Effect of protocatechuic acid on insulin responsiveness and inflammation in visceral adipose tissue from obese individuals: possible role for PTP1B.

BACKGROUND/OBJECTIVES: The occurrence of chronic inflammation in visceral adipose tissue (VAT) in obese subjects precipitates the development of insulin resistance and type 2 diabetes (T2D). Anthocyanins and their main metabolite protocatechuic acid (PCA) have been demonstrated to stimulate insulin signaling in human adipocytes. The aim of this study was to investigate whether PCA is able to modulate insulin responsiveness and inflammation in VAT from obese (OB) and normal weight (NW) subjects. SUBJECTS/METHODS: VATs obtained from NW and OB subjects were incubated or not (control) with 100 µM PCA for 24 h. After incubation, tissues untreated and treated with PCA were acutely stimulated with insulin (20 nM, 20 min). PTP1B, p65 NF-κB, phospho-p65 NF-κB, IRS-1, IRß, Akt, GLUT4 as well as basal and insulin-stimulated Tyr-IRS-1 and Ser-Akt phosphorylations were assessed by Western blotting in NW- and OB-VAT. Samples were assessed for PTP1B activity and adipocytokine secretion. RESULTS: PCA restored insulin-induced phosphorylation in OB-VAT by increasing phospho-Tyr-IRS-1 and phospho-Ser-Akt after insulin stimulation as observed in NW-VAT (p < 0.05). PTP1B activity was lower in OB-VAT treated with PCA with respect to untreated (p < 0.05). Compared to non-treated tissues, PCA reduced phospho-p65 NF-κB and IL-6 in OB-VAT, and IL-1ß in NW-VAT (p < 0.05); and increased adiponectin secretion in NW-VAT (p < 0.05). CONCLUSION: PCA restores the insulin responsiveness of OB-VAT by increasing IRS-1 and Akt phosphorylation which could be related with the lower PTP1B activity found in PCA-treated OB-VAT. Furthermore, PCA diminishes inflammation in VAT. These results support the beneficial role of an anthocyanin-rich diet against inflammation and insulin resistance in obesity.

Culture, religion and gender: considerations in facing migration related health inequalities in Italy.

BACKGROUND: The presence in Italy of a significant foreign population (5-6 million including both formally residents and not officially registered ones) introduces significant transformations in the Italian demography with important challenges on ensuring fundamental rights including work, education and above all, health. Access to healthcare. Issues common to the entire migrant population concern the difficulty of accessing the health system of the host country due to the lack of knowledge of its rules and its functioning, the linguistic and cultural barriers and the distrust towards a system that is not recognized as his own, as well as the difficulties and misunderstandings encountered in the relationship with health professionals. Religion, culture and gender may even increase these difficulties. Conlusion and future perspective. Culture and religion should be taken into account when designing and implementing healthcare services and healthcare workers need to be trained in acknowledging these challenges. The National Health Service should become more sensitive to the increasing cultural and religious pluralism of patients starting with investing more in the training of health professionals.

Predominant role of obesity/insulin resistance in oxidative stress development.

BACKGROUND: Hyperlipidaemia, hyperglycaemia and hyperinsulinaemia, hallmarks of the postprandial state, have been also associated with increased oxidative stress and lipoprotein oxidation contributing to vascular injury and atherosclerosis. However, the specific links among metabolic disorders, postprandial state, insulin resistance and oxidative stress are still to be clarified. This study aimed at investigating the individual role played by obesity, insulin resistance and type 2 diabetes in the occurrence of fasting and postprandial oxidative stress. DESIGN: Biomarkers of oxidative stress [F2-isoprostanes and circulating oxidized low-density lipoproteins (LDL)], LDL oxidability (conjugated diene kinetic, thiobarbituric acid reactive substances (TBARs) formation and electronegativity increase) and antioxidant vitamins (ß-carotene, α-tocopherol and retinol) were evaluated at fasting and 6 h after a standard fat-rich meal in 10 obese diabetic (ObD), 11 obese and 11 normal-weight control men. Insulin sensitivity was evaluated by euglycaemic hyperinsulinaemic clamp. RESULTS: ObD and obese subjects, characterized by a similar level of adiposity and insulin resistance, showed higher urinary F2-isoprostanes and circulating oxidized LDL, an increased susceptibility to oxidation of plasma LDL (lower lag phase, higher TBARs formation, and higher relative electrophoretic mobility), and lower plasma content of ß-carotene and retinol than control subjects, both at fasting and after the test meal. CONCLUSIONS: Obesity and insulin resistance, more than type 2 diabetes, play the most relevant role in oxidative stress development. The correction of obesity and insulin resistance might be a useful strategy in counteracting systemic oxidative stress.

