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.     

New advances in osteoporosis nutritional prevention

With the human race experiencing a progressive increase in life expectancy, we are facing a growing prevalence of chronic age-related conditions, among which osteoporosis is a generalised condition of bone, whose hallmark is increased bone fragility. Based on the overwhelming body of evidence emphasising that gonadal failure at the time of menopause causes osteopenia and the administration of estrogens in postmenopausal women prevents this loss, hormone replacement therapy (HRT) has been widely recommended. However HRT should be limited due to its potential adverse effects. In this light, an effort should be made to integrate alternative therapies of proven values to provide new options for women in midlife. Research in nutrition over the past 30 years has led to exciting and significant progress. Although the primary role of diet is to provide sufficient nutrients to fulfill the metabolic requirements of an individual, there is an emerging rationale to support the hypothesis that, by modulating specific target functions in the body, diet can help to achieve optimal health and also play an important role in reducing the risk of disease. Specifically, it has been recognized that human diet contains, in addition to essential macro- and micronutrients, a complex array of naturally occurring bioactive molecules, the phytochemicals, that may confer significant long-term health benefits. Indeed, besides calcium, micronutrients such as vitamins, polyphenols, phytoestrogens, trace elements or minerals remain a source for putative new and innovative dietary health intervention in the nutritional prevention of osteoporosis.     

Isoflavones and calcified tissues

The data about osteotropic action of isoflavones are presented in this review. Isoflavones are the compounds of phytoestrogenes group--hormone-like bioregulators of plant origin. Animal experiments as well as bone tissue and bone cells cultures investigations demonstrate anabolic effect of isoflavones on bone metabolism. Isoflavones prevent bone loss in ovariectomized animals. They inhibit bone resorbition and enhance bone formation. Because of this natural and synthetic isoflavones hold great promise in the prevention and treatment of osteoporosis. These compounds may also be effective in preventing bone loss associated with hypodynamia or immobility, ovariectomy or postmenopausal hypoestrogenia, chronic corticosteroid use, renal osteodystrophy, hyperparathyroidism and other metabolic disorders affecting the calcified tissues, including alveolar bone loss in periodontal disease as well as dental hard tissues destruction.     

Dietary flavonoids: Role of (-)-epicatechin and related procyanidins in cell signaling

Plant polyphenols are among the most abundant phytochemicals present in human diets. Increasing evidence supports the health-promoting effects of certain polyphenols, including flavonoids. This review discusses current knowledge of the capacity of monomeric flavanols, i.e., (−)-epicatechin and (+)-catechin, and their derived procyanidins to modulate cell signaling and the associations of these actions with better health. Flavanols and procyanidins can regulate cell signaling through different mechanisms of action. Monomers and dimeric procyanidins can be transported inside cells and directly interact and modulate the activity of signaling proteins and/or prevent oxidation. Larger and nonabsorbable procyanidins can regulate cell signaling by interacting with cell membrane proteins and lipids, inducing changes in membrane biophysics, and by modulating oxidant production. All these actions would be limited by the bioavailability of flavanols at the target tissue. The protection from cardiac and vascular disease and from cancer that is associated with a high consumption of fruit and vegetables could be in part explained by the capacity of flavanols and related procyanidins to modulate proinflammatory and oncogenic signals.     

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.     

OPG/RANKL: role and therapeutic target in osteoporosis

Given the increasing risk of fractures with aging in western countries, there is a need for the development of safe and efficient anti-osteoporotic drugs for the prevention and treatment of osteoporosis. Recent studies have provided evidence for an essential role of RANKL (Receptor Activator of Nuclear Factor-kappa B Ligand) and its decoy receptor osteoprotegerin in the control of osteoclast differentiation and survival. Post-menopausal osteoporosis results from an imbalance between resorption and formation associated with decreased OPG/RANKL. Targeting the OPG/RANKL system may therefore have a beneficial impact in osteoporosis. Accordingly, the development of novel strategies targeting OPG/RANKL using anti-RANKL or therapeutic intervention proved to be efficient to reduce bone resorption and to prevent bone loss in postmenopausal osteoporosis. This opens the way for novel therapeutic strategies for correcting bone metabolism in various pathologic disorders characterized by increased bone remodelling and bone loss.     

