Acute myocardial infarction is characterized by changes in biochemical properties during ischemia and reperfusion. The heart can survive a short period of ischemia by reducing myocardial contractility, increasing glucose uptake, and switching metabolism to glycolysis.
However, considering that the heart is one of the most energy-demanding tissues in the body, sustained oxygen and nutrient deprivation results in irreversible damage. Thus, reperfusion of the ischemic heart is a prerequisite for survival.

Paradoxically, reperfusion can further increase the myocardial damage that occurs during ischemia. The severity of reperfusion injury depends on the duration of the preceding ischemia and the effectiveness of blood flow during reperfusion. Several lines of evidence demonstrate that reperfusion injury is directly associated with cardiac mitochondrial dysfunction and increased ROS and RNS generation.

An imbalance of oxidants and antioxidants resulting in increased levels of ROS, RNS, or both can result in damage to lipids, proteins, carbohydrates, and DNA.
ROS are oxygen radicals generated in the body due to exposure from polluted air

Hearse et al. noted that reperfusion of isolated hearts after ischemia resulted in abrupt cardiomyocyte death. Following this paper, several studies showed that ischemia reperfusion is associated with a burst of H2O2, O2•;−, NO•, and ONOO−, but the exact mechanism of their generation is debated.
Although some ROS may be generated by NADPH oxidase and xanthine oxidase, it is likely that complexes I and III of the mitochondrial respiratory chain are the main sources of ROS during myocardial ischemia reperfusion.

In fact, studies using mitochondrial respiratory inhibitors show that the electron leak along the oxidative phosphorylation most likely occurs at the Fe-S centers of complex I and at some components of complex III.
During the early stages of reperfusion, ROS generation levels increase drastically. Interestingly, low amounts of ROS generated by mitochondria during brief and intermittent episodes of ischemia, termed ischemic preconditioning, significantly protect the heart against prolonged ischemia.

Dietary antioxidants are substances that have been shown to decrease the effects of ROS and RNS in humans.
Redox (reduction-oxidation) reactions include all chemical reactions in which atoms have their oxidation state changed. This can be either a simple redox process, such as the oxidation of carbon to yield carbon dioxide (CO2) or the reduction of carbon by hydrogen to yield methane (CH4), or a complex process such as the oxidation of glucose (C6H12O6) in the human body through a series of complex electron transfer processes.

Redox reactions are concerned with the transfer of electrons between species. The term comes from the two concepts of reduction and oxidation. It can be explained in simple terms:
• Oxidation is the loss of electrons or an increase in oxidation state by a molecule, atom, or ion.
• Reduction is the gain of electrons or a decrease in oxidation state by a molecule, atom, or ion.

Although oxidation reactions are commonly associated with the formation of oxides from oxygen molecules, these are only specific examples of a more general concept of reactions involving electron transfer.

Redox reactions, or oxidation-reduction reactions, have a number of similarities to acid–base reactions. Like acid–base reactions, redox reactions are a matched set, that is, there cannot be an oxidation reaction without a reduction reaction happening simultaneously. The oxidation alone and the reduction alone are each called a half-reaction, because two half-reactions always occur together to form a whole reaction. When writing half-reactions, the gained or lost electrons are typically included explicitly in order that the half-reaction be balanced with respect to electric charge.

TABLE 1 Examples of Reactive Oxygen and Nitrogen Species
Name Formula Comments
Superoxide O2- An oxygen-centered radical. Has limited reactivity.
Hydroxyl OH• A highly reactive oxygen-centered radical. Very reactive indeed: Attacks all molecules in the human body.
Peroxyl, alkoxyl RO2•, RO• Oxygen-centered radicals formed (among other routes) during the breakdown of organic peroxides.
Oxides of nitrogen NO•, NO2• Nitric oxide (NO•) is formed in vivo from the amino acid L-arginine. Nitrogen dioxide (NO2•) is made when NO reacts with O2 and is found in polluted air and smoke from burning organic materials (e.g., cigarette smoke).

SOURCE: Adapted from Halliwell, 1996, with permission; © International Life Sciences Institute, Washington, D.C.

