Looh

LOO', 1O2

Nonradical

Singlet oxygen

1O,

Photo-oxidation, 3O2

Nonradical

Nitric oxide

NO'

Arginine

Radical

Nitric dioxide

NO,'

LOO'2 + NO

Radical

Peroxynitrite

ONOO-

O2'- + NO'

Nonradical

a Reactivity of ROS and NOS varies and H2O2, NO', and O' 2 react quickly and with specificity, whereas 'OH also reacts quickly without specificity and LOO', NO'2, and ONOO- have intermediate reactivity.

a Reactivity of ROS and NOS varies and H2O2, NO', and O' 2 react quickly and with specificity, whereas 'OH also reacts quickly without specificity and LOO', NO'2, and ONOO- have intermediate reactivity.

a- and b-tocopherol, ascorbic acid, and b-carotene). Factors that balance initiation of oxidative stress and antioxidant capacity are critical to prevent the biomolecular damage that underlies the pathogenesis of many chronic diseases caused by the overgeneration of oxidative species (e.g., ischemic injury) (Lefer and Granger, 2000; Serracino-Inglott et al., 2001).

Antioxidants are defined as substances that can potentially reduce or delay the rate of oxidation of auto-oxidizable materials. There are many naturally occurring antioxidants present in plant products that have proven efficacy for reducing the generation of free radicals that precede oxidative stress. Echinacea is one excellent example of a plant that contains bioactive phytochemicals with antioxidant properties. The purpose of this chapter is to detail the chemistry of antioxidant constituents present in Echinacea and to describe the mechanism of action.

generation of reactive oxygen species (ros)

Oxidations occurring both in vitro and in vivo are generally characterized by three distinct reactions, including initiation, propagation, and termination (Equation 6.1 to Equation 6.3).

Initiation:

Propagation:

Termination:

Hall and Cuppett (1997) proposed two mechanisms of lipid oxidation whereby oxygen is required but is not necessarily exclusive. Transition metal ions and high-energy irradiation (e.g., ultraviolet light) are potential radical acceptors that generate radicals from a reaction that requires oxygen and leads to the formation of alkoxyl and peroxyl radicals. With photo-oxidation, light-sensitizing agents (such as chlorophyll) mediate the generation of a highly reactive singlet oxygen 0O2) species, which is 1500 times more reactive than its stable triplet oxygen (3O2) counterpart. This reaction in turn initiates lipid oxidation by catalyzing hydroperoxide decomposition. Antiox-idants that effectively inhibit chain reactions and are characteristic of initiating free radical formation and subsequent propagation of more ROS will delay the onset of lipid oxidation, or retard the rate of chain reaction, respectively (Simic et al., 1992). Aspects of antioxidant function include mechanisms that involve free radical chain breaking, metal sequestering, and oxygen quenching (Hall and Cuppett, 1997). For example, a chain-breaking antioxidant (AH) interferes with either the initiation or propagation step and generates more stable intermediate radicals or a nonradical product (St. Angelo, 1996). Chain-breaking antioxidants are also classified as chain-breaking electron donors and chain-breaking acceptors. The chain-breaking electron donor antioxidant competes with the unsaturated fatty acid (LH) for the peroxyl radical (LOO*, Equation 6.4), thus reducing the rate of propagation (Equation 6.2). On the other hand, a chain-breaking acceptor antioxidant competes with the triplet oxygen (3O2, Equation 6.5), and as a result, reduces the propagation of free radicals by preventing the generation of LOO* (Equation 6.2).

Antioxidants are derived from both synthetic and natural sources. Numerous synthetic chemical agents have been used as primary antioxidants in the food industry, primarily focusing on the retention of essential nutrients (e.g., polyunsaturated fatty acids, essential amino acids) and sensory perception of quality (e.g., color pigments). Common examples of synthetic antioxidants include butylated hydroxylanisole (BHA), butylated hydroxytolulene (BHT), tetra-butyl-hydroquinone (TBHQ), and propyl gallate (PG). Concerns regarding the controversy over the safety of synthetic food antioxidants (Shahidi et al., 1992; Williams et al., 1999) have led to the effort to discover natural sources of materials that could be used as food antioxidants or supplements. An example of a natural antioxidant is ascorbic acid and the long-chain fatty-acid esterified form of ascorbic acid, which improves lipid solubility for the application for hydrophobic food systems (St. Angelo, 1996). Other natural sources of antioxidants reported from herbs and spices include rosemary (Rosmarinus officinalis) and sage (Salvia) extracts (Hall and Cuppett, 1997). These examples contain active phenolic compounds (e.g., carnosol, carnosic acid, rosmanol, rosmaridiphenol, and rosmarinic acid) with noted antioxidant activity. Other natural antioxidants derived from plants with potential application for health benefits include the flavonoids from Ginkgo biloba extracts (Yan et al., 1995; Haramaki et al., 1998), tea catechins such as epicatechin, epicatechin gallate, epigallocatechin, and epigallocatechin gallate (Weisburger, 1998; Hu and Kitts, 2001), and lignan from flaxseed (Kitts et al., 1999).

prevention of oxygen radical-induced damage by ECHINACEA constituents

Phenolics

Caffeic acid derivatives represent a major group of phenolic constituents that are present in all Echinacea species (e.g., E. angustifolia, E. purpurea, and E. pallida) with bioactive properties that have potential uses for various medicinal purposes (Bauer and Wagner, 1991; Bauer, 1999; Bauer, 2000). Of the two major caffeic acid derivatives, cichoric acid has greater pharmacological relevance compared to echinacoside (Bauer, 2000). Structures of echinacoside and cichoric acids are shown in Figure 6.1. It is noteworthy that E. purpurea does not contain echinacoside (Borchers et al., 2000), which enables partial identification of E. purpurea from the other two species. Phenyleth-anoid glycosides are common constituents of the Echinacea species E. pallida and E. angustifolia (Bauer, 2000; Sloley et al., 2001; Hu and Kitts, 2000) and contribute to the antioxidant activity associated with free-radical scavenging properties of Echinacea (Zheng et al., 1993; Wang et al., 1996; Hu and Kitts, 2000).

Antioxidant activities of Echinacea species have been studied in different model systems using methanol extracts of E. angustifolia, E. purpurea, and E. pallida roots (Hu and Kitts, 2000). In both water-soluble and ethanol-soluble free-radical scavenging models, extract of E. pallida presented higher free radical-scavenging capacity than the other two species, which was attributed to the higher content of caffeic acid derivative found in E. pallida. Methanol extracts of roots of E. angustifolia, E. purpurea, and E. pallida were tested for suppressing peroxyl radical-induced, reconstructed, phospholipid liposome peroxidation. In this system, peroxyl radicals were generated through thermolysis of 2, 2'-azobis(2-amidinopropane) dihydrochloride (Niki, 1990), which in turn triggered the oxidation chain reaction. Delay of onset of liposome peroxidation was similar with the addition of Echinacea extracts and Trolox (a water-soluble analogue of a-tocopherol) (Figure 6.2).

The addition of root extracts from all three sources of Echinacea resulted in characteristically different, albeit greater, reduction of lipid peroxidation compared to controls (Figure 6.2). For

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