Regulation of cellular signals from nutritional molecules: a specific role for phytochemicals, beyond antioxidant activity

Phytochemicals (PhC) are a ubiquitous class of plant secondary metabolites. A "recommended" human diet should warrant a high proportion of energy from fruits and vegetables, therefore providing, among other factors, a huge intake of PhC, in general considered "health promoting" by virtue of their antioxidant activity and positive modulation, either directly or indirectly, of the cellular and tissue redox balance. Diet acts through multiple pathways and the association between the consumption of specific food items and the risk of degenerative diseases is extremely complex. Recent literature suggests that molecules having a chemical structure compatible with a putative antioxidant capacity can actually "perform" activities and roles independent of such capacity, interacting with cellular functions at different levels, such as affecting enzyme activities, binding to membrane or nuclear receptors as either an elective ligand or a ligand mimic. Inductive or signaling effects may occur at concentrations much lower than that required for effective antioxidant activity. Therefore, the "antioxidant hypothesis" is to be considered in some cases an intellectual "shortcut" possibly biasing the real understanding of the molecular mechanisms underlying the beneficial effects of various classes of food items. In the past few years, many exciting new indications elucidating the mechanisms of polyphenols have been published. Here, we summarize the current knowledge of the mechanisms by which specific molecules of nutritional interest, and in particular polyphenols, play a role in cellular response and in preventing pathologies. In particular, their direct interaction with nuclear receptors and their ability to modulate the activity of key enzymes involved in cell signaling and antioxidant responses are presented and discussed.     

Enhancing beneficial antioxidants in fruits: a plant physiological perspective

The aim of this review is to present an outline of the physiological perspectives of beneficial antioxidant production in fruit. The drive to enhance the consumption of fruit and vegetables in the human diet is linked with positive effects of beneficial antioxidants impacting on health promotion. We briefly outline our physiological understanding of environmental processes which induce the production of reactive oxygen species and how antioxidants prevent plant cellular damage. More specifically, we describe the impact that environmental stresses, such as drought and radiation, have on the production of endogenous antioxidants and how these stresses can be incorporated into novel experimental crop growing systems to achieve high antioxidant concentrations in fruits. This includes in particular the use of irrigation application techniques and enhanced light reflectance to increase the concentrations of bioactive compounds such as ellagic acid and ascorbic acid.     

Phenolic phytochemicals and bone

Concerning the prevention of osteoporosis, recognized as a major public health problem, nutrition may appear as an alternative strategy for optimizing health skeleton. The importance of adequate calcium and vitamin D intakes for bone health is now well documented. But, in addition to essential macro- and micronutrients, human diet contains a complex array of non-nutrient natural bioactive molecules, namely the phytochemicals that may act and protect bone. Among phytochemicals, emphasis has been so far placed upon polyphenols. Indeed, subsequent epidemiological studies have suggested associations between long-term consumption of diets rich in polyphenols and protection against chronic diseases. With respect to human health, flavonoids are the most extensively studied polyphenols. These compounds may be partly responsible for some of the positive links found between fruit and vegetables intake and higher bone mineral density in adults and children. However, no long-term intervention studies in humans have investigated the effect of specific phenolic phytochemicals on the prevention of bone loss in postmenopausal women, except for phytoestrogens (soy isoflavones, lignans). Besides, in animal models of postmenopausal osteoporosis, consumption of some dietary flavonoids has been shown to prevent ovariectomy-induced bone loss. Finally, few in vitro experiments with bone cells have reported cellular and molecular mechanisms of phytochemicals involved in bone metabolism. To date, investigations providing some evidence of a positive impact of some phytochemicals on bone metabolism are accumulating but further studies, notably clinical trials, are needed to explore the various bioactivities offered by such compounds. Anyway, it can be postulated that increased consumption of plant-derived foods, especially fruit and vegetables, may be positive in the prevention of osteoporosis.     