Mitochondrial function is fundamental to metabolic homeostasis. In addition to converting the nutrient flux into the energy molecule ATP, the mitochondria generate intermediates for biosynthesis and reactive oxygen species (ROS) that serve as a secondary messenger to mediate signal transduction and metabolism.
Alterations of mitochondrial function, dynamics, and biogenesis have been observed in various metabolic disorders, including aging, cancer, diabetes, and obesity. However, the mechanisms responsible for mitochondrial changes and the pathways leading to metabolic disorders remain to be defined.
In the last few years, tremendous efforts have been devoted to addressing these complex questions and led to a significant progress. In a timely manner, the Forum on Mitochondria and Metabolic Homeostasis intends to document the latest findings in both the original research article and review articles, with the focus on addressing three major complex issues:
(1) mitochondria and mitochondrial oxidants in aging—the oxidant theory (including mitochondrial ROS) being revisited by a hyperfunction hypothesis and a novel role of SMRT in mitochondrion-mediated aging process being discussed;
(2) impaired mitochondrial capacity (e.g., fatty acid oxidation and oxidative phosphorylation [OXPHOS] for ATP synthesis) and plasticity (e.g., the response to endocrine and metabolic challenges, and to calorie restriction) in diabetes and obesity;
(3) mitochondrial energy adaption in cancer progression—a new view being provided for H+-ATP synthase in regulating cell cycle and proliferation by mediating mitochondrial OXPHOS, oxidant production, and cell death signaling.
It is anticipated that this timely Forum will advance our understanding of mitochondrial dysfunction in metabolic disorders.
Antioxidants. Redox Signal. 00, 000–000.

Measurement of Quantities in Foods
In order to meet the definition of a dietary antioxidant proposed here, the dietary intakes of the nutrient or food component must be able to be calculated from available national databases. These databases include the U.S. Department of Agriculture’s National Nutrient Databank, the Canadian Nutrient File, and other databases that contain a nationally representative sample of foods commonly eaten in the United States or Canada and that report concentrations for the antioxidant of interest and others. It is recognized that limitations exist in the use of food composition databases to accurately estimate intakes.
Decreased Adverse Effects of Some ROS and RNS
In order to meet the definition of a dietary antioxidant proposed here, the nutrient or food component must decrease the adverse effects of some ROS and RNS (see Table 1 for examples of ROS and RNS). An explanation of the biochemical and physiological mechanisms of these adverse effects follows.
Role of ROS and RNS in Health and Disease
ROS and RNS are produced metabolically by the body. It has been estimated that about 1 to 3 percent of the oxygen we utilize goes to make ROS. In addition, exposure to UV radiation or to air pollutants such as cigarette smoke (which contains oxidants) or ozone can cause the body to increase the levels of reactive radical species.

ROS is a collective term that includes several oxygen radicals—superoxide (O2•-) and its protonated form, hydroperoxyl (HO2•), hydroxyl (OH•), peroxyl (RO2•), alkoxyl (RO•)—and nonradicals—hydrogen peroxide (H2O2), hypochlorous acid (HOCl), ozone (O3), and singlet oxygen (O2)—that are oxidizing agents or are easily converted into radicals. RNS includes nitric oxide (NO•), peroxynitrite (ONOO-), and peroxynitrous acid (ONOOH).
Various compounds in the human body generate free radicals in their metabolism. Examples are catecholamines and compounds found in the mitochondrial electron-transport chain.
In addition, activated phagocytes produce ROS as one of the defense mechanisms they use to kill microbes. Thus, in this situation, ROS are used by the body as a defense mechanism against infection.
An imbalance of oxidants and antioxidants resulting in increased levels of ROS, RNS, or both can result in damage to lipids, proteins, carbohydrates, and DNA.
A considerable body of biological evidence shows that ROS and RNS can damage cells and other body components and could in theory contribute to dysfunction and disease states.
It has been postulated that oxidative damage caused by increased levels of production of ROS or RNS may contribute to the development of many chronic diseases, including age-related eye disease, atherosclerosis, cancer, coronary heart disease, diabetes, inflammatory bowel disease, neurodegenerative diseases, respiratory disease, and rheumatoid arthritis.

Antioxidant Mechanisms
The mechanisms of antioxidant action for decreasing the adverse effects of ROS or RNS are varied. They include (1) decreasing ROS or RNS formation; (2) binding metal ions needed for catalysis of ROS generation; (3) scavenging ROS, RNS, or their precursors; (4) up-regulating endogenous antioxidant enzyme defenses; (5) repairing oxidative damage to biomolecules, such as glutathione peroxidases or specific DNA glycosylases; and (6) influencing and up-regulating repair enzymes.
Some antioxidants remove free radicals by reacting directly with them in a noncatalytic manner before the radicals react with other cell components. For example, vitamin E inhibits lipid peroxidation by scavenging radical intermediates in the radical chain reaction with polyunsaturated fatty acids.
The effectiveness of each dietary antioxidant depends on which ROS or RNS is being scavenged, how and where they are generated, the accessibility of the antioxidants to this site, and what target of damage, or oxidizable substrate, is involved.
Antioxidant defense mechanisms include not only low-molecular-weight compounds, but also some antioxidant defense systems in the human body that are enzymatic, such as: (1) superoxide dismutase enzymes, which remove superoxide (O2•-) by accelerating its conversion to H2O2 and O2; (2) glutathione peroxidases, which convert H2O2 to water and O2 and which convert various hydroperoxides to harmless compounds; and (3) catalase, which converts H2O2 to water and O2 but only functions at relatively high concentrations of the ROS.

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