The modifying effects of flavonoids diosmin and hesperidin during the initiation and post-initiation phases of oesophageal carcinogenesis initiated with N-methyl-N-amylnitrosamine (MNAN) were investigated in male Wistar rats. At 7 weeks of age, all animals except those treated each test chemical alone and control groups were given weekly intraperitoneal injections of MNAN (12.5 mg/kg body weight/injection) for 12 weeks to induce oesophageal neoplasms. For examining the modifying effects of 'initiation' treatment of test compounds, groups of animals were fed the diets containing 1000 ppm diosmin and 1000 ppm hesperidin, and the diet containing both compounds (900 ppm diosmin and 100 ppm hesperidin) for 13 weeks, starting 7 days before the MNAN dosing and then switched to the basal diet. For examining the modifying effects of 'post-initiation' treatment of these compounds, the groups given MNAN and a basal diet were switched to the experimental diets containing diosmin, hesperidin or diosmin combined with hesperidin at 1 week after the stop of MNAN injection, and maintained on these diets for 7 weeks. The other groups consisted of rats given test compounds alone or untreated rats. All animals were necropsied at the termination of the study (week 20) to determine the incidences of oesophageal neoplasms and preneoplasms, blood polyamine levels, and cell proliferation activity estimated by 5-bromodeoxyuridine (BrdU)-labelling index and by morphometric analysis of silver-stained nucleolar organizer regions' protein (AgNORs). A number of oesophageal neoplasms developed in rats treated with MNAN alone (75% and 100% incidences of carcinoma and papilloma, respectively). 'Initiation' feeding of diosmin significantly decreased the incidence of squamous cell carcinoma (P < 0.05). Also, 'initiation feeding' of both compounds singly or in combination caused a significant reduction in the multiplicities of oesophageal carcinoma and papilloma (diosmin, 78 and 58% reduction; hesperidin, 70 and 50% reduction; and the combination regimen, 70 and 30% reduction, P < 0.005). 'Post-initiation' feeding slightly decreased the multiplicities of these oesophageal neoplasms. Also, these dietary regimens reduced the multiplicities of preneoplastic lesions (hyperplasia and severe dysplasia; P < 0.05). There were no pathological alterations in rats treated with both compounds alone or the combined regimen alone or those in an untreated control group. Similarly, feeding of these compounds significantly decreased the expression of cell proliferation biomarkers (BrdU-labelling index and AgNORs number) of the non-lesional oesophageal epithelium (P < 0.05). Blood polyamine concentrations were also lowered in rats given the carcinogen and test compounds, both alone and in combination, when compared with those of rats given MNAN alone (P < 0.05). These findings suggest that diosmin and hesperidin supplementation, individually or in combination, is effective in inhibiting the development of oesophageal cancer induced by MNAN when given during the initi...
The effects of prolonged intake of juice prepared from Satsuma mandarin (Citrus unshiu MARC.) containing β-cryptoxanthin on circulating biochemical markers of bone metabolism in subjects, including menopausal woman, were investigated. Ninety volunteers, aged 27-65 years (19 men and 71 women), were enrolled in this study. The 71 females included 35 premenopausal women (ages, 27-50 years) and 36 postmenopausal women (ages, 46-65 years). Volunteers were divided into four groups; placebo juice without β-cyptoxanthin (5 men and 19 women), juice containing β-cyptoxanthin at 1.5 mg/200 ml of juice/day (4 men and 17 women), 3.0 mg/day (5 men and 17 women), and 6.0 mg/day (5 men and 18 women). Placebo or juice (200 ml) was ingested once a day for 28 or 56 days. Serum β-cryptoxanthin concentrations were significantly increased after the intake of juice containing β-cryptoxanthin (1.5, 3.0, or 6.0 mg/day) for 28 or 56 days, and the increases were dose-dependent. Bone-specific alkaline phosphatase and γ-carboxylated osteocalcin are serum bone markers of bone formation, and bone tartrate-resistant acid phosphatase (TRACP) and N-telopeptides of type I collagen are markers of bone resorption. Bone-specific alkaline phosphatase activity was significantly increased after the intake of juice containing β-cryptoxanthin (3.0 or 6.0 mg/ day) for 56 days as compared with the value obtained before intake. γ-Carboxylated osteocalcin concentration was significantly increased after the intake of juice containing β-cryptoxanthin (3.0 or 6.0 mg/day) for 28 or 56 days as compared with the value obtained before intake or after the intake of placebo juice. Serum TRACP activity and type I collagen N-telopeptide concentration were significantly decreased after the intake of juice containing β-cryptoxanthin (3.0 or 6.0 mg/day) for 28 or 56 days as compared with the value obtained before intake or after intake of placebo juice, and significant decreases were also seen after the intake of 1.5 mg/day β-cryptoxanthin as compared with the value obtained before intake. In menopausal women, bone-specific alkaline phosphatase activity and γ-carboxylated osteocalcin concentration were significantly increased after the intake of juice containing β-cryptoxanthin (3.0 or 6.0 mg/day) for 56 days as compared with the value obtained after placebo intake. Also, this intake caused a significant decrease in bone TRACP activity. Meanwhile, serum calcium, inorganic phosphorous, and parathyroid hormone (intact) were not changed after the intake of β-cryptoxanthin-containing juice for 28 or 56 days. This study demonstrates that the prolonged intake of juice fortified with β-cryptoxanthin has stimulatory effects on bone formation and inhibitory effects on bone resorption in humans, and that the intake has an effect in menopausal women.
