Plant polyphenols: how to translate their in vitro antioxidant actions to in vivo conditions

Epidemiological evidence demonstrates that diets rich in fruit and vegetables promote health, and attenuate, or delay, the onset of various diseases, including cardiovascular disease, diabetes, certain cancers, and several other age-related degenerative disorders. The chemical components and the physiological and molecular mechanisms by which fruit and vegetables reduce the risk for these pathophysiological conditions are matters of intense investigation. Regarding plant components, polyphenols are a group of phytochemicals that are gaining acceptance as responsible for the health benefits offered by fruit and vegetables. Because of their chemical structure, plant polyphenols are able to scavenge free radicals and inactivate other pro-oxidants. The connection of these chemical properties to a physiological antioxidant action has triggered extensive research aimed to relate the consumption of plant polyphenols with human health. Although significant progress has been made, there are still some critical areas that need to be elucidated to arrive at definitive conclusions on the mechanisms linking plant polyphenol consumption, reduction in oxidative damage, and health improvement. Some of these topics will be discussed in this review of alternative molecular mechanisms, based on polyphenol-membranes and polyphenol-proteins interactions that develop in an antioxidant protection but are not directly related to free radical scavenging or metal chelating.     

Nutraceuticals: facts and fiction

Epidemiological studies show a link between the consumption of plant-derived foods and a range of health benefits. These benefits have been associated, at least partially, to some of the phytochemical constituents, and, in particular, to polyphenols. In the last few years, nutraceuticals have appeared in the market. These are pharmaceutical forms (pills, powders, capsules, vials, etc.) containing food bioactive compounds as active principles. The bioactive phytochemicals have become a very significant source for nutraceutical ingredients. Scientific research supports the biological activity of many of these food phytochemicals, but the health claims attributed to the final marketed nutraceutical products have often little or doubtful scientific foundation. This is due to the fact that a lot of the scientific evidence is derived from animal testing and in vitro assays, whereas human clinical trials are scarce and inconclusive. Some key issues such as bioavailability, metabolism, dose/response and toxicity of these food bioactive compounds or the nutraceuticals themselves have not been well established yet. Amongst the phytochemicals, several groups of polyphenols (anthocyanins, proanthocyanidins, flavanones, isoflavones, resveratrol and ellagic acid) are currently used in the nutraceutical industry. In this report, we have reviewed the most recent scientific knowledge on the bioavailability and biological activity of these polyphenols ('fact'), as well as the health claims (which are not always supported by scientific studies) ascribed to the polyphenols-containing nutraceuticals ('fiction'). The in vitro antioxidant capacity, often used as a claim, can be irrelevant in terms of in vivo antioxidant effects. Bioavailability, metabolism, and tissue distribution of these polyphenols in humans are key factors that need to be clearly established in association to the biological effects of these polyphenols-containing nutraceuticals. The future trends of phytochemistry research regarding nutraceuticals are discussed.     

The "French Paradox" and beyond: neuroprotective effects of polyphenols

Chronic ethanol ingestion is known to cause oxidative damage to a number of organs including the brain. This is partly due to the ability of ethanol to enhance oxygen free radical production and lipid peroxidation. Increase in oxidative stress has been regarded as an important underlying factor for a number of human health problems including cardiovascular diseases, aging, as well as many age-related neurodegenerative diseases. The strikingly low incidences of coronary heart diseases (CHD) in France, despite intake of a high-fat diet, have been attributed to the consumption of red wine containing high levels of polyphenolic compounds. In recent years, understanding the "French Paradox" has stimulated new research interest to investigate whether polyphenolic antioxidants may offer protective effects beyond the cardiovascular system, and whether polyphenols from other botanical sources may similarly offer beneficial effects to human health. Our studies with animal models have provided information clearly indicating the ability of grape polyphenols to ameliorate neuronal damages due to chronic ethanol consumption. Studies with resveratrol, an important component of grape polyphenols, also show protective effects on neuron cell death induced by ethanol and other oxidative agents. These studies demonstrate an urgent need to extend research beyond the "French Paradox" towards better understanding molecular mechanisms of action of polyphenolic compounds and their application to human health.     

