Piceatannol Protects Brain Endothelial Cell Line (bEnd.3) against Lipopolysaccharide-Induced Inflammation and Oxidative Stress

Dysfunction of the blood–brain barrier (BBB) is involved in the pathogenesis of many cerebral diseases. Oxidative stress and inflammation are contributing factors for BBB injury. Piceatannol, a natural ingredient found in various plants, such as grapes, white tea, and passion fruit, plays an important role in antioxidant and anti-inflammatory responses. In this study, we examined the protective effects of piceatannol on lipopolysaccharide (LPS) insult in mouse brain endothelial cell line (bEnd.3) cells and the underlying mechanisms. The results showed that piceatannol mitigated the upregulated expression of adhesion molecules (ICAM-1 and VCAM-1) and iNOS in LPS-treated bEnd.3 cells. Moreover, piceatannol prevented the generation of reactive oxygen species in bEnd.3 cells stimulated with LPS. Mechanism investigations suggested that piceatannol inhibited NF-κB and MAPK activation. Taken together, these observations suggest that piceatannol reduces inflammation and oxidative stress through inactivating the NF-κB and MAPK signaling pathways on cerebral endothelial cells in vitro.     

Dose-dependent effect of resveratrol on proliferation and apoptosis in endothelial and tumor cell cultures

Experimental data suggest that Resveratrol, a compound found in grapes and other fruits may influence cell proliferation and apoptosis. The aim of our experiments was to study the effect of Resveratrol on tumor cell cultures and an endothelial cell culture in order to examine the effect of various doses of this compound on active cell death and cell proliferation. Human tumor (HT-29, SW-620, HT-1080) and endothelial (HUV-EC-C) cells were treated with various doses of (0.1 to 100.0 microg/ml) Resveratrol in vitro. Cell number, apoptotic and mitotic index was measured 24, 48 and 72 h after treatment. Low doses (0.1-1.0 microg/ml) of Resveratrol enhance cell proliferation, higher doses (10.0-100.0 microg/ml) induce apoptosis and decrease mitotic activity, which is reflected in changes of cell number. Resveratrol influences dose dependently the proliferative and apoptotic activity of human tumor and endothelial cells. The possible role of formaldehyde in the mechanism of action of Resveratrol is discussed.     

Antioxidant constituents of Caragana tibetica

Caragana tibetica KOM. (Fabaceae) is a medicinal plant that has been traditionally used in western part of China. In the course of our screening study on antioxidant activity of medicinal plants, the 70% acetone extract of the stems of C. tibetica was found to have a potent superoxide anion scavenging activity. Tibeticanol (1), a new piceatannol dimer possessing antioxidant activity, was isolated along with eleven known aromatic compounds. Their structures were elucidated on the basis of NMR and MS data. Enzyme oxidation of monomeric stilbene, piceatannol (3), with horseradish peroxidase and hydrogen peroxide yielded cassigarol E (5) and G (6) as major products. Most of the isolated compounds exhibited superoxide anion scavenging activity.     

Determination of piceatannol in rat serum and liver microsomes: pharmacokinetics and phase I and II biotransformation

A method of analysis of piceatannol in biological fluids is necessary to study the kinetics of in vitro and in vivo metabolism and determine its concentration in foodstuffs. A novel and simple high-performance liquid chromatographic method was developed for simultaneous determination of piceatannol and products of its metabolism in rat serum and liver microsomes. Serum, or microsomes (0.1 mL), were precipitated with acetonitrile after addition of the internal standard, 4-methylumbelliferone. Separation was achieved on a phenomenex C(18) column (250 x 4.6 mm i.d., 5 microm) equipped with a phenomenex C(18) (4 x 3.0 mm i.d., 5 microm) guardcolumn with fluorescence excitation at 320 nm and emission at 420 nm. Separation was also possible with UV detection at 310 nm. The fluorescent calibration curves were linear ranging from 0.05 to 100 microg/mL. The mean extraction efficiency was >95%. Precision of the assay was <10% (coefficient of variation), and was within 10% at the limit of quantitation (0.05 ng/mL). Bias of the assay was lower than 7%. The limit of detection was 50 ng/mL for a 0.1 mL sample. The assay was applied successfully to the in vitro kinetic study of metabolism of piceatannol in rat liver microsomes and pharmacokinetics in rats. Three metabolites of piceatannol have been identified. .     