Recent advances in understanding the anti-diabetic actions of dietary flavonoids

Flavonoids are polyphenolic compounds that are abundant in fruits and vegetables, and increasing evidence demonstrates a positive relationship between consumption of flavonoid-rich foods and disease prevention. Epidemiological, in vitro and animal studies support the beneficial effects of dietary flavonoids on glucose and lipid homeostasis. It is encouraging that the beneficial effects of some flavonoids are at physiological concentrations and comparable to clinically-used anti-diabetic drugs; however, clinical research in this field and studies on the anti-diabetic effects of flavonoid metabolites are limited. Flavonoids act on various molecular targets and regulate different signaling pathways in pancreatic β-cells, hepatocytes, adipocytes and skeletal myofibers. Flavonoids may exert beneficial effects in diabetes by (i) enhancing insulin secretion and reducing apoptosis and promoting proliferation of pancreatic β-cells; (ii) improving hyperglycemia through regulation of glucose metabolism in hepatocytes; (iii) reducing insulin resistance, inflammation and oxidative stress in muscle and fat and (iv) increasing glucose uptake in skeletal muscle and white adipose tissue. This review highlights recent findings on the anti-diabetic effects of dietary flavonoids, including flavan-3-ols, flavanones, flavonols, anthocyanidins, flavones and isoflavones, with particular emphasis on the studies that investigated the cellular and molecular mechanisms involved in the beneficial effects of the compounds.     

Food safety and epidemiology: new database of functional food factors

More than 600 functional non-nutrient food factors (FFFs) in vegetables and fruits are considered to be effective for health promotion and disease prevention. However, phytochemicals studied thus far have failed to yield predicted results in randomized intervention studies. To assess the health effects of phytochemicals, a breakthrough in epidemiological methods was necessary. We constructed a database of non-nutrient FFFs to estimate the chemical classes and total amount of FFF-intake in order to facilitate estimation and calculation for nutritional research. So far, flavonoids, terpenoids, carotenoids, and sulfur compounds are included in our FFF database. We calculated the intake of various phytochemicals per capita from 79 subjects' dietary records by FFF database, and estimated that subjects ingested more than 10 micromole per day of phytochemicals such as catechin, isoflavones, isothiocyanate, ferulic acid, quercetin, cinnamic acid and chlorogenic acid. Chief component analysis yielded 12 factors (80%), of which only a few factors showed negative associations with serum cholesterol and LDL concentration. Many factors showed adverse relationships with liver function and serum triacylglycerol concentration. Weekly self-reported daily dietary records including name of dish, constituent foods and their amounts were separately collected for 6 months and analyzed in Kyoto women. Seasonal changes of phytochemical intake showed significant variation according to the seasonal consumption of fruits and vegetables. Lycopene increased in the summer due to watermelon and tomato intake in this season. Seasonal variation of FFF was quite large compared to the variation of macro- and micronutrients. Careful evaluation of the effects of FFF intake on health is necessary, especially when supplements are also consumed. The most effective combinations of FFF intake for human health could be elucidated by using our FFF-DB in conjunction with population-based cohort studies.     

Consumption of flavonoid-rich foods and increased plasma antioxidant capacity in humans: cause, consequence, or epiphenomenon?

Increased fruit and vegetable consumption is associated with a decreased incidence of cardiovascular diseases, cancer, and other chronic diseases. The beneficial health effects of fruits and vegetables have been attributed, in part, to antioxidant flavonoids present in these foods. Large, transient increases in the total antioxidant capacity of plasma have often been observed after the consumption of flavonoid-rich foods by humans. These observations led to the hypothesis that dietary flavonoids play a significant role as antioxidants in vivo, thereby reducing chronic disease risk. This notion, however, has been challenged recently by studies on the bioavailability of flavonoids, which indicate that they reach only very low concentrations in human plasma after the consumption of flavonoid-rich foods. In addition, most flavonoids are extensively metabolized in vivo, which can affect their antioxidant capacity. Furthermore, fruits and vegetables contain many macro- and micronutrients, in addition to flavonoids, that may directly or through their metabolism affect the total antioxidant capacity of plasma. In this article, we critically review the published research in this field with the goal to assess the contribution of dietary flavonoids to the total antioxidant capacity of plasma in humans. We conclude that the large increase in plasma total antioxidant capacity observed after the consumption of flavonoid-rich foods is not caused by the flavonoids themselves, but is likely the consequence of increased uric acid levels.     