How do dietary flavanols improve vascular function? A position paper

Epidemiological and clinical studies revealed that high-flavanol diet or isolated (−)-epicatechin improves the function of the vascular endothelium, as assessed by flow-mediated dilation, through elevation of bioavailability and bioactivity of NO^•. We have demonstrated that exposure of human endothelial cells to (−)-epicatechin elevates the cellular levels of NO^• and cyclic GMP and protects against oxidative stress elicited by proinflammatory agonists. (−)-Epicatechin acts like a prodrug, since these effects involve O-methylation of the flavanol and are attributed to apocynin-like inhibition of endothelial NADPH oxidase. Thus, generation of superoxide and peroxynitrite is diminished and, consequently, the cellular NO^• level is preserved or augmented. We propose therefore that endothelial NO^• metabolism rather than general antioxidant activity is a major target of dietary flavanols and that NADPH oxidase activity is a crucial site of action. Moreover, flavonoid glucuronides appear to serve as plasma transport metabolites to target cells rather than solely as excretion products. Implications for the interpretation of the role of dietary polyphenols for cardiovascular health are discussed.     

Medicinal plants and antioxidants: What do we learn from cell culture and Caenorhabditis elegans studies?

Traditional medicinal plants have a long history of therapeutic use. The beneficial health effects of medicinal plants rich in polyphenols are often attributed to their potent antioxidant activities, as established in vitro, since diets rich in polyphenols are epidemiologically associated with a decreased incidence of age-related diseases in humans. However, medicinal plants may also exert pro-oxidant effects that up-regulate endogenous protective enzymes. Care is needed when studying the biological effects of medicinal plants in cell culture because some polyphenols oxidize readily in culture media. This review summarizes the data we have obtained from in vitro and in vivo (Caenorhabditis elegans) studies examining the diverse effects of traditional medicinal plants and their modes of action.     

Dietary polyphenols link extracellular histones and nonhistone proteins

Numerous studies have demonstrated antioxidant, anti-inflammatory, antimicrobial, anticancer, and cardio-protective activities of dietary polyphenols, but due to diverse structures and subclasses of polyphenols, little is known about their mechanisms of action. The study by Yamaguchi et al. published in JBC provides mechanistic insights into how dietary polyphenols confer histone-binding ability on certain proteins and motivates the research community to further explore health benefits of polyphenols.     

天然抗氧化剂茶多酚的健康作用及其机理

喝茶有助于健康,可以预防一些疾病,这已被流行病学研究所证实。研究表明,茶叶中对身体健康非常有益的物质是具有很强抗氧化能力的茶多酚,茶多酚占茶叶干重的30%左右。茶多酚可以有效地清除氧自由基和脂类自由基,预防脂质过氧化,而且具有抑制肿瘤发生、延缓衰老等功能。本文就茶多酚的健康作用及其分子机理做一综述,其中大部分为我们实验室研究和发表在国内外杂志上的成果。     

The effects of Sambucus nigra polyphenols on oxidative stress and metabolic disorders in experimental diabetes mellitus

The paper focuses on certain natural polyphenolic extracts from common elder fruit (Sambucus nigra), and also on their effects in diabetes mellitus. The results reveal that the glycosylated hemoglobin values are much higher in the diabetic group and they are significantly lower in the group protected by polyphenols. The natural polyphenol compounds reduce the lipids peroxides, neutralize the lipid peroxil radicals and inhibit the LDL oxidation. Following the perturbation of the lipid metabolism in the diabetic rats, atherogen risk has significantly increased values in comparison to the rats from the witness groups. It is found that due to the polyphenolic protection of the rats from the diabetic group treated with polyphenols, the atherogen risk is preserved at normal limits. The serum activity of glutathione-peroxidase and superoxide-dismutase has significantly lower values in the diabetic group as compared to the group protected by polyphenols. Through the hypoglycemiant, hypolipemiant and antioxidant effects,Sambucus nigra represents a possible dietary adjunct for the treatment of diabetes and a potential source for the discovery of new orally active agent(s) for future diabetes therapy. Understanding the mechanism through which the natural polyphenols have effects on the functionality of the endothelium cells, including on the membrane sensitivity and intracellular signalling, could represent a new way of therapeutically approaching chronic metabolic diseases and cardiovascular illnesses.     