An Investigation of the Antioxidant Activity of Black Tea Using Enhanced Chemiluminescence

Antioxidants are important species which possess the ability to protect the body from damage caused by free radical-induced oxidative stress. A variety of free radical-scavenging antioxidants exist within the body many of which are derived from dietary sources. There is currently much interest in the antioxidant role of flavonoids and other polyphenols found in tea, wine, fruit and vegetables. Enhanced chemiluminescence is a simple technique which can be used as a rapid and sensitive assay for measuring the antioxidant activity of beverages such as green and black tea. This article examines the impact of water temperature, stewing time, leaf concentration and the addition of milk upon the antioxidant activity of black tea solutions. The antioxidant activity of a range of commercially available black and green teas has also been measured.     

Role of diet modification in cancer prevention

Carcinogenesis encompasses a prolonged accumulation of injuries at several different biological levels and include both genetic and biochemical changes in the cells. At each of these levels, there are several possibilities of intervention in order to prevent, slow down or even halt the gradual march of healthy cells towards malignancy. Diet modification is one such possibility. A number of natural foodstuffs, especially fruits and vegetables contain substantial quantities of molecules that have chemopreventive potential against cancer development. Such compounds include vitamins, trace elements and a variety of other molecules with antioxidant properties. Carotenoids, flavanoid polyphenols, isoflavones, catechins, and several other components that found in cruciferous vegetables are molecules that are known to protect against the deleterious effect of reactive oxygen species. A number of epidemiological and experimental studies have shown that vitamin C and E, Beta-carotene and the essential trace element selenium can reduce the risk of cancer. Consistent observations during the last few decades that cancer risk is reduced by a diet rich in vegetables, fruits, legumes, grains and green tea have encouraged research to identify several plant components especially phytochemicals that protect against DNA damage. Many of these substances block specific carcinogen pathways. Dietary supplements are part of an overall health program, along with a high intake of fruits and vegetables that help to combat damage to cells, which in turn may initiate cancer development. This paper will review current knowledge concerning diet modification and cancer prevention with special reference to minerals and trace elements.     

Products of DNA, protein and lipid oxidative damage in relation to vitamin C plasma concentration

Oxidative stress plays an important role in the pathogenesis of numerous chronic age-related free radical-induced diseases. Improved antioxidant status minimizes oxidative damage to DNA, proteins, lipids and other biomolecules. Diet-derived antioxidants such as vitamin C, vitamin E, carotenoids and related plant pigments are important in antioxidative defense and maintaining health. The results of long-term epidemiological and clinical studies suggest that protective vitamin C plasma concentration for minimum risk of free radical disease is higher than 50 micromol/l. Products of oxidative damage to DNA (DNA strand breaks with oxidized purines and pyrimidines), proteins (carbonyls) and lipids (conjugated dienes of fatty acids, malondialdehyde) were estimated in a group of apparently healthy adult non-smoking population in dependence on different vitamin C plasma concentrations. Under conditions of protective plasma vitamin C concentrations (>50 micromol/l) significantly lower values of DNA, protein and lipid oxidative damage were found in comparison with the vitamin C-deficient group (<50 micromol/l). The inhibitory effect of higher fruit and vegetable consumption (leading to higher vitamin C intake and higher vitamin C plasma concentrations) on oxidation of DNA, proteins and lipids is also expressed by an inverse significant correlation between plasma vitamin C and products of oxidative damage. The results suggest an important role of higher and frequent consumption of protective food (fruit, vegetables, vegetable oils, nuts, seeds and cereal grains) in prevention of free radical disease.     

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.     