Comparison of Ferroptosis-Inhibitory Mechanisms between Ferrostatin-1 and Dietary Stilbenes (Piceatannol and Astringin)

Synthetic arylamines and dietary phytophenolics could inhibit ferroptosis, a recently discovered regulated cell death process. However, no study indicates whether their inhibitory mechanisms are inherently different. Herein, the ferroptosis-inhibitory mechanisms of selected ferrostatin-1 (Fer-1) and two dietary stilbenes (piceatannol and astringin) were compared. Cellular assays suggested that the ferroptosis-inhibitory and electron-transfer potential levels decreased as follows: Fer-1 >> piceatannol > astringin; however, the hydrogen-donating potential had an order different from that observed by the antioxidant experiments and quantum chemistry calculations. Quantum calculations suggested that Fer-1 has a much lower ionization potential than the two stilbenes, and the aromatic N-atoms were surrounded by the largest electron clouds. By comparison, the C4′O-H groups in the two stilbenes exhibited the lowest bond disassociation enthalpies. Finally, the three were found to produce corresponding dimer peaks through ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry analysis. In conclusion, Fer-1 mainly depends on the electron transfer of aromatic N-atoms to construct a redox recycle. However, piceatannol and astringin preferentially donate hydrogen atoms at the 4′-OH position to mediate the conventional antioxidant mechanism that inhibits ferroptosis, and to ultimately form dimers. These results suggest that dietary phytophenols may be safer ferroptosis inhibitors for balancing normal and ferroptotic cells than arylamines with high electron-transfer potential.     

A study of resveratrol-copper complexes by electrospray ionization mass spectrometry and density functional theory calculations

Resveratrol is a polyphenolic compound found in plants and human foods which has shown biological activities including chemoprevention, acting through a mechanism which involves the reduction of Cu(II) species. By electrospray ionization (ESI) mass spectrometry we have produced and detected the resveratrol-copper complexes [Resv+Cu](+), [Resv+Cu+H(2)O](+) and [2Resv+Cu](+) by using a resveratrol/CuSO(4) solution in CH(3)CN/H(2)O. The most stable structures of the detected complexes have been calculated at the B3LYP/6-311G(d) level of theory. Resveratrol interacts with the copper ion through nucleophilic carbon atoms on the aromatic ring and the alkenyl group. The fact that only singly charged ions were observed implies that Cu(II) is reduced to Cu(I) in the ESI process. For investigating the structure-reactivity correlation, we have carried out a similar study on the synthetic analogue dihydroresveratrol (DHResv). For the latter only the [DHResv+Cu](+) complex has been detected.     

Resveratrol in management of bone and spinal cancers

Bone cancer is a malignant primary tumour of the bone with different typing, such as, osteosarcoma, chondrosarcoma, Ewing’s sarcoma and fibrosarcoma. Despite the clinical efficacy of conventional therapies of bone cancer, most patients eventually relapse and the disease remains incurable. Therefore, new therapeutic strategies are needed to improve patient outcome. In this review article, we have discussed the role of resveratrol in preventing bone and spinal cancers and therapeutics. Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is a natural polyphenol, which has been widely reported as an anticancer molecule. Resveratrol exhibits multiple tumour-suppressing activities in bone cancer by affecting a series of critical events. It has the protective effects against oxidative injury, possesses antiproliferative activity and induces apoptosis in cancer cells. Resveratrol might be a good option for the treatment of different types of bone and spinal cancers.     

The Role of Resveratrol in Human Male Fertility

Resveratrol (RSV) (3,4′,5 trihydroxystilbene) is a natural non-flavonoid polyphenol widely present in the Mediterranean diet. In particular, RSV is found in grapes, peanuts, berries, and red wine. Many beneficial effects of this molecule on human health have been reported. In fact, it improves some clinical aspects of various diseases, such as obesity, tumors, hypertension, Alzheimer’s disease, stroke, cardiovascular diseases, and diabetes mellitus. However, little is known about the relationship between this compound and male fertility and the few available results are often controversial. Therefore, this review evaluated the effects of RSV on human male fertility and the mechanisms through which this polyphenol could act on human spermatozoa.     

