene in age-old darakchasava, an ayurvedic medicine from India.

Paul B1, Masih I, Deopujari J, Charpentier C.

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‘Darakchasava’ is a well known Indian herbal preparation of which the main ingredient is Vitis vinifera L. This ‘ayurvedic’ medicine is prescribed as a cardiotonic and also given for other disorders. HPLC analysis of this age old formulation revealed the presence of polyphenols like resveratrol and pterostilbene. These phenolic compounds are now known as antioxidants, cancer chemopreventive agents, and also known to reduce mortality from coronary heart disease by increasing high density lipoproteins like cholesterol and inhibiting platelet aggregation (Soleas, J.S., Diamandis, E.P., Goldberg, D.M., 1997. Resveratrol: a molecule whose time has come? and gone? Clin. Biochem. 30 (2), 91-113). The study of darakchasava becomes interesting in the light of these findings. A brief introduction of this medicinal preparation, its formulation, its analysis by HPLC, and some of its properties are discussed in this article.

PMID: 10624864

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

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

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

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

PMID: 24831090

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 and TNF-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

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.

Copyright © 2014 Elsevier Ltd. All rights reserved.

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

PMID: 25111660

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 are being 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 secondary screening, 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. Molecular analysis 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

Pharmacol Rep.2015 Dec;67(6):1264-72. doi: 10.1016/j.pharep.2015.05.009. Epub 2015 May 30.

A pterostilbene derivative suppresses osteoclastogenesis by regulating RANKL-mediated NFκB and MAPK signaling in RAW264.7 cells.

Nikhil K1,Sharan S1, Roy P2.

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BACKGROUND: A dysfunctional osteoclast activity is often the cause of bone destructive diseases, such as osteoporosis, periodontitis, erosive arthritis, and cancer. The NFκB ligand (RANKL) has been identified as a major mediator of bone resorption. Agents that suppress RANKL signaling have the potential to inhibit bone resorption or osteoclastogenesis. The present study aimed to determine the effect of a pterostilbene derivative (PTERC-T) for suppressing RANKL or tumor cells-induced osteoclastogenesis in RAW264.7 murine macrophages.

METHODS: Cytotoxicity was measured by MTT assay and inhibitory effect on osteoclastogenesis was analyzed by counting the number of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells and measuring the expression levels of the osteoclast-specific genes. The reactive oxygen species (ROS) generation was detected by FACS. Further, signaling pathways were analyzed by immunofluorescence and immunoblot analyses.

RESULTS: PTERC-T suppressed the differentiation of monocytes to osteoclasts in a dose and time-dependent manner. The expression of osteoclast marker genes like TRAP, cathepsin K (CTSK), matrix metalloproteinase 9 (MMP9) and transcription factors c-Fos, and nuclear factor of activated T cells cytoplasmic 1 (NFATc1) were also diminished by PTERC-T. PTERC-T scavenged intracellular ROS generation within osteoclast precursors during RANKL-stimulated osteoclastogenesis. Mechanistically, PTERC-T abrogated the phosphorylation of MAPKs (ERK and JNK) and inhibited RANKL-induced activation of NFκB by suppressing IκBα phosphorylation and preventing NFκB/p65 nuclear translocation.

CONCLUSIONS: This study thus identifies PTERC-T as an inhibitor of osteoclast formation and provides evidence for its role in preventing osteoporosis and other bone related disorders. However, further studies are needed to establish its efficacy in vivo.

Copyright © 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

KEYWORDS: MAPK; NFκB; Osteoclastogenesis; PTERC-T; RANKL

PMID: 26481551

Pterostilbene is a naturally-occurring phytoalexin identified in several plant species. It belongs to a group of phenolic compounds known as stilbenes, and is found in the heartwood of sandalwood (Pterocarpus santalinus) [1] and P. marsupium [2]. It was also identified in the leaves of Vitis vinifera [3], in infected grape berries of var. Chardonnay and Gamay [4], and in healthy and immature berries of var. Pinot Noir and Gamay [5]. Pterostilbene has also been found in berries of some Vacciunium species [5]. Pterostilbene, one of the most extensively studied secondary metabolites found in grapes and wine, is a dimethylether analog of resveratrol that is well known for its hypolipidemic activity. A considerable amount of research effort has been expended to address the biochemical and physiological effects of pterostilbene in animal and microbial systems. For example, the antioxidative activity of pterostilbene was first demonstrated in vitro by its inhibition of methyl linoleate oxidation [6]. Pterostilbene was reported to scavenge 1,1-diphenyl-2-picryl-hydrazyl (DPPH) free radicals and to inhibit the oxidation of citronellal, and lipid peroxidation in rat liver microsomes and in cultured human fibroblasts [7]. Pterostilbene isolated from Anogeissus acuminata (Family Combretaceae) is cytotoxic against a number of cancer cell lines, including human breast cancer and murine lymphoid neoplasma cells [8,9]. More recently, it has been demonstrated that pterostilbene can reduce cholesterol levels in vivo in hamsters through the activation of the peroxisome proliferator-activated receptor α (PPARα) [10]. Pterostilbene has been reported to reduce glucose and increase plasma insulin levels significantly in normal and diabetic rats [11]. Furthermore, pterostilbene has been shown to be cancer-chemopreventive [8,12] and anti-inflammatory [13].

Investigation of the pathogen-host interactions of Vitis vinifera has led to the hypothesis that resistance is not due to preformed physical or chemical factors, but rather to an active defense mechanism that is triggered by the pathogen, of which stress metabolites including resveratrol, α-viniferin and ε-viniferin are an important component [14]. Pterostilbene, produced in leaf tissues by various species of the Vitaceae family following fungal infection, proved to have more potent antifungal activity than resveratrol (reviewed in [3,15,16]). However, the mechanism by which pterostilbene inhibits fungi is not well understood. Results from early studies suggested that the biological activities of the compound mainly involved effects on the plasma membrane [5,17], and destruction of ribosomes, endoplasmic reticulum, and mitochondrial membranes [17]. Further information on its precise mechanism of action would be useful not only for its potential development as a drug, but also in understanding its ecological significance to producing plant species. In the present study, using transcript profiling analysis, we monitored the gene expression profile of yeast cells treated with pterostilbene in an effort to identify the molecular pathways affected by this compound.