C

Cabbage

see also Brassica and Crucifera The antioxidant and antiproliferative activities of 10 common vegetables (broccoli, spinach, yellow onion, red pepper, carrot, cabbage, potato, lettuce, and celery) were recently studied by Chu and coworkers (2002). The phenolic content and antioxidant activity of cabbage fell in the middle, while antiproliferative activity, using HepG(2) human liver cells, was highest in spinach, followed by cabbage. Thus, cabbage had the second-highest bioactivity index (BI) suggested as an alternative biomarker for future dietary cancer-prevention studies.

Bresnick and coworkers (1990) reported that a diet containing cabbage significantly decreased the incidence of mammary cancer in female Sprague-Dawley rats injected with a carcinogen, N-methyl-N-nitrosourea (MNU). Later work by Mehta et al. (1995) reported that a synthetic brassinin [3-(S-methyldithiocar-bamoyl)aminomethylindole], a phytoalexin first identified in cabbage, inhibited 7,12-dimethyl-benz [a] anthracene (DMBA) induction of mouse skin tumors.

References

Bresnick, E., Birt, D.F., Wolterman, K., Wheeler, M., and Markin, R.S., Reduction in mammary tumorigenesis in the rat by cabbage and cabbage residue, Carcinogenesis, 11:1159–1163, 1990.

Chu, Y.F., Sun, J., Wu, X., and Liu, R.H., Antioxidant and antiproliferative activities of common vegetables, J. Agric. Food Chem., 50:6910–6916, 2002.

Mehta, R.G., Liu, J., Constantinou, A., Thomas, C.F., Hawthorne, M., You, M., Gerhauser, C., Pezzuto, J.M., Moon, R.C., and Moriarty, R.M., Cancer chemopreventive activity of brassinin, a phytoalexin from cabbage, Carcinogenesis, 16:399–404, 1995.

Cacao

see Cocoa

Caesalpinia ferrea

The fruit of Caesalpinia ferrea or Juca, a leguminous tree in northern and northeastern regions of Brazil, was reported to have analgesic and anti-inflammatory properties (Carvalho et al., 1996). In addition, it was also used to treat diabetes (Balbach, 1972) and coughs and injuries (Hashimoto, 1996). The popular use of aqueous extracts of these fruit to treat cancer led to an investigation of its antitumor properties by Nakamura and coworkers (2002) using the in vitro Epstein-Barr virus early-antigen (EBV-EA) screening test. They identified the active constituents in Caesalpinia ferrea fruits responsible for antitumor effects as gallic acid and methylgallate. A total of 49 related compounds were also identified, of which three acetophenone derivatives, 2,6-dihydroxyacetophenone, 2,3,4-trihydroxyace-tophenone, and 2,4,6-trihydroxyacetophenone, proved to be the most potent activity.

Acetophenone structure. (From Nakamura et al., Cancer Lett., 177:119–124, 2002.)

References

Balbach, A., in As Plantas que Curam, Tree Press, Sao Paulo, 1972, pp. 302–303.

Carvalho, J.C.T., Teixeira, J.R.M., Souza, P.J.C., Bastos, J.K., Santos Filho, D., and Sarti, S.J., Preliminary studies of analgesic and anti-inflammatory properties of Caesalpinia ferrea crude extract, J. Ethnopharm., 53:175–178, 1996.

Hashimoto, G., in Illustrated Cyclopedia of Brazilian Medicinal Plants. Japan, pp. 552–558, 1996.

Nakamura, E.S., Kurosaki, F., Arisawa, M., Mukainaka, T., Okuda, M., Tokuda, H., Nishino, H., and Pastore, F., Jr., Cancer chemoprotective effects of constituents of Caesalpinia ferrea and related com pounds, Cancer Lett., 177:119–124, 2002.

Caffeic acid

Caffeic is one of the phenolic compounds in fruits and vegetables with strong antioxidant properties. Uz and coworkers (2002) showed that caffeic acid phenethyl ester (CAPE), a new antioxidant and anti-inflammatory agent, had a protective role on rat testicular tissue from reactive-oxygen species produced by testicular artery occlusion. In propolis (honeybee resin), caffeic acid is also present as the phenylethyl ester (Michaulart et al, 1999). Like caffeic acid, CAPE was shown in both in vivo and in vitro studies to be an anti-inflammatory compound (Huang et al., 1996; Michaulart et al., 1999; Orban et al., 2000). The anti-inflammatory properties of CAPE were attributed by Natarajan and coworkers (1996) to its inhibitory action on the transcription factor nuclear factor-B (NF-B). CAPE was also reported to induce apoptosis (Chiao et al., 1995; Chen et al., 2001). Fitzpatrick and coworkers (2001) showed CAPE inhibited NF-B and cytokine production in cell types for inflammatory-bowel disease (IBD). Lee and coworkers (2000) showed that synthetic caffeic phenylethyl ester-like compounds were cytotoxic on oral submucous fibroblasts, neck metastasis of Gigiva carcinoma, and tongue squamous-cell carcinoma cells. Further work was proposed to establish the efficacy of CAPE-like compounds as chemopreventive agents against oral cancer.

(From Celli et al., J. Chromatogr. B., 810:129–136, 2004.)

References

Celli, N., Mariani, B., Dragani, L.K., Murzulli, S., Rossi, C., and Rotilio, D., Development and validation of a liquid chromatographic-tandem mass spectrometric method for the determination of caffeic acid phenylether ester in rat plasma and urine, J. Chromatogr. B., 810:129–136, 2004.

Chen, Y.J., Shiao, M.S., and Wang, S.Y., The antioxidant caffeic acid phenylethyl ester induces apoptosis associated with selective scavenging of hydrogen peroxide in human leukemic HLcells, Anticancer Drugs, 12:143–149, 2001.

Chiao, C., Carothers, A.M., Grunberger, D., Solomon, G., Preston, G.A., and Barret, J.C., Apoptosis and altered redox state induced by caffeic acid phenylethyl ester (CAPE) in transformed rat fibroblast cells, Cancer Res., 55:3576–3583, 1995.

Fitzpatrick, L.R., Wang, J., and Lee, T., Caffeic acid phenylethyl ester, an inhibitor of nuclear factor-B, attenuates bacterial peptidogylcan polysaccharideinduced colitis in rats, J. Pharmacol. Therapeutics, 299:915–920, 2001.

Huang, M.T., Ma, W., Yen, P., Xie, J.G., Han, J., Frenkel, K., Grunberger, D., and Conney, A.H., Inhibitory effects of caffeic acid phenylethyl ester (CAPE) on 12-O-tetradecanoylphorbol-13- acetate-induced tumor promotion in mouse skin and synthesis of DNA, RNA and protein in HeLa cells, Carcinogenesis, 17:761–765, 1996.

Lee, Y.-J., Liao, P.-H., Chen, W.-K., and Yang, C.-C., Preferential cytoxicity of caffeic acid phenylester analogues on oral cancer cells, Cancer Lett., 153:51–56, 2000.

Michaulart, P., Masferer, J.L., Carothers, A.M., Subbaramaiah, K., Zweifel, B.S., Koboldt, C., Metre, J.R., Grunberger, D., Sacks, P.G., and Tanabe, T., Inhibitory effects of caffeic acid phenylethyl ester on the activity and expression of cyclooxygenase-2 in human oral epithelial cells and in a rat model of inflammation, Cancer Res., 59:2347–2352, 1999.

Natarajan, K., Singh, Burke, T., Jr., Grunberger, D., and Aggarwal, B.B., Caffeic acid phenylethyl ester is a potent and specific inhibitor of activation of nuclear transcription factor NF-κB, Proc. Natl. Acad. Sci., 93:9090–9095, 1996.

Orban, Z., Mitsiades, N., Burke, T.R., Grunberger, D., and Aggarwal, G.P., Caffeic acid phenylethyl ester induces leukocytes apoptosis, modulates nuclear factor-κB and suppresses acute inflammation, Neuroimmunomodulation, 7:99–105, 2000.

Uz, E., Sogut, S., Sahin, S., Var, A., Ozyyurt, H., Gulec, M. and Akyol, O., The protective role of caffeic acid phenyl ester (CAPE) on testicular tissue after testicular torsion and detorsion, World J. Urol., 20:264–270, 2002.

Caffeine

Caffeine, 1,3,7-trimethylxanthine, consumed in such drinks as coffee and tea, is well-known for its biochemical and physiological activities. In recent years, evidence has accrued that caffeine can inhibit carcinogenesis in mice and rat lungs exposed to a nicotinederived carcinogen (Chung, 1999; Chung et al., 1998), in mice skin exposed to ultraviolet light (Lu et al., 2001), and in rat stomachs exposed to a carcinogen and sodium chloride (Nishikawa et al., 1995). In contrast, however, no inhibition was observed when mammary glands were exposed to specific carcinogens in the presence of caffeine (VanderPloeg et al., 1991). Hagiwara and coworkers (1999) reported caffeine exerted a chemoprotective action against the carcinogen 2-amino-1-methyl-6-phenyl-imidazo [4,5-b]pyridine (PhIP) in female F344 rats for 54 weeks by significantly reducing mammary-gland tumor formation. Takeshita et al. (2003) were unable to explain how caffeine differentially modifies PhIP-induced colon and mammary carcinogenesis. The only parameter they found contributing to the elevation of colon carcinogenesis was elevation in PhIP-DNA adduct formation. Caffeine at a concentration of 2 mM enhanced the radiosensitivity of two rat yolk-sac cell lines with a mutant-type p53 by inducing apoptosis through a p5 3-independent pathway (Higuchi et al., 2000). Ito et al. (2003) also showed caffeine-induced G₂/M phase cell-cycle arrest in NB4 promyelocytic leukemia cells and apoptosis via activation of p53 by a novel pathway.

Structure of caffeine. (From Nafisi et al., J. Mol. Struct., 705:35–39, 2004. With permission.)

Kitamoto et al. (2003) reported that caffeine, combined with paclitaxel, a naturally occurring chemotherapeutic agent from the bark of the Western yew, suppressed cell proliferation in a dose-dependent manner. Examination of the dose responses of paclitaxel alone and in combination with caffeine on the survival of a human lung adenocarcinoma cell line, A549, is shown in Figure C.17. The cell-killing effect of paclitaxel increased in a dose-response manner up to a maximum of 50 nM, with no further improvement at 100 nM. Combining with 5 mM caffeine, however, reduced the cytotoxicity of paclitaxel, which was further dramatically suppressed in the presence of 20 mM caffeine. These researchers showed that in the cell-cycle analysis, caffeine caused early G1 accumulation, while paclitaxel caused an early increase in G2-M and a decrease in G1. These effects suggested that while cell-modifying agents, like caffeine, can diminish the cytotoxic effects of paclitaxel, caution should be exercised in combining these substances.

FIGURE C.17 Dose-response of A549 on paclitaxel alone, paclitaxel with 1, 5, and 20 mM of caffeine for 24 h, paclitaxel alone, (○), paclitaxel+caffeine 1.0 mM, (●), paclitaxel+caffeine 5.0 mM, (□), paclitaxel+caffeine 20 mM (■). Bar shows±SE where these exceed the size of the symbol. (From Kitamoto et al., Cancer Lett., 191:101–107, 2003. With permission.)

References

Chung, F.L., The prevention of lung cancer induced by a tobacco-specific carcinogen in rodents by green and black tea, Proc. Soc. Exp. Biol. Med., 220:244–248, 1999.

Chung, F.L., Wang, M., Rivenson, A., Iatropoulos, M.J., Reinhardt, J.C., Pittman, B., Ho, C.T., and Amin, S.G., Inhibition of lung carcinogenesis by black tea in Fischer rats treated with a tobacco-specific carcinogen: Caffeine as an important constituent, Cancer Res., 58:4096–4101, 1998.

Hagiwara, A., Boonyaphiphat, H., Tanaka, H., Kawabe, M., Tamano, S., Kaneko, H., Matsui, M., Hirose, N., Ito, N., and Shirai, T., Organ-dependent modifying effects of caffeine, and two naturally occurring antioxidants -tocopherol and n-tritriacontane-16,18-dione, on 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine(PhIP)-induced mammary and colonic carcinogenesis in female F344 rats, Jpn. J. Cancer Res., 90:399–405, 1999.

Higuchi, K., Mitsuhashi, N., Saitoh, J., Maebayashi, K., Sakurai, H., Akimoto, T., and Niibe, H., Caffeine enhanced radiosensitivity of rat tumor cells with a mutant-type p53 by inducing apoptosis in a p5 3-independent manner, Cancer Lett., 152:157–162, 2000.

Ito, K., Nakazato, T., Miyakawa, Y., Yamato, K., Ikeda, Y., and Masahiro, K., Caffeine induces G2.M arrest and apoptosis via a novel p5 3-dependent path-way in NB4 promyelocytic leukemia cells, J. Cell. Physiol., 2003 (in press).

Kitamoto, Y., Sakurai, H., Mitsuhashi, N., Akimoto, T., and Nakano, T., Caffeine diminishes cytotoxic effects of paclitaxel on a human lung adenocarcinoma cell line, Cancer Lett., 191:101–107, 2003.

Lu, Y.P., Lu, Y.R., Lin, Y., Shih, W.J., Huang, M.T., Yang, C.S., and Conney, A.H., Inhibitory effects of orally administered green tea, black tea and caffeine on skin carcinogenesis in mice previously treated with ultraviolet B light (high-risk mice): Relation-ship to decreased tissue fat, Cancer Res., 61:5002–5009, 2001.

Nafisi, S., Manajemi, M., and Ebrahimi, S., The effects of mono- and divalent metal cations on the solution structure of caffeine and theophylline, J. Mol. Struct., 705:35–39, 2004.

Nishikawa, A., Furukawa, F., Imizaka, T., Ikezaki, S., Hasegawa, T., and Takahasi, M., Effects of caffeine on glandular stomach carcinogenesis induced in rats by N-methyl-N-nitro-Nnitrosoguanidine and sodium chloride, Food Chem. Toxicol., 33:21–26, 1995.

Takeshita, F., Ogawa, K., Asomoto, M., and Shirai, T., Mechanistic approach of contrasting modifying effects of caffeine on carcinogenesis in the rat colon and mammary gland induced with 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine, Cancer Lett., 194:25–35, 2003.

VanderPloeg, L.C., Wolfrom, D.M., and Welsch, C.W., Influence of caffeine on development of benign and carcinomatous mammary gland tumors in female rats treated with the carcinogens, 7,12-dimethylbenz(a)anthracene and N-methyl-N-nitrosourea, Cancer Res., 51:3399–3404, 1991.

Calcium

Because of its importance in bone formation, particularly in relation to osteoporosis, calcium is now added to such beverages as orange juice. In addition, calcium also appears to exert cancer-preventive properties. Enhanced cell proliferation, an early biological event in the carcinogenesis process, combined with an abnormal distribution of proliferating cells in the colon, was evident in animals exposed to carcinogens and in humans with a high risk for colon cancer. Studies with human subjects have shown that calcium supplementation may reduce epithelial-cell proliferation, particularly in patients with a high risk for colon cancer (Wargovich et al., 1992; Bostick et al., 1993; O’Sullivan et al., 1993). Karkare et al. (1990) reported that supplemental calcium, relative to the standard concentration of 5.07 g/kg diet, decreased colon-tumor incidence in rats, although a lower concentration of 2.0 g/kg also reduced the incidence. However, Whitfield et al. (1995) cautioned that increasing calcium in the diet could actually promote colon cancer. Nevertheless, there is a large body of scientific evidence that increasing dietary calcium above normal levels may reduce colon cancer (War-govitch et al., 1990; Bostick et al., 1993; O’Sullivan et al., 1993) and that this risk could also be reduced by decreasing calcium below this level (Karkare et al., 1990).

Li and coworkers (1998) showed that both low (0.5 and 1.0 g/kg) and high (10.0 and 15.0 g/kg) levels of calcium reduced the yield of azoxymethane (AOM)-induced aberrant crypt foci (ACF) in rat colons, relative to 5.0 g/kg of calcium (Figure C.18). A reduction in the yield of ACF with two or more crypts suggested that calcium levels above and below the standard level of 5.0 g/kg inhibited the promotion/progression of foci into tumors. A decrease in cell proliferation was also observed in the presence of low and high calcium levels by a reduction in both the PCNA-labeling index and the size of the PCNA-proliferative. Beaty and coworkers (1993) reported a nonstatistically significant reduction in tumor incidence of 1,2-dimethylhydrazine-induced colon carcinogenesis in rats fed high-fat diets containing vitamin D and calcium. Using diets containing 5000 and 15,000 ppm calcium with and without the presence of vitamin D and acetylsalicylic acid (ASA), Molck et al. (2002) found calcium levels affected ACF and tumor development differently. The number of ACF decreased with the higher calcium concentration, while the number of tumor-bearing animals increased with increasing calcium, either directly or indirectly, by adding vitamin D3 together with ASA. This study showed calcium was a strong modulator of ACF and tumor development and masked the effect of vitamin D and ASA. Low calcium levels increased both the development of advanced ACF, as well as tended to increase tumor incidence. The latter can be avoided by adding vitamin D and ASA. These findings suggest that a high calcium intake may interact with other dietary or therapeutic components. These researchers cautioned against increasing calcium levels above recommended levels, as it could give initiated cells growth advantages compared to normal cells.

FIGURE C.18 Effect of calcium on the yield of AOM/induced ACF. Results of means±SE treatment group containing 12 rats. Statistically different results for the treatment group administered 5.0 g/kg as calcium are labeled, respectively, *p<0.05 and **p<0.01. (From Li et al., Cancer Lett., 124:39–46, 1998. With permission.)

References

Beaty, M.M., Lee, E.Y., and Glauert, H.P., Influence of dietary calcium and vitamin D on colon epithelial cell proliferation and 1,2-dimethylhydrazine-induced colon carcinogenesis in rats fed high-fat diets, J. Nutr., 123:144–152, 1993.

Bostick, R.M., Potter, J.D., Fosdick, L., Grambsh, P., Lampe, J.W., Lampe, J.R., Wood, T.A., Louis, T.A., Ganz, R., and Grandits, G., Calcium and colorectal epithelial cell proliferation: A preliminary randomized, double-blind, placebo-controlled clinical trial, J. Natl. Cancer Inst., 85:132–141, 1993.

Karkare, M.R., Clark, T.D., and Glauert, H.P., Effect of dietary calcium on colon carcinogenesis induced by a single injection of 1,2-dimethylhydrazine in rats, J. Nutr., 121:568–577, 1990.

Li, H., Kramer, P.M., Lubet, R.A., Steele, V.E., Kelloff, G.J., and Pereira, M.A., Effect of calcium on azoxymethane-induced aberrant crypt foci and cell proliferation in the colon of rats, Cancer Lett., 124:39–46, 1998.

Molck, A.-M., Poulsen, M., and Meyer, O., The combination of 1α,25(OH)2-vitamin D3, calcium and acetylsalicylic acid affects azoxymethane-induced aberrant crypt foci and colorectal tumors in rats, Cancer Lett., 186:19–28, 2002.

O’Sullivan, K.R., Mathias, P.M., Beattie, S., and O’Morain, C., Effect of oral calcium supplementation on colonic crypt cell proliferation in patients with adenomatrous polyps of the large bowel, Eur. J. Gastroenterol. Hepatol., 5:85–89, 1993.

Wargovich, M.J., Allnut, D., Palmer, C., Anaya, P., and Stephens, L.C., Inhibition of the promotional phase of azoxymethane-induced colon carcinogenesis in theF344 rats by calcium lactate: Effect of stimulating two human nutrient density levels, Cancer Lett., 53:17–25, 1990.

Whitfield, J.F., Bird, R.P., Chakravarhy, B.R., Isaacs, R.J., and Morley, P., Calcium-cell cycle regulator, differentiator, killer, chemopreventor, and maybe tumor promotor, J. Cell Biochem., Issue 22 Suppl., 74–91, 1995.

Calendula officinalis L.

Calendula officinalis L. (Marigold), an annual herb found in the Mediterranean region, is grown for ornamental and medicinal purposes in Europe and North America. Many properties have been associated with tinctures and decoctions from its flowers, including anti-inflammatory, antitumoral, and analgesic (Duke, 1991). Cytotoxic effects were reported for extracts from its leaves, flowers, and whole plant against three cells lines from Ehrlich carcinoma. One of these extracts, rich in saponins, exhibited antitumoral activity in an in vivo Ehrlich mouse carcinoma model (Boucaud-Maitre et al., 1988). Ramos and coworkers (1998) found a 60 percent aqueous-alcohol extract from Calendula flowers was not mutagenic in the Ames test but did report a genotoxic effect in the mitotic segregation assay of the heterozygous diploid D-30 of Aspergillus nidulans. This fraction was shown to contain a terpene lactone, tentatively identied as (−) oli-olide (calendin), together with acyclic hydrocarbons. Two polar (aqueous and aqueous-alcohol) extracts from C. officinalis flowers were shown by Perez-Carreon et al. (2002) to be antigenotoxic at low concentrations by protecting rat-liver cell cultures from diethylnitrosamine (DEN) treatment. The opposite was observed at high concentrations, in which genotoxic effects were observed by the same extracts containing flavonols. These researchers pointed out that the concentration effect of these extracts must be clarified if these polyphenols are to be considered for therapeutic treatment.

Hamburger and coworkers (2003) developed a relatively simple, efficient preparative method for purifying the major anti-inflammatory triterpenoid esters from Calendula flower heads. The major compounds identified were faradiol esters, while the minor triterpenoid esters included maniladiol 3-O-laurate and myristate.

References

Boucaud-Maitre, Y., Algernon, O., and Raynaud, J., Cytotoxic and antitumoral activity of Calendula officinalis extracts, Die Pharmazie, 43:220–222, 1988.

Duke, J.A., in Handbook of Medicinal Herbs, CRC Press, Boca Raton, Florida, 1991, pp. 87–88.

Hamburger, M., Adler, S., Baumann, D., Forg, A., and Weinreich, B., Preparative purification of the major anti-inflammatory triterpenoid esters from Marigold (Calendula officinalis), Fitoperia, 74:328–338, 2003.

Perez-Carreon, J.I., Cruz-Jimenez, G., Licea-Vega, J.A., Popoca, E.A., Fazenda, S.F., and Villa- Trevino, S., Genotoxic and anti-genotoxic properties of Calendula officinalis extracts in rat liver cell cultures treated with diethytlnitrosamine, Toxicol. In Vitro, 16:253–258, 2002.

Ramos, A., Edeira, A., Vizoso, A., Betancourt, J., Lopez, M., and Decalo, M., Genotoxicity of an extract of Calendula officinalis L., J. Ethnopharmacol., 61:49–55, 1998.

Cane sugar

The pressed juice from sugar cane (Saccharum officinarum L.) is used in Japan for the production of Kokuto. Previous studies isolated and characterized a number of phenolic compounds in Kokuto exhibiting antioxidant activity (Nakasone et al., 1996; Takara et al., 2000). Takara and coworkers (2002) recently isolated seven new phenolic glycosides, together with two known phenolic glycosides. Using the 2-deoxyribose oxidation method, all of these compounds exhibited antioxidant activity.

References

Nakasone, Y., Tanakara, K., Wada, K., Tanaka, J., and Yogi, S., Antioxidative compounds isolated from Kokuto, non-centrifuged cane sugar, Biosci. Biotechnol. Biochem., 60:1714–1716, 1996.

Takara, K., Kinjo, A., Matsui, D., Wada, K., Nakasone, Y., and Yogi, S., Antioxidative compounds from the non-sugar fraction in Kokuto, non-centrifuged cane sugar, Nippon Nogeikagaku Kaishi, 74:885–890, 2000.

Takara, K., Matsui, D., Wada, K., Ichiba, T., and Nakasone, Y., New antioxidative phenolic glucosides isolated from Kokuto non-centrifuged cane sugar, Biosci. Biotechnol. Biochem., 66:29–35, 2002.

