Current Pharmaceutical Design - Volume 19, Issue 34, 2013

Grape polyphenols are abundant. They play essential roles in the plant’s life, particularly in defence mechanisms. Moreover, the grape, fresh or dried, is a widely consumed fruit by humans, as are its by-products, grape juice and wine. They also contain vast and highly varied quantities of polyphenols. Like other phytophenols, grape and wine resveratrol is considered a protective micronutrient. Resveratrol is a well known antioxidant, for example, a protector of low-density lipoproteins against oxidation. Its applications are therefore highly varied. Research supports the idea that wine consumed regularly, without excess, is a natural biological product possesses preventive properties, and not only well-known properties against vascular diseases (illustrated by the so-called French paradox). At least in experimental models so far, resveratrol prevents infections, inflammation, neurodegenerative diseases, and cancer. This review addresses whether the pro-longevity properties of resveratrol are preserved in the human species. If such is the case, it will be possible to imagine new ways of eating based on natural foods, with or without supplements, based on resveratrol. On the other hand, studies such as ours are investigating the synergies between resveratrol and some of the many polyphenols found in wine. These studies should fill in the gaps between the study of a molecule tested in isolation or in a binary system (e.g., with alcohol) and this same molecule in its biological context.

Resveratrol (3,5,4’-trihydroxy-trans-stilbene) is a non-flavonoid polyphenol that may be present in a limited number of foodstuffs such as grapes and red wine. Resveratrol has been reported to exert a plethora of health benefits through many different mechanisms of action. This versatility and presence in the human diet have drawn the worldwide attention of many research groups over the past twenty years, which has resulted in a huge output of in vitro and animal (preclinical) studies. In line with this expectation, many resveratrol- based nutraceuticals are consumed all over the world with questionable clinical/scientific support. In fact, the confirmation of these benefits in humans through randomized clinical trials is still very limited. The vast majority of preclinical studies have been performed using assay conditions with a questionable extrapolation to humans, i.e. too high concentrations with potential safety concerns (adverse effects and drug interactions), short-term exposures, in vitro tests carried out with non-physiological metabolites and/or concentrations, etc. Unfortunately, all these hypothesis-generating studies have contributed to increased the number of ‘potential’ benefits and mechanisms of resveratrol but confirmation in humans is very limited. Therefore, there are many issues that should be addressed to avoid an apparent endless loop in resveratrol research. The so-called ‘Resveratrol Paradox’, i.e., low bioavailability but high bioactivity, is a conundrum not yet solved in which the final responsible actor (if any) for the exerted effects has not yet been unequivocally identified. It is becoming evident that resveratrol exerts cardioprotective benefits through the improvement of inflammatory markers, atherogenic profile, glucose metabolism and endothelial function. However, safety concerns remain unsolved regarding chronic consumption of high RES doses, specially in medicated people. This review will focus on the currently available evidence regarding resveratrol’s effects on humans obtained from randomized clinical trials. In addition, we will provide a critical outlook for further research on this molecule that is evolving from a minor dietary compound to a possible multi-target therapeutic drug.

Slowing aging is a widely shared goal. Plant-derived polyphenols, which are found in commonly consumed food plants such as tea, cocoa, blueberry and grape, have been proposed to have many health benefits, including slowing aging. In-vivo studies have demonstrated the lifespan-extending ability of six polyphenol-containing plants. These include five widely consumed foods (tea, blueberry, cocoa, apple, pomegranate) and a flower commonly used as a folk medicine (betony). These and multiple other plant polyphenols have been shown to have beneficial effects on aging-associated changes across a variety of organisms from worm and fly to rodent and human.

