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1.
Aza- and Azo-Stilbenes: Bio-Isosteric Analogs of Resveratrol.
Lizard, G, Latruffe, N, Vervandier-Fasseur, D
Molecules (Basel, Switzerland). 2020;(3)
Abstract
Several series of natural polyphenols are described for their biological and therapeutic potential. Natural stilbenoid polyphenols, such as trans-resveratrol, pterostilbene and piceatannol are well-known for their numerous biological activities. However, their moderate bio-availabilities, especially for trans-resveratrol, prompted numerous research groups to investigate innovative and relevant synthetic resveratrol derivatives. This review is focused on isosteric resveratrol analogs aza-stilbenes and azo-stilbenes in which the C=C bond between both aromatic rings was replaced with C=N or N=N bonds, respectively. In each series, synthetic ways will be displayed, and structural sights will be highlighted and compared with those of resveratrol. The biological activities of some of these molecules will be presented as well as their potential therapeutic applications. In some cases, structure-activity relationships will be discussed.
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2.
Metabolism of Rhaponticin and Activities of its Metabolite, Rhapontigenin: A Review.
Chen, D, Liu, JR, Cheng, Y, Cheng, H, He, P, Sun, Y
Current medicinal chemistry. 2020;(19):3168-3186
Abstract
Rhaponticin is a stilbenoid glucoside compound, found in medicinal plant of rhubarb rhizomes. Rhapontigenin (RHAG), the stilbene aglycone metabolite of rhaponticin, has shown various biological activities including anticancer activities to act a potential human cytochrome P450 inhibitor, antihyperlipidemic effect, anti-allergic action, antioxidant and antibacterial activities. Moreover, it was reported to scavenge intracellular Reactive Oxygen Species (ROS), the 1,1-Diphenyl-2-Picrylliydrazyl (DPPH) radical, and Hydrogen Peroxide (H2O2). Meanwhile, RHAG exhibited the inhibitory activity for the synthesis of DNA, RNA and protein, and also presented the capacity of inducing morphological changes and apoptosis of C. albicans. Here, the structure, pharmacokinetics, pharmacological effects as well as underlying mechanisms of rhaponticin and its metabolite, RHAG, have been extensively reviewed. This review will provide a certain reference value for developing the therapeutic drug of rhaponticin or RHAG.
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3.
Biosynthesis of resveratrol and piceatannol in engineered microbial strains: achievements and perspectives.
Shrestha, A, Pandey, RP, Sohng, JK
Applied microbiology and biotechnology. 2019;(7):2959-2972
Abstract
Resveratrol (3,5,4'-trihydroxystilbene) and piceatannol (3,5,3',4'-tetrahydroxystilbene) are well-known natural products that are produced by plants. They are important ingredients in pharmaceutical industries and nutritional supplements. They display a wide spectrum of biological activity. Thus, the needs for these compounds are increasing. The natural products have been found in diverse plants, mostly such as grapes, passion fruit, white tea, berries, and many more. The extraction of these products from plants is quite impractical because of the low production in plants, downstream processing difficulties, chemical hazards, and environmental issues. Thus, alternative production in microbial hosts has been devised with combinatorial biosynthetic systems, including metabolic engineering, synthetic biology, and optimization in production process. Since the biosynthesis is not native in microbial hosts such as Escherichia coli, Saccharomyces cerevisiae, and Corynebacterium glutamicum, genetic engineering and manipulation have made it possible. In this review, the discussion will mainly focus on recent progress in production of resveratrol and piceatannol, including the various strategies used for their production.
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4.
Engineering stilbene metabolic pathways in microbial cells.
