Current Topics in Medicinal Chemistry - Volume 11, Issue 14, 2011

This special issue of Current Topics in Medicinal Chemistry is based on the elucidation of various mechanisms of action of antioxidants present in human diet and on their potential use for attaining a healthy status. The highlights of this topic are illustrated in the next paragraphs. Puertollano and associates point out the ability of dietary antioxidants to modulate the immune response under antigenic pressure. Macrophages (Mφ) and polymorphonuclear cells (PMN) in the course of a given inflammatory event produce free radicals and H2O2 as defence against invading pathogens. Production of reactive oxygen species (ROS) by activated phagocytes needs to be counterbalanced by antioxidant nutrients in order to maintain the immune homeostasis in unfavourable conditions for the host, e.g., infections. In particular, vitamin E, vitamin C, β-carotene, copper, iron and zinc (Zn) are able to improve Mφ and PMN functions in the course of pathological circumstances such as sepsis. In addition, further studies are required in order to determine the levels of supplemented antioxidants in groups of individuals such as aged people and smokers for optimizing their effects on multiple biological system. Kawaguchi and associates emphasize the role of polyphenols, contained in natural sources, on tumor necrosis factor-α related diseases. In particular, supplementation of hydroxytyrosol, tyrosol and oleouropein and naringin (olives), hesperidin (Citrus fruits), resveratrol, procyanidins, and oligomeric procyanidin (grapes or grape seed extract), (-)-epigallocatechin gallate (green tea) and quercetin (grapes, green tea) seems to attenuate the severity of chronic diseases such as type 2 diabetes, rheumatoid arthritis and inflammatory bowel disease. In this framework, fermented grape marc from Koshu (K-FGM) (a Japanese grape strain) prepared in the presence of Lactobacillus plantarum was very much effective in KK-Ay mice. In fact, treatment with K-FGM decreases weight gain, abdominal fat, blood glucose and tryclyceride concentration, enhancing levels of adiponectin. Magrone and Jirillo illustrate the effects of dietary polyphenols on cancer, neurodegenerative disease, obesity, metabolic syndrome and atherosclerosis. In particular, polyphenols from an Italian red wine, Negroamaro, are able to activate both innate and adaptive immune responsiveness in an in vitro system. In particular, using human healthy lymphomonocytes red wine polyphenols induce production of nitric oxide (NO), of interleukin (IL)-12 and IL-10 and immunoglobulins (Ig). Taken together, these data suggest that moderate consumption of Negroamaro and absorption of polyphenols may confer protection to the host in terms of anti-atherogenic activities (vasodilation induced by NO), maintenance of the immune homeostasis (IL- 12/IL-10 ratio in equilibrium) and mucosal (IgA) and systemic (IgG) protection against invading pathogens. Bullo and associates focus their review on the healthy effects of Mediterranean diet (MD). In particular, olive oil and nuts are source of potentially oxidized fat which exert important antioxidant properties in major diseases. Nuts and olive oil are rich in phytochemicals and phenolic compounds with high free radical scavenging or metal-chelating capacity. Therefore, they are able to modulate several enzymatic systems involved in the oxidation process. The broadest study conducted to analyze the effect of olive oil consumption on oxidative damage was EUROLIVE (Effect of olive oil consumption on oxidative damage in European populations). The results of this study provide contrasted evidence for recommending olive oil rich in phenolic compounds to improve lipid profile and decrease oxidative damage to lipids and DNA. Another large clinical trial was conducted in the framework of the PREDIMED study. The change in oxidized LDL levels in the group of the MD enriched with virgin olive oil reached significance vs that of the lower fat group (but not vs that of the MD enriched with nuts). Further data on the long term effects of MD enriched in nuts and olive oil will be necessary to support its beneficial role. Hunter and associates report on the healthy properties of kiwifruit. In particular, using extract from twenty kiwifruit genotypes the ability of kiwifruits to exert cytoprotection in response to hydrogen peroxide insult has been evaluated. Results suggest that more hydrophobic components in organic extracts, such as carotenoids and phenolic compounds, contribute to the observed cytoprotective effects. Furthermore, human studies investigating the interaction between kiwifruit and damage from oxidative stress and endogenous levels of antioxidant compounds and enzymes, provide the first steps to understanding the implications of improved antioxidant activity in vivo. However, it remains to be proven whether long-term consumption of kiwifruit provides a health benefit. Serafini and associates raise the question about the identification of biomarkers for evaluating in plasma polyphenol non enzymatic antioxidant capacity (NEAC). Actually, the low decrease of absorption and the complex metabolic pathways of polyphenols in the body does not allow to determine their exact antioxidant contribution. In fact, there is a discrepancy between polyphenol concentration in body fluids and plasma NEAC increase. In acute ingestion studies on healthy subjects evidence exists for a direct role of dietary plant foods in modulating plasma/serum NEAC. However, when long term studies are considered, dietary efficiency is reduced, and other factors such as an endogenous influence of the antioxidant network might play an important role.....