Separation procedures for naturally occurring antioxidant phytochemicals

Phytochemicals in fruits, vegetables, spices and traditional herbal medicinal plants have been found to play protective roles against many human chronic diseases including cancer and cardiovascular diseases (CVD). These diseases are associated with oxidative stresses caused by excess free radicals and other reactive oxygen species. Antioxidant phytochemicals exert their effect by neutralizing these highly reactive radicals. Among the tens of thousands of phytochemicals found in our diets or traditional medicines, polyphenols and carotenoids stand out as the two most important groups of natural antioxidants. However, although collectively these phytochemicals are good antioxidants, the roles and effect of individual compounds are often not well known. Hundreds of carotenoids and thousands of polyphenols have been identified so far from various plants. A single plant could contain highly complex profiles of these compounds, which sometimes are labile to heat, air and light, and they may exist at very low concentrations in the plants. This makes the separation and detection of these antioxidant phytochemicals a challenging task. The present review focuses on the antioxidant activity, chemical types, sampling and sample processing procedures, and separation using various chromatographic and electrophoretic techniques. Detection and quantification using ultraviolet-visible-diode array and mass spectrometry will be discussed.     

Flavonoids and steroid hormone-dependent cancers

Steroid-hormone dependent cancers, including those of the breast, prostate and colon, are leading causes of morbidity and mortality in western countries. In rural Asian areas, these diseases are relatively uncommon. Dietary factors, including low consumption of fruit, vegetables and soy in the west have been shown in various epidemiologic studies as reasons for these differences. This review discusses flavonoids, one component of these plant foods that is being investigated for their role in chemoprevention. Epidemiological, in vitro, animal and human studies shall be explored to look at mechanisms involved, including steroid hormone activity, effects on cell growth, antioxidant activities, inhibition of chemical carcinogenesis and influences on modulators of cancer risk. Although the in vitro and animal models point to several pathways by which flavonoids may reduce incidence of these cancers, the clinical data are still relatively lacking. More research is needed to determine how best to use foods containing these compounds to reduce steroid hormone-dependent cancer risk.     

Dietary polyphenols in chemoprevention and synergistic effect in cancer: Clinical evidences and molecular mechanisms of action

BackgroundEpidemiological studies has revealed that a diet rich in fruits and vegetables could lower the risk of certain cancers. In this setting, natural polyphenols are potent anticancer bioactive compounds to overcome the non-target specificity, undesirable cytotoxicity and high cost of treatment cancer chemotherapy.PurposeThe review focuses on diverse classifications of the chemical diversity of dietary polyphenol and their molecular targets, modes of action, as well as preclinical and clinical applications in cancer prevention.ResultsThe dietary polyphenols exhibit chemo-preventive activity through modulation of apoptosis, autophagy, cell cycle progression, inflammation, invasion and metastasis. Polyphenols possess strong antioxidant activity and control multiple molecular events through activation of tumor suppressor genes and inhibition of oncogenes involved in carcinogenesis. Numerous in vitro and in vivo studies have evidenced that these dietary phytochemicals regulate critical molecular targets and pathways to limit cancer initiation and progression. Moreover, natural polyphenols act synergistically with existing clinically approved drugs. The improved anticancer activity of combinations of polyphenols and anticancer drugs represents a promising perspective for clinical applications against many human cancers.ConclusionThe anticancer properties exhibited by dietary polyphenols are mainly attributed to their anti-metastatic, anti-proliferative, anti-angiogenic, anti-inflammatory, cell cycle arrest, apoptotic and autophagic effects. Hence, regular consumption of dietary polyphenols as food or food additives or adjuvants can be a promising tactic to preclude adjournment or cancer therapy.     

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.     

Modification of flavonoid biosynthesis in crop plants

Flavonoids comprise the most common group of polyphenolic plant secondary metabolites. In plants, flavonoids play an important role in biological processes. Beside their function as pigments in flowers and fruits, to attract pollinators and seed dispersers, flavonoids are involved in UV-scavenging, fertility and disease resistance. Since they are present in a wide range of fruits and vegetables, flavonoids form an integral part of the human diet. Currently there is broad interest in the effects of dietary polyphenols on human health. In addition to the potent antioxidant activity of many of these compounds in vitro, an inverse correlation between the intake of certain polyphenols and the risk of cardiovascular disease, cancer and other age related diseases has been observed in epidemiological studies. The potential nutritional effects of these molecules make them an attractive target for genetic engineering strategies aimed at producing plants with increased nutritional value. This review describes the current knowledge of the molecular regulation of the flavonoid pathway and the state of the art with respect to metabolic engineering of this pathway in crop plants.     