Jeandet, P, Sobarzo-Sánchez, E, Clément, C, Nabavi, SF, Habtemariam, S, Nabavi, SM, Cordelier, S
Biotechnology advances. 2018;(8):2264-2283
Abstract
Numerous in vitro and in vivo studies on biological activities of phytostilbenes have brought to the fore the remarkable properties of these compounds and their derivatives, making them a top storyline in natural product research fields. However, getting stilbenes in sufficient amounts for routine biological activity studies and make them available for pharmaceutical and/or nutraceutical industry applications, is hampered by the difficulty to source them through synthetic chemistry-based pathways or extraction from the native plants. Hence, microbial cell cultures have rapidly became potent workhorse factories for stilbene production. In this review, we present the combined efforts made during the past 15 years to engineer stilbene metabolic pathways in microbial cells, mainly the Saccharomyces cerevisiae baker yeast, the Escherichia coli and the Corynebacterium glutamicum bacteria. Rationalized approaches to the heterologous expression of the partial or the entire stilbene biosynthetic routes are presented to allow the identification and/or bypassing of the major bottlenecks in the endogenous microbial cell metabolism as well as potential regulations of the genes involved in these metabolic pathways. The contributions of bioinformatics to synthetic biology are developed to highlight their tremendous help in predicting which target genes are likely to be up-regulated or deleted for controlling the dynamics of precursor flows in the tailored microbial cells. Further insight is given to the metabolic engineering of microbial cells with "decorating" enzymes, such as methyl and glycosyltransferases or hydroxylases, which can act sequentially on the stilbene core structure. Altogether, the cellular optimization of stilbene biosynthetic pathways integrating more and more complex constructs up to twelve genetic modifications has led to stilbene titers ranging from hundreds of milligrams to the gram-scale yields from various carbon sources. Through this review, the microbial production of stilbenes is analyzed, stressing both the engineering dynamic regulation of biosynthetic pathways and the endogenous control of stilbene precursors.
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5.
Chemoprevention by resveratrol and pterostilbene: Targeting on epigenetic regulation.
Lee, PS, Chiou, YS, Ho, CT, Pan, MH
BioFactors (Oxford, England). 2018;(1):26-35
Abstract
Epigenetic mechanisms are essential in regulating normal cellular functions and play an important role during the disease developmental stages. However, aberrant epigenetic mechanisms may lead to pathological consequences such as cancer, neurological disorders, bone and skeletal diseases, cardiovascular dysfunction, and metabolic syndrome. The molecular mechanisms of epigenetic modification include DNA methylation, histone modification (acetylation, methylation and phosphorylation), and microRNAs (miRNAs). Unlike genetic modifications, epigenetic states of genes are reversible and can be altered by certain intrinsic and extrinsic factors. In the past few decades, accumulated evidence shows that dietary phytochemicals with chemopreventive effects are also potent epigenetic regulators. Resveratrol and pterostilbene are stilbenoids, which have been reported to have anti-cancer, anti-inflammatory, anti-lipid, and anti-diabetic properties. Stilbenoids are also reported to improve cardiovascular disease. By altering DNA methylation and histone modification or by modulating miRNA expression, resveratrol, and pterostilbene become potent epigenetic modifiers. In this review, we summarize these studies and underlying mechanisms of resveratrol and pterostilbene and their influence on epigenetic mechanisms. © 2017 BioFactors, 44(1):26-35, 2018.
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6.
Resveratrol and Amyloid-Beta: Mechanistic Insights.
Jia, Y, Wang, N, Liu, X
Nutrients. 2017;(10)
Abstract
The amyloid-beta (Aβ) hypothesis that dyshomeostasis between Aβ production and clearance is a very early, key molecular factor in the etiology of Alzheimer's disease (AD) has been proposed and examined in the AD research field. Scientists have focused on seeking natural products or drugs to influence the dynamic equilibrium of Aβ, targeting production and clearance of Aβ. There is emerging evidence that resveratrol (Res), a naturally occurring polyphenol mainly found in grapes and red wine, acts on AD in numerous in vivo and in vitro models. Res decreases the amyloidogenic cleavage of the amyloid precursor protein (APP), enhances clearance of amyloid beta-peptides, and reduces Aβ aggregation. Moreover, Res also protects neuronal functions through its antioxidant properties. This review discusses the action of Res on Aβ production, clearance and aggregation and multiple potential mechanisms, providing evidence of the useful of Res for AD treatment.
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7.
Resveratrol Supplementation in Patients with Non-Alcoholic Fatty Liver Disease: Systematic Review and Meta-analysis.