Role of plant polyphenols in genomic stability

Polyphenols are a large and diverse class of compounds, many of which occur naturally in a range of food plants. The flavonoids are the largest and best-studied group of these. A range of plant polyphenols are either being actively developed or currently sold as dietary supplements and/or herbal remedies. Although, these compounds play no known role in nutrition (non-nutrients), many of them have properties including antioxidant, anti-mutagenic, anti-oestrogenic, anti-carcinogenic and anti-inflammatory effects that might potentially be beneficial in preventing disease and protecting the stability of the genome. However not all polyphenols and not all actions of individual polyphenols are necessarily beneficial. Some have mutagenic and/or pro-oxidant effects, as well as interfering with essential biochemical pathways including topoisomerase enzyme activities, prostanoid biosynthesis and signal transduction. There is a very large amount of in vitro data available, but far fewer animal studies, and these are not necessarily predictive of human effects because of differences in bacterial and hepatic metabolism of polyphenols between species. Epidemiological studies suggest that high green tea consumption in the Japanese population and moderate red wine consumption in the French population may be beneficial for heart disease and cancer, and these effects may relate to specific polyphenols. A small number of adequately controlled human intervention studies suggest that some, but not all polyphenol extracts or high polyphenol diets may lead to transitory changes in the antioxidative capacity of plasma in humans. However, none of these studies have adequately considered long-term effects on DNA or the chromosome and unequivocally associated these with polyphenol uptake. Furthermore, clinical trials have required intravenously administered polyphenols at concentrations around 1400mg/m(2) before effects are seen. These plasma concentrations are unlikely to be achieved using the dietary supplements currently available. More focused human studies are necessary before recommending specific polyphenolic supplements at specific doses in the human population.     

Pharmacokinetics and metabolism of dietary flavonoids in humans

Flavonoids are components of fruit and vegetables that may be beneficial in the prevention of disease such as cancer and cardiovascular diseases. Their beneficial effects will be dependent upon their uptake and disposition in tissues and cells. The metabolism and pharmacokinetics of flavonoids has been an area of active research in the last decade. To date, approximately 100 studies have reported the pharmacokinetics of individual flavonoids in healthy volunteers. The data indicate considerable differences among the different types of dietary flavonoids so that the most abundant flavonoids in the diet do not necessarily produce the highest concentration of flavonoids or their metabolites in vivo. Small intestinal absorption ranges from 0 to 60% of the dose and elimination half-lives (T_1/2) range from 2 to 28 h. Absorbed flavonoids undergo extensive first-pass Phase II metabolism in the small intestine epithelial cells and in the liver. Metabolites conjugated with methyl, glucuronate and sulfate groups are the predominant forms present in plasma. This review summarizes the key differences in absorption, metabolism and pharmacokinetics between the major flavonoids present in the diet. For each flavonoid, the specific metabolites that have been identified so far in vivo are indicated. These data should be considered in the design and interpretation of studies investigating the mechanisms and potential health effects of flavonoids.     

Natural flavonoids for the prevention of colon cancer: A comprehensive review of preclinical and clinical studies

Flavonoids comprise a group of natural polyphenols consisting of more than 5,000 subtypes mostly existing in fruits and vegetables. Flavonoids consumption could potentially attenuate the incidence and recurrence risk of colorectal cancers through their antiperoxidative, antioxidant, and anti-inflammatory effects. In addition, these compounds regulate the mitochondrial function, balance the bacterial flora and promote the apoptosis process in cancerous cells. However, some previous data failed to show the effectiveness of flavonoids in reducing the risk of colorectal cancer. In this study, we have reviewed the efficacy of different flavonoids subtypes on the risk of colon cancer and molecular mechanisms involved in this process in both clinical and animal studies. In addition, we tried to elucidate the potential synergy between these compounds and current colorectal cancer treatments.     