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.     

Proposed criteria for assessing the efficacy of cancer reduction by plant foods enriched in carotenoids, glucosinolates, polyphenols and selenocompounds

BACKGROUND AND AIMS: The cancer-protective properties of vegetable consumption are most likely mediated through 'bioactive compounds' that induce a variety of physiologic functions including acting as direct or indirect antioxidants, regulating enzymes and controlling apoptosis and the cell cycle. The 'functional food' industry has produced and marketed foods enriched with bioactive compounds, but there are no universally accepted criteria for judging efficacy of the compounds or enriched foods. SCOPE: Carotenoids, glucosinolates, polyphenols and selenocompounds are families of bioactive compounds common to vegetables. Although numerous studies have investigated the agricultural and human health implications of enriching foods with one or more of these compounds, inadequate chemical identification of compounds, lack of relevant endpoints and inconsistencies in mechanistic hypotheses and experimental methodologies leave many critical gaps in our understanding of the benefits of such compounds. This review proposes a decision-making process for determining whether there is reasonable evidence of efficacy for the both the compound and the enriched food. These criteria have been used to judge the evidence of efficacy for cancer prevention by carotenoids, polyphenols, glucosinolates and selenocompounds. CONCLUSIONS: The evidence of efficacy is weak for carotenoids and polyphenols; the evidence is stronger for glucosinolates and lycopene, but production of enriched foods still is premature. Additionally there is unacceptable variability in the amount and chemical form of these compounds in plants. The evidence of efficacy for selenocompounds is strong, but the clinical study that is potentially the most convincing is still in progress; also the variability in amount and chemical form of Se in plants is a problem. These gaps in understanding bioactive compounds and their health benefits should not serve to reduce research interest but should, instead, encourage plant and nutritional scientists to work together to develop strategies for improvement of health through food.     

Role of nutrition in toxic injury

The importance of nutrition in protecting the living organism against the potentially lethal effects of reactive oxygen species and toxic environmental chemicals has recently been realized. This new perspective has prompted re-evaluation of the food constituents of human diet from the point of view of their nutritional adequacy, deficiency and toxicity. The biological antioxidant defense system is an integrated array of enzymes, antioxidants and free radical scavengers. These include glutathione reductase, glutathione-s-transferase, glutathione peroxidase, phospholipid hydroperoxide glutathione peroxidase, superoxide dismutase (SOD) and catalase, together with the antioxidant vitamins C, E and A. The individual components of this system get utilized in various physiological process and for chemoprotection and therefore require replenishment from the diet. Other components of the diet like carbohydrates, proteins and lipids are important for maintaining the levels of various enzymes required in body's defense system providing protection against carcinogens. However, the emerging newer concepts focus on the role of trace elements and other dietary components in antioxidant defense and detoxification mechanisms. Trace elements like Iron, zinc magnesium, selenium, copper, and manganese are some of the elements involved in antioxidant defense mechanisms. Inadequate intake of these nutrients has been associated with ischemic heart disease, arthritis, stroke and cancer, where pathogenic role of free radicals is suggested. Further the importance of diet in the prevention of chemical induced toxicity can not be undetermined. Recent reports on the role of bioflavonoids as antioxidents and their potential use to reduce the risks of coronary heart disease and cancer in human beings have opened a new arena for future research. Induction of the cytochrome P450 isoenzymes by food pyrolysis, mutagens, alcohol and fasting, on the other hand is reported to contribute to chemical toxicity and carcinogenecity. Certain chemicals moieties in the food are mutagenic and carcinogenic.     