Influence of feed on anti-inflammatory and antioxidant effects of Zophobas morio

In this study, the antioxidant and anti-inflammatory effects of superworm as one of the potential species for the food industry were investigated. This type of insect was bred on three different types of feed and, at the end of the breeding experiment, the total polyphenols (TPC), antiradical activity, degree of hydrolysis, and anti-inflammatory effects of the peptides were determined. The highest value of polyphenols content was demonstrated in whole enzymatically hydrolysed insects (W), especially in the group fed on soy feed (Wso = 4.2014 ± 0.27 mg GAE/100 g). This group also achieved the highest antiradical activity, as measured by ABTS and DPPH, and the highest anti-inflammatory effect, as measured by COX inhibition. Insects fed on soy feed are unsuitable for food despite their high polyphenol content and antioxidant activity, as high mortality occurs. The largest length in a worm breeding experiment was identified in the group fed the control diet (co = 4.93 ± 0.27 cm) and the heaviest weight in the group on the maize diet (ma = 0.77 ± 0.11 g).     

The antioxidant and pro-oxidant activities of green tea polyphenols: A role in cancer prevention

Green tea (Camellia sinensis) is rich in catechins, of which (−)-epigallocatechin-3-gallate (EGCG) is the most abundant. Studies in animal models of carcinogenesis have shown that green tea and EGCG can inhibit tumorigenesis during the initiation, promotion and progression stages. Many potential mechanisms have been proposed including both antioxidant and pro-oxidant effects, but questions remain regarding the relevance of these mechanisms to cancer prevention. In the present review, we will discuss the redox chemistry of the tea catechins and the current literature on the antioxidant and pro-oxidative effects of the green tea polyphenols as they relate to cancer prevention. We report that although the catechins are chemical antioxidants which can quench free radical species and chelate transition metals, there is evidence that some of the effects of these compounds may be related to induction of oxidative stress. Such pro-oxidant effects appear to be responsible for the induction of apoptosis in tumor cells. These pro-oxidant effects may also induce endogenous antioxidant systems in normal tissues that offer protection against carcinogenic insult. This review is meant point out understudied areas and stimulate research on the topic with the hope that insights into the mechanisms of cancer preventive activity of tea polyphenols will result.     

Antioxidant and xanthine oxidase inhibitory activities of total polyphenols from onion

Onions (Allium cepa L.) comprise a valuable vegetable crop in many countries. Modern scientific research has shown that onions possess many biological activities, including antibacterial, anticancer, hypoglycemic, hypolipidemic, antiplatelet aggregation, and antioxidant activities. The goal of this study was to investigate the impact of total onion polyphenols on antioxidant and xanthine oxidase (XO) inhibitory activities. Total onion polyphenols showed significant antioxidant activity in DPPH, FRAP, and OH-assays (IC₅₀ [µg/mL]), 43.24, 560.61, and 12.97, respectively). In a X/XO system, antioxidant properties of these polyphenols significantly inhibited XO activity (IC₅₀ [µg/mL], 17.36). These results indicated that total onion polyphenols showed promising antioxidant and anti-gout properties and might be used as potential, natural drugs against oxidative diseases after successful studies in vivo as well as clinical trials.     