Canola

Canola oil, the major edible in Canada, is recognized as a well-balanced oil, low in saturates, high in monounsaturates, and a good source of polyunsaturated acids (Table C.16). It is particularly low in saturated fatty acids (<7.0 percent), accounting for half the level found in olive or soybean oil. In addition, the high level of monounsaturated fatty acids in canola oil provides possible protection against oxidation of LDL. This is important as uptake of LDL and formation of fatty streaks in the intima of blood vessels, an early lesion of atherosclerosis, is characterized by enhanced oxidation of LDL (Steinberg et al., 1989; Parathasarathy and Rankin, 1992). Canola oil is high in linoleic acid (>20 percent), a member of the ω-6 family of essential fatty acids that are precursors of arachidonic acid and eicosanoids, hormone-like substances involved in many functions, such as blood clotting to immune responses. Canola oil is one of the few oils high in α-linolenic acid (>9 percent), an essential ω-3 fatty acid that is a precursor of docosahexaenoic acid (C22:6 ω-3), a major component of lipids in the brain and retina of the eye, and eicosapentaenoic acid (C22:5 ω-3), a precursor of another group of eicosanoids. There is a favorable balance in canola oil of 1:2 for the ratio of α-linolenic acid (10 percent) and linoleic acid (21.7 percent).

TABLE C.16
Fatty-Acid Composition of Canola Oil

Animal studies have shown that diets high in polyunsaturated and monounsaturated fatty acids promote reduced fat accumulation compared to diets high in saturated fatty acids. Ellis and coworkers (2002) confirmed the ability of canola oil (high in monounsaturated fatty acids) to reduce fat deposition in growing female rats compared to corn oil (high in polyunsaturated fatty acids) and coconut oil (high in saturated fatty acids). In high-fat diets (40 percent calories), rats fed corn oil had a much larger fat-cell size compared to either canola or coconut oils, although the number of fat cells was much greater in coconut-oil-fed animals than the other oils. On the low-fat diet (6 percent calories), canola oil had a definite advantage over corn oil, as the animals had a lower body-weight gain. This study demonstrated the benefits of a diet high in monounsaturated fatty acids because of its ability to reduce adiposity and plasma lipids.

Wakamatsu (2001) isolated a potent antioxidant in crude canola oil, which was subsequently identified as 4-vinyl-2,6-dimethoxylphenol, or canolol. Recent work by Kuwahara et al. (2004) found canolol prevented apoptosis in mammalian cells induced by oxidative stress. Canolol proved toxic to cultured human colon cancer cells in vitro when present at 560 μM (Figure C.19A) as well as prevented apoptosis induced by oxidative stress by tert-butyl hydroperoxide (t-BuOOH) (Figure C.19B).

Canolol. (From Kuwahara et al., J. Agric. Food Chem., 52:4380–4387, 2004.)

In addition, canolol also prevented DNA-strand breakage by peroxynitrite in a dose-dependent manner. The chemopreventive effects of canolol indicate its potential as a new nutraceutical.

References

Ellis,, J., Lake, A., and Hoover-Plow, J., Monounsaturated canola oil reduces fat deposition in growing female rats fed a high or low fat diet, Nutr. Res., 22: 609–621, 2002.

Kuwahara, H., Kanazawa, A., Wakamatu, D., Morimura, S., Kida, K., Akaike, T., and Maeda, H., Antioxidative and antimutagenic activities of 4-vinyl-2,6-dimethoxyphenol (canolol) isolated from canola oil, J. Agric. Food Chem., 52:4380–4387, 2004.

Mattson, R.S. and Grundy, S.M., Comparison of effects of dietary saturated, monounsaturated and polyunsaturated fatty acids on plasma lipids and lipoproteins in man, J. Lipid Res., 26:194–202, 1985.

Parathasarathy, S. and Rankin, S.M., Role of oxidized low density lipoprotein in atherogenesis, Prog. Lipid Res., 31:127–143, 1992.

Przybylski, R., Eskin, N.A.M., Mag, T., and McDonald, B.E., Canola/rapeseed oil, in Bailey’s Industrial Oil & Fat Products, Edible Oil & Fat Products: Oils and Oilseeds, vol. 7, Hui, Y., Ed., John Wiley & Sons Inc., New York, 2003, chap. 1, pp. 1–95.

Steinberg, D., Parthasarathy, S., Carew, T.E., Khoo, J.C., and Witztum, J.L., N. Engl. J. Med., 320:915– 1989.

Wakamutsa, D., Isolation and identification of radical scavenging compound, canolol, in canola oil, Master’s thesis, Graduate School of Natural Science, Kumamoto University, Kumamoto City, Japan, 2001, pp. 1–48.

FIGURE C.19 (a,b) Inhibition of t-BOOH-induced cytotoxicity in mammalian cells by canolol [values are means (n=6 wells); bars indicate SE; *p<0.05). (From Kuwahara et al., J. Agric. Food Chem., 52:4380–4387, 2004. With permission.)

Capsaicin

Capsaicin (trans-8-N-vamllyl-6-nonenamide) is an acrid, volatile alkaloid responsible for hotness in peppers. While it is used as an ingredient in pepper sprays, capsaicin and its dihydro derivatives all exhibit antiinflammatory properties (Sancho et al., 2002). Kim et al. (2003) examined the anti-inflammatory mechanism of capsaicin on the production of inflammatory molecules in liposaccharides (LPS)-stimulated murine peritoneal macrophages. Capsaicin suppressed PGE2 production by inhibiting COX-2 enzyme and inducible nitric-oxide synthase (iNOS) expression in a dose-dependent manner. The inflammatory action of capsaicin was independent of the vanilloid-receptor 1 (VR-1) but involved the following signaling pathway (Scheme C.13). Capsazepine, a known VR-1 antagonist, did not eliminate capsaicin action, but inhibited COX-2 and iNOS expression. Both compounds inactivated NF-κB via stabilization of IkB-a protein and may be useful in ameliorating inflammatory diseases and cancer.

Capsaicin is also used as a topical cream for treating various neuropathic conditions. Richeux and coworkers (1999) cautioned against the misuse of preparations containing 0.075 percent of capsaicin, which could lead to DNA-strand lesions, with detrimental effects to cellular functions, resulting in cell death or mutagenesis. The chemoprotective effects of topical application of capsaicin on the dorsal skin of female ICR mice was attributed by Han et al. (2001) to its suppression of phorbol esterinduced activation of NF-κB and activator protein-1 (AP-1) transcription factors. Lee et al.(2000) showed capsaicin induced apoptosis in A172 human glioblastoma cells in a time-and dose-dependent manner. The mechanism whereby capsaicin induced apoptosis may involve reduction of the basal generation of ROS. Capsaicin’s ability to induce apoptosis in SK-Hep-1 heptacarcinoma cells was shown by Jung and coworkers (2001) to be due to its ability to reduce the ratio of antiapoptotic Bcl-2 to proapoptotic Bax and by activation of caspase-3.

Capsaicin. (Adapted from Zhou et al., Life Sci., 74:935–968, 2004.)

SCHEME C.13 Proposed intracellular signaling pathways for the anti-inflammatory action of capsaicin or capsazepine in perotoneal macrophages, TRAP, tumor necrosis factor; CAP capsaicin; CZE Capsazepine. (From Kim et al., Cell. Sig., 15:299–306, 2003. With permission.)

While an early Italian case-control study showed chili consumption protected against stomach cancer (Buiatti et al., 1989), a subsequent epidemiologic study in Mexico City found a greater risk of developing stomach cancer (Lopez-Carrillo et al., 1994). Based on a number of studies, capsaicin appeared to both promote and inhibit chemically induced carcinogenesis. Further work is needed to confirm its chemopreventive properties.

References

Buiatti, E., Palli, D., Decarli, A., Amadori, D., Avellini, S., Biachi, S., Biserni, R., Cipriani, F., Cocco, P., and Giacosa, A., A case-control study of gastric cancer and diet in Italy, Int. J. Cancer, 44:611–616, 1989.

Han, S.S., Keum, Y.S., Seo, H.J., Chun, K.S., Lee, S.S., and Surh, Y.J., Capsaicin suppresses phorbol ester-induced activation of NF-κB/Rel and AP-1 transcription factors in mouse epidermis, Cancer Lett., 164:119–126, 2001.

Jung, M.Y., Kang, H.J., and Moon, A., Capsaicininduced apoptosis in SK-Hep-1 hepatocarcinoma cells involves Bcl-2 down-regulation and caspase-3 activation, Cancer Lett., 165:139–145, 2001.

Kim, C.-S., Kawada, T., Kim, B.-S., Han, I.-S., Choe, S.-Y., Krata. T., and Yu, R., Capsaicin exhibits antiinflammatory property by inhibiting IkB-a degradation in LPS-stimulated pertiotoneal macrophages, Cell. Sig., 15:299–306, 2003.

Lee, Y.S., Nam, D.H., and Kim, J.A., Induction of apoptosis by capsaicin in A172 human glioblastoma cells, Cancer Lett., 161:121–130, 2000.

Lopez-Carrillo, L., Hernandez, A.M., and Dubrow, R., Chili pepper consumption and gastric cancer in Mexico: A case control study, Am. J. Epidemiol., 139:263–271, 1994.

Richeux, F., Cascante, M., Ennamay, R., and Saboureau, D., Cytotoxicity and genotoxicity of capsaicin in human neuroblastoma cells SHSY-5Y, Arch. Toxicol., 73:403–409, 1999.

Sancho, R., Lucena, C., Machio, A., Caldzado, M.A., Blanco-Molina, M., Minassi, A., Appendino, G., and Munoz, E., Immunosuppresive activity of capsaicinoids: Capsiate derived from sweet peppers inhibits NF-κB activation and is a potent anti-inflammatory compound in vivo, Eur. J. Immunol., 32:1753- 1763, 2002.

Zhou, S., Koh, H.-L., Gao, Y., Gong, Z.-Y., and Lee, E.J., Herbal bioactivation: The good, the bad and the ugly, Life Sci., 74:935–968, 2004.

Capsicum

see Paprika

Caraway

A reference-controlled doubleblind equivalence study by Madisch et al. (1999) showed a mixture of caraway and peppermint oil was comparable to the prokinetic agent cisapride in the treatment of functional dyspepsia. Further research by Freise and Kohler (1999) on nonulcer dyspepsia confirmed that an enteric-coated capsule containing peppermint and caraway oil was comparable in efficacy to that of an enteric-soluble formulation composed of peppermint and caraway oil. Micklefield and coworkers (2000) subsequently demonstrated the safe application of entericcoated and nonenteric-coated peppermint-caraway oil combinations for the treatment of gastroduodenal motility.

References

Freise, J. and Kohler, S., Peppermint oil-caraway oil fixed combination in non-ulcer dyspepsia-comparison of the effects of enteric preparations, Pharmazie, 54:210–215, 1999.

Madisch, A., Heydenreich, C.J., Wieland, V., Hufnagel, R., and Holtz, J., Treatment of functional dyspepsia with a fixed peppermint oil and caraway oil combination as preparation as compared to cisapride. A multicenter, reference-controlled double-blind equivalence study, Arzneimittel-Forschung, 49:925–932, 1999.

Micklefield, G.H., Greving, I., and May, B., Effects of peppermint oil-caraway oil on gastroduodenal motility, Phytotherap. Res., 14:20–23, 2000.

L-Carnitine

L-Carnitine (β-hydroxy-γ-tri-methylammonium butyric acid), a small, water-soluble compound, is synthesized endogenously in humans, but most comes from the diet. The majority of L-carnitine on the market is produced by chemical synthesis. L-Carnitine plays an important role in mammalian fat metabolism as a fatty-acid carrier across the inner mitochondrial membrane, which undergoes β-oxidation for energy production. It has a number of important clinical applications, including the treatment of heart disease, hemodialysis, and Alzheimer’s disease (Cederbaum et al., 1984; Breningstall, 1990; Seim et al., 2001). Dayanandan and coworkers (2001) showed L-carnitine protected atherosclerotic rats by significantly reducing lipid-peroxidation levels in their hearts, as well as restoring the levels of enzymatic oxidants, superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), and glucose 6 phosphate dehydrogenase (G6PD), and antioxidant vitamins C, E, and B₆ (Table C.17). A similar pattern was observed for the antioxidants and lipid peroxidation in the liver from the same atherosclerotic rats. By restoring the levels of these antioxidants, carnitine ensured that normal cell function was maintained.

L-Carnitine. (From Ilias et al., Mitochondrion, 4:163–168, 2004. With permission.)

Doxorubicin (DOX), an anthracycline antibiotic, is effective in reducing soft and solid tumors. However, its clinical application is somewhat limited by its severe cardiotoxicity due to the generation of cytotoxic aldehydes (Luo et al., 1999). These same researchers showed it was possible to attenuate the production of these peroxidation products by DOX by administering L-carnitine. The protective effect of L-carnitine was attributed to improving cardiac-energy metabolism and reduction in lipid peroxidation.

Male infertility is a serious problem in Western countries due, in part, to a decline in semen quality. The drugs used by practitioners and specialists for improving sperm quality have never really been tested. Lenzi et al. (1993) examined the effect of antioxidant therapies on sperm maturation. Both free and acetylated forms of L-carnitine are used by the spermatozoa for β-oxidation and for the transfer of acyl to mitochondrial CoA (Frenkel and McGarry, 1980; Peluso et al., 2000). Lenzi and coworkers (2003) treated 100 infertile patients (20–40 years) in a placebo-controlled, double-blind, crossover study with 2 g/day L-carnitine or the placebo over two two-month periods. L-Carnitine therapy significantly improved semen quality, as measured by sperm concentration and total and forward motility. The potential of L-carnitine as a treatment for male infertility needs to be repeated using a much larger clinical trial and in vitro studies.

TABLE C.17
Lipid Peroxidation and Antioxidant Levels in the Heart of Normal and Atherosclerotic Rats¹

References

Breningstall, G.N., Carnitine deficiency syndromes, Pediatr. Neurol., 6:75–81, 1990. Cederbaum, S.D., Auestad, N., and Bernar, J., Fouryear treatment systemic carnitine deficiency, N. Engl. J. Med., 10:1395–1396, 1984.

Dayanandan, A., Kumar, P., and Panneerselvam, C., Protective role of L-carnitine on liver and heart lipid peroxidation in atherosclerotic rats, J. Nutr. Biochem., 12:254–257, 2001.

Frenkel, R.A. and McGarry, J.D., Carnitine Biosynthesis, Metabolism, and Function, Italian ed., Academic Press, New York, pp. 321–340, 1980.

Ilias, I., Manoli, I., Blackman, M.R., Gold, P.W., and Alesci, S., L-Carnitine and acetyl-L-carnitine in the treatment of complications associated with HIV infection and antiretroviral therapy, Mitochondrion, 4:163–168, 2004.

Lenzi, A., Culasso, F., Gandini, L., Lombardo, L., and Dondero, F., Placebo-controlled, doubleblind, cross-over trial of glutathione therapy in male infertility, Hum. Reprod., 8:1657–1662, 1993.

Lenzi, A., Lombardo, F., Sgro, P., Salacone, P., Caponecchia, L., Dondero, F., and Gandini, L., Use of L-carnitine therapy in selected cases of male factor infertility: A double-blind crossover trial, Fertil. Steril., 79:292–300, 2003.

Luo, X., Reichietzer, B., Trines, J., Benson, L.N., and Lehotay, D.C., L-Carnitine attenuates doxorubicin-induced lipid peroxidation in rats, Free Rad. Biol. Med., 26:1158–1165, 1999.

Peluso, G., Nicolai, R., Reda, E., Benatti, P., Barbarisi, A., and Calvai, M., Cancer and anticancer therapy-induced modifications on metabolism mediated by carnitine, J. Cell. Physiol., 182:339– 350, 2000.

Seim, H., Eichler, K., and Kleber, H.-P., L(−)-Carnitine and its precursor, γ-butyrbetaine, in Neutraceuticals in Health and Disease Prevention, Kramer, K., Hoppe, P.-P., and Packer, L., Eds., Marcel Dekker, New York, 2001, pp. 217–256.

L-Carnosine

L-Carnosine (β-alanyl-L-histidine) and its related compounds, anserine and homocarnosine, are found in the skeletal muscle and brain of mammals (Kohen et al., 1988). In addition to their antioxidant properties, they are efficient, copper-chelating agents with a possible role in copper metabolism (Gercken et al., 1980). Choi and coworkers (1999) showed carnosine-related compounds protected Cu, Zn-SOD (superoxide dismutase) from fragmentation by hydrogen peroxide. Carnosine and related compounds were shown by Ukeda and coworkers (2002) to protect human Cu, Zn-SOD from inactivation by glycoaldehyde, a Maillard-reaction intermediate, and from fructose. This protection was attributed to its hydroxyl radical-scavenging activity. Kang and coworkers (2002) showed L-carnosine’s antioxidant properties protected rat liver epithelial cells from 12-O-tetradecanoyl-phorbol-13-acetate (TPA) or hydrogen peroxide-induced apoptosis via the mitochondria.

L-Carnosine. (From Hobart et al., Life Sci., 75:1379–1389, 2004. With permisson.)

Carnosine, a histidine dipeptide in mammalian brain, has been shown to prevent neuralcell toxicity (Hipkiss et al., 1997), ischemic injury (Stvolinsky et al., 1999), thermal injury (Deev et al., 1997), and β-amyloid aggregation (Munch et al., 1997). The anticross-linking property of carnosine appeared to be responsible for its potential use in the treatment of Alzheimer’s disease (Hobart et al., 2004). The imidazolium group of histidine in carnosine may stabilize adducts formed with the primary amino group.

References

Choi, S.Y., Kwon, H.Y., Kwon, O.B., and Kang, J.H., Hydrogen peroxide-mediated Cu, Zn-superoxide disutase fragmentation: Protection by carnosine, homocarnosine and anserine, Biochem. Biophys. Acta, 1472:651–657, 1999.

Deev, L.I., Goncharenko, E.N., Baizhumanov, A.A., Akhalaia, M.Ia., Antonova, S.V., and Shestokova, S.W., Protective effect of carnosine in hyperthermia, Bull. Experiment. Biolog. Med., 124(7):50–52, 1997.

Gercken, G., Bischoff, H., and Trotz, M., Myocardial protection by a carnosine-buffered cardioplegic solution, Arzneimmitelforschung, 30:2140–2143, 1980.

Hipkiss, A.R., Michaelis, J., and Syms, P., Non-enzymatic glycosylation of the dipeptide L-carnosine, a potential anti-protein-cross-linking agent, FEBS Lett., 371:81–85, 1995.

Hobart, L.J., Seibel, I., Yeargans, G.S., and Seidler, N.W., Anti-crosslinking properties of carnosine: Significance of histidine, Life Sci., 75:1379–1389, 2004.

Kang, K.-S., Yun, J.-W., and Lee, Y.-S., Protective effect of L-carnosine against 12-Otetradecanoylphorbol- 13-acetate- or hydrogen peroxideinduced apoptosis on v-myc transformed rat liver epithelial cells, Cancer Lett., 178:53–62, 2002.

Kohen, R., Yamamoto, Y., Cundr, K.C., and Ames, B.N., Antioxidant activity of carnosine, homocarnosine and anserine present in muscle and brain, Proc. Natl. Acad. Sci. U.S.A., 85:3175–3179, 1988.

Munch, G., Mayer, S., Michaelis, J., Hipkiss, A.R., Riederer, P., Muller, R., Neumann, A., Schinzel, R., and Cunningham, A.M., Influence of advanced glycation end-products and AGEinhibitors on nucleation-dependent polymerization of beta-amyloid peptide, Biochem. Biophys. Acta, 1360:17–19, 1997.

Stvolinsky, S.L., Kukley, M.L., Dobrata, D., Matejovicova, M., Tkac, I., and Boldyrev, A.A., Carnosine: An endogenous neuroprotector in the ischemic brain cell, Mol. Neurobiol., 19:45– 56, 1999.

Ukeda, H., Hasegawa, Y., Harada, Y., and Sawamura, M., Effect of carnosine and related compounds on the inactivation of human Cu, Zn-superoxide dismutase by modification of fructose and glycoaldehyde, Biosci. Biotechnol. Biochem., 66:36–43, 2002.

Carnosol

see also Rosemary Carnosol is a phenolic dieterpene antioxidant obtained from the herb rosemary (Rosemarinus officinalis Labiatae). Its anticancer properties were demonstrated in animal models for breast and skin tumors (Huang et al., 1994; Singletary et al., 1996). Carnosol was shown to strongly inhibit the activity of phase I enzyme, CYP 450, while stimulating the activities of phase II enzymes, glutathione S-transferase (GST), and NAD (P)H-quinone reductase (QR) in the liver (Offord et al., 1998). Dorrie and coworkers (2001) showed carnosol was effective against several pro-B and pre-B acute lymphoblastic leukemia (ALL) lines, a disease prevalent among infants during early childhood. Carnosol induced apoptosis in B-lineage leukemias by down-regulating the antiapoptotic protein Bcl2, suggesting it was a novel chemotherapeutic agent against other types of cancers. It proved cy to toxic against all five acute leukemia lines, with the percentage of dead cells ranging from 40 to 75 percent with the effect of 6 μg/mL of carnosol not statistically different from that of 9 μg/mL (Figure C.20). A recent study by Huang et al. (2005) showed the potential of carnosol for treating lung metastasis of B16/F10 mouse melanoma cells by inhibiting NF-6B and AP-1 binding activity. Following this, carnosol inhibited metalloproteinase (MMP)-9 gene expression which is associated with increased matastic potential for many types of cancers.

Carnosol. (From Huang et al., Biochem. Pharmacol., 69:221–232, 2005. With permission.)

The antioxidant properties of carnosol were demonstrated by Lo and coworkers (2002) by its ability to scavenge DPPH free radicals and protect DNA from the Fenton reaction.

FIGURE C.20 Carnosol is cytotoxic to the leukemia cells (a). The leukemia cells lines; or (B), Peripheral blood mononuclear cells (PMBCs) from healthy volunteers were untreated, or treated with 3 (gray), 6 (hatched), and 9 μg/mL (black) carnosol, and the percentage cell death was measured after four days by propidium iodide staining of nuclei and a FACS-Calibur fluorescence-activated cell scorer (FACS). The data presented represent the mean of the percentage cell death±SE of five separate experiments for (A) and three healthy donors for (b). The control is white. (From Dorrie et al., Cancer Lett., 170:33–39, 2001. With permission.)

Carnosol markedly reduced lipopolysaccharide (LPS)-stimulated NO production in mouse macrophages in a concentration-dependent manner, with an IC₅₀ of 9.4 μM, while only slight changes were observed for the other rosemary compounds (carnosic, rosmarinic, and ursolic acids). Multiple stages of carcinogenesis and inflammation are characterized by large amounts of NO produced by inducible NO synthase (iNOS). The mechanism for carnosol’s anticancer and anti-inflammatory properties appears to be related to its suppression of NO production and iNOS gene expression through inhibition of nuclear factor-κB (NF-κB).

References

Dorrie, J., Sapala, K., and Zunino, S.J., Carnosolinduced apoptosis and down regulation of Bcl-2 in B-lineage leukemia cells, Cancer Lett., 170:33–39, 2001.

Huang, S.-C., Ho, C.-T., Lin-Shiau, S.-Y., and Lin, J.-K., Carnosol inhibits the invasion of B16/F10 mouse melanoma cells by suppressing metalloproteinase-9 through down regulating nuclear factor-κB and c-Jun, Biochem. Pharmacol., 69:221- 232, 2005.

Huang, M.-T., Ho, C.T., Yuan Wang, Z., Ferraro, T., Lou, Y.-R., Stauber, K., Ma, W., Georgiadis, C., Laskin, J.D., and Conney, A.H., Inhibition of skin tumorigenesis by rosemary and its constituents carnosol and ursolic acid, Cancer Res., 54:701–708, 1994.

Lo, A.-H., Liang, Y.-C., Lin-Shiau, S.-Y., Ho, C.-T., and Lin, J.-K., Carnosol, an antioxidant in rosemary, suppresses inducible nitric oxide synthase through down-regulating nuclear factor-κB in mouse macrophages, Carcinogenesis, 23:983–991, 2002.

Offord, E.A., Mace, K., Avanti, O., and Pfeifer, A.M., Mechanisms involved in the chemoprotective effects of rosemary extract in human liver and bronchial cells, Cancer Lett., 114:275–281, 1997.

