The immune system is an important source of reactive oxygen species (ROS) generation for cellular defense against invading microbes, viruses, and parasites. During this process, phagocytic cells produce oxidizing agents such as superoxide, nitric oxide, peroxynitrite, hydrogen peroxide, and hypochlorite. Subsequent inflammation can result in neutrophil and macrophage accumulation leading to further accumulation of ROS and subsequent oxidative stress. Under certain circumstances, many of these oxidizers can be mutagenic. A large body of clinical evidence suggests that chronic inflammation of certain tissues increases the risk of cancer development within those tissues. This is particularly evident for conditions of the colon such as ulcerative colitis.1,86 Many studies have shown anthocyanins to have anti-inflammatory activity. Wang et al.87 demonstrated that cya-nidin and glycosides of cyanidin isolated from tart cherries exhibited anti-inflammatory activities in vitro. Additionally, a blackberry extract rich in antho-cyanins was observed to act as a potent anti-inflammatory agent in a model of lung inflammation induced by carrageenan in rats.88 Anthocyanins have been observed to suppress inflammatory mediators such as tumor necrosis factor alpha, interleukin-1, interleukin-6, and cytokine-induced neutrophil chemoattractant-1,89 to prevent antioxidant enzyme decline, and to inhibit enzymatic radical production during inflammation.33,75-7787 8990

20.5.1 Inflammation and Arachidonic Acid Metabolism

Endothelial cells, smooth muscle cells, leukocytes, platelets, and parenchymal cells are all capable of producing a variety of reactive products as a result of arachidonic acid (AA) metabolism via oxygenase-mediated enzymatic activity and subsequent reactions. The metabolism of AA involves the formation of intermediate peroxy compounds and hydroxyl radicals, both of which may result in the initiation of lipid peroxidation chain reactions. Additionally, the damage caused by the resulting lipid hydroperoxides, in the presence of iron, results in the formation of alkoxyl radicals thus amplifying the lipid chain reaction. In a high lipid environment, such as in membranes, this effect can be devastating to cellular function. As anthocyanins are reported to be active against lipid peroxidation, one likely mechanism for their anti-inflammatory activity would be through their antioxidant activities against radicals produced as a result of AA metabo-lism.9091 Anthocyanins from dealcoholized red wine92 and carrot cell extract66 have been reported to inhibit enzymatic and non-enzymatic polyunsaturated fatty acid peroxidation induced by radicals in vitro. Furthermore, Tsuda et al.28 demonstrated anthocyanins (glycosides and aglycones) to prevent lipid peroxidation induced by ultraviolet (UV) irradiation in a liposomal system. All pigments used (cyanidin-3-glucoside, delphinidin-3-glucoside, pelargonidin-3-glucoside, cyani-din, delphinidin, pelargonidin) in this investigation were reported to scavenge superoxide and hydroxyl radicals to varying extents. In addition to their capacity for scavenging radicals produced as a result of AA metabolism, anthocyanins also appear to have direct effects on cyclooxygenase (COX) and lipoxygenase; two enzymes involved in the metabolism of AA.

Specific prostaglandins and leukotrienes produced from the metabolism of AA, released from membrane phospholipids via phospholipases, are potent mediators of inflammation. COX is the enzyme responsible for the metabolism of AA thereby producing prostaglandins, and lipoxygenase is involved in the production of leukotrienes. Both cyclooxygenase- and lipoxygenase-mediated metabolism of AA involves the formation of intermediate peroxy compounds and hydroxyl radicals, which can result in the initiation of lipid peroxidation chain reactions.

There are two known COX isoforms, referred to as COX-1 and COX-2. COX-1 is commonly regarded as a "housekeeping enzyme" and is expressed in most cells, performing protective functions. COX-2 is highly inducible by inflammatory stimuli and is associated with deleterious effects when expressed at high levels. COX-2 is present in low concentrations under basal conditions; however, under inflammatory conditions it is subject to induction in the presence of mitogens and cytokines resulting in overexpression. The overexpression of COX-2 has been reported in neoplasms of the colorectum, prostate, gastric tissue, liver, lung, breast, and skin, thereby suggesting its role in tumorigenesis. COX-2 is therefore recognized as a potential enzyme to target for preventative interventions against cancer.90,91

Cyanidin and cyanidin-3-glycosides have been shown to have anti-inflammatory properties in various in vitro assays. Wang et al.87 demonstrated cyanidin and glycosides of cyanidin isolated from tart cherries to exhibit in vitro anti-inflammatory activities when assaying cyclooxygenase activity. Interestingly, the isolated cyanidin was reported to have more anti-inflammatory activity than aspirin. Additionally, in a study conducted by Seeram et al.,90 both cyanidin and malvidin showed significant COX inhibitory activities in vitro when compared to commercial anti-inflammatory drugs such as ibuprofen, naproxen, Vioxx®, and Celebrex™. The authors reported that the 3',4'-dihydroxyls of the B-ring were responsible for elevated COX inhibitory activity. Anthocyanins have also been shown to inhibit lipoxygenase activity in certain cell model systems.

Lipoxygenases are involved in the metabolism of AA forming various bio-active compounds referred to collectively as leukotrienes. Leukotrienes have multiple biological activities including chemo-attraction and vasoactivity. Many of these compounds are implicated in inflammatory processes.15 The mechanism responsible for lipoxygenase inhibition by anthocyanins and flavonoids is believed to be a result of iron-reducing and iron-chelating properties;15 6693 however, the biological implications of the latter have yet to be determined.

20.5.2 Inflammation, Oxidation, and Carcinogenesis

Nitrated compounds are recognized human carcinogens and are strongly associated with an increased risk of stomach and colorectal cancer.94,95 Nitrogen oxides are produced in excess during host response to infection as a consequence of reactions involving nitric oxide and superoxide. The accumulation of nitrogen oxides (during immune cell-mediated oxidative burst) within inflamed tissues can result in the production of primary and secondary amines yielding nitrosamines.86 Additionally, nitrosamines and nitrosamides can also be formed in cigarette smoke and in selected foods. Antioxidants are known to prevent nitrosation, and epidemi-ological evidence has suggested that they are protective against stomach cancer.94 Although anthocyanins appear to affect nitric oxide production, the biological relevance of this activity is still unclear. A recent study revealed that anthocyanins and anthocyanidins exhibited strong inhibitory activity toward nitric oxide production in cell culture models using activated macrophages.96 Furthermore, cya-nidin 3-0-P-D-glucoside has been shown to inhibit nitric oxide synthase generation in cell culture.89 Even though nitric oxide is associated with oxidation and inflammation, it is also a biological signal in smooth muscle relaxation and neurotransmission. The physiological consequence of interactions between anthocyanins and nitric oxide is inherently complicated and it will likely be many years before the biological implications of their actions in various cells and tissue are realized.

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