Chromatographic Analysis of Trans Resveratrol in Italian Wines: Comparisons between FL, UV and MS Detection

Resveratrol (3,5,4′-trihydroxystilbene) is a phytoalexin that belongs to the group of stilbenes, known to occur in grapes and consequently in grape products. Its presence in wine is an important qualitative parameter because of the several beneficial effects on human health. The aim of this work is the development of a high-performance liquid chromatographic (HPLC) method for the determination of trans resveratrol in wines, and comparisons between the results obtained by different detection techniques: UV-vis spectroscopy, fluorescence spectroscopy and mass spectrometry. Resveratrol is analysed on a C-18 column using gradient elution. The method permits direct injection of sample, revealing to be time-saving, overcoming the need of sample pre-treatment steps. Detection limits were 154.8 ng mL⁻¹ by HPLC-UV, 118.0 ng mL⁻¹ by HPLC-FL and 48.0 ng mL⁻¹ by HPLC-MS. Trans resveratrol has been then quantified in a group of 52 wines derived from different Italian regions, cultivars and winemaking technologies by HPLC-UV.     

Enzymatic Activation of the Emerging Drug Resveratrol

The plant originated stilbene “resveratrol” (3,4′,5-trans-trihydroxystilbene) is well known for its diverse health benefits including anti-tumor, anti-inflammatory, anti-microbial, and anti-oxidant properties. Besides a significant amount of reports on different aspects of its application as prodrug in the last 50 years, still, a strategy leading to the production of the active drug is missing. The aim of this work was to evaluate the enzymatic activation of prodrug resveratrol to the effective drug piceatannol, without engaging expensive cofactors. Five different heme proteins were analyzed for the transformation of resveratrol. Kinetic parameters of resveratrol transformation and analysis of the transformed products were conducted through HPLC and GC-MS. Effect of pH and organic solvent on the transformation process had also been evaluated. Among all tested heme proteins, only a variant of cytochrome P450_BM3 from Bacillus megaterium (CYP_BM3F87A) was found suitable for piceatannol production. The most suitable pH for the reaction conditions was 8.5, while organic solvents did not show any effect on transformation. For resveratrol transformation, the turnover rate (k _cat) was 21.7 (± 0.6) min^?1, the affinity constant (K _M) showed a value of 55.7 (± 16.7) μM for a catalytic efficiency (k _cat/K _M) of 389 min^?1 mM^?1. GC-MS analysis showed that the only product from resveratrol transformation by cytochrome P450_BM3 is the biologically active piceatannol. The enzymatic transformation of resveratrol, an emerging compound with medical interest, to active product piceatannol by a variant of cytochrome P450_BM3 in the absence of expensive NADPH cofactor is demonstrated. This enzymatic process is economically attractive and can be scaled up to cover the increasing medical demand for piceatannol.     

Liquid chromatographic/electrospray ionization mass spectrometric identification of the oxidation end‐products of trans‐resveratrol in aqueous solutions

trans‐Resveratrol (3,5,4′‐trihydroxystilbene) is a natural polyphenolic compound that exhibits antioxidant properties. Our study aimed at studying the HO ^. ‐induced oxidation of resveratrol (100 µmol.L^?1) in aerated aqueous solutions. Gamma radiolysis of water was used to generate HO ^. /O free radicals (I = 10 Gy.min^?1, dose = 400 Gy). Oxidation products were identified by direct infusion mass spectrometry and high‐performance liquid chromatography/mass spectrometry. For each product, structural elucidation was based on simple mass spectra, fragmentation spectra and deuterium/hydrogen exchange spectra; the comparison with mass spectra of synthetic products provided valuable information allowing the complete identification of the oxidation products. Four products resulting from the direct attack of HO ^. radicals towards resveratrol were identified respectively as piceatannol (trans‐3,5,3′,4′‐tetrahydroxystilbene), 3,5‐dihydroxybenzoic acid, 3,5‐dihydroxybenzaldehyde and 4‐hydroxybenzaldehyde. Copyright © 2010 John Wiley & Sons, Ltd.     

白藜芦醇结构修饰及药理活性

从自然界中寻找活性先导化合物,再进行结构修饰,以提高化合物的活性和降低毒性是目前创新药物的一条重要思路。白藜芦醇是在葡萄等植物中广泛存在的植物抗毒素,对人类目前的疾病如肿瘤、心血管疾病、神经退行性疾病和病毒感染等具有良好的预防作用,是一种具有开发潜力的先导化合物。近年来越来越多的科学家对其进行结构改造以得到高活性化合物,例如对双键、苯环的修饰。本文就目前对白藜芦醇修饰及其药理活性进行阐述和讨论。     

Application of β-Glucosidase in a Biphasic System for the Efficient Conversion of Polydatin to Resveratrol

Resveratrol, an ingredient of traditional Chinese medicine, has beneficial effects on human health and huge potential for application in modern medicine. Polydatin is extracted from plants and then deglycosylated into resveratrol; enzymatic methods are preferred for this reaction. In this study, a β-D-glucosidase from Sphingomonas showed high efficiency in transforming polydatin into resveratrol and was tolerant toward organic solvents. Applying this enzyme in a biphasic transformation system resulted in 95.3% conversion of 20% concentration crude polydatin to resveratrol in 4 h. We thus report a new method for high-efficiency, clean production of resveratrol.     