Carotenoids: separation methods applicable to biological samples

Epidemiologic and clinical studies have shown that a high intake of vegetables and fruit, with consequently high intakes and circulating concentrations of carotenoids, is associated with reduced risk of cardiovascular and other chronic diseases. The antioxidant properties of carotenoids are thought to contribute to these effects. The analysis of carotenoids in plasma, foods and tissues has thus become of interest in studies examining the role of diet in chronic disease prevention and management. High-performance liquid chromatography with ultra-violet or photodiode array detection is most often employed in routine use. We review these and other current methods for carotenoid analysis and information on sample stability relevant to epidemiological studies. The carotenoids remain an important and intriguing subject of study, with relevance to prevention of several important "lifestyle-related" diseases. Research into their physiological functions and their use as dietary markers requires sensitive, accurate and precise measurement. Further advances in these methodological areas will contribute to basic, clinical and public health research into the significance of carotenoid compounds in disease prevention.     

Molecular and physiological strategies to increase aluminum resistance in plants

Aluminum (Al) toxicity is a primary limitation to plant growth on acid soils. Root meristems are the first site for toxic Al accumulation, and therefore inhibition of root elongation is the most evident physiological manifestation of Al toxicity. Plants may resist Al toxicity by avoidance (Al exclusion) and/or tolerance mechanisms (detoxification of Al inside the cells). The Al exclusion involves the exudation of organic acid anions from the root apices, whereas tolerance mechanisms comprise internal Al detoxification by organic acid anions and enhanced scavenging of free oxygen radicals. One of the most important advances in understanding the molecular events associated with the Al exclusion mechanism was the identification of the ALMT1 gene (Al-activated malate transporter) in Triticum aestivum root cells, which codes for a plasma membrane anion channel that allows efflux of organic acid anions, such as malate, citrate or oxalate. On the other hand, the scavenging of free radicals is dependent on the expression of genes involved in antioxidant defenses, such as peroxidases (e.g. in Arabidopsis thaliana and Nicotiana tabacum), catalases (e.g. in Capsicum annuum), and the gene WMnSOD1 from T. aestivum. However, other recent findings show that reactive oxygen species (ROS) induced stress may be due to acidic (low pH) conditions rather than to Al stress. In this review, we summarize recent findings regarding molecular and physiological mechanisms of Al toxicity and resistance in higher plants. Advances have been made in understanding some of the underlying strategies that plants use to cope with Al toxicity. Furthermore, we discuss the physiological and molecular responses to Al toxicity, including genes involved in Al resistance that have been identified and characterized in several plant species. The better understanding of these strategies and mechanisms is essential for improving plant performance in acidic, Al-toxic soils.     

Chemical composition and nutritional function of olive (<Emphasis Type="Italic">Olea europaea</Emphasis> L.): a review

The olive (Olea europaea L.) is a widely-distributed plant that originated in the Mediterranean region. Its fruit is commonly used to produce olive oil, table olives, and other by-products. The main nutrient of the olive fruit is fat, predominantly monounsaturated fatty acids (MUFA). Olives are also rich in carbohydrates, vitamins, and minerals. Increasing numbers of investigations show that the health benefits of the ‘Mediterranean diet’ are associated with lower incidences of chronic degenerative diseases and higher life expectancy. These benefits have been attributed to the dietary consumption of olive oil. Furthermore, epidemiological data suggest that phenolic components and other antioxidants in olive oil are responsible for some of these benefits. Remarkably, these minor components play significant roles in reducing the incidences of atherosclerosis, cardiovascular disease, neurodegenerative diseases, and certain types of cancer. We reviewed the main olive products and the nutritional composition of olive oil focusing on fatty acids, phenolic compounds, and other antioxidants. We also discuss the chief chemical constituents relevant to the biological activity of olive oil, the metabolism and bioavailability of olive oil phenolic compounds, and the antioxidant activity of metabolites. Finally, we outline recent advances, potential applications, and limitations of developments in the olive oil industry, aiming to provide a theoretical basis for further research and to broaden the prospect of its application to healthy diets.     

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.