Cocoa flavanols and cardiovascular health

Fruits and vegetables have historically been considered rich sources of essential dietary micronutrients, soluble fiber, and antioxidants. More recently they are have been recognized as important sources for a wide array of phytochemicals that individually, or in combination, may benefit vascular health. Flavonoids are the largest, and most widely distributed class of phytochemicals, and can be further subdivided into several different sub-classes. Several epidemiology studies have observed an inverse association between flavonoid intake and risk of cardiovascular mortality. One sub-class of flavonoids, the flavanols, is found in foods such as grapes, red wine, tea, cocoa and chocolate; however, it is important to note that common food processing practices can significantly reduce the levels of these compounds found in finished food products. Recent studies have examined the potential of flavanol-rich cocoa and chocolates to influence vascular health. In this review, we discuss evidence for the hypothesis that the consumption of flavanol-rich cocoa can reduce the risk for cardiovascular disease through a multiplicity of mechanisms, including changes in oxidant defense mechanisms, vascular reactivity, cytokine production, and platelet function. This revised version was published online in June 2006 with corrections to the Cover Date.     

Dietary phytochemicals and neuro-inflammaging: from mechanistic insights to translational challenges

An extensive literature describes the positive impact of dietary phytochemicals on overall health and longevity. Dietary phytochemicals include a large group of non-nutrients compounds from a wide range of plant-derived foods and chemical classes. Over the last decade, remarkable progress has been made to realize that oxidative and nitrosative stress (O&NS) and chronic, low-grade inflammation are major risk factors underlying brain aging. Accumulated data strongly suggest that phytochemicals from fruits, vegetables, herbs, and spices may exert relevant negative immunoregulatory, and/or anti-O&NS activities in the context of brain aging. Despite the translational gap between basic and clinical research, the current understanding of the molecular interactions between phytochemicals and immune-inflammatory and O&NS (IO&NS) pathways could help in designing effective nutritional strategies to delay brain aging and improve cognitive function. This review attempts to summarise recent evidence indicating that specific phytochemicals may act as positive modulators of IO&NS pathways by attenuating pro-inflammatory pathways associated with the age-related redox imbalance that occurs in brain aging. We will also discuss the need to initiate long-term nutrition intervention studies in healthy subjects. Hence, we will highlight crucial aspects that require further study to determine effective physiological concentrations and explore the real impact of dietary phytochemicals in preserving brain health before the onset of symptoms leading to cognitive decline and inflammatory neurodegeneration.     

Perspectives on using nonhuman primates to understand the etiology and treatment of postmenopausal osteoporosis

The reproductive physiology and skeletal anatomy of nonhuman primates are very similar to those of women and these similarities have prompted studies of the effects of ovariectomy in monkeys on bone metabolism. Following ovariectomy, monkey bone exhibits increases in remodeling activity resulting in bone loss. Since similar bone changes occur after menopause in women, ovariectomized monkeys provide an excellent model of the early skeletal events following menopause and have been employed to study the skeletal actions of drugs designed to treat postmenopausal osteoporosis. This review describes the motivations for examining monkeys, practical aspects of working with monkeys, comparisons of human and monkey bone anatomy, endocrinological aspects of monkey bone metabolism, and the available data obtained in monkeys related to postmenopausal and other forms of osteoporosis.     

Sympathetic neural influence on bone metabolism in microgravity (Review)

Bone loss is one of the most important complications for astronauts who are exposed to long-term microgravity in space and also for bedridden elderly people. Recent studies have indicated that the sympathetic nervous system plays a role in bone metabolism. This paper reviews findings concerning with sympathetic influences on bone metabolism to hypothesize the mechanism how sympathetic neural functions are related to bone loss in microgravity. Animal studies have suggested that leptin stimulates hypothalamus increasing sympathetic outflow to bone and enhances bone resorption through noradrenaline and β-adrenoreceptors in bone. In humans, even though there have been some controversial findings, use of β-adrenoblockers has been reported to be beneficial for prevention of osteoporosis and bone fracture. On the other hand, microneurographically-recorded sympathetic nerve activity was enhanced by exposure to microgravity in space as well as dry immersion or long-term bed rest to simulate microgravity. The same sympathetic activity became higher in elderly people whose bone mass becomes generally reduced. Our recent findings indicated a significant correlation between muscle sympathetic nerve activity and urinary deoxypyridinoline as a specific marker measuring bone resorption. Based on these findings we would like to propose a following hypothesis concerning the sympathetic involvement in the mechanism of bone loss in microgravity: An exposure to prolonged microgravity may enhance sympathetic neural traffic not only to muscle but also to bone. This sympathetic enhancement increases plasma noradrenaline level and inhibits osteogenesis and facilitates bone resorption through β-adrenoreceptors in bone to facilitate bone resorption to reduce bone mass. The use of β-adrenoblockers to prevent bone loss in microgravity may be reasonable.     

