5ème Symposium Nutrition, Biologie de l’Oxygène et Médecine – Paris 2013
OP1
Novel antioxidant reactions of cinnamates in wine
Waterhouse, Andrew L. Gislason, Nick E.
Viticulture and Enology
University of California, Davis
Polyphenolic compounds have been the subject of many studies due to their ability to quench high-energy free radicals in many food, beverage and other systems, protecting those systems from oxidative change. It is the phenolic functional group that has been attributed the ability of these compounds to scavenge free radicals as these hydrogen atoms can be easily donated. Here, the cinnamates and the ubiquitous hydroxycinnamates were found to equally suppress the formation of oxidation products in wine exposed to the Fenton reaction. Investigations provided the unexpected result that the α,β-unsaturated side chain of cinnamic acids could efficiently trap 1-hydroxyethyl radicals. This represents a newly discovered mode of antioxidant radical scavenging activity for these broadly occurring compounds in a food system. The proposed pathway is supported by prior basic studies with radiolytically generated radicals.
OP2
From free radical scavengers to nucleophilic tone : a paradigm shift in nutraceutical effects of fruits and vegetables.
Ursini Fulvio
Department of Molecular Medicine, University of Padova, Padova, Italy
Arguments are presented for an evolution in our understanding of how antioxidants in fruits and vegetables exert their health-protective effects. There is much epidemiological evidence for disease prevention by dietary antioxidants and chemical evidence that such compounds react in one-electron reactions with free radicals in vitro. Nonetheless, kinetic constraints indicate that in vivo scavenging of radicals is ineffective in antioxidant defense. Instead, enzymatic removal of non-radical electrophiles, such as hydroperoxides, in two-electron redox reactions (Sn2 mechanism) is the major antioxidant process. Furthermore, we propose that a major mechanism of action for nutritional antioxidants is the paradoxical oxidative activation of the Nrf2 (NF-E2-related factor 2) signaling pathway, which maintains protective oxidoreductases and their nucleophilic substrates. By undergoing an oxidation, while sensing the cellular environment, phenolic antioxidants produce the electrophiles competent for the activation of the adaptive response. This maintenance of ‘Nucleophilic Tone,’ by a mechanism that can be called ‘Para-Hormesis,’ provides a means for regulating physiological non-toxic concentrations of the non-radical oxidant electrophiles that boost antioxidant response, damage removal and repair systems. As a whole, the mechanism we propose is seen consistent with the promotion of a healthy ageing more than just the prevention of specific diseases.
OP3
Potential of polyphenol-rich products to improve ageing-related impairment of the vascular function
Schini-Kerth Valérie
UMR CNRS 7213, Faculty of Pharmacy, Strasbourg University
It is well established in experimental animals and humans that endothelial cells, which cover the luminal surface of all blood vessels, have a pivotal role in the control of vascular homeostasis. The protective effect of endothelial cells is mostly due to their ability to respond to hormones, autacoids, blood- and platelet-derived factors by inducing vasodilatation via the release of nitric oxide (NO) and protacyclin (PGI2), and the induction of endothelium-derived hyperpolarization. The most important one of these mechanisms is the release of NO, which is generated from L-arginine by the enzyme termed endothelial NO synthase. In addition to inhibiting vascular tone, NO is also a potent inhibitor of platelet activation and it has anti-thrombotic and anti-atherosclerotic properties. An endothelial dysfunction characterized by a reduced generation of these endothelium-dependent vasodilator mechanisms associated with vascular oxidative stress and the formation of endothelium-dependent contracting factors such as contractile prostanoids is often observed in most types of cardiovascular diseases including hypertension, hypercholesterolemia, diabetes, and also during physiological ageing in both experimental animals and humans. Nutrition-derived polyphenols such as grape products, tea catechins, cocoa, and berries have been shown to increase the endothelial formation of NO by causing the Src/PI3-kinase/Akt-dependent activation of endothelial NO synthase leading to a sustained formation of NO. Moreover, polyphenols have also been shown to both improve an established endothelial dysfunction and delay the onset of the induction of an endothelial dysfunction in several experimental models of cardiovascular diseases and as shown recently in ageing. Several findings suggest that the local angiotensin system is a key mediator of the ageing-related endothelial dysfunction. Indeed, an increased expression level of both angiotensin II and the angiotensin type 1 receptor is observed throughout the old arterial wall, and sartans and angiotensin-converting enzyme inhibitors have been shown to improve the ageing-related endothelial dysfunction. It is also supported by the fact that angiotensin II is a strong inducer of endothelial dysfunction and NADPH oxidase-derived vascular oxidative stress. The protective effect of polyphenols in ageing-related endothelial dysfunction involves their ability to reduce vascular oxidative stress in part by inhibiting the overexpression of nox1 and p22phox NADPH oxidase subunits, and this effect is most likely the consequence of the normalization of the local angiotensin system in the arterial wall. Thus, nutrition-derived polyphenols may be an interesting approach to maintain a healthy endothelial function and, hence, prevent the initiation and development of cardiovascular diseases.