Theoretical investigation of the electronic absorption spectrum of Piceatannol in methanolic solution

In the current work, we use a combination of Monte Carlo (MC) simulation and the Intermediate Neglect of Differential Overlap/Spectroscopic-Configuration Interaction (INDO/S–CI) scheme to investigate the solvent effects on the electronic absorption spectrum of piceatannol molecule in methanolic solution. The investigation was conducted by carrying out a posteriori INDO/S–CI calculations on 125 statistically relevant configurations produced by the MC simulation. Furthermore, a careful study of hydrogen bonds formed in the course of the MC simulation was performed. In general, our results are in very good agreement with the available experimental result.     

Modeling of the inclusive complexation of natural drug trans 3,5,3′,4′-tetrahydroxystilbene with β-cyclodextrin

In this study, the complexation of trans 3,5,3′,4′-tetrahydroxystilbene, also known as piceatannol (PIC), with β-cyclodextrin (β-CD) was investigated using the semi-empirical PM3 method in vacuum. Two orientations were assessed for the encapsulation of piceatannol in the cavity of β-cyclodextrin. The orientation in which the A aromatic ring of PIC was directed toward the inner cavity of β-CD was named ‘A’ and that in which the B aromatic ring is located inside the β-CD cavity was named ‘B’. The results indicated that both orientations were favorable for the complexation of PIC/β-CD. Indeed, the energy difference between the two orientations was less than 1 kcal/mol. Additionally, the negative interaction energies obtained for a 1:1 stoichiometry suggest that the complexation process is exothermic and indicate that the PIC/β-CD complex was highly stable and enthalpically driven. HOMO and LUMO investigations confirmed these results.     

One-pot palladium-catalyzed highly chemo-, regio-, and stereoselective synthesis of trans-stilbene derivatives. A concise and convenient synthesis of resveratrol

A convenient, efficient and highly chemo-, regio-, and stereoselective one-flask synthetic method is reported for the construction of unsymmetrical (or symmetrical) trans-stilbene derivatives based on two sequential Heck-type reactions using tetraalkylammonium salt-based catalyst systems and vinyltrimethylsilane as double bond equivalents. Resveratrol has thus been concisely synthesized.     

Rapid separation of three glucosylated resveratrol analogues from the invasive plant Polygonum cuspidatum by high‐speed countercurrent chromatography

Three glucosylated resveratrol analogues (piceid, piceatannol glucoside, resveratroloside) were successfully isolated from the crude MeOH extract of the invasive plant species Polygonum cuspidatum by semi‐preparative high‐speed countercurrent chromatography with a two‐phase solvent system composed of cyclohexane‐ethyl acetate‐methanol‐water (1:5:1:5, v/v/v/v). Piceid (23 mg), resveratroloside (17 mg), piceatannol glucoside (15 mg) of purities over 80% were isolated from 500 mg crude MeOH extract in one step. Subsequent passage over a SPE column was used to quickly bring their purities to over 90%. The purities were determined by HPLC analysis and their structures were elucidated by proton nuclear magnetic resonance (¹H‐NMR), HMBC, ESI‐MS and HR‐MS.     

Analysis of trans-Resveratrol in Grapes by Micro-High Performance Liquid Chromatography

Resveratrol, existing in two isomeric trans-and cis-forms, is a phytoalexin that has pharmacological activities, like anti-cancer and anti-cardiovascular diseases as well as life-span increasing properties. Grapes are good sources for resveratrol introduction in the human diet not only directly, but also through its products: wine. In the present work, trans-resveratrol determination and the separation of resveratrol isomers were investigated by the use of micro-high performance liquid chromatography. The analysis conditions were optimized. The baseline separation of trans-and cis-resveratrol was obtained. Further, a trans-resveratrol determination of some grapes growing in Shacheng, Huailai, Hebei province, China was carried out with our analytical method. The concentrations were 6.77 +/- 0.12 and 3.95 +/- 0.18 (microg/g fresh weight) for merlot and cabernet sauvignon grapes, respectively.