Natural antioxidants may be defined as molecules that prevent cell damage against free radicals and are critical for maintaining optimum health in both animals and humans. In all living systems, cells require adequate levels of antioxidant defenses in order to avoid the harmful effect of an excessive production of reactive oxygen species (ROS) and to prevent damage to the immune cells. During the inflammatory processes, the activation of phagocytes and/or the action of bacterial products with specific receptors are capable of promoting the assembly of the multicomponent flavoprotein NADPH oxidase, which catalyzes the production of high amounts of the superoxide anion radical (O2-). Under these particular circumstances, neutrophils and macrophages are recognized to produce superoxide free radicals and H2O2, which are essential for defence against phagocytized or invading microbes. In this state, antioxidants are absolutely necessary to regulate the reactions that release free radicals. Antioxidant nutrients commonly included in the diet such as vitamin E, vitamin C, β-carotene, selenium, copper, iron and zinc improve different immune function exhibiting an important protective role in infections caused by bacteria, viruses or parasites. As a result, dietary antioxidants have been related to modulate the host susceptibility or resistance to infectious pathogens. Overall, numerous studies have suggested that the development of tolerance, and control of inflammation are strongly correlated with specific immune mechanisms that may be altered by an inadequate supply of either macronutrients or micronutrients. Therefore, the present paper will review the effects of dietary antioxidants on immune cell function and the impact on protection against infectious microorganisms.

Oxidative stress and inflammatory responses sustained for a long period of time cause many diseases. A proinflammatory cytokine, tumor necrosis factor α (TNF-α), plays a pivotal role in the pathogenesis of chronic and autoimmune diseases. The present review, supplemented by hitherto unpublished data of the authors and their coworkers, shows that the intake of polyphenols contained in natural sources, such as hydroxytyrosol, tyrosol, oleuropein (olives), naringin and hesperidin (Citrus fruits), resveratrol, procyanidins or oligomeric procyanidin (grapes or grape seed extracts), (-)-epigallocatechin gallate (green tea) and quercetin (grapes, green tea) etc., are able to modulate chronic inflammatory diseases, such as type 2 diabetes, rheumatoid arthritis, inflammatory bowel disease, and affect the formation and interaction of advanced glycation end products with their respective receptors. Furthermore, potent activities of fermented grape marc, prepared as a fine lyophilized powder from fresh skin and seeds of a Japanese grape strain (Koshu) and then fermented with Lactobacillus plantarum, are described. Finally, the bioavailability of representative polyphenols will be discussed.

Polyphenols are ubiquitous compounds present in the vegetal kingdom and endowed with an array of beneficial activities to human health. In this review, the effects of dietary polyphenols on the prevention and/or mitigation of cancer, neurodegenerative diseases, obesity, metabolic syndrome and atherosclerosis will be illustrated. Moreover, emphasis will be placed on our own data concerning the in vitro effects performed by polyphenols from an italian red wine “Negroamaro” on human healthy peripheral blood mononuclear cells. Particularly, production of nitric oxide and maintenance of the inflammatory/anti-inflammatory cytokine network will be discussed also in relation to potential application to human age-related diseases. In conclusion, polyphenols in virtue of the plethora of protective effects manifested in various experimental models and clinical trials seem to be appropriate as dietary supplements for preventing the functional decline of organs with age.

Oxidative stress has been involved in the aetiology of hypertension, insulin resistance, the metabolic syndrome, cardiovascular disease and other chronic conditions. Several epidemiological studies suggest that a diet rich in natural antioxidants is associated with protective effects against major diseases, especially cardiovascular disease. The Mediterranean diet is rich in fat and foods with important antioxidant properties, such as fruits and vegetables, olive oil, and nuts. In this review we focus on epidemiological evidence and clinical trials that relate the Mediterranean diet with oxidative stress markers. We focus our review on two important Mediterranean vegetable sources of potentially oxidized fat-olive oil and nuts.

Kiwifruit are nutrient-dense fruit with a reputation for promoting good health. Although this could be attributed to the high vitamin C content of kiwifruit, other phytochemicals could also provide health benefits. Kiwifruit are commonly reported to be a good source of vitamin E and in addition contain phenolics and carotenoids. The antioxidant properties of kiwifruit have received attention as possible mechanisms for their health-promoting effects. In this review, the antioxidant capacity of kiwifruit is discussed in the context of biologically relevant in vitro assays for predicting antioxidant activity in a biological setting compared with chemical antioxidant assays, and the ability of kiwifruit to protect cells from dying after exposure to an oxidative insult by hydrogen peroxide (cytoprotection). Some recent data are included, where extracts from twenty kiwifruit genotypes, derived from germplasm held at The New Zealand Institute for Plant & Food Research Ltd, were compared for their cellular antioxidant activity and cytoprotection, using human gutderived epithelial cell lines. Our knowledge of how this type of result is currently reflected in vivo is summarised, together with the ‘naturally protective’ properties of kiwifruit that involve modulating immune responses in a positive way. Finally, the ways in which these antioxidant and natural protective properties of kiwifruit may influence human health and wellness are discussed. P>