Role of polyphenols in cell death control.

Dietary consumption of fruit, vegetables, fish, and olive oil has been demonstrated to exert beneficial effects on human health. This finding may be due to the high content of antioxidant compounds including polyphenols. Current evidence strongly supports a contribution of polyphenols to the prevention of several chronic degenerative diseases such as cancer, atherosclerosis and cardiovascular diseases, central nervous system disorders, as well as aging. Apoptosis is a genetically controlled and evolutionarily conserved form of cell death of critical importance for the maintenance of tissue homeostasis in the adult organism. The malfunction of the death machinery may play a primary role in various pathologic processes, leading to proliferative or degenerative diseases. Polyphenols can interact with specific steps and/or proteins regulating the apoptotic process in different ways depending on their concentration, the cell system, the type or stage of the pathological process. Because of their ability to modulate cell death, polyphenols have been proposed as chemopreventive and therapeutic agents. This paper reviews and discusses the last 3-year findings related to the principal molecular mechanisms involved in the control of the balance between apoptosis and cell proliferation exerted by polyphenols.

Improving Nutrition Knowledge and Skills by the Innovative Education Program MaestraNatura in Middle School Students of Italy.

Promoting a healthy diet, mainly in youths, is the most effective action to prevent and fight dietary excesses and nutritional imbalance in the population. MaestraNatura (MN) is an innovative nutritional education program aimed at promoting a healthy lifestyle in first-level secondary school students. The study evaluated the effectiveness of the MN program in improving knowledge in students following the MN program (MN group) with respect to a control group (CO group) undergoing a "traditional" nutritional education path. To this end, the nutrition knowledge of the two groups was assessed by three multi-choice questionnaires. The results showed a significant improvement in knowledge (p < 0.001) in the MN group with respect to the CO group for all the questionnaires. Furthermore, the students' ability to transfer the principles of nutrition guidelines to the real context of daily meals was determined by asking the MN group to create a weekly food plan before (T0) and after (T1) the completion of the MN program. The MN group demonstrated improved performance in organizing the weekly menu plan at T1 with respect to T0 (p = 0.005). In conclusion, the MN nutritional education program appears to be an effective tool for improving knowledge and skills on nutritional issues, especially in those students with a lower starting level of knowledge and ability.

Obesity-Associated Inflammation: Does Curcumin Exert a Beneficial Role?

Curcumin is a lipophilic polyphenol, isolated from the plant turmeric of Curcuma longa. Curcuma longa has always been used in traditional medicine in Asian countries because it is believed to have numerous health benefits. Nowadays it is widely used as spice component and in emerging nutraceutical food worldwide. Numerous studies have shown that curcumin possesses, among others, potential anti-inflammatory properties. Obesity represents a main risk factor for several chronic diseases, including type 2 diabetes, cardiovascular disease, and some types of cancer. The establishment of a low-grade chronic inflammation, both systemically and locally in adipose tissue, occurring in obesity most likely represents a main factor in the pathogenesis of chronic diseases. The molecular mechanisms responsible for the onset of the obesity-associated inflammation are different from those involved in the classic inflammatory response caused by infections and involves different signaling pathways. The inflammatory process in obese people is triggered by an inadequate intake of nutrients that produces quantitative and qualitative alterations of adipose tissue lipid content, as well as of various molecules that act as endogenous ligands to activate immune cells. In particular, dysfunctional adipocytes secrete inflammatory cytokines and chemokines, the adipocytokines, able to recruit immune cells into adipose tissue, amplifying the inflammatory response also at systemic level. This review summarizes the most recent studies focused at elucidating the molecular targets of curcumin activity responsible for its anti-inflammatory properties in obesity-associated inflammation and related pathologies.

Promoting Health and Food Literacy through Nutrition Education at Schools: The Italian Experience with MaestraNatura Program.