OP4
Flavanols improving health : evidence and potential mechanisms
Fraga, Cesar G.
Physical Chemistry-PRALIB, School of Pharmacy and Biochemistry, University Buenos Aires-CONICET, Buenos Aires, Argentina.
Polyphenols include several groups of naturally occurring plant compounds, which biological effects could explain some of the health benefits linked to the consumption of fruit and vegetables. Among the large amount of different plant polyphenols present in most human diets, flavanols are compounds which consumption has been associated to improved health conditions in population studies. Their potential mechanisms of action have been partially elucidated from clinical and laboratory studies. Especially in terms of the effects of cocoa flavanols and cardiovascular health, the collected results are of great potential.
In terms of potential mechanisms of action, flavanol molecular actions depend on the active chemical species (parent compound or metabolite), and on the amount available to interact with the target entity. Tissue flavanol concentrations, range from sub-nanomolar to high micromolar, and are mainly dependent on the tissue and the conditions of polyphenol administration. Within the interest of the free radical field, flavonoids have and are being extensively studied as antioxidants. However, when compared with other molecules with antioxidant actions, polyphenols can only be efficient in scavenging radicals in a limited number of cells and tissues. Under these considerations, the study of the flavanol effects on vascular health has advanced steadily in recent years, providing evidence on the mechanisms relating flavanol consumption/presence and the regulation of vascular function. Among the events explaining the effects of flavanols on the vasculature, the following are relevant: i) regulation of NADPH oxidase activity and superoxide production; ii) regulation of eNOS activity and NO production; iii) regulation of NF-κB and other redox-sensitive signaling molecules involved in inflammation. Many of these actions seem to be interrelated, e.g. superoxide and NO regulation; and/or those mediated by membrane related events, i.e. TNFα-mediated effects. It can be concluded that flavanols are molecules that could provide health effects and antioxidant protection associated to their interactions with specific molecules and molecular structures. It can be concluded that flavanols could provide health benefits and antioxidant protection associated to their interactions with specific molecules and molecular structures
Supported by UBACyT (20020090100111) and PIP-CONICET (20110100752). CGF is member of CIC, CONICET, Argentina.
OP5
Nutrition and healthy ageing - calorie restriction or “MediterrAsian” diet?
Rimbach, G.
Institute of Human Nutrition and Food Science, University of Kiel, Germany
Calorie restriction (CR) has been shown to exert a number of beneficial effects including the prolongation of lifespan. One of the mechanisms by which CR leads to these advantages seems to be the induction of endogenous antioxidant defense and stress response mechanisms. However, little is known about the persistence of CR benefits after return to an ad libitum diet. In this study, male mice were fed 75% of a normal diet for 6 months (CR) followed by 6 months of ad libitum re-feeding (RF) and compared to a continuously ad libitum fed control group. To study the impact of CR and RF on the liver transcriptome, a global gene expression profile was generated using microarray technology. In comparison the CR group showed lower body weight, triglyceride and cholesterol levels and reduced lipid peroxidation. mRNA transcription and activity of antioxidant and phase II enzymes (e.g. NADPH quinone oxidoreductase) were increased and autophagy was induced. Shifting from longterm CR to RF abolished 96% of the CR-mediated changes in differential gene expression within 2 weeks and after 6 months of re-feeding all of the previously differentially expressed genes were similar in both groups. These results indicate that CR has to be maintained continuously to keep its beneficial effects. Alternatively constituents of the so-called “MediterrAsian” diet (e.g., secondary plant metabolites) mimic some of the beneficial effects of CR as far as the murine liver transcriptome is concerned.
OP6
Flavonoids : phytochemicals, phytonutrients, or dietary antioxidants?
Frei Balz
Linus Pauling Institute, Oregon State University, 307 Linus Pauling Science Center, Corvallis, OR 97331
Increased fruit and vegetable consumption is associated with a decreased incidence of cardiovascular diseases and certain cancers. Most of the health benefits of fruits and vegetables are derived from their high content of micronutrients (vitamins and essential minerals) as well as fiber. For example, potassium, magnesium, vitamin C, and fiber all play important roles in lowering blood pressure. In addition, fruits and vegetables contain a large number of non-nutrient plant chemicals (phytochemicals), e.g., flavonoids, isothiocyanates, and cholorphyll, that also may exert beneficial health effects. Flavonoids have antioxidant properties, as shown by various in vitro assays, but cannot make significant contributions to “free-radical scavenging” in vivo. Acting as xenobiotics rather than nutrients, flavonoids elicit Phase I and II responses and, via Nrf2 activation, increase endogenous GSH synthesis. This may “indirectly” increase antioxidant protection in vivo, although there is currently no compelling human data, e.g., based on F2-isoprostanes, that consumption of flavonoid-rich foods lowers oxidative stress or damage. An additional “indirect antioxidant effect” of flavonoids may be inhibition of NADPH oxidase activity by certain flavonoid metabolites, which has been demonstrated in vitro, but again in vivo evidence is sparse. The health benefits of certain flavonoids with respect to cardiovascular diseases seem to be derived primarily from effects on cell signaling pathways resulting in increased endothelial nitric oxide synthase activity, which in turn improves vasodilation and inhibits platelet aggregation. Another non-antioxidant mechanism may be decreased vascular inflammation, as indicated by lower CRP levels and less endothelial adhesion molecule and chemokine expression. Hence, flavonoids are phytochemicals, but neither phytonutrients nor dietary antioxidants. In contrast, vitamin C is a phytonutrient––and hence also a phytochemical––as well as a dietary antioxidant.