Differential protective effects of quercetin, resveratrol, rutin and epigallocatechin gallate against mitochondrial dysfunction induced by indomethacin in Caco-2 cells

The beneficial effects of dietary polyphenols on health are due not only to their antioxidant properties but also to their antibacterial, anti-inflammatory and/or anti-tumoral activities. It has recently been proposed that protection of mitochondrial function (which is altered in several diseases such as Alzheimer, Parkinson, obesity and diabetes) by these compounds, may be important in explaining the beneficial effects of polyphenols on health. The aim of this study was to evaluate the protective effects of dietary polyphenols quercetin, rutin, resveratrol and epigallocatechin gallate against the alterations of mitochondrial function induced by indomethacin (INDO) in intestinal epithelial Caco-2 cells, and to address the mechanism involved in such damaging effect by INDO, which generates oxidative stress. INDO concentration dependently decreases cellular ATP levels and mitochondrial membrane potential in Caco-2 cells after 20min of incubation. INDO also inhibits the activity of mitochondrial complex I and causes accumulation of NADH; leading to overproduction of mitochondrial O(2)()(-), since it is prevented by pyruvate. Quercetin (0.01mg/ml), resveratrol (0.1mg/ml) and rutin (1mg/ml) protected Caco-2 cells against INDO-induced mitochondrial dysfunction, while no protection was observed with epigallocatechin gallate. Quercetin was the most efficient in protecting against mitochondrial dysfunction; this could be due to its ability to enter cells and accumulate in mitochondria. Additionally its structural similarity with rotenone could favor its binding to the ubiquinone site of complex I, protecting it from inhibitors such as INDO or rotenone. These findings suggest a possible new protective role for dietary polyphenols for mitochondria, complementary of their antioxidant property. This new role might expand the preventive and/or therapeutic use of PPs in conditions involving mitochondrial dysfunction and associated with increased oxidative stress at the cellular or tissue levels.     

Irrigation of Solanum lycopersicum L. with magnetically treated water increases antioxidant properties of its tomato fruits

Antioxidant effects of tomatoes (Solanum lycopersicum L.) have been studied and an association between dietary intake of tomatoes and lowered risk of cancer, neurodegenerative, and cardiovascular diseases has been suggested. Here we used magnetically treated water (MTW; 0.03–0.15 T), which promotes better germination and productivity in tomatoes, and we investigated the effects of aqueous and ethanolic (10–400 μg/ml) extracts of S. lycopersicum as potential antioxidant against 10 μM Fe(II)-induced thiobarbituric acid reactive species (TBARS) in liver and brain homogenates from rats. The ethanolic extracts from magnetically treated plants were more effective than aqueous extracts in preventing TBARS formation in brain and liver. The protective effects of ethanolic extract can be associated with antioxidants (polyphenols and flavonoids), lycopene and other lipophilic components found in the extract. In effect, magnetically treated plants had higher content of polyphenolic and flavonoid compounds than nontreated plants and they can be a better source of antioxidants than nontreated plants. Consequently, MTW can be used to produce functional foods with high contents of antioxidant components and may have better beneficial health effects than traditionally produced foods.     

Ellagitannin geraniin: a review of the natural sources,biosynthesis, pharmacokinetics and biological effects

The discovery of the ellagitannin geraniin was made exactly 40 years ago. It is a secondary metabolite found in plants and is categorised as a hydrolysable tannin under the huge family of polyphenolic compounds. At present, the occurrence of geraniin has been verified in at least 71 plant species, many of which are used in traditional medicine. Hence, like other polyphenols, geraniin has also received widespread interest as a research focus to unearth its beneficial biological effects and therapeutic values apart from understanding its chemical properties, biosynthesis and interaction with the body system. Indeed, it has been demonstrated that geraniin possesses antioxidant, antimicrobial, anticancer, cytoprotective, immune-modulatory, analgesic properties besides exerting promising therapeutic effects on hypertension, cardiovascular disease and metabolic dysregulation. The objective of this review is to summarise the current knowledge about the basic chemistry, natural sources, isolation techniques, biosynthesis, pharmacokinetics and pharmacodynamics of geraniin. With reference to this information, the clinical significance, obstacles and future perspectives in geraniin research will also be scrutinised.     