MaestraNatura is an innovative nutrition education program aimed at both enhancing awareness about the importance of a healthy food-lifestyle relationship and the ability to transfer the theoretical principles of nutrition guidelines to everyday life. The educational contents of the program resulted from the analysis of the answers to a questionnaire submitted to students aged 6-13 in order to assess their degree of knowledge about nutritional facts. Educational paths were specifically designed and implemented to address the main knowledge gaps identified through the analysis of the answers and were then tested for teachers' satisfaction in a sample of 56 schools in the north, centre, and south of Italy, involving 790 classes, 600 teachers, and 15,800 students. The results showed an approval rating from teachers from 90% to 94%. Said paths were designed for primary (6-10 years old) and first-level secondary (11-13 years old) school students. In addition, in a pilot study carried out in nine Educational Institutes located in an area close to Rome (Lazio region), a specific path was tested for effectiveness in increasing students' knowledge about fruit and vegetables by conducting questionnaires before (T0) and after (T1) the didactic activities. Results showed a significant increase in right answers at T1 with respect to T0 (z = 2.142, p = 0.032). Fisher's exact probability test showed an answer variability depending on the issue considered. In conclusion, this work could be considered as a first necessary step toward the definition of new educational program, aimed at increasing food literacy and favouring a healthier relationship with food, applicable in a widespread and effective manner, also outside of Italy.

Oxidised LDL up-regulate CD36 expression by the Nrf2 pathway in 3T3-L1 preadipocytes.

The effect of oxLDL on CD36 expression has been assessed in preadipocytes induced to differentiate. Novel evidence is provided that oxLDL induce a peroxisome proliferator-activated receptor gamma-independent CD36 overexpression, by up-regulating nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2). The nuclear translocation of Nrf2 appeared to depend on PKC pathway activation. In adipocytes, the CD36 up-regulation may indicate a compensation mechanism to meet the demand of excess oxLDL and oxidised lipids in blood, reducing the risk of atherogenesis. Besides strengthening the hypothesis that oxLDL can contribute to the onset of insulin-resistance, data herein presented highlight the significance of oxLDL-induced CD36 overexpression within the cellular defence response.

Apoptosis induced by oxidized lipids is associated with up-regulation of p66Shc in intestinal Caco-2 cells: protective effects of phenolic compounds.

In this study, we investigated the alterations of the redox balance induced by the lipid fraction of oxLDL in Caco-2 intestinal cells, and the effects of tyrosol and protocatechuic acid, two dietary phenolic compounds. We found that oxidized lipids extracted from oxLDL (LipE) induced oxidative stress by determining, 6 h after treatment, ROS overproduction (about a 100% and a 43% increase of O*2 and H2O2 production, respectively, P<.05: LipE vs. control) and, 12 h after treatment, GSH depletion (about a 26% decrease, P<.05: LipE vs. control), and by impairing the activities of superoxide dismutase, catalase and glutathione peroxidase. In response to the induced oxidative stress, we observed significant overexpression of glutathione peroxidase (6 h after treatment: P<.05), glutathione reductase and gamma-glutamylcysteine synthetase (12 h after treatment: P<.05). Notably, when GSH depletion occurred, p66Shc protein expression increased by about 300% with respect to control (P<.001; LipE vs. control). These effects were fully counteracted by dietary phenolics which inhibited ROS overproduction and GSH consumption, rendered the reactive transcription of glutathione-associated enzymes unnecessary and blocked the intracellular signals leading to the overexpression and rearrangement of p66Shc signalling molecule. Altogether, these results suggest that the impairment of the antioxidant system hijacks intestinal cells towards an apoptotic-prone phenotype via the activation of p66Shc molecule. They also propose a reappraisal of dietary polyphenols as intestinal protecting agents, indicating the antiapoptotic effect as a further mechanism of action of these antioxidant compounds.

Modulatory effects of polyphenols on apoptosis induction: relevance for cancer prevention.

Polyphenols, occurring in fruit and vegetables, wine, tea, extra virgin olive oil, chocolate and other cocoa products, have been demonstrated to have clear antioxidant properties in vitro, and many of their biological actions have been attributed to their intrinsic reducing capabilities. However, it has become clear that, in complex biological systems, polyphenols exhibit several additional properties which are yet poorly understood. Apoptosis is a genetically controlled and evolutionarily conserved form of cell death of critical importance for the normal embryonic development and for the maintenance of tissue homeostasis in the adult organism. The malfunction of the death machinery may play a primary role in various pathological processes, since too little or too much apoptosis can lead to proliferative or degenerative diseases, respectively. Cancer cells are characterized by a deregulated proliferation, and/or an inability to undergo programmed cell death. A large body of evidence indicates that polyphenols can exert chemopreventive effects towards different organ specific cancers, affecting the overall process of carcinogenesis by several mechanisms: inhibition of DNA synthesis, modulation of ROS production, regulation of cell cycle arrest, modulation of survival/proliferation pathways. In addition, polyphenols can directly influence different points of the apoptotic process, and/or the expression of regulatory proteins. Although the bulk of data has been obtained in in vitro systems, a number of clinical studies suggesting a preventive and therapeutic effectiveness of polyphenols in vivo is available. However, a deeper knowledge of the underlying mechanisms responsible for the modulation of apoptosis by polyphenols, and their real effectiveness, is necessary in order to propose them as potential chemopreventive and chemotherapeutic candidates for cancer treatment.