Seeds and sprouts from legume crop plants have received attention as functional foods, because of their nutritive values including amino acid, fiber, trace elements, vitamins, flavonoids, and phenolic acids. Consumption of seeds and sprouts has become increasingly popular among people interested in improving and maintaining their health status by changing dietary habits. The seeds and sprouts are excellent examples of functional food defined as lowering the risk of various diseases and/or exerting health promoting effects in addition to its nutritive value. Phenolic compounds are considered as secondary metabolites that are synthesized by plants during normal development and in response to stress conditions, and the compounds occur ubiquitously in plants as the diversified group of phytochemicals derived from phenylalanine and tyrosine. Plant phenolics include simple phenols, phenolic acids, coumarins, flavonoids, stilbenes, hydrolyzable and condensed tannins, lignans, and lignins. In plant, phenolics may act as phytoalexins, antifeedants, attractants for pollinators, contributors to the plant pigmentation, antioxidants, and protective agents against UV light, among others. In food, phenolics may contribute to the bitterness, astringency, color, flavor, odor, and oxidative stability of products. In addition, health-protecting capacity of some and antinutritional properties of other plant phenolics are of great importance to producers, processors and consumers. Several researches were conducted to compare the content of phenolics and flavonoids, antioxidant activity and antioxidant enzyme activity from seeds and sprouts of legume plants. Total phenolics (TP) content and total flavonoids (TF) level were highest in soybean sprout extracts, followed by cowpea and mungbean sprout extracts (p < 0.05). DPPH (1, 1-diphenyl-2-picryl hydrazyl radical) free radical scavenging activity was higher in cowpea or mungbean sprouts than in soybean sprouts. Among antioxidant enzymes, ascorbate peroxidase (APX) and peroxidase (POX) activities were highest in cowpea sprouts and catalase (CAT) and superoxide dismutase (SOD) activities in soybean sprouts. During sprouting in mungbean, TP and TF levels significantly increased and improved free radical scavenging, tyrosinase inhibition, anticancer, and ADH (alcohol dehydrogenase) activities, showing higher contents and activities in sprouts than in seeds. Sprouting of seeds is known to increase the nutritive value such as phenolics and flavonoids and the health qualities of foods in a natural way. Phasic bioactive responses from dry seeds to 7-day-old seedlings of cowpea showed differential growth, contents of TP and TF, antioxidant activity and antioxidant enzyme activity. Plant length and weight of cowpea sprouts were significantly increased until 7 days after seeding. TP content, however, was highest in dry seed (DS) extracts of cowpea (63.9 mg kg-1), followed by imbibed seed (IS) (56.8 mg kg-1) and 1-day-old sprout (1DOS) (46.4 mg kg-1) extracts, and significantly reduced with increase of sprout age (p < 0.05). DPPH free radical scavenging activity was higher in DS or IS than in cowpea sprouts. APX, POX, and POX activities were highest in 7DOS and lowest in DS. SOD activity was lowest in DS and much higher in additional sprouting days.

Endogenous estrogens, such as 17β-estradiol (E2), are implicated in the development of breast cancer. The putative mechanisms by which estrogens exert the carcinogenic effects have been recognized to involve the redox cycling of estrogen metabolites and subsequent estrogen-DNA adduct formation as well as the estrogen receptor-dependent pathway of estrogen-induced cell growth. The former pathway is regulated by phase I enzymes, mainly cytochrome P450 (CYP) 1A1, 1A2, and 1B1. Among them, CYP1B1 predominantly catalyzes the C4-position of E2 and forms carcinogenic 4-hydroxy-E2 (4-OHE2), whereas CYP1A1 and CYP1A2 convert E2 to noncarcinogenic 2-hydroxy-E2. Formed 4-OHE2 is further oxidized to semiquinones and quinones, which form DNA adducts, leading to mutagenic lesions. Consequently, CYP1B1 is highly expressed, and 4-OHE2 is predominantly detected in estrogen target neoplastic tissues. Moreover, invasion and metastasis are also involved in the development of breast cancer. Epidemiological studies suggest an inverse association between a higher intake of flavonoids and breast cancer risk. Flavonoids, which are widely distributed in the plant kingdom, have been recently reported as candidate compounds that can exert chemopreventive effects in estrogen-dependent or independent breast cancer. In this review, we provide a comprehensive overview of breast cancer and chemoprevention by flavonoids, mainly focusing on ER-mediated hormonal regulation, redox cycling of estrogen metabolites, and selective inhibition of CYP1B1.