Elgebaly, A, Radwan, IA, AboElnas, MM, Ibrahim, HH, Eltoomy, MF, Atta, AA, Mesalam, HA, Sayed, AA, Othman, AA
Journal of gastrointestinal and liver diseases : JGLD. 2017;(1):59-67
Abstract
BACKGROUND Resveratrol is a potential treatment option for management of non-alcoholic fatty liver disease (NAFLD) due to its anti-inflammatory, antioxidant properties, and calorie restriction-like effects. We aimed to synthesise evidence from published randomized clinical trials (RCTs) about the efficacy of resveratrol in the management of NAFLD. METHODS A computer literature search of PubMed, Scopus, Web of Science, and Cochrane Central was conducted using relevant keywords. Records were screened for eligible studies and data were extracted and synthesized using Review Manager Version 5.3 for windows. Subgroup analysis and sensitivity analysis were conducted. RESULTS Four RCTs (n=158 patients) were included in the final analysis. The overall effect estimates did not favor resveratrol group in terms of: serum ALT (MD -2.89, 95%CI [-15.66, 9.88], p=0.66), serum AST (MD -3.59, 95%CI [-13.82, 6.63], p=0.49), weight (MD -0.18, 95%CI [-0.92, 0.55], p=0.63), BMI (MD -0.10, 95 %CI [-0.43, 0.24], p=0.57), blood glucose level (MD -0.27, 95%CI [-0.55, 0.01], p=0.05), insulin level (MD -0.12, 95%CI [-0.69, 0.46], p=0.69), triglyceride level (MD 0.04, 95%CI [-0.45, 0.53], p=0.87), and LDL level (MD 0.21, 95%CI [-0.41, 0.83], p=0.51). Pooled studies were heterogeneous. CONCLUSION Current evidence is insufficient to support the efficacy of resveratrol in the management of NAFLD. Resveratrol does not attenuate the degree of liver fibrosis or show a significant decrease in any of its parameters.
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8.
An Overview of Stress-Induced Resveratrol Synthesis in Grapes: Perspectives for Resveratrol-Enriched Grape Products.
Hasan, M, Bae, H
Molecules (Basel, Switzerland). 2017;(2)
Abstract
Resveratrol is the most important stilbene phytoalexin synthesized naturally or induced in plants, as a part of their defense mechanism. Grapes and their derivative products, including juice and wine, are the most important natural sources of resveratrol, consisting of notably higher amounts than other natural sources like peanuts. Consumption of red wine with its presence of resveratrol explained the "French Paradox". Hence, the demand of resveratrol from grapes is increasing. Moreover, as a natural source of resveratrol, grapes became very important in the nutraceutical industry for their benefits to human health. The accumulation of resveratrol in grape skin, juice, and wine has been found to be induced by the external stimuli: microbial infection, ultrasonication (US) treatment, light-emitting diode (LED), ultra violet (UV) irradiation, elicitors or signaling compounds, macronutrients, and fungicides. Phenylalanine ammonia lyase, cinnamate-4-hydroxylase, coumaroyl-CoA ligase, and stilbene synthase play a key role in the synthesis of resveratrol. The up-regulation of those genes have the positive relationship with the elicited accumulation of resveratrol. In this review, we encapsulate the effect of different external stimuli (biotic and abiotic stresses or signaling compounds) in order to obtain the maximum accumulation of resveratrol in grape skin, leaves, juice, wine, and cell cultures.
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9.
A Critical Assessment of the Therapeutic Potential of Resveratrol Supplements for Treating Mitochondrial Disorders.
De Paepe, B, Van Coster, R
Nutrients. 2017;(9)
Abstract
In human cells, mitochondria provide the largest part of cellular energy in the form of adenosine triphosphate generated by the process of oxidative phosphorylation (OXPHOS). Impaired OXPHOS activity leads to a heterogeneous group of inherited diseases for which therapeutic options today remain very limited. Potential innovative strategies aim to ameliorate mitochondrial function by increasing the total mitochondrial load of tissues and/or to scavenge the excess of reactive oxygen species generated by OXPHOS malfunctioning. In this respect, resveratrol, a compound that conveniently combines mitogenetic with antioxidant activities and, as a bonus, possesses anti-apoptotic properties, has come forward as a promising nutraceutical. We review the scientific evidence gathered so far through experiments in both in vitro and in vivo systems, evaluating the therapeutic effect that resveratrol is expected to generate in mitochondrial patients. The obtained results are encouraging, but clearly show that achieving normalization of OXPHOS function with this strategy alone could prove to be an unattainable goal.
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10.
Resveratrol and inflammatory bowel disease.
Shi, Y, Zhou, J, Jiang, B, Miao, M
Annals of the New York Academy of Sciences. 2017;(1):38-47
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract, comprising ulcerative colitis (UC) and Crohn's disease (CD). Progression of IBD leads to long-term impairment of intestinal structure and function. The pathogenesis of IBD is complex, involving environmental, immunological, genetic, microbial, and psychological factors. The conventional therapies and many existing biopharmaceuticals for IBD have limited efficacy or adverse effects. As a promising safe and effective therapy for IBD, resveratrol has been studied widely, as it has shown anti-inflammatory and antioxidant activity. Resveratrol's mechanism of action involves multiple immune responses and signaling pathways; it is absorbed quickly and metabolized into various derivatives. However, the poor water solubility and low bioavailability of resveratrol limit its clinical applications. Further research should attempt to improve the stability and oral bioavailability of resveratrol by modification and various delivery systems.