Bone loss with aging induces osteoporosis, which is widely recognized as a major public health problem.1-3) A decrease in bone mass leads to bone fracture. Bone loss may be due to decreased bone formation and increased bone resorption. Pharmacologic and nutritional factors are needed to prevent bone loss with increasing age. Chemical factors in food may help to prevent bone loss with aging.4) The chemical compounds in food which act on bone metabolism, however, are poorly understood.Recent studies have shown that isoflavones (increasing genistein and daidzein), which are contained in soybean, have a stimulatory effect on bone formation, [5][6][7][8] thereby increasing bone mass. 9) Also, menaquinone-7, an analogue of vitamin K 2 which is essential for the g-carboxylation of osteocalcin of bone matrix protein, is abundant in fermented soybean.10) Menaquinone-7 has been demonstrated to stimulate osteoblastic bone formation 11) and to inhibit osteoclastic bone resorption 12) in vitro. The supplementation of isoflavones and vitamin K 2 has a preventive effect on bone loss induced by ovariectomy in rats, which is an animal model of osteoporosis. [13][14][15][16] Food chemical factors thus play a role in bone health and may be important in the prevention of bone loss with increasing age.Carotenoids are present in fruit and vegetables. The effects of carotenoids on bone metabolism, however, have not yet been clarified. Recently, it has been shown that b-cryptoxanthin has a unique anabolic effect on bone calcification in vitro.17) Lutein, lycopene, and b-carotene do not have an effect on bone calcification in vitro. 17,18) b-Cryptoxanthin has a direct stimulatory effect on bone formation and an inhibitory effect on bone resorption in cultured in vitro. 18)The present study was undertaken to determine the effect of the administration of b-cryptoxanthin on bone components in growing rats in vivo. The oral administration of bcryptoxanthin, which was isolated from Satsuma mandarin, was found to induce anabolic effects on bone components in vivo. MATERIALS AND METHODSChemicals Dulbecco's modified Eagle's medium (DMEM) (high glucose, 4.5 g/dl) and a penicillin-streptomycin solution (5000 units/mg penicillin and 5000 mg/ml streptomycin) were obtained from Gibco Laboratories (Grand Island, NY, U.S.A.). Bovine serum albumin (BSA), cycloheximide, and corn oil were obtained from Sigma Chemical (St. Louis, MO, U.S.A.). b-Cryptoxanthin (100% purity) was supplied from Ehime Beverage Inc. (Matsuyama, Japan). All other chemicals were reagent grade from Wako Pure Chemical Industries (Osaka, Japan). All water used was glassdistilled.Animals Male Wistar rats (4 weeks old) were obtained from Japan SLC (Hamamatsu, Japan). The animals were fed commercial laboratory chow (solid) containing 57.4% Ca and 1.1% P for 7 d at room temperature of 25°C and had free access to distilled water.Bone Culture The femurs were removed aseptically after exsanguination and soaked in ice-cold 0.25 M sucrose solution. The femur was cleaned of soft tissue and mar...
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