Singletary, K., MacDonald, C., and Wallig, M., Inhibition by rosemary and carnosol of 7,12- dimethyl-ben[α]anthracene (DMBA)-induced rat mammary tumorigenesis and in vivo DMBA-DNA adduct formation, Cancer Lett., 104:43–48, 1996.

Carotenoids

Consumption of diets high in fruits and vegetables has been associated with a decrease in cancer and cardiovascular diseases and possibly other degenerative diseases (Block et al., 1992; Willett, 1994; Ames et al., 1995). Of the 600 dietary carotenoids identified in fruits, vegetables, and fish, many of them are reported to protect against atherosclerosis, cancer, and macular degeneration, as well as act as photoprotectants against sun damage to the skin (Mares-Perlman et al., 1995; D’Odorico et al., 2000; Nishino et al., 2000; Ziegler and Vogt, 2002). As antioxidants, they scavenge free radicals or quench singlet oxygen. The association between oxygen radicals, such as superoxide (^·O₂−) and nitric oxide (NO), and chronic diseases, such as cancer, makes carotenoids potentially important antioxidants in human health. However, a recent ATBC Study suggested that β-carotene, under certain circumstances, may enhance carcinogenesis (Rautalahtu et al., 1997). In addition to β-carotene, Murakami and coworkers (2000) examined the ability of 18 natural carotenoids to inhibit tumor-promoting 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ^·O₂− generation in differentiated human promyelocytic cell HL-60 cells (Scheme C.14). No cytotoxicity was observed for any of the carotenoids at 25 μM with inhibitory rates (IRs) ranging from −3.4 percent (for β-cryptoxanthin) to 52.6 percent (for halocynthiaxanthin). The 11 carotenoids all had superior or similar inhibitory rates (IRs=25.1–52.6 percent) to β-carotene (21.3 percent) and the green tea polyphenol, (−) epigallocatechin gallate (IR=15.6 percent). Murakami et al. (2000) proposed that carotenoids in fruits and vegetables suppressed leukocyte-induced oxidative stress by attenuating ^·O₂− production systems, such as NADPH oxidase. From a structural point of view, the presence of a single, 3-hydroxy-κ-end group in carotenoids appeared important for this activity. For example, capsanthin 3,6-epoxide, with 3hydroxy-κ-end group, had a significantly higher inhibitory rate of 40.9 percent compared to 28.4 percent for cucurbitaxanthin, with a 3-hydroxy-β-end group. The ability of these same carotenoids to inhibit lipopolysaccharide (LPS)and interferon (IFN-γ)-induced NO generation by mouse macrophage RAW 264.7 cells ranged from −45.2 percent to+94.7 percent with no cytoxicity reported for any of carotenoids at 50 μM. Halocynthiaxanthin from the Sastumas mandarin (Citrus unshui) exhibited the greatest inhibitory activity of 94.7 percent, indicating the importance of the 3-hydroxy-κ-end group for inhibiting NO production.

Kozuki and coworkers (2000) suggested the antioxidant properties of carotenoids, α-carotene, β-carotene, lycopene, β-cryptoxanthin, zeaxanthin, lutein, canthaxanthin, and astaxanthin, were responsible for inhibiting invasion of rat ascites hepatoma AH 109A cells in a dosedependent manner up to 5 μM. Using a model membrane environment composed of unilamellar dipalmitoyl phosphatidylcholine, Cantrell and coworkers (2003) found singlet oxygen quenching varied with the particular carotenoid incorporated. Lycopene and β-carotene had the fastest singlet oxygen-quenching rate, while lutein the least, with astaxanthin and canthanxin intermediate.

SCHEME C.14 Structure of carotenoids (1–19) and ECGC (20). (From Murakami et al, Cancer Lett., 149:115–123, 2000. With permission.)

Considerable variability between the efficacy of different carotenoids was also shown by Pool-Zobel and coworkers (1997). These researchers showed that carotenoid-rich plant products, such as tomato juice, carrot juice, and spinach powder, consumed by 23 healthy, nonsmoking males between the ages of 27–40, all exerted cancer-protective effects. Using the Comet assay for DNA damage, which specifically measures oxidation of pyrimidines in DNA, only carrot juice reduced endogenous oxidative damage (Figure C.21).

FIGURE C.21 Levels of DNA-strand breaks I peripheral blood lymphocytes from humans receiving different vegetable products. The extent of DNA damage is indicated by the percentage of fluorescence in the comet tail (“tail intensity”). Results are shown as means±SEM, n=21–23 subjects, means of three slides per subject. *Statistically significant in comparison to sampling time 1; two-sided Student’s t-test, p<0.05. (From Pool- Zobel et al., Carcinogenesis, 18:1847– 1850, 1997. With permission.)

References

Albanes, D., Heinonen, O.P., Taylor, P.R., Virtano, J., Edwards, B.K., Rantalahti, M., Hartman, A.M., Palmgren, J., Freedman, L.S., Haapakoshi, J., Barret, M.J., Prietinen, P., Malila, N., Tala, E., Lippo, K., Salomaa, E.R., Tangrea, J.A., Teppo, L., Askin, F.B., Taskinen, E., Erozan, Y., Greenwald, P., and Huttumen, J.K., Alpha-tocopherol and beta-carotene supplement and lung cancer incidence in the alphatocopherol, beta-carotene cancer prevention study: Effects of baseline characteristics and study compliance, J. Natl. Cancer Inst., 88:1560–1570, 1996.

Ames, B.N., Gold, L.S., and Willett, W.C., The causes and prevention of cancer, Proc. Natl. Acad. Sci., 92:5258–5265, 1995.

Block, G., Patterson, B., and Subar, A., Fruit and vegetables, and cancer prevention: A review of the epidemiological evidence, Nutr. Canc., 18:1–29, 1992.

Cantrell, A., McGarvey, D.J., Truscott, T.G., Rancan, F., and Bohm, F., Singlet oxygen quenching by dietary carotenoids in a model membrane environment, Arch. Biochem Biophys., 412:47–54, 2003.

D’Odorico, A., Martines, D., Kiechl, S., Egger, G., Oberhollenzer, F., Bonvicini, P., Sturniolo, G.C., Naccarato, R., and Willett, J., Atherosclerosis, 153: 231–239, 2000.

Kozuki, Y., Miura, Y., and Yagasaki, K., Inhibitory effects of carotenoids on the invasion of rat ascites hepatoma cells in culture, Cancer Lett., 151:111–115, 2000.

Mares-Perlman, J.A., Brady, WE., Klein, R., Klein, B.E.K., Bowen, P., Stacewicz-Sapuintzakis, M., and Palta, M., Arch. Ophthamol., 113:1518–1523, 1995.

Murakami, A., Nakashima, M., Koshiba, T., Maoka, T., Nishino, H., Yano, M., Sumida, T., Kim, A.K., Koshimizu, K., and Ohigashi, H., Modifying effects of carotenoids on superoxide and nitric oxide generation from stimulated leukocytes, Cancer Lett., 149: 115–123, 2000.

Nishino, H., Tokuda, H., Murakoshi, M., Satomi, Y., Masuda, M., Onozuka, M., Yamaguchi, S., Takayasu, J., Tsuruta, J., Okuda, M., Khachik, F., Narisawa, T., Takasuka, N., and Yano, M., Biofactors, 13:89–94, 1995.

Pool-Zobel, B.L., Bub, A., Muller, H., Wolloowski, I., and Rechkemmer, G., Consumption of vegetables reduces genetic damage in humans: First results of a human intervention trial with carotenoid-rich foods, Carcinogenesis, 18:1847–1850, 1997.

Willett, W.C., Diet and health: What should we eat? Science, 264:532–537, 1994.

Ziegler, R.G. and Vogt, T.M., Tomatoes, lycopene, and risk of prostate cancer, Pharm. Biol., 40(Suppl.): 59–69, 2002.

Carrot

Carrot (Daucus carota L.), a biennial of the Umbelliferae family, is grown throughout the world. It is an excellent source of carotenoids, particularly β-carotene. Pool-Zobel et al. (1997) conducted a human-intervention study in which he fed healthy, young men 330 mL carrot juice, tomato juice, and dried-spinach powder. The carrot juice, containing 22.3 mg β-carotene and 15.7 mg α-carotene, was the only one to decrease base oxidation, an indicator of oxidative damage, which was attributed to the ability of α-carotene and β-carotene to quench free radicals in vivo.

However, in spite of carrots being high in β-carotene, there are conflicting data with respect to their health benefits. For example, supplementing well-nourished populations with β-carotene did not prevent cancers or other health disorders (The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study Group, 1994; Greenberg et al., 1996; Hennekens et al., 1996). In other cases, the incidence of cancer actually increased in smokers taking β-carotene supplements (Omenn et al., 1996). The beneficial health effects associated with the consumption of β-carotene-rich vegetables seems contradictory and, in the case of carrots, may be due to the presence of other bioactive compounds. Such compounds may be poly acetylenes, falcarinol, and falcarindiol, found in vegetables such as carrots. Falcarinol or panaxynol, (9Z)-hepta-deca-1,9-dien-4,6-diyn-3-ol, is reported to be one the most bioactive components in carrots (Brandt and Christensen, 2000). While it has been shown to be cytotoxic against several human tumor cells (Saita et al., 1993; Bernart et al., 1996), falcarinol is also a potent skin sensitizer and irritant, as well as a neurotoxic at high concentrations (Hansen and Boll, 1986; Hansen et al., 1986). Recent work by Hansen and coworkers (2003) found falcarinol had biphasic activity, stimulating human cancer growth and cell proliferation between 0.01–0.05 μg/mL, while inhibiting cell proliferation at concentrations greater than 1 μg/mL. Thus, the effect of falcarinol on cell proliferation was concentration-dependent. In comparison, β-carotene had no effect as either a stimulator or inhibitor. Long-term storage, however, resulted in a 35 percent loss of falcarinol, while carrot pieces boiled in water suffered a 70 percent loss (Figure C.22). To maximize the health benefits derived from carrots, eating them raw was recommended.

Falcarinol. (From Brandt et al., Trends Food Sci. Technol., 15:384– 393, 2004. With permission.)

Stoll et al. (2003) developed a pilot-plant scale process for recovering carotenoids from carrot pomace. The total carotene content (α-and β-carotene) of the concentrated hydroly sate was 64 g/kg, making it an excellent functional-food ingredient. Chau and coworkers (2004) showed carrot pomace was rich in insoluble fibers composed mainly of pectin material, hemicellulose, and cellulose. In particular, the water-insoluble solids exhibited significantly (p<0.05) greater glucose absorption and amylase-inhibitory activities compared to cellulose. The hypoglycemic effects of some of these fractions could be useful in controlling postprandial glucose levels.

References

Alpha-tocopherol, Beta-Carotene Cancer Prevention Study Group, The effect of vitamin E and β-carotene on the incidence of lung cancer and other cancers in male smokers, N. Engl. J. Med., 330:1029–1035, 1994.

Bernart, M.W., Cardellina, J.H., II, Balaschak, M.S., Alexander, M., Shoemaker, R.H., and Boyd, M.R., Cytotoxic falcarinol oxylips from Dendropanax arboreus, J. Nat. Prod., 59:748–753, 1996.

Brandt, K. and Christensen, L.P., Vegetables as neutraceuticals-falcarinol in carrots and other root crops, in Dietary Anticarcinogens and Antimutagens, Johnson, I.T., and Fenwick, G.R., Eds., Royal Society of Chemistry, Cambridge, 2000, pp. 386–391.

Brandt, K., Christensen, L.P., Hansen-Moller, J., Hansen, S.L., Heraldsdotter, J., Jesperen, L., Purups, S., Kharazmi, A., Barkholt, V., Frokiaer, H., and Kobaek-Larsen, M., Health promoting compounds in fruits and vegetables: A systematic approach for identifying plant components with impact on human health, Trends Food Sci. Technol., 15:384–393, 2004.

Chau, C.-F., Chen, C.-H., and Lee, M.-H., Comparison of the characteristics, functional properties, and in vitro hypoglycemic effects of various carrot insoluble fiber-rich fractions, Lebensm.- Wiss. u.-Technol., 37:155–160, 2004.

Greenberg, E.R., Baron, J.A., Karagas, M.R., Stukel, T.A., Niererberg, D.W., Stevens, M.M., Mandel, J.S., and Haile, R.W., Mortality associated with low plasma concentration of β- carotene and effect of oral supplementation, J. Am. Med. Assoc., 275:699–703, 1996.

Hansen, S.L. and Boll, P.M., The polyacetylenic falcarinol as the major allergen in Schefflera arboricola, Phytochemistry, 25:529–530, 1986.

Hansen, S.L., Hammershoy, O., and Boll, P.M., Allergic contact dermatitis from falcarinol isolated from Schefflera arboricola, Contact Derm., 14:91–93, 1986.

Hansen, S.L., Purup, S., and Christensen, L.P., Bioactivity of falcarinol and the influence of processing and storage on its content in carrots (Daucus carota L.), J. Sci. Food Agric., 83:1010–1017, 2003.

Hennekens, C.H., Buring, J.E., Manson, J.E., Stampfer, M., Rosner, B., Cook, N.R., Belanger, C., LaMotte, F., Gaziano, J.M., Ridker, P.M., Willett, W., and Peto, R., Lack of effect of long-term supplementation with β-carotene on the incidence of malignant neoplasms and cardiovascular disease, N. Eng. J. Med., 334:1145–1149, 1996.

Omenn, G.S., Goodman, G.E., Thornquist, M.D., Balmes, J., Cullen, M.R., Glass, A., Keogh, J.P., Meyskens, F.L., Jr., Valanis, B., and Williams, J.H., Jr., Effects of a combination of β-carotene and vitamin A on lung cancer and cardiovascular disease, N. Engl. J. Med., 334:1150–1155, 1996.

Pool-Zobel, B.L., Bub, A., Muller, H., Wollowski, I., and Rechkemmer, G., Consumption of vegetable reduces genetic damage to humans: First results of a human intervention trial with carotenoid-rich foods, Carcinogenesis, 18:1847–1850, 1997.

Saita, T., Katano, M., Yamamoto, H., Fujito, H., and Mori, M., The first specific antibody against cytotoxic polyacetylenic alcohol, panaxynol, Chem. Pharm. Bull., 41:549–552, 1993.

Stoll, T., Schweiggert, U., Schieber, A., and Carle, R., Process for the recovery of a carotene-rich functional food ingredient from carrot pommace by enzymatic liquefaction, Innov. Food Sci. Emerging Technol., 4:415–423, 2003.

FIGURE C.22 Reduction in falcarinol content in carrot pieces during boiling in water. Values are mean±SD of three processing replications. FW=fresh weight. (From Hansen et al., J. Sci. Food Agric., 83:1010–1017, 2003.)

Casein

Casein is an important nutritional source of milk protein. Early studies showed that casein inhibited lipid oxidation by molecular encapsulation of the 1,4-pentadiene fatty acids (Laakso, 1984). To determine the primary sequence in casein responsible for its free-radical-scavenging activity, Suetsuna and coworkers (2000) examined peptides produced by peptic digestion of casein. A number of peptides exhibiting superoxide anionscavenging activity (SOSA) were isolated in which the amino-acid sequence was Tyr-Phe-Tyr-Pro-Glu-leu (YFYPEL). Of the amino acids in the peptide, Glu-Leu appeared important for activity. Casein protein was also recognized as an important source of biologically active peptides (Chabance et al., 1998). Such peptides play an important role in the development of the immune system in newborns. Immunostimulating peptides identified in bovine casein were LLY (residues 191–193 β-casein), TTMPLW (C-terminal hexapeptide of α_s1-casein), and PGPIPN (residues 63–68 of β-casein) (Fiat et al., 1993). Xiao and coworkers (2000) investigated the effect of these three peptides on the production of tumor necrosis factor-α (TNF-α) and interleukine-6 (IL-6). The latter are multifunctional cytokines released by macrophages and play an important role in immunoregulation and host defenses (Akira et al., 1990). Xiao et al. (2000) also found that incubation of these three bovine-casein peptides with murine bonemarrow macrophages in the presence of lipopolysaccharide enhanced TNF-α and IL-6 production and nitric-oxide release. These changes could be important in the defense by the host against infection by pathogens.

References

Akira, S., Hirano, T., Taga, T., and Kishimoto, T., Biology of multifunctional cytokines: IL-6 and related molecules (IL-1 and TNF), FASEB, 4:2860–2867, 1990.

Chabance, B., Martean, P., Rambaud, J.C., MiglioreSamour, D., Boynard, M., Perrotin, P. Guillet, R., Jolles, P., and Fiat, A.M., Casein peptide release and passage to the blood in human during digestion of milk or yogurt, Biochemie, 80:155–165, 1998.

Fiat, A., Migliore-Samour, D., Jolles, P., Drouet, L., Sollier, C., and Caen, J., Biologically active peptides from milk proteins with emphasis on two examples concerning antithrombotic and immunomodulating activities, J. Dairy Sci., 76:301–310, 1993.

Laakso, S., Inhibition of lipid peroxidation by casein: Evidence of molecular encapsulation of 1,4- pentadiene fatty acids, Biochem. Biophys. Acta, 792:11–15, 1984.

Suetsuna, K., Ukeda, H., and Ochi, H., Isolation and characterization of free radical scavenging activities of peptides derived from casein, J. Nutr. Biochem., 11:128–131, 2000.

Xiao, C., Jin, L.Z., and Zhao, X., Bovine casein peptides co-stimulate naive macrophages with lipopoly-saccharides for proinflammatory cytokine production and nitric oxide release, J. Sci. Food Agric., 81:300–304, 2000.

Catechins

Catechins are polyphenols widely distributed in fruits and vegetables, especially in tea (Scheme C.15). They have been shown to be anticarcinogenic, antiatherosclerotic, antimicrobial, and to act as antioxidants (Wang et al., 2000; Yang et al, 2000; Yang et al, 2001; McKay and Blumberg, 2002). In addition to scavenging free radicals, tea catechins may also modulate some cellular enzymes. Blache et al. (2002) studied the effect of (+)-catechin on acute iron-load-induced model of platelet hyperactivity. Beneficial effects were only observed in the iron-loaded animals and attributed to antioxidant properties of catechin or its metabolites. The presence of galloyl and gallate moieties in tea catechins, such as (−)-epicatechin gallate (ECG) and (−)-epigallocatechin gallate (EGCG), appears to enhance the antibacterial, anticancer, and radical-scavenging properties of catechin (Ikigai et al., 1993; Rice-Evans, 1995; Kitano et al., 1997). Caturla and coworkers (2003) examined the interaction of four catechins from green tea and vegetables, (+)-catechin (C), (−)-epicatechin (EC), (−)- epicatechin gallate (ECG), and (−)epi-gallocatechin gallate (EGCG), with phospholipidmodel membranes composed of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) or 1,2-dielaidoyl-sn-glycero-3-phosphoethanolamine (DEPE). Galloylated catechins, particularly ECG, affected the physical properties of phospholipid membranes by increasing lipid order and promoting the formation of detergentresistant structures deep inside. In comparison, the nongalloylated catechins were located close to the phospholipid/water interface. ECG exhibited the highest antioxidant activity in this system, while EGCG produced leakage from E. coli-isolated membranes via a specific interaction with phosphatidylethanolamine. The effects on the membranes by galloylated catechins could explain their multiple biological activities.

SCHEME C.15 Tea catechin structures. (From Nishitani and Sagesaka, J. Food. Comp. Anal., 17:675–685, 2004. With permission.)

References

Blache, D., Durand, P., Prost, M., and Loreau, N., (+)-Catechin inhibits platelet hyperactivity induced by an acute iron load in vivo, Free Rad. Biol. Med., 33:1670–1680, 2002.

Caturla, N., Vera-Samper, E., Villalain, J., Mateo, C.R., and Micol, V., The relationship between the antioxidant and the antibacterial properties of galloylated catechins and the structure of phospholipid model membranes, Free Rad. Biol. Med., 34: 648–662, 2003.

Ikigai, H., Nakae, T., Hara, Y., and Shimamura, T., Bacteriacidal catechins damage the lipid bilayer, Biochem. Biophys. Acta, 1147:132–136, 1993.

Kitano, K., Nam, K.Y., Kimura, S., Fujiki, H., and Imanishi, Y., Sealing effects of (−)epigallocatechin gallate on protein kinase C and protein phosphatase 2A, Biophys. Chem., 65:157–164, 1997.

McKay, D.L. and Blumberg, J.B., The role of tea in human health, J. Am. Coll. Nutr., 21:1–13, 2002.

Nishitani, E. and Sagesaka, Y.M., Simultaneous determination of catechins, caffeine and other phenolic compounds in tea using new HPLC method, J. Food. Comp. Anal., 17:675–685, 2004.

Rice-Evans, C., Plant polyphenols: Free radical scavengers or chain-breaking antioxidants, Biochem. Soc. Sym., 61:103–116, 1995.

Wang, H., Provan, G.J. and Helliwell, K., Tea flavonoids: their functions, utilization, and analysis. Trends Food Sci. Technol., 11:152–160, 2000.

Yang, C.S., Landau, J.M., Huang, M.T., and Newmark, H.L., Tea and tea polyphenols in cancer prevention, J. Nutr., 130:472S-478S, 2000.

Yang, C.S., Landau, J.M., Huang, M.T., and Newmark, H.L., Inhibition of carcinogenesis by dietary polyphenolic compounds, Ann. Rev. Nutr., 21:381–406, 2001.

Cat’s claw (Uncaria tomentosa)

see also Quinic acid Cat’s claw, a vine grown in Peru, has been used as a traditional medicine for treating a wide range of ailments, particularly digestive problems and arthritis. An in vitro oxidantinduced stress study by Sandoval and coworkers (1998) showed Cat’s claw acted as an antiinflammatory agent by protecting the cells from oxidative stress, as well as inhibiting activation of NF-κB. Of the two species examined, U. guianensis, with much lower levels of oxindole or pentacyclic alkaloids, was far more potent. This suggested the latter compounds did not contribute to Cat’s claw’s antioxidant and antiinflammatory properties. Further work by Sandoval et al. (2000) examined the effect of Cat’s claw on other NF-κB-regulated genes implicated in inflammation as other examples of oxidative injury. Freeze-dried and micropulverized aqueous extracts from Cat’s claw both inhibited DPPH in a dose-dependent manner. Of the two extracts, the freeze-dried one was far more effective (Figure C.23). In addition, there was a significant reduction in TNF-α, an NF-κB-dependent cytokine involved in chronic inflammation. The freeze-dried extract again proved to be the more potent inhibitor of TNF-α and was 1.5×10⁴ more effective than its antioxidant activity. Ganzera et al. (2001) reported the alkaloid content of different samples of Cat’s claw and its market products ranged from 0.156–0.962 percent. Anguilar and coworkers (2002) showed a spray-dried hydroalcoholic extract from Cat’s claw had a significantly higher (p<0.05) anti-inflammatory activity compared to an aqueous freeze-dried extract using the carrageenan-induced paw oedema model. The presence of pentacyclic oxindole alkaloids acting alone or synergistically with other metabolites were effective at concentrations as low as 0.001 μg/mL. Recent research, however, points to quinic-acid esters as active ingredients in Cat’s claw water extracts (Sheng et al., 2005).

FIGURE C.23 Antioxidant activity of micropulverized and freeze-dried aqueous Cat’s claw extracts, assessed by the DPPH radical method. Values are mean±SEM of three experiments with three samples each. *Significant inhibition (p<0.001) compared to same concentration of micropulverized Cat’s claw. (From Sandoval et al., Free Rad. Biol. Med., 29:1–78, 2000. With permission.)

References

Anguilar, J.L., Rojas, P., Marcelo, A., Plaza, A., Bauer, R., Reininger, E., Klaas, A., and Merfort, I., Anti-inflammatory activity of two different extracts of Uncaria tomentosa (Rubinaceae), J. Ethnopharmacol., 81:271–276, 2002.

Ganzera, M., Muhammad, I., Khan, R.A., and Khan, I.A., Improved method for the determination of oxindole alkaloids in Uncaria tomentosa by high performance liquid chromatography, Planta Med., 67:447–450, 2001.