Recent Evidence on the Role of Dietary PUFAs in Cancer Development and Prevention.

BACKGROUND: Scientific evidence has been accumulated about the effects of polyunsaturated fatty acids (PUFAs) on human health. The hypothesis that n-3 PUFAs might improve the efficiency of anticancer drugs has recently been considered. The role of n-6 PUFAs, in contrast, needs to be better assessed. However, the effective mechanisms of action of PUFAs have not been fully clarified yet. This review aims to report the most updated evidence on the role of n-6 and n-3 PUFAs in the development and treatment of human cancers, focusing on the potential mechanisms by which PUFAs exert their effects. METHODS: We undertook a structured search in PubMed on February 17th 2017 for peer-reviewed research articles published from 2013. The search syntax used was: PUFA or PUFAs and cancer. RESULTS: Contradictory results were found, most likely due to the genetic background, the different dietary sources used, the interaction among different nutrients, and the tumor subtypes. However, the more recent findings strongly support the use of n-3 PUFAs in cancer prevention and treatment. On the other hand, n-6 PUFAs are often associated with an increased risk of cancer, even if recently their beneficial effects have also been highlighted. CONCLUSION: N-3 PUFAs may represent a potential therapeutic agent contributing to treat at least some type of human cancers. However, studies with larger sample sizes and longer follow-up times are still needed. To increase the knowledge about how food and nutrition can improve human health it is advisable to deliver an open access nutritional database.

Anti-inflammatory Activity of Extra Virgin Olive Oil Polyphenols: Which Role in the Prevention and Treatment of Immune-Mediated Inflammatory Diseases?

BACKGROUND AND OBJECTIVE: Altered inflammatory response characterizes chronic immunemediated inflammatory diseases (IMID) such as rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus, and psoriasis. Accumulating evidence indicates that regular consumption of extra virgin olive oil (EVOO), the main source of fat in the Mediterranean diet, is associated with a reduced risk of developing chronic degenerative disorders such as cardiovascular diseases, type 2 diabetes and cancer. The beneficial effects on health of EVOO have been attributed, besides to the monounsaturated fats content, to the presence of phenolic compounds that have antioxidant, anti-inflammatory and immunomodulatory properties. The purpose of this review is to provide an overview of the effects of EVOO polyphenols on IMID highlighting the potential mechanisms of action. METHODS: Scientific papers were found by searching in PubMed up to May 2017 using the following key words: rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus, and psoriasis also in combination with EVOO, phenolic compounds, oleuropein, oleocantal, hydroxytyrosol,tyrosol and oleochantal. RESULTS: In vitro and in vivo studies indicate that EVOO and its polyphenols can improve diseases symptoms in IMID, by acting both at local and systemic levels and by modulating several molecular pathways. Nevertheless, there are not sufficient data to achieve specific nutritional guidelines. CONCLUSION: Further research is needed to evaluate the real contribution of EVOO and its phenolic compounds in modulating the IMID-associated inflammatory perturbations, in order to develop appropriate nutritional recommendations.

Role of glutathione in apoptosis induced by radiation as determined by 1H MR spectra of cultured tumor cells.