OP7
Micronutrient intake in the Western World – status and implications on public health
Dr. Eggersdorfer, Manfred
SM Nutritional Products
Micronutrients are essential for life and optimal health. The link between a sufficient intake and long term health, cognition, healthy development from child to adulthood and healthy aging is more and more supported by science as well as health organizations. It is well established and documented that in low income countries still hundreds of million people suffer from vitamin deficiencies. The UN and its organizations, NGOs and private donors have set up programs to fight these issues and to reduce malnutrition. Also the consequences of the deficiencies for people are documented and expressed in economic values and life years lost. According data from WHO two million lives are lost every year among children below five years due to vitamin A, iron iodine and zinc deficiency and millions of babies are born year by year mentally impaired or going blind.
Less obvious and accepted is that inadequate micronutrient intake and status is also an issue in industrialized countries. However there is growing evidence from food and intake surveys in many countries that a sufficient intake of micronutrients is not reached according recommendations using RDAs as reference. A significant scientific and medical consensus exists as to the importance of an appropriate level of micronutrient intake throughout the life course to support growth, foster health, and prevent the onset of diseases. Reasons for the inadequate intake are changes in life-style and eating patterns, along with increasing dependency on pre-cooked and processed foods, which require more attention to nutrition. Appropriate micronutrient intake – as part of a balanced diet and in combination with a healthy lifestyle – encourages health and well-being. Micronutrient deficiencies and inadequate micronutrient intake compared to recommendations have serious health consequences for individuals and a wider impact on societies, economies, and healthcare and welfare systems. As the insufficient intake does not result in immediate consequences like deficiency symptoms the impact and long term effects on health, wellness and healthcare costs are often neglected. Assessments by different research groups indicate that the financial burden on direct and indirect health care costs can be in the range of billions of dollars.
The presentation will provide an overview on nutritional needs, an approach on the analysis of intake surveys and the consequences for long term health and risk for non-communicable diseases.
OP8
Mitochondrial Redox Metabolism in Cancer
Cell Fate Signaling
Pervaiz, Shazib M.B.B.S., Ph.D.
Department of Physiology, Yong Loo Lin School of Medicine and Cancer Science Institute, National University of Singapore; Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore; Singapore-MIT Alliance, Singapore
Over the years, our work has highlighted the critical role of an altered redox metabolism in cell survival and death signaling in cancer cells (Clement, M-V. and Pervaiz, S. 2007). A significant contribution has been in redefining the role that cellular redox metabolism plays in cell fate regulation, particularly the link between cellular pro-oxidant state and survival signaling. Using a variety of model systems such as drug-induced apoptosis, receptor mediated death signaling and oncogene-induced cell survival, we demonstrated that the intracellular ratio between the two main reactive oxygen species (ROS), superoxide and hydrogen peroxide, determines cancer cell response to death signals; a tilt in favor of superoxide promotes cell survival whereas an increase in hydrogen peroxide favors death execution (Clement, M-V. et al. 2003; Ahmad, K. A. et al. 2004; Hirpara, J. et al., 2001). Of note, results from a collaborative study demonstrated that mice implanted with glioma-propagating cells (GPCs) of reduced ROS Index demonstrated extended survival, and patients with reduced ROS Index demonstrated better survival (Tang, C et al. 2013 In Press). At the molecular level, our work has focused on identifying the underlying mechanisms of differential signaling by the two reactive oxygen intermediates on cell fate. To that end, we have unraveled a novel biological activity of Bcl-2 by providing experimental evidence linking Bcl-2-induced increase in mitochondrial superoxide levels to its anti-apoptotic activity. To that end, we identified two novel Bcl-2 interacting partners (Va subunit of mitochondrial complex IV and the small GTPase Rac1), and linked these interactions to not only the anti-apoptotic activity of Bcl-2 but also to the ability of Bcl-2 to regulate mitochondrial metabolism and cellular redox status (Chen, Z. X. and Pervaiz, S. 2007; 2010; Velaithan, R. et al. 2011). Furthermore, a redox-dependent mechanism of regulating the phosphorylation status of Bcl-2 and its stabilization has been recently identified. These findings provide a novel facet of cellular redox metabolism and underscore a new paradigm in the context of carcinogenesis with potential therapeutic implications.