The pulp of avocado (Persea americana, Lauraceae) has been reported to have beneficial cardiovascular health effects. Avocado oil is used for dermatological applications and its unsaponifiable portion is reported to have beneficial effects against osteoarthritis. Although the seed represents a considerable percentage of the total fruit, scientific research on the phytochemistry and biological effects of avocado seeds is in the nascent stages,. Currently, the seed represents an under-utilized resource and a waste issue for avocado processors. There is ethno-pharmacological information on the use of seeds for the treatment of health-related conditions, especially in South American countries where avocados are endemic and currently grown on a large scale. Current research has shown that avocado seeds may improve hypercholesterolemia, and be useful in the treatment of hypertension, inflammatory conditions and diabetes. Seeds have also been found to possess insecticidal, fungicidal, and anti-microbial activities. The avocado seeds and rich in phenolic compounds, and these may play a role in the putative health effects. Historically, extracts of avocado seeds were also used as ink for writing and research in our laboratory has explored the potential colorant properties of a polyphenol oxidase-produced colored avocado seed extract. Here, we review the currently-available data on the bioactivity and other functional properties of avocado seeds. We discuss the strength of the available data, the putative active compounds, and potential directions for future studies.

Tea, next to water is the cheapest beverage humans consume. Drinking the beverage tea has been considered a healthpromoting habit since ancient times. The modern medicinal research is providing a scientific basis for this belief. The evidence supporting the health benefits of tea drinking grows stronger with each new study that is published in the scientific literature. Tea plant Camellia sinensis has been cultivated for thousands of years and its leaves have been used for medicinal purposes. Tea is used as a popular beverage worldwide and its ingredients are now finding medicinal benefits. Encouraging data showing cancer-preventive effects of green tea from cell-culture, animal and human studies have emerged. Evidence is accumulating that black tea may have similar beneficial effects. Tea consumption has also been shown to be useful for prevention of many debilitating human diseases that include maintenance of cardiovascular and metabolic health. Various studies suggest that polyphenolic compounds present in green and black tea are associated with beneficial effects in prevention of cardiovascular diseases, particularly of atherosclerosis and coronary heart disease. In addition, anti-aging, antidiabetic and many other health beneficial effects associated with tea consumption are described. Evidence is accumulating that catechins and theaflavins, which are the main polyphenolic compounds of green and black tea, respectively, are responsible for most of the physiological effects of tea. This article describes the evidences from clinical and epidemiological studies in the prevention of chronic diseases like cancer and cardiovascular diseases and general health promotion associated with tea consumption.

Many previous epidemiological studies have revealed that green tea or green tea catechins contributed to the preveintion of lifestyle-related diseases. Several cohort studies on the relationship between green tea consumption and cardiovascular disease (CVD) risk/type 2 diabetes mellitus risk have been conducted. The results showed that green tea consumption (5 or more cups/day) was inversely associated with mortality from CVD and all causes. Within CVD mortality, the strongest inverse association was observed for stroke mortality. Furthermore, consumption of green tea, coffee, and total caffeine was associated with a reduced risk for type 2 diabetes. On the other hand, the analysis of randomized clinical trial (RCT) studies showed that the administration of green tea beverages or extracts resulted in significant reductions in serum total cholesterol and LDL-cholesterol concentrations, but had no apparent effect on HDL-cholesterol. Green tea reduced fasting blood glucose levels in a small intervention trial, although no improvements in HbA1c levels were seen. Continuous intake of green tea containing catechins and caffeine (5 or more cups per day) may be beneficial for body weight management, vascular disease risk reduction via LDL-cholesterol improvement, and type 2 diabetes risk reduction through the lowering of fasting blood glucose levels. Epigallocatechin-3-O-(3-O-methyl) gallate (EGCG3”Me) isolated from cv. “Benifuuki” green tea has been shown to strongly inhibit mast cell activation and histamine release after FcepsilonRI cross-linking through the suppression of tyrosine phosphorylation (Lyn) of cellular protein kinase, and the suppression of myosin light chain phosphorylation and high-affinity IgE receptor expression via the binding to 67 kDa laminin receptors. A double-blind clinical study on subjects with Japanese cedar pollinosis was carried out. At the eleventh week after starting intake, which was coincident with the most severe period of cedar pollen-scattering, symptoms such as nose blowing and eye itching were significantly relieved in the Benifuuki group compared with the placebo group. Six weeks of intake of Benifuuki green tea containing O-methylated catechins was useful for reducing some of the symptoms derived from Japanese cedar pollinosis, and did not affect any of the normal immune responses in the subjects with Japanese cedar pollinosis. Based on an investigation into the effects of the cultivars, tea seasons of crops and manufacturing methods, it was concluded that green or semi-fermented tea made from fully-matured Benifuuki in the second crop season should be consumed.