The relationship between apoptosis induced by gamma radiation and glutathione in cells of two human cancer cell lines, HeLa from cervix carcinoma and MCF-7 from mammary carcinoma, was examined. MCF-7 cells appeared to be more radioresistant than HeLa cells, and radiation-induced apoptosis, which was monitored by assessing phosphatidylserine externalization, was observed in HeLa cells but not in MCF-7 cells. Glutathione levels monitored by (1)H MRS were higher in MCF-7 cells than in HeLa cells, while the opposite was true for the free glu signals. MCF-7 cells became more radiosensitive when treated with 0.1 mM buthionine sulfoximine, which inhibits GSH synthesis through inactivation of gamma-glutamylcysteine synthetase, with the concomitant appearance of radiation-induced apoptosis. We can thus reasonably associate, at least in part, the resistance of MCF-7 cells to apoptosis with a high level of glutathione and probably with a high activity of gamma-glutamylcysteine synthetase. A late decrease in glutathione concentration after irradiation was observed in MCF-7 cells, but not in HeLa cells and to a lesser degree in buthionine sulfoximine-treated MCF-7 cells. This would indicate that the radiation-induced decrease in glutathione concentration is not related to the onset of apoptosis, but it is more likely related to glutathione consumption as a result of detoxification reactions.

Tyrosol, the major extra virgin olive oil compound, restored intracellular antioxidant defences in spite of its weak antioxidative effectiveness.

BACKGROUND AND AIM: Extra virgin olive oil has been associated with a reduced incidence of risk factors for coronary heart disease also owing to the presence of antioxidant biophenols. This study compared the protective effects of tyrosol and hydroxytyrosol, two biophenols greatly different in antioxidant power, on J774 A.1-mediated oxidation of LDL. METHODS AND RESULTS: Cell-mediated oxidation of LDL was evaluated by TBARS formation, and relative electrophoretic mobility increase. Redox imbalance was studied by: (i) cytofluorimetric determination of intracellular ROS and GSH, and (ii) evaluation of GSH-related enzyme activities and gene expressions by colorimetric and RT-PCR analyses, respectively. The cellular uptake of the biophenols was evaluated by HPLC. Both biophenols inhibited cell-mediated oxidation of LDL but to a different extent (100% hydroxytyrosol vs 40% tyrosol), and counteracted the impairment of antioxidant cellular defence, i.e., GSH and related enzymes. Tyrosol was effective in inhibiting about 30% of ROS production only at later time-points (12h for superoxide, 24h for hydrogen peroxides). Interestingly, both biophenols were effective when added to the cells for 2h and removed before LDL treatment. This was probably related to cell-biophenol interactions: hydroxytyrosol was rapidly found inside the cells (1.12+/-0.05ng/mg cell protein) and disappeared within 18h, while tyrosol accumulated intracellularly with time (0.68+/-0.09 vs 1.72+/-0.13ng/mg cell protein at minute 5 and hour 18, respectively). CONCLUSIONS: In spite of its weak antioxidant activity, tyrosol was effective in preserving cellular antioxidant defences, probably by intracellular accumulation. These findings give further evidence in favour of olive oil consumption to counteract cardiovascular diseases.

Polyphenols, dietary sources and bioavailability.

Fruit and beverages such as tea and red wine represent the main sources of polyphenols. Despite their wide distribution, the healthy effects of dietary polyphenols have come to the attention of nutritionists only in the last years. The main factor responsible for the delayed research on polyphenols is the variety and the complexity of their chemical structure. Emerging findings suggest a large number of potential mechanisms of action of polyphenols in preventing disease, which may be independent of their conventional antioxidant activities. To establish evidence for the effects of polyphenol consumption on human health and to better identify which polyphenols provide the greatest effectiveness in disease prevention, it is first of all essential to determine the nature and the distribution of these compounds in our diet, and secondly to better know their bioavailability.

Apoptosis in cancer and atherosclerosis: polyphenol activities.

Polyphenols have been demonstrated to have clear antioxidant activities in vitro. However, in complex biological systems, they exhibit additional properties which are yet poorly understood. Apoptosis is a genetically controlled and evolutionarily conserved form of cell death of critical importance for the normal embryonic development and for the maintenance of tissue homeostasis in the adult organism. The malfunction of the death machinery may play a primary role in various pathologic processes, leading to proliferative or degenerative diseases. Polyphenols can directly interact with specific steps and/or proteins regulating the apoptotic process in different ways depending on their concentration, the cell system, the type or stage of the pathological process. A growing body of in vitro evidence has provided interesting insights in the comprehension of the cellular and molecular mechanisms responsible for the modulation of apoptosis. However additional and harder studies are needed to better elucidate the mechanisms of action and the real in vivo effectiveness of polyphenols in order to propose them as potential candidates for chemoprevention and treatment of cancer and cardiovascular diseases.

Oxidised LDL modulate adipogenesis in 3T3-L1 preadipocytes by affecting the balance between cell proliferation and differentiation.