Sandoval, C.M., Thompson, J.H., Zhang, X.J., Liu, X., Mannick, E.E., Sadowska-Krowicka, H., Charbonnet, R.M., Clark, D.A., and Miller, M.J., Antiinflammatory actions of Cat’s claw: The role of NF-κB, Aliment. Pharmacol. Ther., 12:1279- 1289, 1998.

Sandoval, M., Charbonnet, R.M., Okuhama, N.N., Roberts, J., Krenova, Z., Trentacosti, A.M., and Miller, M.J.S., Cat’s claw inhibits TNF-α production and scavenges free radicals: Role in cytoprotection, Free Rad. Biol. Med., 29:1–78, 2000.

Sheng, Y., Akesson, C., Holmgren, K., Bryngelsson, C., Giamapa, V., and Pero, R.W., An active ingredient of Cat’s claw water extracts, identification and efficacy of quinic acid, J. Ethnopharmacol., 96: 577–584, 2005.

Cauliflower

see S-methylmethane thio-sulfonate

Cereal grains

see also Barley, Oats, Wheat, and Rice Cereal grains contribute approximately 30 percent of the total dietary energy intake in adults in Britain and many other Western countries. Truswell (2002) reviewed the possible relationship between cereal-grain consumption and coronary heart disease (CHD). For example, in the scientific literature, oat fiber was far more effective in lowering total and LDL cholesterol compared to wheat fiber. Rice bran also lowers cholesterol. Based on his review, the author validates the health claim that whole-grain cereal foods and oat meal or bran lower cholesterol and the risk for CHD.

References

Truswell, A.S., Cereal grains and coronary heart disease, Eur. J. Clin. Nutr., 56:1–14, 2002.

Chamomile

Chamomile, a perennial flowering plant, grows well in the wild in Europe, particularly Croatia and Hungary. Many plants are called chamomile or have it as part of their common name. Five species in the United Kingdom and Europe include German chamomile (Matricaria recucita), Roman chamomile (Chamaemelum nobile or Anthenis nobile), foetid or stinking weed (A. Cotula), corn chamomile (A. Arvensis), and yellow chamomile. Roman chamomile (Chamaemelum nobile or Anthenis nobile) is the one most often referred to in English herbals. Commercially grown as a double-flowered form and, like chamomile, has an aromatic bitterness, the chamomile plant (Matricaria chamomilla), a member of the Asteracea family, is used as a medicinal tea for treating fever, diarrhea, menstrual pain, and inflammation, as well as intestinal and hepatic disorders (Mann and Staba, 1986). It is also the active principle in creams for atopic eczema (Patzelt-Wenczler and Ponce-Poschl, 2000).

One of the major components in chamomile is the flavonoid apigenin (see Apigenin), which was found to inhibit adhesion-molecular expression, prostaglandin, and cyclooxygenase, as well as the proinflammatory cytokine interleukin (IL)-6 in cell culture (Panes et al., 1986). Smolinski and Pestka (2003) showed chamomile apigenin inhibited LPS-induced IL-6 and TNF-α production in cell culture, further confirming its anti-inflammatory properties.

TABLE C.18
Main Components in Chamomile Essential Oil

The oil component in chamomile, comprising less than 2 percent, contains the terpene bisabolol, and the sesquiterpenes matricine and chamazulene, both of which exhibit antiinflammatory properties (Jakolev et al., 1983; Villegas et al., 2001). Hernandez-Ceruelos and coworkers (2002) identified 13 compounds in chamomile essential oil (Table C.18). α-Bisabolol oxide A and (E)-β-farnesene accounted for just under 70 percent of the total, while the remainder included smaller amounts of various bisabolol oxides, chamazulene and germacrene. These researchers clearly demonstrated the effectiveness of chamomile essential oil to inhibit sister chromatid exchanges induced by mutagens, daunorubicin and methyl methanesulfonate, in mouse bone-marrow cells. The antineoplastic daunorubicin acts on DNA through the production of free radicals, causing genotoxic damage, such as an increase in the rate of sister chromatid exchanges (Noviello et al., 1994). The results for daunorubicin, summarized in Table C.19, show Chamomile (CO) significantly reduced genotoxic damage in a dose-dependent manner. Addition of 5, 50, and 500 mg/kg of CO, in the presence of 10 mg/kg of dauorubicin, resulted in an antigenotoxic response corresponding to 25.8 percent, 63.1 percent, and 75.6 percent, respectively. A similar effect was observed for methyl methanesulf onate (MMS), in which the corresponding antigenotic responses for 250, 500, and 1000 mg/kg of CO, in the presence of 25 mg/kg MMS, were 24.8 percent, 45.8 percent, and 60.6 percent, respectively. While consumption of green tea was reported to reduce human oxidative stress, the ability of chamomile tea to act in a similar manner requires further investigation.

References

Hernandez-Ceruelos, A., Madrigal-Bujaidar, E., and de la Cruz, C., Inhibitory effect of chamomile essential oil on the sister chromatide exchanges induced by daunorubicin and methyl methanesulfonate in mouse bone marrow, Toxicol. Lett., 135:103–110, 2002.

Jakolev, V., Isaac, O., and Flaskamp, E., Pharmacological investigation with compounds of chamazulene and matricine, Planta Med., 49:67–73, 1983.

Mann, C. and Staba, E., 1986. Herbs, spices and medicinal plants, in Advances in Botany, Horticulture and Pharmacy, vol. 1, Food Products Press, Binghamton, NY, 1986, pp. 235–280.

Noviello, E., Alnigi, M.G., Cimoli, G., Rovini, E., Mazzoni, A., Parodi, S., De Sessaf, F., and Russo, P., Sister chromatide exchanges, chromosomal aberrations and cytotoxicity produced by topoisomerase II-targeted drugs in sensitive (A2780) and resistant (A2780-DX-3) human ovarian cells: Correlation with the formation of DNA double-strand breaks, Mutat. Res., 311:21–29, 1994.

Panes, J., Gerritsen, M.E., Anderson, D.C., Miyasaka, M., and Granger, D.N., Apigenin inhibits tumor necrosis factor-induced intercellular adhesion moecule-1 upregulation in vivo, Microcirculation, 3: 279–286, 1996.

Patzelt-Wenczler, R. and Ponce-Poschl, E., Proof of efficacy of Kamillos (R) cream in atopic cream, Eur. J. Med. Res., 19:171–175, 2000.

Smolinski, A.T. and Pestka, J.J., Modulation of lipopolysaccharide-induced pro-inflammatory cytokine production in vitro and in vivo by herbal constituents apigenin (chamomile), ginseonide Rb₁ (ginseng) and partenolide (feverfew), Food Chem. Toxicol., 41:1381– 1390, 2003.

Villegas, L.F., Marcalo, A., Martin, J., Fernandez, I.D., Maldonado, H., Vaisberg, A.J., and Hammond, G.B., (+)-epi-α-bisabolol is the wound-healing principle of Peperomia galiodes: An investigation of the in vivo wound-healing activity of related terpenoids, J. Nat. Prod., 64:1357– 1358, 2001.

TABLE C.19
Effect of Chamomile Oil (CO) on Sister Chromatide Exchanges (SCEs) Induced by Dauorubicin (Dau) in Mouse Bone-Marrow Cells

Chasteberry

The dried ripe fruit from the Chasteberry tree (Vitex) has been used to treat female reproductive problems since ancient Greece (Brown, 1994). It was also used to decrease sexual desire in men during medieval times, hence, the name chaste tree or monk’s pepper (Snow, 1996). In Germany, it is a well-recognized treatment for menstrual irregularities and premenstrual syndrome (PMS) (Blumenthal et al., 1998). Extracts of chasteberry tree berries were shown to bind dopamine receptors in the anterior pituitary, decreasing the basal- and thyrotropin-release-hormone that secretes prolactin (Jarry et al., 1994; Sliutz et al., 1993). In the second and third week of their cycles, women suffering from PMS have markedly higher levels of prolactin (Halbreich, 1976). The successful treatment of PMS by Vitex was attributed to its ability to reduce prolactin (Bohnert, 1997; Mayo, 1997). The active ingredients in chasteberry are iridoid glycosides-agnuside (0.6 percent) and aucubin (0.3 percent), together with flavonoids and essential oils (Gomaa et al., 1978). Dittmar and coworkers (1992) treated 175 women suffering from PMS with Vitex or pyridoxine and evaluated them during the second half of their menstrual cycle with a Premenstrual Tension Scale and the CGI scale. The efficacy of the CGI score for Vitex was 77.1 percent compared to 60.6 percent for pyridoxine. While no drug interactions have been reported for Vitex, it could counteract the effectiveness of birth-control pills because of its effect on prolactin (Feldmann et al., 1990).

References

Blumenthal, M., Gruenwald, J., and Hall, T., The Complete German Commission E. Monograph: Therapeutic Guide to Herbal Medicines, Intergrative Medicine Communications, Boston, 1998.

Bohnert, K.J., The use of Vitex agnus-castus tincture, Der Frauenartz, 32:867–870, 1997.

Brown, D.J., Herbal research review: Vitex agnus castus clinical monograph, Quarterly Rev. Natural Med., Summer: 111–121, 1994.

Dittmar, F., Bohnert, J.J., and Peeters, M., Premenstrual syndrome: Treatment with a phytopharmaceutical, Therapiewoche Gynakol., 5:867–870, 1992.

Feldmann, H.U., Abrecht, M., and Lamertz, M., Therapie bei Gelbkorschwache bzw. Pramenstruellem Syndrom mit vitex-agnus-castus Tinktur, Gyne., 11:421–425, 1990.

Gomaa, C.S., El-Moghazy, M.A., and Halim, F.A., Flavonoids and iridoids from Vitex agnuscastus, Planta Med., 33:277, 1978.

Halbreich, V., Serum prolactin in women with premenstrual syndrome, Lancet, 2:654–656, 1976.

Jarry, H., Leonhardt, S., and Gorkow, C., In vitro prolactin but not LH and FSH release is inhibited by compounds in extracts of Agnus castus: Direct evidence for dopaminergic principle by the dopamine receptor assay, Exp. Clin. Endocrinol. Diabetes, 102: 448–454, 1994.

Mayo, J., Premenstrual syndrome: A natural approach to management, Clin. Nutr. Insights, 5:1–8, 1997.

Sliutz, G., Speiser, P., and Schultz, A.M., Agnus castus extracts inhibit prolactin secretion of rat pituitary cells, Horm. Metab. Res., 25:253–255, 1993.

Snow, J.M., Vitex agnus-castus L. (Verbenaceae), Protocol J. Bot. Med., 1:20–23, 1996.

Cherries

Cherries are highly colored fruit rich in anthocyanins. For example, Wang and coworkers (1999a) showed that anthocyanins and cyanidin isolated from tart cherries had antioxidant and anti-inflammatory properties similar to commercial products. These researchers (Wang et al., 1999b) identified, in addition to chlorogenic acid methyl ester, three novel antioxidants in tart cherries, such as 2hydroxy-3-(o-hydroxyphenyl) propanoic acid, 1-(3′,4′-dihydroxycinnamoyl)-cyclopenta-2,5-diol, and 1-(3′,4′-dihydroxycinnamoyl)-cyclo-penta-2,3-diol. Tart-cherry anthocyanin extracts were shown by Tall et al. (2004) to be beneficial for treating inflammatory pain. Using an acute-inflammation rat model, an equivalent reduction in inflammation-induced thermal hyper algesia, mechanical hyperalgesia, and paw edema was evident with the highest dose of tartcherry extract (400 mg/kg) compared to the drug indomethacin (5 mg/kg). The potential of tart-cherry anthocyanins to reduce persistent and chronic pain in patients is promising, but requires further clinical studies.

(Adapted from Kang et al., Cancer Lett., 194:13–19, 2003.)

Kang et al. (2003) showed tart-cherry anthocyanins and the aglycone cyanidin all inhibited the development of intestinal tumors in Apc^Min mice, as well as the growth of colonic tumors in human colon-cancer cell lines HT29 and HCT 116. Cyanidin was far more effective than anthocyanins in inhibiting the growth of these human colon-cancer cells, as shown in Figure C.24.

This was evident by the IC₅₀ values for cyanidin being 85 and 63 μM for the HCT 116 and HT 29 cells compared to 260 and 585 μM for the anthocyanins.

FIGURE C.24 Effect of cyanidin on the growth of human colon-cancer cells. Gray bars, HCT 116 cells; black bars, HT 29 cells. Error bars=Standard error of the mean. (From Kang et al., Cancer Lett., 194:13–19, 2003. With permission.)

References

Kang, S.-Y., Seeram, N.P., Nair, G.M., and Bourquin, L.D., Tart cherry anthocyanins inhibit tumor development in Apc^Min mice and reduce proliferation of human colon cancer cells, Cancer Lett., 194:13–19, 2003.

Tall, J.M., Seeram, N.P., Zhao, C., Nair, G.M., Meyer, R.A., and Raja, S.N., Tart cherry anthocyanins suppress inflammation-induced pain behavior in rat, Behav. Brain Res., 153:181– 188, 2004.

Wang, H., Nair, M.G., Strasburg, G.M., Chang, Y.-C., Booren, A.M., Gray, J.I., and DeWitt, D., Antioxidant and anti-inflammatory activities of anthocyanins and their aglycon, cyanidin, from tart cherries, J. Nat. Prod., 62:294–296, 1999a.

Wang, H., Nair, M.G., Strasburg, G.M., Booren, A.M., and Gray, J.I., Novel antioxidants from tart cherries (Prunus cerasus), J. Nat. Prod., 62:86–88, 1999b.

Chickpea

Chickpea (Cicer arietinum L.) is the third most important grain legume based on total production (FAO, 1994). It is a rich source of dietary protein because of its well-balanced amino-acid composition, bioavailability, and low levels of antinutritional factors compared to other legumes (Friedman, 1996). The importance of legumes such as chickpeas is related to it being one of the low-glycemic index (GI) foods. The importance of such foods is due to their ability to improve metabolic control of hyperlipidemia in diabetic and healthy individuals (Frost et al., 1999; Jenkins et al., 1994). The classification of GI is based on the postprandial blood-glucose response based on the rate of digestion and absorption of carbohydrates present in the food. Goni and ValentinGamazo (2003) prepared three test meals of 50 g carbohydrates, including a spaghetti, in which wheat was partially replaced with chickpea flour (25 percent), a wheat spaghetti, and white bread. While the two spaghettis had similar levels of resistant starch and dietary fiber, the indigestible fraction was significantly higher in the chickpea-containing product. When fed to 12 healthy volunteers, the postprandial rise in blood glucose was much smaller with the chickpea product with a GI of 58±6 compared to 73±5 for the corresponding 100 percent wheat pasta. The low glycemic response observed for the product containing chickpea could lead to its incorporation to produce other low-GI foods.

TABLE C.20
Inhibition of ACE by Peptidic Fractions Obtained by Reverse-Phase Chromatography of a Chickpea Legumin Hydrolysate. Effluent from C₁₈ HPLC Were Pooled in Six Fractions and Analyzed for ACE-Inhibitory Activity

The main storage protein of chickpea is legumin, a globulin composed of six αβ subunits. Yust et al. (2003) examined the production of bioactive peptides by subjecting chickpea leguinexpensive and nonspecific protease. Of the min to proteolytic digestion with alcalase, an peptidic fractions isolated by reverse-phase chromatography, only those with the longest retention times (35–45 min) had high ACE-inhibitory activity (Table C.20). This is not unexpected, as ACE-inhibitory activity peptides usually contain hydrophobic amino acids, which interact more with the column, taking a longer time to be eluted. Further examination of these peptides confirmed the presence of hydrophobic amino acids, with methionine detected as the most abundant. Identification of chickpea peptides with ACE-inhibitory activity suggests their possible use in lowering blood pressure in vivo.

References

FAO, FAO Yearbook Production, FAO, Rome, 1994.

Friedman, M., Nutritional value of proteins from different food sources, a review, J. Agric. Food Chem., 44:6–29, 1996.

Frost, G., Leeds, A.A., Dore, C.J., Madieros, S., Brading, S., and Dornhorst, A., Glycaemic index as a determinant of serum HDL-cholesterol concentration, Lancet, 353:1045–1048, 1999.

Goni, I. and Valentin-Gamazo, C., Chickpea flour ingredient slows glycemic response to pasta in healthy volunteers, Food Chem., 81:511–515, 2003.

Jenkins, D.J.A., Jenkins, A.L., Wolever, T.M.S., Vuksan, V., Rao, A.V., Thompson, L.U., and Joss, R.G., Low glycemic index: Lente carbohydrates and physiological effects of altered food frequency, Am. J. Clin. Nutr., 54:S706-S709, 1994.

Yust, M.M., Pedroche, J., Giron-Calle, J., Alaiz, M., Millan, F., and Vioque, J., Production of ace inhibitory peptides by digestion of chickpea legumin with alcalase, Food Chem., 81:363–369, 2003.

Chilean berry (Aristotelia chilensis)

Chilean berry (ach) is an edible, black-colored fruit with medicinal properties. Ach was found to contain six indole alkaloids (Kan et al., 1997). Recent studies by Miranda-Rottmann and coworkers (2002) showed ach was a much richer source of phenolic antioxidants compared to cranberry, blueberry, blackberry, strawberry, raspberry, and red wine. In addition, ach also had the highest scores for total radicaltrapping potential and total antioxidant reactivity in in vitro antioxidant tests. Most of ach’s antioxidant properties were in the anthocyaninrich fraction of the juice. It was responsible for the effective inhibition of copper-induced LDL oxidation and the dose-response protection of hydrogen-peroxide-induced intracellular oxidative stress in human endothelial-cell cultures.

References

Kan, H., Valcic, S., Timmerman, B.N., and Montenegro, C., Indole alkaloids from Aristotelia chilensis (Mol.) Stuntz, Int. J. Pharmacogn., 35:215–217, 1997.

Miranda-Rottmann, S., Aspillaga, A.A., Perez, D.D., Vasquez, L., Martinez, A.L.F., and Leighton, F., Juice and phenolic fractions of the berry Aristotelia chilensis inhibit LDL oxidation in vitro and protect human endothelial cells against oxidative stress, J. Agric. Food Chem., 50:7542– 7547, 2002.

Chili peppers

see also Capsaicin Chili peppers, a member of the Capsicum family, are consumed extensively as spices. The principal pungent and irritant ingredient in chili peppers is capsaicin. A discussion of the health-related properties of chili peppers can be found under capsaicin.

Chinese herbs

In China, the idea that food and medicine were equally important for preventing and curing diseases has been passed down to the present day from the ancient legend describing an herbalist, Shennong, who tasted many different types of herbs (Zhang, 1990). With the development of functional foods and nutraceuticals, attempts are being made to bridge the typical Chinese medicated diet and functional foods and nutraceuticals (Xu, 2001). Chinese herbal extracts have been used to treat a variety of cancers, but their efficacy on pancreatic cancer has not been reported. Schwartz and coworkers (2003) examined the effect of ethanol extracts of two quality-controlled, dried, encapsulated supplements of 15 (SPES) and eight (PC-SPES) Chinese herbs on eight human pancreatic-cancer-cell lines. Both extracts were significantly toxic to the pancreatic-cancer cells and induced apoptosis. Both extracts, however, need further evaluation as agents for the clinical treatment of pancreatic cancer. SPES could be combined with cellcycle-independent cytotoxic drugs, while PCSPES, because of its G2-blocking pattern, may be useful as a radiation sensitizer.

References

Schwartz, R.E., Donohue, C.A., Sadava, D., and Kane, S.E., Pancreatic cancer in vitro toxicity mediated by Chinese herbs SPES and PC-SPES: Implications for monotherapy and combination treatment, Cancer Lett., 189:59–68, 2003.

Xu, Y., Perspectives on the 21st century development of functional foods: Bridging Chinese medicated diet and functional foods, Inter. J. Food Sci. Technol., 36: 229–242, 2001.

Zhang, E.Q., Chinese Medicated Diet, Shangai Publishing House, Shangai College of Traditional Chinese Medicine, 1990, pp. 1–15.

SCHEME C.1 6 Preparation of chitin derivatives. (From Shahidi et al., Trends Food Sci. Technol., 10:97–105, 1999. With permission.)

Chitin and chitosan

Chitin is the next most abundant polysaccharide in nature after cellulose. It is a natural polymer composed of the aminosugar N-acetylglucosamine. The major deacylated form of chitin, chitosan, is found in crustaceans, such as crabs, lobsters, and shrimp. It is a versatile biopolymer with many derivatives formed, as shown in Scheme C.16 (Shahidi et al., 1999). Since chitin and chitosan are both capable of complexing transition metals, Kamil and coworkers (2002) examined its potential as an antioxidant. Using chitosans of different viscosity, these researchers found that lower-viscosity chitosan exhibited strong antioxidant activity and could be a potential source of natural antioxidant for stabilizing lipid-containing foods. Chitosan also appeared to enhance intestinal permeability, permitting the absorption of hydrophillic drugs (Kotze et al., 1997). Recent work by Ranaldi and coworkers (2002) suggested that chitosan ingestion altered intestinal-barrier function, permitting the entry of potentially toxic or allergenic substances. Taha and Swailam (2002) noted that 0.04 percent of chitosan suppressed the growth and hemolysin production of Aeromonas hydrophilia. Song and coworkers (2002) improved the solubility of chitosan by conjugating it with lysozyme via a Maillard-type reaction. The resulting chitosan-lysozyme conjugate had enhanced emulsifying properties and bactericidal action against Escherichia coli K-12.

Chitosan was also found to increase fat elimination in the stool of rats (Sugano et al., 1980; Ebihara and Schneeman, 1989). In addition, dietary chitosan reduced cholesterol in rats, suggesting it as a possible dietary supplement. Bokura and Kobayashi (2003) recently reported chitosan significantly reduced total cholesterol in female volunteers with mild to moderate hypercholesterolemia. In the subgroup, more than 60 years of age, there was a greater tendency for cholesterol reduction in the chitosan group compared to the placebo group (Table C.21). After eight weeks of treatment, total cholesterol in the chitosan group decreased from 241 to 226 mg/dL, while the placebo remained essentially the same. A significant reduction was also observed for LDL cholesterol in the chitosan group, while the placebo group remained unchanged.

References

Bokura, H. and Kobayashi, S., Chitosan decreases total cholesterol in women: A randomized, double-blind, placebo-controlled trial, Eur. J. Clin. Nutr., 57: 721–725, 2003.

Ebihara, K. and Schneeman, B.O., Interaction of bile acids, phospholipids, cholesterol and triglyceride with dietary fibres in the small intestine of rats, J. Nutr., 119:1100–1106, 1989.

Kamil, Y.V.A., Jeon, Y.J., and Shahidi, F., Antioxidative activity of chitosans of different viscosity in cooked comminuted flesh of herring (Clupea harengus), Food Chem., 79:69–77, 2002.

Kotze, A.F., de Leeuw, B.J., Lue Ben, H.L., de Boer, A.G., Verhoef, J.C., and Junginger, H.L., Chitosan for enhanced delivery of therapeutic peptides across intestinal epithelia: In vitro evaluation of Caco-2 cell monolyers, Int. J. Pharm., 159:243–243, 1997.

Ranaldi, G., Marigliano, I., Vespignani, I., Perozzi, G., and Sambuy, Y., The effect of chitosan and other polycations on tight junction permeability in human intestinal Caco-2 cell line, J. Nutr. Biochem., 13:157–167, 2002.

Shahidi, F., Kamil, J.Y.V.A., and Jeon, Y.J., Food applications of chitin and chitosans, Trends Food Sci. Technol., 10:97–105, 1999.

Song, Y., Babiker, E.E., Usui, M., Saito, A., and Kato, A., Emulsifying properties and bacteriocidal action of chitosan-lysozyme conjugates, Food Res. Inter., 35:459–466, 2002.

Sugano, M., Fujikama, T., Hiratsuji, Y., Nakashima, K., Fukuda, N., and Hasegawa, Y., A novel use of chitosan as a hypocholesterolemic agent in rats, Am. J. Clin. Nutr., 33:787–793, 1980.

Taha, S.M.A. and Swailam, M.H., Antibacterial activity of chitosan against Aeromonas hydrophilia, Nahrung, 46:337–340, 2002.