An epigenetic change is defined as an alteration in gene expression that does not involve a change in the DNA sequence. Epigenetic modifications, including DNA methylation, histone modification (acetylation, methylation and phosphorylation) and miRNA, are critical for regulating developmental events. However, aberrant epigenetic mechanisms may lead to pathological consequences such as cardiovascular disease (CAD), neurodegenerative disease, obesity, metabolic disorder, bone and skeletal diseases and various cancers. Given that epigenetic modifications are heritable and reversible, in contrast to genetic changes, they have been identified as promising targets for disease prevention strategies. Over the past few decades, polyphenols, which are widely present in foods such as fruits and vegetables, have been shown to exhibit a broad spectrum of biological activities for human health. Polyphenols reverse adverse epigenetic regulation by altering DNA methylation and histone modification, and they modulate microRNA expression or directly interact with enzymes that result in the reactivation of silenced tumor suppressor genes or the inactivation of oncogenes. Therefore, dietary polyphenol- targeted epigenetics becomes an attractive approach for disease prevention and intervention. In this review, we summarize the current knowledge and underlying mechanisms of the most common dietary polyphenols and their influence on major epigenetic mechanisms associated with disease intervention.

Polyphenols are bioactive natural molecules biogenerated through secondary metabolic pathways. They are involved in different functions in the ecology, physiology, and biochemistry of plants such as chemical defense against predators and in plant-plant interferences. These compounds are known to have important biological activities related to human health such as antioxidant action, antiinflammatory and antimicrobial effects. The immense health benefits as well as use of many polyphenolic compounds as anti-infective agents against human pathogens have heightened the need for continuous supply of rare and expensive secondary metabolites. It has been demonstrated that the chemical structure of dietary polyphenols, such as the number and position of hydroxyl groups, can change their biological properties and bioavailability. This review focuses on prospects for, and success in metabolic engineering, including manipulation of structural regulatory genes to develop plants with tailor-made, optimized levels and composition of polyphenols.

Tea polyphenol “catechin”, which is a major constituent of green tea extract, has received special attention for its important bioactivities. In this article, we review the recent various syntheses of catechins by classifying the mode of of flavan ring-construction. Additionally, we also take notice of the application of the modified catechins that were created to uncover the mechanism of bioactivities and discover new activities.

While the chemotherapeutic effect of curcumin, one of three major curcuminoids derived from turmeric, has been reported, largely unexplored are the effects of complex turmeric extracts more analogous to traditional medicinal preparations, as well as the relative importance of the three curcuminoids and their metabolites as anti-cancer agents. These studies document the pharmacodynamic effects of chemically-complex turmeric extracts relative to curcuminoids on human breast cancer cell growth and tumor cell secretion of parathyroid hormone-related protein (PTHrP), an important driver of cancer bone metastasis. Finally, relative effects of structurallyrelated metabolites of curcuminoids were assessed on the same endpoints. We report that 3 curcuminoid-containing turmeric extracts differing with respect to the inclusion of additional naturally occurring chemicals (essential oils and/or polar compounds) were equipotent in inhibiting human breast cancer MDA-MB-231 cell growth (IC50=10-16µg/mL) and secretion of osteolytic PTHrP (IC50=2-3µg/mL) when concentrations were normalized to curcuminoid content. Moreover, these effects were curcuminoid-specific, as botanically-related gingerol containing extracts had no effect. While curcumin and bis-demethoxycurcumin were equipotent to each other and to the naturally occurring curcuminoid mixture (IC50=58µM), demethoxycurcumin did not have any effect on cell growth. However, each of the individual curcuminoids inhibited PTHrP secretion (IC50=22-31µM) to the same degree as the curcuminoid mixture (IC50=16µM). Degradative curcuminoid metabolites (vanillin and ferulic acid) did not inhibit cell growth or PTHrP, while reduced metabolites (tetrahydrocurcuminoids) had inhibitory effects on cell growth and PTHrP secretion but only at concentrations ≥10-fold higher than the curcuminoids. These studies emphasize the structural and biological importance of curcuminoids in the anti-breast cancer effects of turmeric and contradict recent assertions that certain of the curcuminoid metabolites studied here mediate these anti-cancer effects.