Phytogenic compounds from avocado (Persea americana L.) extracts; antioxidant activity,amylase inhibitory activity,therapeutic potential of type 2 diabetes

Diabetes is a worldwide public health disease. Currently, the most effective way to treat diabetes is to mitigate postprandial hyperglycemia by inhibiting carbohydrate hydrolysis enzymes in the digestive system. Plant extracts are rich in bioactive compounds, which can be used in diabetes treatment. This study aims to evaluate the polyphenols content in ethanolic extracts of avocado fruit and leaves (Persea americana Mill.). Additionally, their antioxidant activity using DPPH, while the inhibition ability of α-amylase was examined by reacting different amounts of the extracts with α-amylase compared to acarbose as standard inhibitor. The active compounds were detected in the extracts by LC/MS. The obtained results showed that the leaf extract recorded a significant content of total phenolic compounds compared to the fruit extract (178.95 and 145.7 mg GAE /g dry weight, respectively). The total flavonoid values ??ranged from 32.5 to 70.08 mg QE/g dry weight of fruit and leaves extracts, respectively. Twenty-six phytogenic compounds were detected in leaf and fruit extract by LC/MS. These compounds belong to fatty acids, sterols, triterpenes, phenolic acids, and flavonoids. The antioxidant activity of the extracts is due to the exist of phytogenic compounds, i.e., polyphenols and flavonoids. The antioxidant activity increased in a concentration dependant manner. Avocado fruit extract (1000 µg/mL) scavenged 95% of DPP? while leaf extract rummaged 91.03% of free radicals compared with Vit C and BHT. Additionally, higher α-amylase inhibitory activity was observed in fruit extract than the leaf extract, where the fruit and leaf extract (1000 μg/ml) inhibited the enzyme by 92.13% and 88.95%, respectively. The obtained results showed that the ethanolic extracts of avocado could have a significant impact on human health due to their high content of polyphenols.     

Antioxidant,metal-binding and DNA-damaging properties of flavonolignans: A joint experimental and computational highlight based on 7-O-galloylsilybin

Besides the well-known chemoprotective effects of polyphenols, their prooxidant activities via interactions with biomacromolecules as DNA and proteins are of the utmost importance. Current research focuses not only on natural polyphenols but also on synthetically prepared analogs with promising biological activities. In the present study, the antioxidant and prooxidant properties of a semi-synthetic flavonolignan 7-O-galloylsilybin (7-GSB) are described. The presence of the galloyl moiety significantly enhances the antioxidant capacity of 7-GSB compared to that of silybin (SB). These findings were supported by electrochemistry, DPPH (2,2-diphenyl-1-picrylhydrazyl) scavenging activity, total antioxidant capacity (CL-TAC) and DFT (density functional theory) calculations. A three-step oxidation mechanism of 7-GSB is proposed at pH 7.4, in which the galloyl moiety is first oxidized at E_p,1 = +0.20 V (vs. Ag/AgCl_{3M KCl}) followed by oxidation of the 20-OH (E_p,2 = +0.55 V) and most probably 5-OH (E_p,3 = +0.95 V) group of SB moiety. The molecular orbital analysis and the calculation of O–H bond dissociation enthalpies (BDE) fully rationalize the electrooxidation processes. The metal (Cu²⁺) complexation of 7-GSB was studied, which appeared to involve both the galloyl moiety and the 5-OH group. The prooxidant effects of the metal-complexes were then studied according to their capacity to oxidatively induce DNA modification and cleavage. These results paved the way towards the conclusion that 7-O-galloyl substitution to SB concomitantly (i) enhances antioxidant (ROS scavenging) capacity and (ii) decreases prooxidant effect/DNA damage after Cu complexation. This multidisciplinary approach provides a comprehensive mechanistic picture of the antioxidant vs. metal-induced prooxidant effects of flavonolignans at the molecular level, under ex vivo conditions.