TABLE C.21
Values of Serum Lipids of Subjects with More Than 60 Y of Age^1,2

Chlorogenic acid

Fruit and vegetable extracts, such as obtained from carrots, burdock (gobou), apricot, and prune, were found to inhibit the formation of 8-hydroxydeoxyguanosine (8-OH-dG) (Kasai et al., 2000). 8-OH-dG, a key marker of cellular oxidative stress during carcinogenesis, induces point mutations in mammalian cells (Kasai, 1997). A common inhibitor in these extracts was chlorogenic acid, which was shown to inhibit 8-OH-dG in a rat-tongue carcinogenesis model.

Chlorogenic acid. (From Wen et al., Food Microbiol., 20:305–311, 2003. With permission.)

Chlorogenic acid (CGA), an esterified product of caffeic acid and quinic acid, was reported by Hemmerle and coworkers (1997) to modulate glucose-6-phosphatase, an enzyme involved in glucose metabolism. Nardini et al. (1995, 1997) also showed it decreased oxidation of LDL cholesterol and total cholesterol, thereby reducing the risk of cardiovascular disease. Rodrigues de Sotillo and Hadley (2002) found a significant reduction in plasma triacylglycerols, total cholesterol, and postprandial glucose in Zucker rats treated with chlorogenic acid.

References

Hemmerle, H., Burger, H.J., Below, P., Schubert, G., Rippel, R., Schindler, P.W., Paulus, E., and Herling, A.W., Chlorogenic acid and synthetic chlorogenic acid derivatives: Novel inhibitors of hepatic glucose-6-translocase, J. Med. Chem., 40:137–145, 1997. .

Kasai, H., Fukada, S., Yamaizume, Z., Sugie, S., and Mori, H., Action of chlorogenic acid in vegetables and fruits as an inhibitor of 8-hydroxydeoxy-guanosine, formation in vitro and in a rat carcinogenesis model, Food Chem. Toxicol., 38:467–471, 2000.

Kasai, H., Analysis of a form of oxidative DNA damage, 8-hydroxy DNA damage, in Antimutagenesis and Anticarcinogenesis Mechanisms III, Brozetti, G., Ed., Plenum Press, New York, 1997, p. 257.

Nardini, M., D’Aquino, M., Tomassi, G., Gentili, V., Di Felice, M., and Scaccini, C., Inhibition of human low-density lipoprotein oxidation by caffeic acid and other hydroxycinnamic acid derivatives, Free Rad. Biol. Med., 19:541–552, 1995.

Nardini, M., Natella, F., Gentili, V., Di Felice, M., and Scaccini, C., Effect of caffeic acid dietary supplementation on the antioxidant defense system in rat: An in vivo study, Arch. Biochem. Biophys., 342: 157–160, 1997.

Rodrigues de Sotillo, D.V. and Hadley, M., Chlorogenic acid modifies plasma and liver concentrations of cholesterol, triaylglycerol, and minerals in (fa/fa) Zucker rats, J. Nutr. Biochem., 13:717–726, 2002.

Wen, A., Delaquis, P., Stanich, K., and Toivonen, P., Antilisterial activity of selected phenolic acids, Food Microbiol., 20:305–311, 2003.

Chlorophyll and chlorophyllin

see also Pheophytin and Pheophorbide Epidemiological studies associated consumption of dark-green vegetables, rich sources of clorophyll pigments, with cancer protection. Antigenotoxic properties of chlorophylls were subsequently demonstrated using short-term genotoxicity assays (Dashwood, 1997; Negishi et al., 1997; Dashwood et al., 1998). Insolubility of chlorophyll in aqueous solutions, however, led to an investigation of the chemoprotective effects of its stable, water-soluble derivative, chlorophyllin (CHL). Porphyrin compounds, such as chlorophyll and CHL, were known to protect against a variety of direct- and indirect-acting mutagens, such as aflatoxin B1, heterocyclic amines, and nitrosamines (Dashwood et al., 1991; Guo et al, 1995; Romert et al., 1992; Hayatsu et al., 1999). Further studies confirmed the anticancer properties of CHL by its inhibition of induction of hepatocarcinogenesis by aflatoxin B1 and dibenzo[α,1]pyrene (DBP) in rainbow trout (Reddy et al., 1996). Xu and Dashwood (1999) found chlorophyllin was a very effective inhibitor of heterocyclic amineinduced colon carcinogenesis in male F344 rats. A clinical trial over 16 weeks involving 180 Chinese individuals living in an area known to have high exposure to dietary aflatoxins by Egner et al. (2003) examined the intervention of administering CHL three times a day. They found CHL effectively reduced by 50 percent the median level of urinary excretion of aflatoxin-N⁷-guanine, a DNA adduct biomarker associated with increased risk for liver cancer, compared to the placebo. This study demonstrated the safety and efficacy of using CHL to reduce the genotoxic and cytotoxic effects of aflatoxins in populations at high risk.

Chlorophyll a and chlorophyllin (Chung et al., Cancer Lett., 145:57– 64, 1999. With permission.)

FIGURE C.25 The transport of carcinogens (DBP and AFB1) f_rom apical to basolateral across Caco-2 monolayers in the presence of increasing molar ratios of CHL. Panels A-B represent the transport of DBP and AFB₁ at concentrations of 1.0 μM with buffer alone (black diamond) and with CHL present in concentrations of 1.0 ()m, 10.0 (Δ), and 100.0 (x) μM. Experiment in panel A was performed in “nonsink” conditions, while experiment in panel B was “in sink” conditions and is displaced as cumulative transport (*). Values for all timepoints within a treatment group are significantly different from the corresponding control value (Panel a, DBP with CHL at 10.0 and 100.0; Panel B, AFB₁ at 100 μMm p<0.05). (From Mata et al., Toxicol., 196:117– 125, 2004. With permission.)

Using Caco-2 cell monolayers, Mata and coworkers (2004) suggested one mechanism for the chemopreventive effect of CHL against carcinogens involved reducing the bioavailability of aflatoxin B1 and DBP. Directly binding CHL with these carcinogens in the intestinal tract could inhibit their transportation from the apical (AP) to the basolateral (BL), as seen in Figure C.25.

Increasing the molar ratios of CHL from 1 to 100 μM significantly reduced the percent of DBP transported, while 100 μM CHL was needed to reduce the transport of aflatoxin B₁ approximately 47 percent.

Using cultured fibroblast cells from Chinese hamster lung (V79), Bez et al. (2001) showed chlorophyll a, chlorophyll b, and chlorophyllin all protected V79 cells from DNA damage induced by methyl methanesulphonate (MMS) by desgenotoxic action and by bioantigenotoxic mechanisms with similar efficiency. Negraes and coworkers (2004) evaluated the anticlastogenicity of chlorophyllin in different phases of the cell cycle by its ability to reverse DNA damage induced by ethyl methane sulfonate. A greater protective effect by CHL against ethyl methyl sulfonate (70–80 percent) was observed during the G2/S phase.

References

Bez, G.C., Jordao, B.Q., Vicentini, V.E.P., and Mantovani, M.S., Investigation of gentoxic and antigenotoxic activities of chlorophylls and chlorophyllin in cultured V79 cells, Mutat. Res., 497:139–145, 2001.

Chung, W.-Y., Leew, J.-M., Park, M.-Y., Yook, J.-I., Kim, J., Chung, A.-S., Surh, Y.-S., and Park, K.-K., Inhibitory effects of chlorophyllin on 7,12-dimethyl-benz[α] anthracene-induced bacterial mutagenesis and mouse skin carcinogenesis, Cancer Lett., 145: 57–64, 1999.

Dashwood, R.H., Chlorophylls as anticarcinogens (review), Int. J. Oncol., 10:721–727, 1997.

Dashwood, R.H., Breinholt, V., and Bailey, G.S., Chemopreventive properties of chlorophyllin: Inhibition of aflatoxin B1 (AFB1)-DNA binding in vivo and antimutagenic activity against AFB1 and two heterocyclic amines in Salmonella mutagenicity test, Carcinogenesis, 12:939– 942, 1991.

Dashwood, R.H., Negishi, T., Hayatsu, H., Breinholt, V., Hendricks, J., and Bailey, G., Chemopreventive properties of chlorophylls towards aflatoxin B1: A review of the antimutagenicity and anticarcinogenicity data in rainbow trout, Mutat. Res., 399:245–253, 1998.

Egner, P.A., Munoz, A., and Kensler, T.W., Chemo prevention with chlorophyllin in individuals exposed to dietary aflatoxin, Mutat. Res., 523–524:209–216, 2003.

Guo, D., Horio, D.T., Grove, J.S., and Dashwood, R.H., Inhibition by chlorophyllin of 2-amino-3- methylimidazo-[4,5-f]quinoline-induced tumorigen-esis in the male F344 rat, Cancer Lett., 95:161–165, 1995.

Hayatsu, H., Sugijama, C., Arimoto-Koboyashi, S., and Negishi, T., Porphyrins as possible preventions of heterocyclic amine carcinogens, Cancer Lett., 143:185–187, 1999.

Mata, J.E., Yu, Z., Gray, J.C., Williams, D.E., and Rodrigues-Proteau, R., Effects of chlorophyllin on transport of dibenzo(α, l)pyrene, 2-amino-1-methyl-6-phenylimidazo-[4,5-b]pyridine, and aflatoxin B1 across Caco-2 cell monolayers, Toxicolology, 196: 117–125, 2004.

Nagraes, P.D., Jordao, B.Q., Vicentini, V.E.P., and Mantovani, M.S., Anticlastogenicity of chlorophyllin in the different cell cycle phases in cultured mammalian cells, Mutat. Res., 557:177–182, 2004.

Negishi, T., Rai, H., and Hayatsu, H., Antigenotox activity of natural chlorophylls, Mutagenesis, 376: 97–100, 1997.

Reddy, A., Coffing, S., Baird, W., Henticks, J., and Bailey, S., Chlorophyllin (CHL), indole-3- carbinol (13C) and β-naphthoflavone (BNF) chemoprevention against dibenzo[α, l]pyrene (DBP) in trout, Proc. Am. Assoc. Cancer Res., 37:1883, 1996.

Romert, L., Curvall, M., and Jenssen, D., Chlorophyllin is both a positive and negative modifier of mutagenicity, Mutat. Res., 7:349–355, 1992.

Xu, M. and Dashwood, R.H., Chemoprotective studies of heterocyclic amine-induced colon carcinogenesis, Cancer Lett., 143:179–183, 1999.

Chocolate

Chocolate contains fats, sugars, and protein, together with small quantities of magnesium, potassium, calcium, iron, and riboflavin, as well as the stimulant caffeine. The main ingredient in all chocolates is cocoa, derived from beans cultivated in West Africa and Southeast Asia. Among the hundreds of compounds in cocoa are a group of polyphenolic compounds or flavonoids. One group of flavonoids, the procyanidins, account for 35 percent of all polyphenols in cocoa. Procyanidins consist of flavan-3-ol(−) epicatechin (epicatechin) and its polymers (Adamson et al., 1999). Evidence from epidemiological studies suggest that diets high in polyphenols reduce the risk of cardiovascular disease and related chronic diseases. Chocolate flavonoids are potent antioxidants capable of protecting LDL from oxidation. Richelle and coworkers (1999) demonstrated a physiologically significant increase in plasma levels of epicatechin (0.7 μmol/L) in eight healthy male volunteers after consuming 80 g of black chocolates. Wang and coworkers (2000) demonstrated a marked increase in plasma levels of epicatechin in healthy adults 2 h following the consumption of procyanidin-rich chocolates. Rein et al., (2000) showed that a polyphenolic-rich cocoa beverage exerted an aspirin-like effect in 30 healthy subjects by suppressing platelet activation and function, key factors in the development of coronary artery disease. A recent study by Mursu et al. (2004) showed that nonsmoking, healthy young volunteers consuming 75 g daily of dark chocolate and dark chocolate enriched with cocoa polyphenols increased their HDL-cholesterol levels by 11.4 percent and 13.7 percent, respectively. In comparison, the control group consuming white chocolate had a small but significant decrease in HDL cholesterol levels of -2.9 percent. No effect of cocoa polyphenols on lipid peroxidation was observed in the young subjects maintained on the study.

Epicatechin. (Adapted from Babich et al., Toxicology, in vitro., 19:231–242, 2005)

Cocoa procyanidins were found by Mao et al. (1999) to exhibit immunomodulatory effects by inhibiting proliferation and suppressing the production of interleukin-2 and human T-lymphocytes. Carnesecchi and coworkers (2002) further examined the antiproliferative effects of cocoa polyphenols using human colon-cancer cells. The cocoa flavonols and procyanidins caused nonapoptotic cell death and blocked the G2/M phase of the cell cycle. They suggested polyamine biosynthesis as one of the targets affected.

References

Adamson, G.E., Lazarus, S.A., Mitchell, A.E., Prior, R.L., Cao, G., Jacobs, P.H., Kramer, B.G., Hammerstone, J.F., Rucker, R.B., Ritter, K.A., and Schmidt, H.H., HPLC method for quantification of procyanidins in cocoa chocolate and correlation to total antioxidant activity, J. Agric. Food Chem., 47:4168–4186, 1999.

Babich, H., Kruska, M.E., Nissim, H.A. and Zuckerbraun, H.L. Differential in vitro cytoxicity of (−)-epicatechin gallate (ECG) to cancer and normal cells from human oral cavity. Toxicol. in vitro. 19:231–241, 2005.

Carnesecchi, S., Schneider, Y., Lazarus, S.A., Coehlo, D., Gosse, F., and Raul, F., Flavonols and procyanidins of cocoa and chocolate inhibit growth and polyamine biosynthesis of human colonic cancer cells, Cancer Lett., 175:147–155, 2002.

Mao, T.U., Powell, J., Van De Water, J., Keenz, C.L., Schmitz, H.H., and Gershwin, M.E., The influence of procyanidins on the transcription of interleukin-2 in peripheral blood mononuclear cells, Int. J. Immunother., 15:23–29, 1999.

Mursu, J., Voutilainen, S., Nurmi, T., Rissanen, T.H., Virtanen, J.K., Kaikkonen, J., Nyyssonen, K., and Salonen, J.T., Dark chocolate consumption increases HDL cholesterol concentration and chocolate fatty acids may inhibit lipid peroxidation in healthy humans, Free Rad. Biol. Med., 37:1351–1359, 2004.

Rein, D., Paglieroni, T.G., Wun, T., Pearson, D.A., Schmitz, H.H., Gosselin, G., and Keen, C.L., Cocoa inhibits platelet activation and function, Am. J. Clin. Nutr., 72:30–35, 2000.

Richelle, M., Tavazzi, I., Enslen, M., and Offord, E.A., Plasma kinetics in man of epicatechin from black chocolate, Eur. J. Clin. Nutr., 53:22–26, 1999.

Wang, J.F., Schramm, D.D., Holt, R.R., Ensunsa, J.L., Fraga, C.G., Schmitz, H.H., and Keen, C.L., A dose-response effect from chocolate consumption on plasma epicatechin and oxidative damage, J. Nutr., 130:2115S-2119S, 2000.

Choline

Choline is a dietary component essential for normal cell functions. In addition to its incorporation into lecithin and sphingomyelin in cell membranes, it is required for the synthesis of the neurotransmitter, acetyl choline. Choline is also involved in methyl metabolism, as well as for lipid transport and metabolism (Zeisel and Blusztajn, 1994). Eggs are particularly high in choline (300 mg/egg), mostly in the form of phosphatidylcholine or lecithin. Animal studies have found a choline diet may lead to mental retardation, renal dysfunction, and hemorrhage, as well as bone abnormalities (Fairbanks and Krider, 1945; Handler and Bernheim, 1949; Newberne and Rogers, 1986). During rodent-brain development, there are two periods where choline availability is important. The first is during embryonic days 12–17, and the second is during postnatal days 16–30. Supplementation with choline during these periods is associated with enhanced memory performance (Meck and Williams, 1997, 1999). While no human studies have been conducted so far, Zeisl (2000) suggested that the inclusion of two eggs a day in the diet of pregnant women would be a prudent measure to ensure the dietary requirements of choline are adequately met.

Since hypertension is considered a risk factor for impairments in memory, learning, and attention processes, De Bruin et al. (2003) examined the combined effect of uridine and choline on these cognitive deficits in 5- to 7-month-old spontaneously hypertensive rats (SHR). They found that SHR had significantly impaired visual attention processes based on the five-choice serial reaction time (5-CSRT), which were normalized following supplementation with uridine and choline. Using the Morris water maze as a measure of spatial learning and mnemonic capabilities, supplementation similarly improved these cognitive disorders in both SHR and normotensive Wistar-Kyoto rats.

This model could be used to screen compounds that may have therapeutic potential for treating these cognitive disorders.

References

De Bruin, N.M.W.J., Kiliaan, A.J., De Wilde, M.C., and Broersen, L.M., Combined uridine and choline administration improves cognitive deficits in spontaneously hypertensive rats, Neurol. Learning Memory, 80:63–79, 2003.

Fairbanks, B.W. and Krider, J.L., Significance of B-vitamins in swine nutrition, N. Am. Vet., 26:18–23, 1945.

Handler, P. and Bernheim, F., Choline deficiency in the hamster, Proc. Exptl. Med., 72:569, 1949.

Meck, W. and Williams, C., Simultaneous temporal processing is sensitive to prenatal choline availability in mature and aged rats, Neuroreport, 8:3045–3051, 1997. Meck, W. and Williams, C., Choline supplementation during prenatal development reduces proactive interference in spatial memory, Dev. Brain Res., 105:51–59, 1999.

Newberne, P.M. and Rogers, A.E., Labile methyl groups and the promotion of cancer, Ann. Rev. Nutr., 6:407–432, 1986.

Zeisel, S.H., Choline: Needed for normal development of memory, J. Am. Coll. Nutr., 19:528S- 531S, 2000.

Zeisel, S.H. and Blusztajn, J.K., Choline and human nutrition, Nutr. Rev., 14:269–296, 1994.

Chondroitin sulfate

Chondroitin sulfate (CS) is a group of heteropolysaccharides that are integral components of articular cartilage. They consist of alternate sequences of sulfated or unsulfated D-glucuronic acid (GlcA) and N-acetyl-D-galactosamine (GalNAc) residues linked through alternating [β (1→3)] and [β (1→4)] bonds (Scheme C.17). It is used for the treatment of osteoarthritis, a condition in which destructive changes of the osteoarthritic joint leads to pain and functional disability. Current treatment is aimed at management via physical, pharmacological, and surgical approaches. Chondroitin sulfate allows the cartilage to resist tensile stresses by giving the cartilage resistance and elasticity (Muir, 1986). Osteoarthritis is characterized by the destruction of cartilage by degradative enzymes, which are completely inhibited by chondroitin sulfate (Bartolucci et al., 1991; Bassleer et al., 1992). In reviewing the literature, Deal and Moskowitz (1999) concluded there is a sufficient number of studies suggesting efficacy of glucosamine, chondroitin sulfate, and collagen sulfate equal to that seen in the symptomatic treatment of osteoarthritis using NSAIDs. The effectiveness of chondroitin sulfate and glucosamine was recently reviewed by Hungerford and Jones (2003).

SCHEME C.17 Structure of chondroitin sulfate disaccharides and compositional properties. (From Sim et al., J. Chromatogr. B., 818:133–139, 2005. With permission.)

References

Bartolucci, C., Cellai, L., Corrandini, C., Corradini, D., Lamba, D., and Velona, I., Chondroprotective action of chondroitin sulfate: Competitive action of chondroitin sulfate on the digestion of hyaluronan by bovine testicular hyaluronidase, Int. J. Tiss. Reac., 13:311–317, 1991.

Bassleer, C., Henrotin, Y., and Franchiment, P., In vitro evaluation of drugs proposed as chondroprotective agents, Int. J. Tiss. Reac., 14:231–241, 1992.

Deal, C.L. and Moskowitz, R.W., Nutraceuticals as therapeutic agents in osteoarthritis, the role of glucosamine, chondroitin sulfate, and collagen hydrolysate, Rheum. Dis. Clin. North. Am., 25:379–395, 1999.

Hungerford, D.S. and Jones, L.C., Glucosamine and chondroitin sulfate are effective in the management of osteoarthritis, J. Arthroplasty, 18:5–9, 2003.

Muir, H., Current and future trends in articular car tilage research and osteoarthritis, in Articular Cartilage and Osteoarthritis, Kuettner, K.E., Schleyerbach, R., and Hascoll, V.C., Eds., Raven Press, New York, 1986, p. 423.

Sim, J.-S., Jun, G., Toida, T., Cho, S.Y., Choi, D.W., Chang, S.-Y., Linhardt, R.J., and Kim, Y.S., Quantitative analysis of chondroitin sulfate in raw materials, ophthalmic solutions, soft capsules and liquid preparations, J. Chromatogr. B., 818:133–139, 2005.

Chromium

After calcium, chromium is the largest-selling mineral supplement in the United States. Around 10 million Americans use chromium supplements, some for the prevention or treatment of diabetes (Nielsen, 1996). Many studies suggested chromium alleviates severe symptoms associated with diabetes (Jeejeebhoy et al., 1977; Fox and Sabovic, 1998; Ravina et al., 1999). Althius and coworkers (2002) carried out a systematic review of the literature and a meta-analysis of randomized clinical trials that assessed the impact of dietary chromium supplements on glucose, insulin, and glycated hemoglobin (HbA_1c) in healthy subjects and in individuals with glucose intolerance or type 2 diabetes. No association was observed between chromium and glucose or insulin in nondiabetic patients. Only one study of 155 diabetic subjects in China found chromium reduced glucose and insulin and HbA_1c levels (Anderson et al., 1997). Althuis and Wittes (2003) defended a number of criticisms made about their study, claiming they only summarized randomized clinical trials that assessed the impact of chromium on glucose, insulin, and Hb A_1c. Further studies, however, were recommended, using controlled, randomized clinical trials, to establish the efficacy of chromium in the treatment of diabetes.

References

Althius, M.D., Jordan, N.E., Ludington, E.A., and Wittes, J.T., Glucose and insulin responses to dietary chromium supplements: A meta-analysis, Am. J. Clin. Nutr., 76:148–155, 2002.

Althius, M.D. and Wittes, J.T., Reply to D.S.Kalman, M.F.McCarty, V.Juturu and J.R.Komorinski, Am. J. Clin. Nutr., 78:192–193, 2003.

Anderson, R.A., Cheng, N., Bryden, N.A., Polansky, M.M., Chi, J., and Feng, J., Elevated intakes of supplemented chromium improve glucose and insulin variables in individuals with type 2 diabetes, Diabetes, 46:1786–1791, 1997.

Fox, G. and Sabovic, Z., Chromium picolate supplementation for diabetes mellitus, J. Fam. Pract., 46: 83–86, 1998.

Jeejeebhoy, K., Chu, R., Marliss, E., Greenberg, G., and Bruce-Robertson, A., Chromium deficiency, glucose intolerance, and neuropathy reversed by chromium supplementation in a patient receiving longterm total perenteral nutrition, Am. J. Clin. Nutr., 30: 531–538, 1977.

Nielsen, F., Controversial chromium: Does the superstar mineral of the mountebanks receive appropriate attention from clinicians and nutritionists, Nutr. Today, 31:226–233, 1996.

Ravina, A., Slezak, L., Mirsky, N., Bryden, N., and Anderson, R., Reversal of corticosteroidinduced diabetes mellitus with supplemental chromium, Diabet. Med., 16:164–167, 1999.

Cinnamaldehyde

Cinnamaldehyde (CNMA), a major component in cinnamon-bark oil, is used extensively as a flavoring agent in beverages, ice cream, sweets, and chewing gum. Because of its inhibitory effect on farnesyl-transferase activity, Cinnamaldehyde derivatives were screened as potential anticancer agents by Koh and associates (1998). CNMA has been detected in tobacco smoke so that a number of contradictory genotoxicity studies were reported (Neudecker, 1992; Mereto et al., 1994; Stammati et al., 1999). Imai et al. (2002) investigated the effects of CNMA on lung carcinogenesis using mice initiated with 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK).