A large body of evidence has described the antioxidant properties of phytochemicals such as PolyPhenols (PP) in different in vitro and ex vivo models. PP have been shown to scavenge oxygen and nitrogen derived free radicals, modulating antioxidant enzymes and cellular redox transcription factors. Dietary intervention studies have shown that consumption of plant foods modulate plasma Non Enzymatic Antioxidant Capacity (NEAC), biomarker of endogenous antioxidant network, in human subjects. However the identification of the molecules responsible for this effect is far to be obtained and evidences of an antioxidant in vivo action of PP are contrasting. There is a clear discrepancy between PP concentration in body fluids and the extent of increase of plasma NEAC. The low degree of absorption and the extensive metabolism of PP within the body have raised questions about their contribution to the in vivo antioxidant network. The available evidence from human intervention studies on the role of plant foods as modulators of plasma/serum NEAC and the involvement of PP will be presented and critically discussed.

Rice bran contains important bioactive phytochemicals. Among these phytochemicals, steryl ferulates including γ-oryzanol and its major components such as cycloartenyl ferulate (CAF), 24-methylenecycloartanyl ferulate (24- mCAF), β-sitosteryl ferulate (β-SF), and campesteryl ferulate have been intensively studied due to their crucial roles in pathological processes. On the basis of experimental studies published during the last decade in relation to antioxidant, anti-inflammatory, anti-ulcerogenic, hypolipidemic, anti-neoplastic, anti-diabetic, and anti-allergic phenomena, these bioactive phytochemicals are reviewed in this paper. Particularly, in vivo and in vitro studies have clarified that rice bran phytosteryl ferulates mediate anti-inflammatory effects by down-regulating the inflammatory transcription factor, nuclear factor κB (NF-κB), which in turn reduces expression of inflammatory enzymes such as COX-2 and iNOS, and proinflammatory cytokines such as IL-1β, IL-6 and TNF-α. Moreover, rice bran phytosteryl ferulates up-regulate blood adiponectin levels via indirect activation of peroxisomal proliferator-activated receptor γ (PPARγ) through NF-κB inhibition. In this review, we discuss potential pharmacological aspects of rice bran phytosteryl ferulates in the clinical setting.

We describe here physiological formation of a unique nitrated cyclic nucleotide, 8-nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP) and its potent antioxidant activity. Our earlier studies revealed the NO-dependent guanine nitration in several types of cells. In fact, we identified physiological formation and functions of 8-nitro-cGMP, which is the first demonstration of a new second messenger derived from cGMP in mammals since the discovery of cGMP more than 40 years ago. Using immunocytochemical methods, we confirmed 8-nitro-cGMP formation in cultured macrophages, hepatocyte-like cells, adipocytes, and endothelial cells, depending on NO production. We further verified 8- nitro-cGMP formation via HPLC plus electrochemical detection and tandem mass spectrometry. 8-Nitro-cGMP as an electrophile reacts efficiently with sulfhydryls of proteins to generate a novel post-translational modification, which we call protein S-guanylation. Particular intracellular proteins can readily undergo S-guanylation by 8-nitro-cGMP. 8-NitrocGMP regulates the redox-sensor signaling protein Keap1, via S-guanylation of the highly nucleophilic cysteine sulfhydryls of Keap1. More importantly, we clarified that S-guanylation of Keap1 is involved in potent antioxidant effects mediated by 8-nitro-cGMP, by inducing oxidative stress-response genes such as heme oxygenase-1. Our discovery of 8-nitrocGMP and its unique antioxidant effects thus shed light on new areas of oxidative stress research. Protein S-guanylation induced by 8-nitro-cGMP thus may have important implications in pharmaceutical chemistry and development of therapeutics for many diseases.

Cardiovascular disease represents an unparalleled proportion of the global burden of disease and will remain the main cause of mortality for the near future. Fortunately, most premature cardiovascular deaths are preventable. Therefore, prevention becomes vital and diet has shown beneficial effects to protect from CVD (CVD). Fruits and vegetables are dietary sources of natural antioxidants and it is generally accepted that antioxidants in these foods are key in explaining the inverse association between fruits and vegetables intake and the risk of developing a cardiovascular event or having elevated levels of cardiovascular risk factors. Available evidence supports the central role of oxidative stress in the atherosclerosis process and the correlation between increased oxidative stress and vascular disease. Theoretically, antioxidants in fruits and vegetables are important in inhibiting oxidative mechanisms that lead to various degenerative diseases including CVD. However, results from many interventional trials using antioxidants given as supplements have not been concordant with previous positive findings from observational epidemiologic cohort studies. The present manuscript gives a brief overview of the relationship between natural antioxidants (specially vitamin C, vitamin E and beta-carotene) intake and the risk of CVD.