Structure‐Activity Relationships Analysis of Monomeric and Polymeric Polyphenols (Quercetin,Rutin and Catechin) Obtained by Various Polymerization Methods

Plant polyphenols, especially flavonoids, are active and pro‐health substances found in fruits and vegetables. Quercetin and its glycoside rutin are representatives of flavonoids, commonly found in plant products. Catechins found in large quantities in tea are also a well‐known group of natural polyphenols. These compounds are based on the structure of flavan‐3‐ol, which is why the number, positions and types of substitutions affect the scavenging of radicals and other properties. Despite some inconsistent evidence, several structure?activity relationships of monomeric flavonoids are well established in vitro. However, the relationships between the activity and other properties of the polymeric forms of flavonoids and their structures are poorly understood so far. The aim of this article is to compare the data on polymerization of quercetin, rutin and catechin, as well as to systematize knowledge about the structure?activity relationship of the polymeric forms of these compounds.     

绝经后骨质疏松运动疗法的研究进展

绝经后骨质疏松是一种发生于绝经后妇女的慢性骨代谢疾病,目前其治疗还主要靠药物,但长期使用药物的一些副作用使一些患者不愿意采用药物疗法。因此,其治疗和预防目前仍具有挑战,正日益成为一个公众健康问题。体育运动是防治绝经后骨质疏松的一种非药物疗法,由于其简便、副作用少,近年来备受医患人员的亲睐。本文在查阅国内外相关文献的基础上,对有氧运动、抗阻力运动、平衡和本体感受训练、振动训练和水中训练等不同运动疗法在绝经后骨质疏松防治中的研究进展进行了综述。     

Biosynthesis and genetic engineering of proanthocyanidins and (iso)flavonoids

Plant natural products have been used since ancient times as medicines and herbal remedies. Over the past two decades, the results of population and intervention studies, or assays in animal or cell model systems, have revealed positive health beneficial effects for various classes of phytochemicals, particularly polyphenols. The results of such studies have ignited an interest in being able to manipulate the levels of such bioactive compounds in plants using biotechnological approaches. Although still in its infancy, this technology promises to deliver health benefits to humans and animals through direct consumption of genetically-modified or -enhanced dietary plant materials. We here review the strategies currently being used for engineering two classes of nutraceuticals, the proanthocyanidins and the isoflavones, in transgenic plants. We also provide an overview of recent advances in our understanding of the biosynthesis of these classes of compounds.     

Phenolic compounds: from plants to foods

Phenolic compounds are a large class of plant secondary metabolites, showing a diversity of structures, from rather simple structures, e.g. phenolic acids, through polyphenols such as flavonoids, that comprise several groups, to polymeric compounds based on these different classes. Phenolic compounds are important for the quality of plant based foods: they are responsible for the colour of red fruits, juices and wines and substrates for enzymatic browning, and are also involved in flavour properties. In particular, astringency is ascribed to precipitation of salivary proteins by polyphenols, a mechanism possibly involved in defence against their anti-nutritional effects. Finally, phenolic compounds are considered to contribute to the health benefits associated to dietary consumption of fruits and vegetables. During food processing and storage, plant phenolics are converted to a variety of derived compounds. While methods to analyse lower molecular weight phenolic compounds are well developed, analysis of polymeric compounds remains a challenge. Indeed, strong interactions of polymeric phenolics with plant cell wall material limit their extraction. Besides, their polydispersity results in poor resolution and detection, especially of derived structures such as oxidation products. However, recent advances of the analytical techniques have allowed some progress in their structural characterisation. This review summarizes the current knowledge on methods to analyse polyphenols. It presents their reactions in foods and beverages and the resulting structures, and highlights some aspects related to their impact on colour, flavour and health properties, with examples taken mostly from wine research.