Cinnamaldehyde (CNMA). (Adapted from Kim et al., J. Stored Prod. Res., 40:55–63, 2004.)

They found CNMA significantly reduced the multiplicity of lung tumors in CB6F1-TgHras2 (rasH2) and non-Tg female mice. Using an oxidation-sensitive fluorescence probe, DCFH-DA, Ka and coworkers (2003) showed CNMA induced apoptosis in human promyelocytic leukemia HL-60 cells by generation of reactive-oxygen species (ROS). ROS induces mitochondrial permeability transition with the dissipation of the transmembrane potential (Δ_ψm), triggering the release of cytochrome c and the subsequent activation of caspase cascades needed for the onset of apoptosis. This work provided the first evidence on the mechanism of the anticancer effect of CNMA, with further work needed to establish CNMA as a chemopreventive agent for use in cancer treatment.

Jeong et al. (2003) examined the antitumor effect of a more stable synthetic Cinnamaldehyde derivative, CB403, by chemically modifying 2′-hydroxycinnamaldehyde extracted from stem bark. CB403 inhibited the tumor growth of 20 human-cell tumor lines, with SW6720, a human colon-cancer line, being the most sensitive. Further work showed CB403 was cytostatic, inducing mitotic arrest in cancer cells with potential as an anticancer agent.

Structure of CB403. (From Jeong et al., Biochem. Pharmacol., 65:1343–1350, 2003. With permission.)

References

Imai, T., Yasuhura, K., Tamura, T., Takizawa, T., Ueda, M., Hirose, M., and Mitsumori, K., Inhibitory effects of Cinnamaldehyde on 4-(methyl nitrosamino)-1-(3-pyridyl)-1-butanoneinduced lung carcinogenesis in raH2 mice, Cancer Lett., 175:9–16, 2002.

Jeong, H.-W., Han, D.C., Son, K.-H., Han, M.Y., Lim, J.-S., Ha, J.-H., Lee, C.W., Kim, H.M., Kim, H.-C., and Kwon, H.K., Antitumor effect of the cinnamaldehyde derivative CB403 through the arrest of a cell cycle progression in the G2/M phase, Biochem. Pharmacol., 65:1343–1350, 2003.

Ka, H., Park, H.-J., Jung, H.-J., Choi, J.-W., Cho, K.S., Ha, J., and Lee, K.-T., Cinnamaldehyde induces apoptosis by ROS-mediated mitochondrial permeability transition in human promyelocytic leukemia HL-60 cells, Cancer Lett., 196:143–152, 2003.

Kim, H.-K., Kim, J.-R., and Ahn, Y.J., Acaricidal activity of Cinnamaldehyde and its cogeners against Tyrophagus putrescentiae (Acri: Acaridae), J. Stored Prod. Res., 40:55–63, 2004.

Koh, W.S., Yoon, S.Y., Kwon, B.M., Jeong, T.C., Nam, K.S., and Han, M.Y., Cinnamaldehyde inhibits lymphocyte proliferation and modulates T-cell differentiation, Int. J. Immunopharmacol., 20:643- 660, 1998.

Mereto, E., Brambilla-Campart, G., Ghia, M., Martelli, A., and Brambilla, G., Cinnamaldehydeinduced micronuclei in rodent liver, Mutat. Res., 322:1–8, 1994.

Neudecker, T., The genetic toxicology of cinnamaldehyde, Mutat. Res., 277:173–175, 1992.

Stammati, A., Bonsi, P., Zucco, F., Moezelaar, R., Alakomi, H.L., and von Wright, A., Toxicity of selected plant volatiles in microbial and mammalian short-term assays, Food Chem. Toxicolol., 37:813–823, 1999.

Cinnamon

see also Cinnamaldehyde Cinnamon is a widely used flavoring agent in foods. Jarvill-Taylor et al. (2001) showed that methyl hydroxychalcone polymer (MHCP) isolated from cinnamon mimicked insulin by triggering glucose uptake, glycogen synthesis, phosphatidyl-3-kinase dependency, glycogen-synthase activation, and glycogen synthase kinase-3β activity. Dual treatment with insulin showed synergism was evident between these two compounds. Based on these results, MHCP appeared a good insulin mimetic, potentially useful in treating insulin resistance. A recent study by Schoene et al. (2005) found water-soluble, polymeric polyphenols from cinnamon inhibited proliferation of hematologic tumorcell lines by altering the proliferative signals regulating progression through the cell cycles.

References

Jarvill-Taylor, K.J., Anderson, R.A., and Graves, D.J., A hydroxychalcone derived from cinnamon functions as a mimetic for insulin in 3T3-L1 adipocytes, J. Am. Coll. Nutr., 20:327–336, 2001.

Schoene, N.W., Kelly, M.A., Polansky, M.M., and Anderson, R.A., Water-soluble polymeric polyphenols from cinnamon inhibit proliferation and alter cell cycle distribution patterns of hematologic tumor cell lines, Cancer Lett., 2005 (in press).

Citrus flavonoids

see Hesperidin, Limonene, Naringenin, and Nobiletin Citrus fruit is a rich source of several groups of flavonoids, such as flavanone and flavone glycosides, as well as highly methoxylated flavones and polymethoxylated flavones (Horowitz and Gentili, 1977). The latter were found to exert antiproliferative activities against cancer cells (Kawaii et al., 1999; Iwase et al., 2001). Manthey and Guthrie (2002) isolated polmethoxylated flavones from orange peel and showed they had strong, antiproliferative activities toward human cancer-cell lines.

References

Horowitz, R.M. and Gentili, B., Flavonoid constituents in citrus, in Citrus Science and Technology, vol. 1, Nagy, S., Shaw, P.E., and Veldius, M.K., Eds., AVI Publishing, Westport, Connecticut, 1977, pp. 397–426.

Iwase, Y., Takemura, Y., Ju-ichi, M., Yano, M., Ito, C., Furikawa, H., Mukainaka, T., Kuchide, M., Tokuda, H., and Nishino, H., Cancer chemopreventative activity of 3,5,6,7,8,3′,4′- heptamethoxyflavone from the peel of citrus plants, Cancer Lett., 163:7–9, 2001.

Kawaii, S., Yomono, Y., Katase, E., Ogawa, K., and Yano, M., Antiproliferative activity of flavonoids on several cancer cell lines, Biosci. Biotechnol. Biochem., 63:896–899, 1999.

Manthey, J. and Guthrie, N., Antiproliferative activities of citrus flavonoids against six human cancer cell lines, J. Agric. Food Chem., 50:5837–5843, 2002.

Citrus fruit

see also Grapefruit, Lemons, Limes, Mandarins, Oranges, and Tangerines Citrus fruits contain significant amounts of limonene in the peel and smaller amounts in the pulp. Limonene is a monocyclic monoterpene formed by the union of two isoprene molecules. Carbon-4 in limonene is assymetric so that it exists as two optically active forms, d and l. Limonene has been shown to block and suppress carcinogenic events due to its inhibitory action on certain biochemical pathways in tumor tissues (Elson and Yu, 1994). Monoterpenoids, such as limonene, have been reported to cause tumor regressions with limited toxicity. Limonene significantly reduced azoxymethane-induced colonic aberrant crypt foci in rats fed 5 percent limonene in their drinking water (Kawamori et al., 1996). Limonene is used as a flavor and fragrant agent and is listed as safe (GRAS) in food by the Food and Drug Administration. Manthey and Guthres (2002) showed that poly-methoxylated flavones in citrus exhibited strong antiproliferative activities against six human cell lines, suggesting their use as anticancer agents in humans.

References

Elson, C.E. and Yu, S.G., The chemoprevention of cancer by mevalonate-derived constituents of fruits and vegetables, J. Nutr., 124:607–614, 1994.

Kawamori, T., Tanaka, T., Hirose, Y., Ohnishi, M., and Mori, H., Inhibitory effects of d-limonene on the development of colonic aberrant crypt foci induced by azoxymethane in F344 rats, Carcinogenesis, 17: 369–372, 1996.

Manthey, J.A. and Guthries, N., Antiproliferative activities of citrus flavonoids against six human cancer cell lines, J. Agric. Food Chem., :5837–5843, 2002.

Club moss

see also Huperzine A An extract from Club moss (Huperzia serrata) has been used for centuries in Chinese medicine to treat swelling, fever, and blood disorders. The principal component extracted is a sesquiterpene alkaloid, huperzine A, shown in clinical trials to have neuroprotective properties, which may be beneficial in the treatment of Alzheimer’s disease (Zangara, 2003). For further information consult the section on huperzine A.

References

Zangara, A., The psychopharmacology of huperzine A: An alkaloid with cognitive enhancing and neuroprotective properties of interest in the treatment of Alzheimer’s disease, Pharmacol. Biochem. Behav., 75:675–686, 2003.

Cocoa (Theobroma cacao)

see also Chocolate Cocoa is a very rich source of procyanidins, oligomeric flavonoids containing flavan-3-ol units. These compounds are extremely beneficial for their protection against cardiovascular disease by scavenging oxygen and nitrogen species (Rice-Evans et al., 1996). In addition, their ability to inhibit oxidant enzymes has also been reported (Middleton et al., 2000). A recent paper by Mursu et al. (2004) showed healthy, young volunteers consuming 73 g per day of dark chocolate or dark chocolate enriched with cocoa polyphenols had their HDL cholesterol increased by 11.4 percent and 13.7 percent. Schewe and coworkers (2001) reported that epicatechin and cocoa procyanidins inhibited mammalian 15-lipoxygenase, a key enzyme in lipid peroxidation of biomembranes and plasma lipoproteins. Recent research by Schewe et al. (2002) concluded that (−)-epicatechin and its low-molecular-weight procyanidins inhibited both dioxygenase and 5,6-leukotriene A₄ (LTA₄) synthase activities of human 5-lipoxygenase, which could account for the antiinflammatory effects of cocoa products. Inhibition of growth and polyamine biosynthesis by human colonic cancer cells by cocoa powder and extracts was reported by Carnesecchi and coworkers (2002). The procyanidin-enriched extracts significantly decreased ornithine decarboxylase and S-adenosyl-methionine decarboxylase, two key enzymes of polyamine biosynthesis. These results suggested polyamine metabolism may be an important target in the antiproliferative effects of cocoa polyphenols. Yamagishi et al. (2002) reported cocoa liquor proanthocyanidins protected the lungs from 2-amino-1 -methyl-6-phenylimidazo[4,5-b] pyridine (PhIP)-induced tumorigenesis, and rat pancreatic carcinogenesis in the initiation stage but not mammary carcinogenesis.

References

Carnesecchi, S., Schneider, Y., Lazarus, S.A., Coehlo, D., Gosse, F., and Raul, F., Flavonols and procyanidins of cocoa and chocolate inhibit growth and polyamine biosynthesis of human colonic cancer cells, Cancer Lett., 175:147–155, 2002.

Middleton, E., Jr., Kandaswami, C., and Theoharides, T.C., The effects of plant flavonoids on mammalian cells: Implications for inflammation, heart disease and cancer, Pharmacol. Rev., 52:673–751, 2000.

Mursu, J., Voutilainen, S., Nurmi, T., Rissanen, T.H., Virtanen, J.K., Kaikkonen, J., Nyyssonen, K., and Salonen, J.T., Dark chocolate consumption increases HDL cholesterol concentration and chocolate fatty acids may inhibit lipid peroxidation in healthy humans, Free Rad. Biol. Med., 37:1351–1359, 2004.

Rice-Evans, C.A., Miller, N.J., and Pangana, G., Structure-antioxidant activity relationship of flavonoids and phenolic acids, Free Rad. Biol. Med., 20:933–956, 1996.

Schewe, T., Sadik, C., Klotz, L.O., Yoshimoto, T., Kuhn, H., and Sies, H., Polyphenols in cocoa: Inhibition of mammalian 15-lipoxygenase, Biol. Chem., 383:1687–1696, 2001.

Schewe, T., Kuhn, H., and Sies, H., Flavonoids of cocoa inhibit recombinant human 15- lipoxygenase, J. Nutr., 132:1825–1829, 2002.

Yamagishi, M., Natsume, M., Osakabe, N., Okazaki, K., Nakamura, H., Furukawa, F., Imazawa, T., Nishikawa, A., and Hirose, M., Effects of cacao liquor proanthocyanidins on PhIP-induced mutagenesis in vitro, and in vivo mammary and pancreatic tumorigenesis in female Sprague- Dawley rats, Cancer Lett., 185:123–130, 2002.

Coconut (Cocos nucifera)

Coconut is the seed of the coconut palm tree native to the Pacific region of the tropics. It is composed of a thick outer fibrous husk surrounding a hard, stony shell. The lining of the shell, or kernel, contains a white, fleshy, oily area called the meat.

Coconut oil is high in saturated fatty acids. Lauric acid, a 12-carbon saturated acid, accounts for almost 50 percent of the total fatty acids present. Feeding healthy Polynesians coconut oil, butter, and safflower diets, however, still showed cholesterol synthesis was lower on the coconut/safflower-oil diets compared to diets rich in butter (Cox et al., 1998). Padmakumaran Nair and coworkers (1999) reported that human volunteers fed a diet of coconut oil and coconut-kernel protein had lower serum-total-and LDL-cholesterol levels compared to feeding coconut oil alone. The beneficial effects of the kernel protein was attributed to its very low lysine/arginine ratio.

References

Cox, C., Sutherland, W., Mann, J., de Jong, S., Chisholm, A., and Skeaff, M., Effects of dietary coconut oil, butter, and safflower oil on plasma lipids, Eur. J. Clin. Nutr., 52:650–654, 1998.

Padmakumaran Nair, K.G., Rajamohan, T., and Kurup, P.A., Coconut kernel protein modifies the effect of coconut oil on serum lipids, Plant Foods Hum. Nutr., 53:133–144, 1999.

Pillai, M.G., Thampi, B.S.H., Menon, V.P., and Leelamma, S., Influence of dietary fiber from coconut kernel (Cocos nucifera) on the 1,2-dimethylhy-drazine-induced lipid peroxidation, J. Nutr. Biochem., 10:555–560, 1999.

Coenzyme

Q₁₀ Coenzyme Q₁₀ (CoQ₁₀), a lipid-soluble ubiquinone found naturally in foods, boosts the immune system, enabling the body to defend against viruses and microorganisms. Beef heart and muscle are the richest sources of CoQ₁₀, although it is still present in other tissues. Plants provide varied amounts of CoQ compounds that can be converted to CoQ₁₀ by the liver. Almonds, pistachios, and peanuts are very good sources, providing 10–30 ppm of CoQ₁₀(Hamid et al., 1995).

Coenzyme Q₁₀. (From Kommuru et al., Int. J. Pharm., 212:233–246, 2001. With permission.)

Crude palm oil contains around 80 ppm but drops to around 10–30 ppm after processing. Shults et al. (2002) conducted the first placebocontrolled, multicenter clinical trial on CoQ₁₀ suggesting it slows down the progression of early-stage Parkinson’s disease. The ability of CoQ₁₀ to enhance mitochondrial function and to act as a potent antioxidant and mop up harmful free radicals generated by normal metabolism appeared to be the underlying mechanism involved. Kwong and coworkers (2002) found that dietary supplementation of CoQ₁₀ to rats elevated CoQ homologues, selectively decreased protein oxidative damage, and increased antioxidative potential.

Several controlled studies showed CoQ₁₀ substantially lowered blood pressure in hypertensive patients (Singh et al., 1999; Burke et al., 2002). Hodgson et al. (2002) showed CoQ₁₀ improved both blood pressure and glycemic control in subjects with type 2 diabetes. The primary effect of CoQ₁₀ was to significantly decrease systolic and diastolic blood pressures and HbA_1c. None of these improvements were associated with reduced oxidative stress, as there was no change in the amount of F₂-isoprostanes.

FIGURE C.26 Unified Parkinson’s Disease Rating Scale (UPDRS) scores. The scores for the total UPDRS (last observation carried forward) are expressed as mean (SEM). Higher scores indicate more severe features of Parkinson’s disease. Results of a test for a linear trend between the dosage and the mean change in the total UPDRS score indicated a trend for coenzyme Q₁₀ to reduce the increasing disability over time (p=.09). The score change for the 1200-mg/d coenzyme Q₁₀ group was significantly different from that of the placebo group (p=.04). (From Shults et al., Arch. Neurol., 59:1541–1550, 2002. With permission.)

Shults et al. (1997) reported lower levels of CoQ₁₀ in the mitochondria isolated from the plasma of patients suffering from Parkinson’s disease (PD). These researchers later showed that oral consumption of dosages of CoQ₁₀ of 400, 600, and 800 mg/day were well-tolerated by patients with PD with significant elevations in blood-plasma levels (Shults et al., 1998). Further work by Shults et al. (2002) showed doses of up to 1200 mg/day were well-tolerated by PD subjects. At the highest dosage, a significant slowing down of PD was observed based on the lower tremor score using the Unified Parkinson’s Disease Rating Scale (UPDRS), as shown in Figure C.26. Muller et al. (2003), using a double-blind study, fed much lower doses of CoQ₁₀ to PD patients of 360 mg/day over a four-week period. A moderate improvement in PD symptoms and visual function, as measured with the Farnsworth-Munsell 100 Hue test (FMT), with studies using higher dosages presently under way. Both these studies point to the potential of CoQ₁₀ in the treatment of PD.

References

Burke, B.E., Neuenschwander, R., and Olson, R.D., Randomised double-blind, placebo-controlled trial of coenzyme Q10 in isolated systolic hypertension, South. Med. J., 94:1112–1117, 2002.

Hamid, A.H., Choo, Y.M., Goh, S.H., and Khor, H.T., The uniquinones of palm oil, in Nutrition, Lipids, Health, and Disease, Ong, Niki, and Packer, Eds., AOCS Press, U.S.A., 1995, p. 122– 128.

Hodgson, J.M., Watts, G.F., Playford, D.A., Burke, V., and Croft, K.D., Coenzyme Q10 improves blood pressure and glycaemic control: A controlled trial in subjects with type 2 diabetes, Eur. J. Clin. Nutr., 56: 1137–1142, 2002.

Kwong, L.K., Kamzalov, S., Rebrin, I., Bayne, A.-C., Jana, C.K., Morris, P., Forster, M.J., and Sohal, R.S., Effects of coenzyme Q10 administration on its tissue concentrations, mitochondrial oxidant generation, and oxidative stress in the rat, Free Rad. Biol. Med., 33:627–638, 2002.

Muller, T., Buttner, T., Gholipour, A.-F., and Kuhn, W., Coenzyme Q10 supplementation provides mild symptomatic benefit in patients with Parkinson’s disease, Neurosci. Lett., 341:201–204, 2003.

Kommuru, T.R., Gurley, B., Khan, M.A., and Reddy, I.K., Self-emulsifying drug delivery systems (SEDDS) of coenzyme Q10: Formulation development and bioavailability assessment, Int. J. Pharm., 212:233–246, 2001.

Shults, C.W., Haas, R.H., Passov, D., and Beal, M.F., Coenzyme Q10 levels correlate with the activities of complexes I and II/III in mitochondria from parkisonian and non-parkinsonian subjects, Ann. Neurol., 42:261–264, 1997.

Shults, C.W., Beal, M.F., Fontaine, S., Nakano, K., and Haas, R.H., Absorption, tolerability and effects on mitochondrial activity of oral coenzyme Q10 in parkinsonian patients, Neurology, 50:793–795, 1998.

Shults, C.W., Oakes, D., Kieburtz, K., Beal, F., Haas, R., Plumb, S., Juncos, J.L., Nutt, J., Shoulson, I., Carter, J., Kompoliti, K., Perlmutter, J.S., Reich, S., Stern, M., Watts, R.L., Kurlan, R., Molho, E., Harrison, M., Lew, M., and the Parkinson’s Study Group, Effects of coenzyme Q10 in early Parkinson’s disease, Arch. Neurol., 59:1541–1550, 2002.

Singh, R.B., Niaz, M.A., Rastogi, S.S., Shukla, P.K., and Thakur, A.S., Effect of hydrosoluble Coenzyme Q10 on blood pressures and insulin resistance in hypertensive patients with coronary artery disease, J. Hum. Hypertens., 13:203–208, 1999.

Coffee

Coffee is a popular beverage that is consumed worldwide. Epidemiological studies on the relationship between coffee and cancer suggests that moderate coffee consumption (2–5 cups/day) does not represent a risk to humans (Schiller et al., 2001a). Many studies, in fact, showed an inverse relationship existed between certain cancer risks and coffee consumption (Nishi et al., 1996; Giovannucci, 1998; Inoue et al., 1998). Meta-analysis of five cohort and 12 case-control studies all pointed to a significant inverse relationship between coffee consumption and colorectal cancer (Giovannucci et al., 1998). The chemoprotective effect of coffee has been demonstrated in experimental animals by its inhibitory effects on carcinogens, nitrosamines, and 1,2-dimethyl-hydrazine (Gershbein, 1994; Nishikawa et al., 1986). Anticarcinogenic effects were also demonstrated for green, as well as roasted, coffees in animal models treated with 7,12-dimethyl-benz[α]anthacene (Miller et al., 1988, 1993).

Caffeine and polyphenols, such as chlorogenic acid and their degradation products, were considered to be among the compounds responsible for the chemoprotective properties of coffee (Stadler, 2001; Schilter et al., 2001b). A specific lipid fraction in coffee was associated with its ability to inhibit DMBA-induced cancer in rats, mice, and hamsters (Lam et al., 1982; Wattenberg et al., 1986; Miller et al., 1991). This fraction contained diterpenes, cafestol, and kahweol C+K.

Structures of coffee diterpenes cafestol (C) and kahweol (K). (From Cavin et al., Food Chem. Toxicol., 40:1155–1163, 2002. With permission.)

The difficulty in isolating these components separately, combined with the instability of kahweol, led to studies using a mixture of these two compounds. Cavin et al. (2002) showed the diterpene mixture prevented DNA binding with aflatoxin B1 and the environmental carcinogen, benzo[a]-pyrene(B[α])P in rat hepatocyte cultures in a dose-dependent response (Figure C.27). These diterpenes also reduced the genotoxicity of several other carcinogens, including 7,12-dimethylbenz[a]-anthracene (DMBA), aflatoxin B1, and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), using animal models and cell cultures. Chemoprotective effects were attributed to induction of conjugating enzymes (e.g., gluthione S-tranferases and glucuronyl S-transferases), increased protein expression involved in antioxidant defense (e.g., γ-glutamyl cysteine synthetase and heme oxygenase-1), and inhibition of expression or activation of cytochromes P450, the latter normally involved in activation of the carcinogen. The molecular mechanism appeared similar to many cancer-chemopreventive blocking agents and involves the Nrf2 transcription factor through regulation of cis-acting, antioxidant-responsive-element (ARE)-driven gene expression. Further work by Cavin and coworkers (2003) showed C+K inhibited B[a]P-DNA adduct formation in primary rat hepatocytes and human bronchial Beas-2B cells. Huber et al. (2003) showed that K/C and Turkish coffee (cafestol alone) both increased hepatic DNA repair protein O6-methylguanine-DNA methyl-transferase (MGMT) in a dose-dependent manner. The increase in MGMT expression provides new insight regarding the antimutagenic/anticarcinogenic potential of these coffee components.

FIGURE C.27 Dose-dependent effect of cafestol and kahweol (C+K) on the formation of aflatoxin B1 metabolites and benzo[α]pyrene-induced DNA adducts in vitro. Results presented are means obtained from five experiments with two independent cultures per treatment (±S.D.). These are expressed as the percentage of the mean value derived from control cultures. In control, the absolute binding rate (equal to 1005) were in average 6.5 pmol AFB1 and 4.5 pmol B[α]P/mg DNA, respectively. *Significantly different from control rat primary hepatocytes (p<0.05) using the Student’s t-test. (From Cavin et al., Food Chem. Toxicol., 40:1155–1163, 2002. With permission.)

Van Dam and Feskens (2002) reported coffee consumption may reduce the risk of type 2 diabetes mellitus. Of 17,111 Dutch men and women between the ages of 30–60, those drinking a minimum of seven cups of coffee a day were 0.50 (95 percent CI 0.35=0.72, p= 0.0002) times as likely to develop diabetes mellitus compared to those drinking two or fewer cups. Components in coffee that could contribute to this effect are caffeine, chlorogenic acid, and magnesium.