The effects of oxidised LDL (oxLDL) on cell proliferation, apoptosis and hormone-induced differentiation have been evaluated for the first time in 3T3-L1 preadipocytes. Unlike control cells, oxLDL-treated preadipocytes showed a high proliferation rate, a low apoptosis level, and an impaired differentiation process with an increased preadipocyte factor-1 (Pref-1) mRNA expression at late times. By silencing Pref-1 mRNA or inhibiting its expression with an increased dexamethasone concentration, differentiation occurred as usual, which demonstrates the key role of Pref-1 overexpression. The results suggest a specific action of oxLDL on the adipogenesis inhibitor Pref-1, as indicated also by its reappearance in mature adipocytes treated with oxLDL. The inhibitory effects of oxLDL on differentiation required oxLDL uptake by CD36, and were associated with lipoprotein lipids. These results point to oxLDL as a modulator of adipose tissue mass and as possible link between obesity and its clinical complications.

[Polyphenols and endogenous antioxidant defences: effects on glutathione and glutathione related enzymes]. / Polifenoli e difese antiossidanti endogene: effetti sul glutatione e sugli enzimi ad esso correlati.

Among diet antioxidants, polyphenols, naturally occurring in vegetables, fruits and plant-derived beverages such as tea, red wine, and extra virgin olive oil, are the most abundant ones. In vitro cell culture experiments have shown that polyphenols possess antioxidant properties, and it is thought that these activities can contribute to the prevention of several oxidative stress-associated diseases. It has however become clear that the mechanisms of action of polyphenols go beyond their intrinsic reducing capabilities, being able to exert other additional effects that are as yet poorly understood. This article gives an overview of the most recent data on the subject and describe the additional functions that polyphenols can have in biological systems, focusing on their effects on glutathione and its related enzymes. Evidence is provided of a tight connection between exogenous and endogenous antioxidants that appear to act in a coordinated fashion. Experimental data indicate that polyphenols may offer an indirect protection by activating endogenous defense systems. It is reasonable to hypothesize that this is achieved, at least in part, through antioxidant responsive elements (ARE) present in the promoter regions of many of the genes inducible by oxidative and chemical stress. The latest studies strongly suggest that dietary polyphenols can stimulate antioxidant enzyme transcription through ARE.

Gender-related differences in lifestyle may affect health status.

Consistent epidemiological and clinical evidence strongly indicates that chronic non-communicable diseases are largely associated with four lifestyle risk factors: inadequate diet, physical inactivity, tobacco use, and excessive alcohol use. Notably, obesity, a worldwide-growing pathological condition determined by the combination between inadequate diet and insufficient physical activity, is now considered a main risk factor for most chronic diseases. Dietary habits and physical activity are strongly influenced by gender attitudes and behaviors that promote different patterns of healthy or unhealthy lifestyles among women and men. Furthermore, different roles and unequal relations between genders strongly interact with differences in social and economic aspects as well as cultural and societal environment. Because of the complex network of factors involved in determining the risk for chronic diseases, it has been promoting a systemic approach that, by integrating sex and gender analysis, explores how sex-specific biological factors and gender-related social factors can interact to influence the health status.

Novel mechanisms of natural antioxidant compounds in biological systems: involvement of glutathione and glutathione-related enzymes.

Polyphenols are wide variety of compounds that occur in fruits and vegetables, wine, tea, extra virgin olive oil, chocolate and other cocoa products. Several polyphenols have been demonstrated to have clear antioxidant properties in vitro, and many of their biological actions have been attributed to their intrinsic reducing capabilities. However, this concept appears now to be a simplistic way to conceive their activity. Evidence is indeed accumulating that polyphenols might exert several other specific biological effects that are as yet poorly understood. In this article we review the most recent data on the subject and describe the additional functions that polyphenols can have in biological systems, focusing on their effects on glutathione and its related enzymes. Experimental data indicate that polyhenols may offer an indirect protection by activating endogenous defense systems. Several lines of evidence suggest a tight connection between exogenous and endogenous antioxidants that appear to act in a coordinated fashion. It is reasonable to hypothesize that this is achieved, at least in part, through antioxidant responsive elements (AREs) present in the promoter regions of many of the genes inducible by oxidative and chemical stress. The latest studies strongly suggest that dietary polyphenols can stimulate antioxidant transcription and detoxification defense systems through ARE.