Tavani and coworkers (2003) observed an inverse relationship between coffee intake and risk of oral, pharyngeal, and esophageal cancers. A total of 749 and 395 cases were studied suffering from oral/pharyngeal and esophageal cancers, respectively. The multivariate odds ratio (OR) for those drinking more than three cups of coffee/day compared to one cup of coffee/day were 0.6 (95 percent CI 0.5–0.9) for oral/pharyngeal and 0.6 (95 percent CI 0.4–0.9) for esophageal cancer, irrespective of age, sex, education, and alcohol consumption. These results suggested coffee consumption may decrease the risk of oral/pharyngeal and esophageal cancers.

References

Cavin, C., Bezencon, C., Guignard, G., and Schilter, B., Coffee diterpenes prevent benzo[a]pyrene genotoxicity in rat and human culture systems, Biochem. Biophys. Res. Commun., 306:488–495, 2003.

Cavin, C., Holzhaeuser, D., Scharf, G., Constable, A., Huber, W.W., and Schilter, B., Cafestol and kahweol, two coffee specific diterpenes with anticarcinogenic activity, Food Chem. Toxicol., 40:1155–1163, 2002.

Gershbein, L.L., Action of dietary trypsin, pressed coffee oil, silmarin and iron salt on 1,2- dimethylhy-drazine tumorigenesis by gavage, Anticancer Res., 14:1113–1116, 1994.

Giovannucci, E., 1998. Meta-analysis of coffee consumption and risk of colorectal cancer, Am. J. Epidemiol., 147:1043–1057, 1998.

Huber, W.W., Scharf, G., Nagel, G., Prustomersky, S., Schulte-Hermann, R., and Kaina, B., Coffee and its chemopreventive components kahweol and cafestol increase the activity of 60- methylguanine-DNA methyltransferase in rat liver-comparison with phase II xenobiotic metabolism, Mutat. Res., 522:57–68, 2003.

Inoue, M., Tajima, K., and Hirose, K., Tea and coffee consumption and the risk of digestive tract cancers: Data from a comparative case-referent study in Japan, Cancer Causes Control, 9:209– 216, 1998.

Lam, L.K.T., Sparnins, V.L., and Wattenberg, L.W., Isolation and identification of kahweol and cafestol palmitate as active constituents of green coffee beans that enhance glutathione Stransferase activity in the mouse, Cancer Res., 42:1193–1198, 1982.

Miller, E.G., Formby, W.A., Rivera-Hidalgo, F., and Wright, J.M., Inhibition of hamster buccal pouch carcinogenesis by green coffee, Oral Surg., 65:745–749, 1988.

Miller, E.G., Gonzales-Sanders, A.P., Couvillon, A.M., Binnie, W.H., Sunahara, G.I., and Bertholet, R., Inhibition of oral carcinogenesis by roasted beans and roasted coffee bean fractions, in Association Scientific International du Café, 15th ASIC International Colloquium on Coffee, Paris, 1993, pp. 420–425.

Miller, E.G., McWhorter, K., Rivera-Hidalgo, F., Wright, J.M., Hirsbrunner, P., and Sunahara, G.I., Kahweol and cafestol: Inhibitors of hamster buccal pouch carcinogenesis, Nutr. Cancer, 14:41– 46, 1991.

Nishi, M., Ohba, S., Hirata, K., and Miyake, H., Dose-response relationship between coffee and the risk of pancreas cancer, Jpn. J. Oncol., 26:42–48, 1996.

Nishikawa, A., Tanaka, T., and Mori, H., An inhibi-tory effect of coffee on nitrosaminehepatocarcinogenesis with aminopyrine and sodium nitrite in rats, J. Nutr. Growth Cancer, 3:161–166, 1986.

Schilter, B., Cavin, C., Tritscher, A., and Constable, A., Coffee: Health and safety considerations, in Coffee Recent Developments, Clarke, R.J., and Vitzhthum, O.G., Eds., Blackwell Science, London, 2001a, pp. 165–183.

Schilter, B., Holzhaeuser, D., and Cavin, C., Health benefits of coffee, Proceedings of the 19th International Scientific Colloqium on Coffee, Trieste, May 14–18, 2001b.

Stadler, R.H., The use of chemical markers and model studies to assess the in vitro pro- and antioxidative properties of methyl xanthine-rich beverages, Food Rev. Int., 17:385–418, 2001.

Tavani, A., Bertuzzi, M., Talamini, R., Gallus, S., Parpinel, M., Franceschi, S., Levi, F., and La Vecchia, C.L., Coffee and tea intake and risk of oral, pharyngeal and esophageal cancer, Oral Oncol., 39:695–700, 2003.

Van Dam, R.M. and Feskens, E.J.M., Coffee consumption and risk of type 2 diabetes mellitus, Lancet, 360:1477–1478, 2002.

Wattenberg, L.W., Hanley, A.B., Barany, G., Sparnins, V.L., and Fenwick, G.R., Inhibition of carcinogenesis by some minor constituents, in Diet, Nutrition and Cancer, Hayashi, Y., Ed., Japan Science Society Press, Tokyo, 1986, pp. 193–203.

Colostrum

The first mammary gland fluid secreted by mammals during the first four days after birth is known as the colostrum. Besides the major nutritional components normally associated with milk, colostrum contains many minor bioactive components capable of treating many human diseases. For example, the presence of immunoglobulins in the colostrum is extremely important, as these antibodies play a crucial role in immune protection. Casswall et al. (1998) showed that oral immunoglobulins from bovine colostrum effectively treated Helicobacter pylori infections in infants in rural Bangladesh. Bovine colostrum, particularly I_g, could provide an immunological supplement in infant formula and other hyperimmune foods (Dominguez and coworkers, 1997). A range of growth factors present include insulin-like growth hormone (IGF) and transforming growth factor (TGF), as well as lactoferrin and lactoperoxidase. For a long time, breast-fed babies were known to be resistant to certain types of infections, particularly intestinal disorders (Jatsky and coworkers, 1985). Among the immune factors in colostrum is an iron-binding protein with antibacterial and antiviral properties, lactoferrin (Wilson, 1997). Purified lactoferrins were shown to inhibit the effects of HIV in cells and fibroblasts (Swart et al., 1998). Colostrum provides a wide range of benefits, including preventing gastrointestinal damage from nonsteroidal, anti-inflammatory drugs (NSAIDs). A number of commercial products are available. An excellent review of colostrum was published by Uruakpa and coworkers (2002).

References

Casswall, T., Sarker, S., Albert, et al., Treatment of Heliobacter pylori infection in infants in rural Bangladesh with oral immunoglobulins from hyper-immune bovine colostrum, Aliment. Pharmacol. Therapies, 12:563–568, 1998.

Dominguez, E., Perez, M.D., and Calvo, M., Effect of heat treatment on the antigen-binding activity of antiperoxidase immunoglobulins in bovine colos-trum, J. Dairy Sci., 80:182–187, 1997.

Jatsky, G.V., Kuvaeva, I.B., and Gribakin, S.G., Immunological protection of the neonatal gastointes-tinal tract: The importance of breast-feeding, Acta Pediatr. Scand., 74:246–249, 1985.

Swart, P.J., Kuipers, E.M., Smit, C., Van-Der-Strate, B.W., Harmsen, M.C., and Meijer, D.K., Lactoferrin: Antiviral activity of lactoferrin, Adv. Exp. Med. Biol., 443:205–213, 1998.

Wilson, J., Immune system breakthrough: Colos-trum, J. Longevity Res., 3:7–10, 1997.

Uruakpa, F.O., Ismond, M.A.H., and Aboundu, E.N.T., Colostrum and its benefits: A review, Nutr. Res., 22:755–767, 2002.

Conjugated linoleic acid

Conjugated linoleic acid (CLA), a class of positional and geometrical conjugated isomers of linoleic acid containing two double bonds separated by a single bond was first reported in dairy products and beef (Pariza et al., 2001). The main isomers identified in foods are cis-9, trans-10 (c9, t11) and trans-10, cis-12 (t10, c12) CLA. CLA has some unique chemoprotective properties (Belury, 1995). For example, it has been reported that CLA lowered total body fat and increased lean body mass (Blankson et al., 2000; Delany et al., 1999). In addition, a number of other health benefits have been associated with CLA, including chemopreventative effects against tumors (Visonneau et al., 1996). CLA is also reported to lower cholesterol and to be antiatherogenic. Wilson and coworkers (2000) showed a diet containing conjugated linoleic acid fed to hypercholesterolemic hamsters over 12 weeks significantly reduced the development of early aortic atherogenesis more effectively than linoleic acid, due possibly to changes in the susceptibility of LDL cholesterol to oxidation. Subsequent work by Kritchevsky et al. (2002) showed that a diet containing as little as 0.05 percent CLA reduced the severity of atherosclerosis in the aortic arch of hamsters by 20 percent and in the thoracic aorta by 8 per-cent. Increasing the level of CLA in the diet was accompanied by a corresponding decrease in the severity of atherosclerosis. Based on the effectiveness in the hamster diet of 0.5 percent CLA level, these researchers felt that a normal human diet could contain an effective level of dietary CLA.

Using a 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced rat mammary carcinogenesis model, Futakuchi and coworkers (2002) reported conjugated linoleic acid from safflower or perilla oil decreased carcinogenesis in the postinitiation period, with inhibition of cell proliferation. The antiproliferative effects of two commercial preparations of CLA, containing isomers (c9, t11-CLA, c9, c11-CLA, and t10, c12-CLA), were examined by Palombo et al. (2002) using human colorectal (HT-29, MIP-101) and prostate (PC3) carcinoma cells. Both the type and concentration of individual CLA isomers determined their antiproliferation effects. The greatest potency against proliferation of colorectal-cancer cells was observed for t10, c12-CLA, while c9, t11 and t10, c12 isomers were only moderately effective against prostate-cancer cells.

CLA isomers. (From Evans et al., J. Nutr. Biochem., 13:508–516, 2002. With permission.)

TABLE C.22
Effect of CFA-S on Cell Proliferation of Mammary Adenocarcinoma and Colon Epithelium

Kimoto et al. (2001) reported that 1 or 0.1 percent CLA safflower oil (CFA-S) suppressed mammary carcinogenesis in a two-stage model in female rats. Recent work by Cheng et al. (2003) showed that the optimal level for inhibiting carcinogenesis in rat mammary glands and colon, induced by 1,2-dimethyl-benz[α]-anthracene (DMBA) and 1,2-dimethylhydrazine (DMH), was 1 percent (Table C.22).

A recent study by Albers and coworkers (2003) showed that supplementation with a 50:50 CLA mixture (c9, t11+t10, c12) enhanced the immune system of healthy males by increasing the sero-protection rate following hepatitis B vaccination. This could be beneficial to those individuals who are slow or low responders to the vaccination. Further research is needed, however, to determine whether similar effects are accrued following exposure to infection. A recent review on conjugated linoleic acid by Wahle et al. (2004) is recom- mended.

References

Albers, R., van der Wielen, R.P.J., Brink, E.J., Hendriks, H.F.J., Dorovska-Taran, V.N., and Mohede, I.C.M., Effects of cis-9, trans-11 and trans-10, cis-12 conjugated linoleic acid (CLA) isomers on immune function in healthy men, Eur. J. Clin. Nutr., 57:595–60, 2003.

Belury, M.A., Conjugated dienoic linoleate: A polyunsaturated fatty acid with unique chemoprotective properties, Nutr. Rev., 53:83–89, 1995.

Blankson, H., Stakkestad, J.A., Fagetun, H., Thorn, E., Wadstein, J., and Gudmundsen, O., Conjugated linoleic acid reduces body fat in overweight and obese humans, J. Nutr., 130:2370– 2377, 2000.

Cheng, J.L., Futakuchi, M., Ogawa, K., Iwata, T., Kasai, M., Tokudome, S., Hirose, M., and Shirai, T., Dose response study of conjugated fatty acid derived from safflower oil on mammary and colon carcinogenesis pretreated with 7,12-dimethylbenzanthracene (DMBA) and 1,2- dimethylhydrazine (DMH) in female Sprague-Dawley rats, Cancer Lett., 196:161–168, 2003.

Delany, J.P., Blohm, F., Truett, A.A., Scimeca, J.A., and West, D.B., Conjugated linoleic acid rapidly reduces body fat content in mice without affecting energy intake, Am. J. Physiol., 276:1172–1179, 1999.

Evans, M.E., Brown, J.M., and McIntosh, M.K., Isomer-specific effects of conjugated linoleic acid (CLA) on adiposity and lipid metabolism, J. Nutr. Biochem., 13:508–516, 2002.

Futakuchi, M., Cheng, J.L., Hirose, M., Kimoto, N., Cho, Y.-M., Iwata, T., Kasai, M., Tokudome, S., and Shirai, T., Inhibition of conjugated fatty acids derived from safflower or perilla oil of induction and development of mammary tumors in rats induced by 2amino-1-methyl-6- phenylimidazo[4,5-b]pyridine (PhIP), Cancer Lett., 178:131–139, 2002.

Kimoto, N., Hirose, M., Futakuchi, M., Iwata, T., Kasai, M., and Shirai, T., Site-dependent modulating effects of conjugated fatty acids from safflower oil in a rat two-stage carcinogenesis model in female Sprague-Dawley rats, Cancer Lett., 168:15–21, 2001.

Kritchevsky, D., Tepper, S.A., Wright, S., and Czarnecki, S.K., Influence of graded levels of conjugated linoleic acid (CLA) on experimental atherosclerosis in rabbit, Nutr. Res., 22:1275– 1279, 2002.

Palombo, J.D., Ganguly, A., Bistrian, B.R., and Menard, M.P., The antiproliferative effects of biologically active isomers of conjugated linoleic acid on human colorectal and prostatic cancer cells, Cancer Lett., 177:163–177, 2002.

Pariza, M.W., Park, Y., and Cook, M.E., The biological active isomer of conjugated linoleic acid, Prog. Lipid Res., 40:283–298, 2001.

Visonneau, S., Cesano, A., Tepper, S.A., Scimeca, J., Santoli, D., and Kritchevsky, D., Effect of different concentrations of conjugated linoleic acid (CLA) on tumor cell growth in vitro, FASEB, 9:A869, 1996.

Wahle, K.W.J., Keys, S.D., and Rotondo, D., Conjugated linoleic acids: Are they beneficial or detrimental to health? Prog. Lipid Res., 43:553–587, 2004.

Wilson, T.A., Nicolosi, R.J., Chrysam, M., and Kritchevsky, D., Conjugated linoleic acid reduces early aortic athersclerosis greater than linoleic acid in hypercholesterolemic hamsters, Nutr. Res., 20: 1795–1805, 2000.

Coriander (Coriandrum sativum L.)

Coriander is an annual herb with delicate, bright leaves. Its seeds are used to flavor foods, while its aromatic oil is used in cream lotions and perfumes. Anilakumar et al. (2001) examined the effect of feeding 10 percent coriander-seed powder on hexachlorocyclohexane-induced oxidative stress in rat livers. The antioxidant properties of coriander-seed powder were evident by a reduction in conjugated dienes, hydroperoxides, and malondialdehyde in the liver. Prefeeding coriander-seed powder appeared to counteract the effect of hexachlorocyclohexane by enhancing the hepatic oxidant system. Guerra et al. (2005) recently isolated five carotenoids, β-carotene, β-cryptoxanthin epoxide, lutein-5,6-epoxide, violaxanthin, and neoxanthin, from an ether extract of coriander. Of these, β-carotene represented 61.4 percent of the total carotenoids isolated. The antioxidant activity of the crude fraction was much greater than the individual fractions, suggesting synergism between the individual fractions. Delaquis et al. (2002) compared the antimicrobial activity of a number of essential oils, including coriander. Distilled fractions of purified coriander oil proved far more effective in inhibiting test microorganisms compared to the crude oil. Several purified fractions were obtained, with the more potent fraction containing a mixture of α-pinene (89.4 percent) and camphene (8.5 per-cent).

References

Anilakumar, K.R., Nagaraj, N.S., and Santhanam, K., Effect of coriander seeds on hexachlorocyclohexane induced lipid peroxidation in rat liver, Nutr. Res., 21:1455–1462, 2001.

Delaquis, P.J., Stanich, K., Girard, B., and Mazza, G., Antimicrobial activity of individual and mixed fractions of dill, cilantro, coriander and eucalyptus essential oils, Int. J. Food Microbiol., 74:101–109, 2002.

Guerra, N.B., de Almeido Melo, E., and Filho, J.M., Antioxidant compounds from coriander (Coriandrum sativum L.) etheric extract, J. Fd. Comp. Anal., 18:193–199, 2005.

Corn bran

Corn bran, produced by dry milling, was shown by several researchers to lower cholesterol (Shane and Walker, 1995; VidalQuintanar et al., 1997). The particle size of corn bran was shown by Ebihara and Nakamoto (2001) to affect plasma cholesterol, fecal output, and cecal fermentation in rats. A fiber-free diet was compared to a corn-bran (50 g/kg) diet, ranging in different particle sizes, from 105 to 500 μm. A reduction in particle size was accompanied by a decrease in plasma cholesterol, fecal wet weight, and fecal bulking effect in the rats. Examination of rat liver showed a corresponding increase in cholesterol concentration, cecal-wall weight, and wet weight of cecal content, together with higher levels of total organic acids in the cecal, such as acetic and n-butyric acids.

References

Ebihara, K. and Nakamoto, Y., Effect of particle size of corn bran on the plasma and cholesterol concentration, cecal output and cecal fermentation in rats, Nutr. Res., 21:1509–1518, 2001.

Shane, J.M. and Walker, P.M., Corn bran supplementation of low-fat controlled diet lowers serum lipids in men with hypercholesterolemia, J. Am. Diet. Assoc., 95:40–45, 1995.

Vidal-Quintanar, R.L., Hernandez, L., Conde, K., Vergara-Jimenes, M. and Fernandez, M.L., Lime treated corn husks lower plasma LDL cholesterol in guinea pigs by altering hepatic cholesterol metabolism, J. Nutr. Biochem., 8:479–486, 1997.

Corn-fiber oil

Corn-fiber oil is a by-product of dry milling of corn. Wilson and coworkers (2000) found that the oil extracted from corn-oil fiber reduced plasma and hepatic cholesterol and increased fecal cholesterol excretion in hamsters fed a hypercholesterolemic diet, to a much greater degree than corn oil. Corn-oil diets containing soy sterols or stanols exhibited similar effects on plasma cholesterol levels and cholesterol excretion to that of corn-fiber oil.

Reference

Wilson, T.A., DeSimone, A.P., Romano, A., and Nicolosi, R.J., Corn fiber oil lowers plasma cholesterol levels and increases cholesterol excretion greater than corn oil to diets containing soy sterols and soy stanols in hamsters, J. Nutr. Biochem., 11: 443–449, 2000.

Corn oil

Corn oil is a premium-quality oil rich in ω-6 fatty acids. Linoleic acid (C18:2 ω-6) accounts for approximately 60 percent of the total fatty acids in corn oil, while oleic acid (C18:1 ω-9) comprises around 26 percent. Many studies have shown corn-oil diets fed over a long duration lower total and LDL cholesterol, while HDL-cholesterol remained unchanged (Iacono and Dougherty, 1991). The greater-than-expected lowering of cholesterol by corn oil was explained, in part, due to the presence of naturally occurring plant sterols in the oil (Mattson et al, 1982; Laraki et al., 1993). Corn oil has been shown to significantly lower elevated blood pressure (Iacono and Dougherty, 1993) and reduce the progression of diabetic angiopathy in adult onset diabetes mellitus (Houtsmuller et al., 1982). However, corn oil appears to increase the rate of growth of established tumors. Rusyn and coworkers (1999) showed corn oil rapidly activated the nuclear factor-κB (NF-κB) in Kupffer cells through an oxidant-dependent mechanism. This is turn triggers the production of the tumor necrosis factor a (TNF-α). An earlier study by Gonzalez et al. in 1991 compared corn oil (high in ω-6 fatty acids) with fish oil (high in ω-3 fatty acids) on the growth of human breastcarcinoma cell lines. Unlike fish oil, which significantly increased lipid peroxidation and decreased tumor volume, corn oil increased human breast-carcinoma volume.

References

Gonzalez, M.J., Schemmel, R.A., Gray, J.I., Dugan, L., Jr., Sheffield, L.G., and Welsch, C.W., Effect of dietary fat on growth of MCF-7 carcinomas in erythmic nude mice: Relationship between carcinoma growth and lipid peroxidation product levels, Carcinogenesis, 12:1231– 1235, 1991.

Houtsmuller, A.J., van Hal-Ferweds, J., Zahn, K.J., and Henkes, H.E., Favourable influences of linoleic acid as the progression of diabetic micro- and macroangiopathy in adult onset diabetes mellitus, Prog. Lipid Res., 20:377–386, 1982.

Iacono, J.M. and Dougherty, R.M., Lack of effect of linoleic acid on the high-density lipoproteincholesterol fraction on plasma lipoproteins, Am. J. Clin. Nutr., 53:660–664, 1991.

Laraki, L., Pelletier, X., Mourot, J., and Derby, G., Effects of dietary phytosterol on liver lipids and lipid metabolism enzymes, Ann. Nutr. Metab., 37:129–133, 1993.

Mattson, F.H., Grundy, S.M., and Grouse, J.R., Optimising the effect of plant sterols on cholesterol absorption in man, Am. J. Clin. Nutr., 35:697–700, 1982.

Rusyn, I., Bradham, C.A., Cohn, L., Schoonhoven, R., Swenberg, J.A., Brenner, D.A., and Thurman, R.G., Corn oil activates nuclear factor-κB on heptic Kupffer cells by oxidantdependent reactions, Carcinogenesis, 20:2095–2100, 1999.

Cranberry fruit

Cranberry (Vaccinium macrocarpon Ait. Ericaceae), a native fruit in North America, has been reported to provide health benefits, such as preventing bacterial adhesion in urinary-tract infections of Escherichia coli and stomach ulcers (Burger et al., 2000; Foo et al., 2000), inhibiting lipoprotein oxidation (Wilson et al., 1998), and exhibiting anticancer properties (Bomser et al., 1996). Many of these health benefits are associated with its phenolic content, which was shown to be highest per serving among 20 fruits examined and ranked sixth in antioxidant capacity (Vinson et al., 2001). Yan and coworkers (2002) found the highest radical-scavenging activity was associated with cranberry extract. Their flavonol glycosides had similar or superior antioxidant activity to vitamin E when assayed using either the diphenyl-2-picrylhydrazyl radical-scavenging method or the low-density lipoprotein oxidation system. Cyanidin 3-galactoside stood out by its superior antioxidant activity to flavonoids and vitamin E using both methods.

FIGURE C.28 Effect of cranberry flavonoid fractions on lag time of Cu²⁺-induced LDL oxidation. Histograms show the mean (n=3) and the error bars the SEM. Significant differences (p<0.05) between treatment means are denoted by different letters above the error bars. Fraction 2 contained a hydroxycinnamic acid peak and several anthocyanins. Fractions 3 and 4 also contained flavonoids. Fraction 4 also contained a few lowmolecular-weight proanthocyanidins. Fractions 5 and 6 both contained proanthocyanidins. (From Porter et al., J. Sci. Food Agric., 81:1306–1313, 2001. With permission.)

Porter and coworkers (2001) showed six cranberry phenolic fractions inhibited Cu²⁺- induced low-density (LDL) oxidation in human serum (Figure C.28). Only several fractions (5 and 6) that contained proanthocyanidins significantly increased the LDL-oxidation lag time. One of these fractions contained trimers through to hep tamers, with the more potent fraction containing pentamers through to nonamers. The anticancer activity of cranberries was attributed to inhibition of ornithine decarboxylase (ODC) by flavonol glycosides and proanthocyanidins (Kandil et al., 2002). This enzyme was previously shown to be involved in tumor proliferation. Two cranberry extracts were reported by Guthrie (2000) to inhibit the proliferation of breast-cancer cells. Yan et al. (2002) also reported the selective inhibition of two of seven tumor-cell lines by a methanolic extract from cranberry fruit ranging from 16–125 μg/mL. Murphy et al. (2003) identified several new triterpenoid hydroxycinnamates from a bioactive cranberry fruit fraction, cis-(1) and trans-(2) 3-O-p-hydroxycinnamoyl ursolic acids (Scheme C.18). Both were found to inhibit tumor-cell growth. The greatest antitumor activity, however, was associated with the s isomer(1), resulting in a 50 percent growth inhibition in MCF-7 breast, ME 180 cervical, and PC3 prostate-tumor lines in the presence approximately 20 μM. Based on these results, cranberries clearly contain an array of compounds with potential health benefits.

References

Bomser, J., Madhavi, D.L., Singletary, K., and Smith, M.A., In vitro anticancer activity of fruit extracts from Vaccinium species, Planta Meet., 62:212–216, 1996.

Burger, O., Ofek, I., Tabak, M., Weiss, E.I., Sharon, I., and Neeman, I., A high molecular mass constituent of cranberry juice inhibits Heliobacter pylori adhesion to human gastric mucus, FEMS Immunol. Med. Microbiol., 29:295–301, 2000.

Foo, L.Y., Howell, A.B., and Vorsa, N., The structure of cranberry proanthocyanidins which inhibit adherence of uropathogenic P-fimbriated Eschrichia coli in vitro. Phytochemistry, 54:173–181, 2000.

Guthrie, N., Effect of cranberry juice and products on human breast cancer cell growth, FASEB J., 14: A771, 2000.

Kandil, F.E., Smith, M.A.L., Rogers, R.B., Pepin, M.F., Song, L.L., Pezzuto, J.M., and Siegler, D.S., Composition of a chemopreventive proanthocyanidin-rich fraction from cranberry fruits responsible for the inhibition of 12-O-tetradecanoyl phorbol-13-acetate (TPA)-induced ornithine decarboxylase (ODC) activity, J. Agric. Food Chem., 50:1063–1069, 2002.

Murphy, B.T., MacKinnon, S.L., Yan, X., Hammond, G.B., Vaisberg, A.J., and Neto, C.C., Identification of triterpene hydroxycinnamates with in vitro antitumor activity from whole cranberry fruit (Vaccinium macrocarpon), J. Agric. Food Chem., 51:3541–3545, 2003.

Porter, M.L., Krueger, C.G., Wiebe, D.A., Cunningham, D.G., and Reed, J., Cranberry proanthocyanidins associate with low-density lipoprotein and inhibit in vitro Cu²⁺-induced oxidation, J. Sci. Food Agric., 81:1306–1313, 2001.

Vinson, J.A., Dabbagh, Y.A., Serry, M.M., and Jang, J., Plant flavonoids, especially tea flavonols, are powerful antioxidants using an in vitro oxidation model for heart disease, J. Agric. Food Chem., 43:2800–2802, 1995.

Wilson, T., Porcari, J., and Harbin, D., Cranberry extract inhibits low density lipoprotein oxidation, Life Sci., 62:381–386, 1998.

Yan, X., Murphy, B.T., Hammond, G.B., Vinson, J.A., and Neta, C.C., Antioxidant activities and antitumor screening of extracts from cranberry fruit (Vaccinium macrocarpon), J. Agric. Food Chem., 50: 5844–5849, 2002.

SCHEME C.18 Bioactive triterpenoids, cis- (a) and trans- (b) 3- O-p-hydroxycinnamoyl ursolic acids. (From Murphy et al., J. Agric. Food Chem., 51:3541–3545, 2003. With permission.)

Cranberry juice

Sobota (1984) first reported that fresh cranberry juice prevented bacterial adhesion, a prerequisite for the development of urinary-tract infection. Later studies by Ahuja et al. (1998) showed cranberry juice had no antibacterial activity but inhibited adhesion by P. fimbriae. The substances in cranberry juice responsible were shown to be the condensed tannins, proanthocyanidins. Howell et al. (1998) found cranberry proanthocyanidins prevented adherence of uropathogenic P-fimbriated Escherichia coli to the urinary tract. The effect was detectable in the presence of 10–50 μg/mL proanthocyanidins. Examination of senior residents (mean age 78.5 years) in a long-care facility by Avorn and coworkers (1994) found that consumption of 300 mL of a cranberry cocktail significantly decreased infections by bacteriuria and pyuria. The protective role of cranberry juice was further supported by Haverkorn and Mandigers (1994), who found fewer cases of bacteriuria in patients given cranberry juice (15 mL) diluted with water twice a day for a month. Based on clinical studies carried out to-date, Lowe and Fagelman (2001) encouraged supplementing cranberries, as juice, concentrate, or in cocktail formulations, because of its beneficial effect in preventing urinary-tract infections. Burger et al. (2000) also showed cranberry juice inhibited adhesion of Helicobacter pylori, a major cause of gastrointestinal infections in humans.

Pedersen and coworkers (2000) reported an increase in plasma antioxidant capacity following consumption of cranberry juice.

References

Ahuja. S., Kaack, B., and Roberts, J., Loss of fimbrial adhesion with the addition of Vaccinium macrocarpon to the growth medium of P-fimbriated Escherichia coli, J. Urol., 159:559–562, 1998.

Avorn, J., Monane, M., Gruwitz, J.H., Glynn, R.J., Choodisovskiy, I., and Lipsitz, A., Reduction of bacteriuria and pyruria after ingestion of cranberry juice, JAMA, 271:751–754, 1994.

Burger, O., Ofek, I., Tabak, M., Weiss, E.I., Sharon, N., and Neeman, I., A high molecular mass constituent of cranberry juice inhibits Helicobacter pylori adhesion to human gastric mucus, FEMS Immunol. Med. Microbiol., 29:295–301, 2000.

Haverkorn, M.J. and Mandigers, J., Reduction of bateriuria and pyuria using cranberry juice (letter), JAMA, 272:590, 1994.

Howell, A.B., Vorsa, N., Marderosian, A.D., and Foo, L.Y., Inhibition of the adherence of pfimbriated Escherichia coli uroepithelial surfaces by proanthocyanidin extracts from cranberries, N. Eng. J. Med., 339:1085–1089, 1998.

Lowe, F.C. and Fagelman, E., Cranberry juice and urinary infections, what is the evidence? Urol., 57:407–413, 2001.

Pedersen, C.B., Kyle, J., Jenkinson, A.M., Garnder, P.T., McPhail, D.B., and Duthie, G.G., Effects of blueberry and cranberry juice consumption on the plasma antioxidant capacity of healthy female volunteers, Eur. J. Clin. Nutr, 54:405–408, 2000.

Sobota, A.E., Inhibition of bacterial adherence by cranberry juice: Potential use for the treatment of urinary tract infections, J. Urol., 131:563–568, 1984.

Crocin

see also Saffron The pistils of Crocus sativus L. have been used in traditional Chinese medicine to treat disorders of the central-nervous system. Extracts obtained from Crocus sativus were shown to prevent tumor formation, atherosclerosis, and hepatic injury (Gainer and Jones, 1975; Salomi et al., 1991; Wang et al., 1991). Ethanol is well-known to impair brain functions, such as learning and memory. Research conducted on Crocus sativus L. showed that components in this extract antagonize ethanol-induced memory impairment. The component responsible was identified as crocin (crocetin di-gentiobiose) (Sagiura et al., 1995). Subsequent work by Abe and coworkers (1998) showed crocin selectively antagonized the inhibitory effect of ethanol on N-methyl-D-aspartate (NDMA) receptor-mediated responses in hippocampal neurons, suggesting it may be useful for treating brain disorders. The pathology of neurode-generative diseases is associated with unexpected neuron deaths occurring during a stroke (Crowe, 1997), trauma (Hill et al., 1995), or in the brains of Alzheimer’s patients (Pettmann and Henderson, 1998). A possible therapeutic strategy for treating these disorders would be to prevent neuronal-cell death as overexpression of the tumor necrosis factor (TNF-α) has been implicated in the pathogenesis of Alzheimer’s disease (Fillit et al., 1991) and Parkinson’s disease (Boka et al., 1994). Using neuronally differentiated PC-12 cells, Soeda and coworkers (2001) showed that in cells treated with 10 μM crocin, the normal features of cell death were not evident due to suppression of TNF-α-induced expression Bcl-2 proteins, which triggers signals that activate caspase-3 and the development of apoptosis.

Crocin. (From Soeda et al., Life Sci., 69:2887–2898, 2001. With permission.)

Escribano and coworkers (1996) compared the effectiveness of crocin, safranal, and picrocrocin, compounds present in saffron (Crocus sativus L.), on their ability to inhibit the growth of human cancer cells. A 50 percent inhibition of cell growth (LD₅₀) was observed with 3 mM crocin in which cells showed wide cytoplasmic vacuole-like areas, reduced cytoplasm, cell shrinkage, and pyknotic nuclei. These researchers viewed crocin as one of the more promising compounds in saffron as a cancer therapeutic agent.

References

Abe, K., Suguira, M., Shoyama, Y., and Saito, H., Crocin antagonizes ethanol inhibition of NMDA receptor-mediated responses in rat hippocampal neurons, Brain Res., 787:132–138, 1998.

Boka, G., Anglade, P., Wallach, D., Javoy-Agid, F., Agid, Y., and Hirsch, E.C., Immunocytochemical analysis of tumor necrosis factor and its receptor in Parkinson’s disease, Neurosci. Lett., 172:151–154, 1994.

Crowe, M.J., Bresnahan, J.C., Shuman, S.L., Masters, J.N., and Beattie, M.S., Apoptosis and delayed degeneration after spinal cord injury in rats and monkeys, Nat. Med., 3:73–76, 1997.

Escribano, J., Alonso, G.-L., Coca-Prados, M., and Fernandez, J.-A., Crocin, safranal and picrocrocin from saffron (Crocus sativus L.) inhibit the growth of human cancer cells in vitro, Cancer Lett., 100:23–30, 1996.

Fillit, H., Ding, W.H., Buee, L., Kalman, L., Altstiel, L., Lawlor, B., and Wolf-Klein, G., Elevated circulating tumor necrosis factor and its receptor in Alzheimer’s disease, Neurosci. Lett., 129:318–320, 1991.

Gainer, J.L. and Jones, J.R., The use of crocetin in experimental atherosclerosis, Experentia, 31:548–549, 1975.

Hill, I.E., MacManus, J.P., Rasquinha, I., and Tuor, U.I., DNA fragmentation indicative of apoptosis following unilateral cerebral hypoxia-ischemia in the neonatal rat, Brain Res., 676:398–403, 1995.

Pettmann, B. and Henderson, C.E., Neuronal cell death, Neuron, 20:633–647, 1998.

Salomi, M.J., Nair, S.C., and Panikkar, K.R., Inhibitory effect of Nigella saliva and saffron on chemical carcinogenesis, Nutr. Cancer, 16:67–72, 1991.

Soeda, S., Ochiai, T., Paopong, L., Tanaka, H., Shoyama, Y., and Shimeno, H., Crocin suppresses tumor necrosis factor-α-induced cell death of neuronally differentiated PC-12 cells, Life Sci., 69: 2887–2898, 2001.

Suguira, M., Shoyama, Y., Saito, H., and Nishiyama, N., Crocin improves the ethanol-induced impairment of learning behaviors of mice in passive avoidance tasks, Proc. Jap. Acad., 71:319– 324, 1995.

Wang, E., Norred, W.P., Bacon, C.W., Riley, R.T., and Merrill, A.H., Jr., Inhibition of sphingolipid biosynthesis by fumonisins: Implications for diseases associated with Fusarium moniforme, J. Biol. Chem., 266:1486–1490, 1991.

Cruciferous vegetables

see also Brassica Cruciferous vegetables, including cabbages, broccoli, Brussels sprouts, radish, mustard, and cress, are all high in glucosinolates. When these vegetables are cut, ground, or damaged, the glucosinolates are hydrolyzed by an enzyme, myrosinase, producing biologically active isothiocyanates (ITC) and indoles. There appears to be an inverse relation between cruciferous vegetables and the risk of cancer (Verhoeven et al., 1997; Talalay and Fahey, 2001). Lampe and Peterson (2002) reviewed the chemoprotective effects of the high glucosinolate content of cruciferous vegetables and their metabolites, ITC and indoles, in relation to cancer prevention. Since isothiocyanates are strong inhibitors of phase I enzymes but inducers of phase II enzymes (Zhang and Talalay, 1998), cruciferous vegetables were considered cancer chemopreventors, which was confirmed in human-intervention studies (Bogaards et al., 1998; Nojhoff et al., 1995). Steinkeller et al. (2001) presented evidence that cruciferous vegetables and their constituents protect against bioactivation of DNA-reactive dietary carcinogens. Induction of uridinediphospho-glucuronsyl transferase (UDPGT) appeared the protective mechanism involved against heterocyclic amines by the cruciferous vegetables.

Isthiocyanates formed in the digestion of cruciferous vegetables are conjugated with glutathione and excreted in the urine as their corresponding mecapturic acids (Scheme C.19). Vermeulen and coworkers (2003) developed an efficient method for monitoring the intake and action of isothiocyanates by measuring the corresponding mercapturic acids as biomarkers.

References

Bogaards, J.J., Verhagen, H,., Willems, M.I., van Poppel, G., and van Bladeren, P.J., Consumption of Brussels sprouts results in elevated glutathione-S-transferase levels in human blood plasma, Carcinogenesis, 15:1073–1075, 1994.

Lampe, J.W. and Peterson, S., Brassica and cancer risk: Genetic polymorphisms alter the preventive effects of cruciferous vegetables, J. Nutr., 132:2991–2992, 2002.

Nojhoff, W.A., Mulder, T.P., Verhagen, H., van Poppel, G., and Peters, W.H., Effects of consumption of Brussels sprouts on plasma and urinary glutathioneS-transferase class-alpha and pi in humans, Carcinogenesis, 16:955–957, 1995.

Steinkeller, H., Rabot, S., Freywald, C., Nobis, E., Scharf, G., Chabicovsky, M., Knasmuller, S., and Kassie, F., Effects of cruciferous vegetables and their constituents on drug metabolizing enzymes involved in the bioactivation of DNA-reactive dietary carcinogens, Mutat. Res., 480– 481:285–297, 2001.

Talalay, P. and Fahey, J.W., Phytochemicals from cruciferous plants protect against cancer by modulating carcinogen metabolism, J. Nutr., 131:3027S-3033S, 2001.

Verhoeven, D.T.H., Verhagen, H., Goldbohm, P.A., Van den Brandt, P.A., and van Poppel, G., A review of mechanism underlying anticarcinogenicity by Brassica vegetables, Chemico-Biol. Interact., 103: 79–129, 1997.

Vermeulen, M., van Roujen, H.J.M., and Vaes, W.H., Analysis of isothiocyanate mercapturic acids in urine: A biomarker for cruciferous vegetable intake, J. Agric. Food Chem., 51:3554–3559, 2003.

Zhang, Y. and Talalay, P., Mechanism of differential potencies of isothiocyanates as inducers of anticarcinogenic Phase 2 enzymes, Cancer Res., 58:4632–4639, 1998.

SCHEME C.19 Glucosinolates enzymatically hydrolyzed to isothiocyanates are then conjugated to glutathione, followed by excretion as mercapturic acids in the urine. (From Vermeulen et al., J. Agric. Food Chem., 51:3554–3559, 2003. With permission.)

Curcumin

Curcumin, the yellow pigment from turmeric, was shown to be a potent inhibitor of radiation-induced initiation of mammary tumors in rats (Inano et al., 2000). The inhibitory effect of curcumin on telomerase reverse-transcriptase (hHERT) activity was reported by Ramachandran and coworkers (2002) in MCF7 breast-cancer cells. This effect was dose dependent, with 93.4 percent inhibition in the presence of 100 μM curcumin. The inhibition of telomerase activity appeared to involve down-regulating hHERT expression by the breast-cancer cells. The ability of curcumin to inhibit the formation of the Fos-Jun-DNA complex led Hahm and coworkers (2002) to synthesize 12 symmetrical cucurminoids. One of these, BJC005, proved to be 90 times more effective than curcumin and more potent than momordin, a potent Fos-Jun inhibitor.

Curcumin. (From May et al., Anal. Biochem., 337:62–69, 2005. With permission.)

References

Hahm, E-R., Cheon, G., Lee, J., Kim, B., Park, C., and Yang, C., New and known symmetrical curcumin derivatives inhibit the formation of Fos-Jun-DNA complex, Cancer Lett., 184:89–96, 2002.

Inano, H., Onoda, M., Inafuku, N., Kubota, M., Kamada, Y., Osawa, T., Kobayashi, H., and Wakabayashi, K., Potent preventive action of curcumin on radiation-induced initiation of mammary tumorigenesis in rats, Carcinogenesis, 21:1835–1841, 2000.

May, L.A., Tourkina, E., Hoffman, S.P., and Dix, T.A., Detection and quantitation of curcumin mouse lung cell cultures by matrix-assisted laser desorption ionization time of flight mass spectrometry, Anal. Biochem., 337:62–69, 2005.

Ramachandran, C., Fonseca, H.B., Jhabvala, P., Escalan, E.A., and Melnick, Curcumin inhibits telomerase activity through human telomerase reverse transcriptase in MCF-7 breast cancer cell line, Cancer Lett., 184:1–6, 2002.

Cucurbita andreana

In Latin America, the flowers, leaves, and vine tips of cucurbita spp. are widely consumed, because they exhibit a wide range of biological activities in plants and animals. Early work identified a group of terpenoid compounds or cucurbitacins present (Metcalf et al., 1982; Miro, 1995). These are highly oxygenated, tetracyclic triterpenes containing a cucirbitane skeleton characterized by a 19-(10→9β)abeo-10α-lanost-5-ene. Some of these cucurbitacins were shown to exhibit antiinflammatory effects linked possibly to inhibition of cyclooxygenase (COX) enzymes.

A recent study by Jayaprakasam et al. (2003) showed these cucurbitacins (B, D, E, and I) exhibited potent anticancer activity, as well as inhibited COX-2 enzyme. Further research is needed to determine the toxicity of these compounds.

Curcurbitacins. (From Jayaprakasam et al., Cancer Lett., 189:11–16, 2003. With permission.)

References

Jayaprakasam, B., Seeram, N.P., and Nair, M.G., Anticancer and anti-inflammatory activities of cucurbitacins from Cucurbita andreana, Cancer Lett., 189:11–16, 2003.

Metcalf, R.L., Rhodes, A.M., and Metcalf, R.A., Cucurbitacin cntent and diabroticites (Coleoptera; Chrysomelidae) feeding upon cucurbita spp., Envi-ron. Entomol., 11:931–937. 1982.

Miro, M., Cucurbitacins and their pharmacological effects, Phytother. Res., 9:159–168, 1995.

Curdlan

Curdlan, a β1,3-glucan synthesized by Alcaligenes faecalis var. myxogenes, was reported to have a number of health benefits (Jezequel, 1998). Shimizu et al. (1999) found rats fed a curdlan diet produced lower cecal pH accompanied by the release of large amounts of short-chain fatty acids (SCFA) and a lower ratio of fecal secondary bile acids. The anticancer properties of curdlan were further demonstrated by Shimizu and coworkers (2002), who showed a diet containing 5 percent curdlan significantly reduced dimethylhydrazine (DMH)-induced aberrant crypt foci development in Sprague-Dawley rats. Curdlan proved more effective than either cellulose or gellan gum in reducing the number of aberrant crypt foci (Figure C.29).

A search for antihuman immunodeficiency virus (HIV) agents to treat AIDS that did not have serious side effects led to the identification of a polysulphonated polysaccharide, curdlan sulfate (Molla et al., 1996). In vitro studies showed the anti-HIV activity in sulfated curdlan was due to its effects on viral replication by preventing binding to HIV virions to CD4⁺ lymphocyte cells and synctium formation (Baha et al., 1988). Further research showed a synthetic curdlan sulfate exhibited high anti-HIV activity and low toxicity. A series of phase I/II clinical tests conducted on curdlan sulfate in the U.S.A. between 1992 and 1996, however, found no significant improvements in patients given intravenous doses of 100 to 300 mg over the short term (Gordon et al., 1997). Jeon and coworkers (2000) analyzed NMR signals for polymeric interactions between curdlan sulfate and an HIV protein but obtained precipitates rather than gels, which did not yield any structural information. Further work is needed to establish the efficacy of curdlan sulfate, based on its anti-HIV properties, as a long-term therapy for AIDS.

Curdlan. (From Jezequel, Cereal Foods World, 43:361–364, 1998. With permission.)

FIGURE C.29 Numbers of DMHinduced aberrant crypt foci (ACF) of rats fed experimental diets. Bars are means±SEM. Each bar with different letters indicates differences from Tukey’s test (p<0.05). (From Shimizu et al., Nutr. Res., 22:867–877, 2002. With permission.)

A recent double-blind, placebo-controlled study on patients suffering from severe and severe/cerebral malaria by Havlik et al. (2005) examined the efficacy and safety of using curdlan sulfate as an adjunct medication with conventional therapy, artesunate. Curdlan sulfate was found to reduce the severity of cerebral malaria by shortening the fever-clearance period. No additional complications were observed with curdlan sulfate, such as renal failure or pulmonary oedema, as it appeared to be well-tolerated. However, the small number of patients in this study suggests further clinical trials with a larger number of patients is warranted.

References

Baba, M., Snoeck, R., Pauwels, R., and Declerq, S., Sulfated polysaccharides are potent and selective inhibitors of various enveloped virus, including herpes simplex virus, cytomegalvirus, vesicular stamatis virus and human immunodeficiency virus. Antimicrob, Agents Chemother., 32:1742–1745, 1988.

Gordon, M., Guralnik, M., Kaneko, Y., Minura, T., Baker, M., and Lang, W., A phase 1 study of curdlan sulfate—an HIV inhibitor. Tolerance, pharmaco kinetics and effects on coagulation and on CD4 lymphocytes. J. Med., 25 (1–4): 163–180, 1994.

Gordon, M., Deeks, S., De Marzo, C., Goodgame, J., Guralink, M., Lang, W., Mimura, T., Pearce, D., and Kaneko, Y., Curdlan sulfate (CRDS) in a 21-day intravenous tolerance study in human immunodeficiency virus (HIV) and cytomealovirus (CMV) infected patients: Indication of anti- CMV activity with low toxicity, J. Med., 28:108–128, 1994, 1997.

Havlik, I., Looareesuwan, S., Vannaphan, S., Wilairatana, P., Krudsood, S., Thuma, P.E., Kozbor, D., Watanabe, N., and Kaneko, Y., Curdlan sulfate in human severe/cerebral Plasmodium falciparum malaria, Trans. Roy. Soc. Trop. Med. Hyg., 2005 (in press).

Jeon, K.-J., Katsuraya, K., Inazu, T., Kaneko, Y., Mimura, T., and Uryu, T., NMR spectroscopic detection of interactions between a HIV protein sequence and a highly anti-HIV active curdlan sulfate, J. Am. Chem. Soc., 122:12536–12541, 2000.

Jezequel, V, Curdlan: A new functional β-glucan, Cereal Foods World, 43:361–364, 1998.

Molla, A., Korneyeva, M., Gao, O., Vasavonda, S., Schipper, P.J., Markowitz, M., Chernyavsky, T., Niu, P., Lyons, N., Hsu, A., Grannerman, G.R., Ho, D.D., Boucher, C.A.B., Leonard, J.M., Norbeck, D.W., and Kemf, D.J., Ordered accumulation of mutations in HIV proteases confers resistance to ritonavir. Nature Med., 2:760–762, 1996.

Shimizu, J., Kudoh, K., Wada, M., Takita, T., Innami, S., Maekawa, A., and Tadokoro, T., Dietary curdlan suppresses dimethylhydrazine-induced aberrant crypt foci formation in Sprague-Dawley rat, Nutr. Res., 22:867–877, 2002.

Shimizu, J., Wada, M., Takita, T., and Innami, S., Curdlan and gellan gum, bacterial gel-forming polysaccharides exhibit different effect on lipid metabolism, cecal formation and fecal bile excretion in man, J. Nutr. Sci. Vitaminol., 45:251–262, 1999.